Archivio Italiano di Urologia e Andrologia - Vol. 92 - n. 3 - 2020

ISSN 1124-3562

Vol. 92; n. 3, September 2020 ORIGINAL PAPERS Poste Italiane S.p.A. - Spedizione in abbonamento postale - D.L. 353/2003 (conv. in L. 27/02/2004 n. 46) Art. 1, comma 1 DCB Milano

165

Predictors of surgical outcomes of retroperitoneal laparoscopic partial nephrectomy Carmine Sciorio, Pier Paolo Prontera, Salvatore Scuzzarella, Paolo Verze, Lorenzo Spirito, Lorenzo Romano, Alberto Trinchieri

169

Comparison of GreenLight 180-W XPS laser vaporization versus transurethral resection of the prostate: Outcomes of a single regional center Daniele Mattevi, Lorenzo Luciani, Rosa Spina, Claudio Divan, Stefania Cicuto, Tommaso Cai, Valentino Vattovani, Marco Puglisi, Stefano Chiodini, Gianni Malossini

173

Tamsulosin plus a new complementary and alternative medicine in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: Results from a retrospective comparative study Ferdinando Fusco, Massimiliano Creta, Francesco Trama, Fabio Esposito, Felice Crocetto, Achille Aveta, Francesco Mangiapia, Ciro Imbimbo, Marco Capece, Roberto La Rocca, Vincenzo Mirone, Nicola Longo

177

The role of Protopine associated with Nuciferine in controlling adverse events during hyperthermic intravesical chemotherapy instillations.

A nutraceutical approach to control adverse event during intravesical instillations Francesco Chiancone, Maurizio Carrino, Maurizio Fedelini, Marco Fabiano, Francesco Persico, Clemente Meccariello, Paolo Fedelini

182

Prepuce-sparing corporoplasty as a safe alternative for patients with acquired penile curvature Aldo Franco De Rose, Francesca Ambrosini, Guglielmo Mantica, Enrico Zero, Riccardo Banchero, Carlo Terrone

186

Penile-scrotal flap vaginoplasty versus inverted penile skin flap expanded with spatulated urethra: A multidisciplinary single-centre analysis Giorgio Gentile, Ardigò Martino, Daniela Nadalin, Martina Masetti, Brigida Lilia Marta, Franco Palmisano, Alessandro Franceschelli, Patrizia Stella, Anna Paola Sanfelici, Eugenio Brunocilla, Fulvio Colombo

192

Diagnosis and treatment of penile injury: Ten years experience of an emergency department Paolo Panella, Pietro Pepe, Michele Pennisi

CASE REPORTS 196

Bone pain palliation outcomes and possibility of Radium-223 re-treatment in mCRPC Viviana Frantellizzi, Julia Lazri, Mariano Pontico, Arianna Pani, Giuseppe De Vincentis

200

Gelatin sponge (Spongostan®) and N-butyl-2-cyanoacrylate: Utility on percutaneous treatment of persistent urinary leakage after partial nephrectomy.

Case report and review of the literature Bernardino de Concilio, Francesca Vedovo, Maria Carmen Mir, Tommaso Silvestri, Andrea Casarin, Antonio Celia

203

Infected kidney stone progressing to perinephric abscess and thoracic empyema Antonio Tufano, Rocco Minelli, Giovanni Di Lascio, Giampaolo Delicato, Giulio Baffigo, Stefano Signore

205

Non-secreting adrenal myelolipoma in a middle-aged male patient manifesting with sudden onset of severe lower back pain Carlo Introini, Fabio Campodonico, Marco Ennas, Antonia Di Domenico, Luca Foppiani

207

Non-invasive removal of self-locking entrapped nephrostomy tubes Fabio Campodonico, Umberto Geremia Rossi, Marco Ennas, Alessandro Valdata, Antonia Di Domenico, Francesco Pinna, Carlo Introini

209

Expression of miR-132 and miR-212 in prostate cancer and metastatic lymph node: Case report and revision of the literature Michele Salemi, Angela Pettinato, Filippo Fraggetta, Aldo E. Calogero, Michele Pennisi, Ludovica Pepe, Pietro Pepe

211

Primary small-cell neuroendocrine carcinoma of the bladder: Case report and literature review Valerio Olivieri, Valentina Fortunati, Luca Bellei, Massimo Massarelli, Gabriele Ruggiero, Danilo Abate, Nicoletta Serra, Daniele Griffa, Flavio Forte, Emanuele Corongiu

213

Fatal infections in andrology. Atypical clinical presentation of a Fournier’s disease Valerio Olivieri, Gabriele Ruggiero, Danilo Abate, Nicoletta Serra, Valentina Fortunati, Daniele Griffa, Flavio Forte, Emanuele Corongiu

215

Management of complications in penile prosthesis reimplantation: A case report Camilla Capretti, Antonio Avolio, Alberto Florio, Silvia Giovannozzi, Domenico De Carolis

217

Clear cell carcinoma of the urinary bladder, A case report: Surgical and oncological management Emanuele Corongiu, Pietro Grande, Emanuele Liberati, Roberto Iacovelli, Mostafà Amini, Paola Mascioli, Giorgio Pagliarella, Stefano Squillacciotti, Angelo Di Santo, Flavio Forte, Valerio Olivieri continued on page III

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

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

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

SIA EDITOR

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

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

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

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

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

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

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

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

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

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

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

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

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

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ORIGINAL PAPERS & CASE REPORTS 219

A global snapshot of endourology residency training

230

Transperitoneal and retroperitoneal approach in laparoscopic partial nephrectomy for posterior cT1 renal tumors: A retrospective, two-center, comparative study

Asad Ullah Aslam, Joseph Philipraj, Sayed Jaffrey, Noor Buchholz

Nikolaos Ferakis, Antonios Katsimantas, Nikolaos Charalampogiannis, Spyridon Paparidis, Jens Jochen Rassweiler, Ali Serdar Gözen

235

Prostate cancer with cribriform pattern: Exclusion criterion for active surveillance?

Rui Miguel Bernardino, Rita Carvalho, Luis Severo, Marta Alves, Ana Luisa Papoila, Luis Campos Pinheiro

239

The impact of tumor invasion to muscularis mucosae- vascular plexus on patient outcome in pT1 bladder urothelial carcinoma Ahmet Sahan, Fatma Gerin, Asgar Garayev, Emine Bozkurtlar, Alkan Cubuk, Orkunt Ozkaptan, Kasım Ertas, Yıloren Tanidir, Haydar Kamil Cam, Ilker Tinay

244

Non-invasive evaluation of obstruction after ureteroscopic stone removal: Role of renal resistive index assessment Bilal Eryildirim, Ahmet Sahan, Özlem Türkoğlu, Murat Tuncer, Övünç Kavukoğlu, Berkan Simsek, Alkan Cubuk, Kemal Sarıca

248

Nephroureterostomy as a treatment of obstructive uropathy: A single center experience Muhammad Faisal Khan, Maira Saeed Babar, Georgios Tsampoukas, Soumya Misra

253

Intralesional injection of the calcium channel blocker Verapamil in Peyronie's disease: A critical review Murad Asali, Muhammad Asali

259

Best time to wait for the improvement of the sperm parameter after varicocelectomy: 3 or 6 months?

Mohammad Ali Ghaed, Seyed Alireza Makkian, Asaad Moradi, Robab Maghsoudi, Alireza Gandomi-Mohammadabadi

263

L-carnitine as primary or adjuvant treatment in infertile patients with varicocele. A systematic review Georgios Tsampoukas, Muhammad Faisal Khan, Antigoni Katsouri, Waseem Akhter, Mohamad Moussa, Konstantinos Deliveliotis, Athanasios Papatsoris, Noor Buchholz

268

A giant adrenal hemorrhagic pseudocyst mimicking a parapelvic renal cyst: A case report and review of the literature Erhan Ates, Arif Kol, Gokce Su Gokce, Ahmet Emre Yildiz, Haluk Erol

271

Cylinder rerouting for lateral extrusion after inflatable penile prosthesis implantation - Surgical technique revision Paulo Jorge Pinto Pe Leve, João Pedro Cardoso Felício, Pedro Simões de Oliveira, José Manuel Palma dos Reis, Francisco Alves Estrócio Martins

273

Renal myxoma: An unforeseen diagnosis Rui Miguel Bernardino, Luis Severo, Luis Mascarenhas Lemos, Luis Campos Pinheiro

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DOI: 10.4081/aiua.2020.3.165

ORIGINAL PAPER

Predictors of surgical outcomes of retroperitoneal laparoscopic partial nephrectomy Carmine Sciorio 1, Pier Paolo Prontera 2, Salvatore Scuzzarella 1, Paolo Verze 3, Lorenzo Spirito 3, Lorenzo Romano 3, Alberto Trinchieri 4 1 Urology

Unit, Manzoni Hospital, ASST Lecco, Lecco, Italy; Unit, S.S. Annunziata Hospital, ASL Taranto, Taranto, Italy; 3 Department of Urology, University of Naples Federico II, Naples, Italy; 4 Urology Department, IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy.

2 Urology

Objectives: To evaluate surgical outcomes in a series of laparoscopic retroperitoneal partial nephrectomies.

Methods: A total of 147 patients who underwent laparoscopic retroperitoneal partial nephrectomy by a single surgeon were evaluated. Pre-operative parameters (body mass index, ASA score, tumour size, cTNM stage, PADUA score risk, surgeon experience) and intraoperative and postoperative outcomes (operative mean time, warm ischemia time, blood loss, transfusion rate, length of hospitalization, and margin-ischaemiacomplications [MIC] success rate) were considered.

Results: For 134 patients (91.1%) the success of the treatment, defined by a MIC = 3, was obtained. When the statistical significance of each of the independent variables was tested, surgeon’s experience added statistical significance to the prediction of operative time (p = 0.000), warm ischemia time (p = 0.000) and blood loss (p = 0.000); tumour size (p = 0.046) to the prediction MIC (p = 0.010), operative time (p = 0.000), warm ischemia time (p = 0.003) and blood loss (p = 0.010); ASA score to the length of hospitalization (p = 0.009).

Conclusions: Laparoscopic retroperitoneal partial nephrectomy represents an adequate and safe technique for the treatment of T1 renal cancer. Optimal MIC success rate can be achieved, although intraoperative outcomes tend to be related to the learning curve even in a very experienced laparoscopic surgeon. Length of hospitalization depends on general health condition of patients.

Summary

KEY WORDS: Laparoscopy; Partial nephrectomy; Kidney neoplasms; Retroperitoneal; PADUA score.

Submitted 10 May 2020; Accepted 11 May 2020

INTRODUCTION Over the past few years, both robotic and laparoscopic partial nephrectomy (LPN) have emerged as a strong alternative to open partial nephrectomy due to several documented advantages including less blood loss, quicker recovery, less complications (1).

In 2006, Carini et al. presented their successful results of their long-term follow-up study of post-operative outcomes after open partial nephrectomy for pT1a tumours (2). The Authors show favourable results as a cancer-specific survival (CSS) of 96.7% and 94.7% at, respectively, 5 and 10 years, with a progression-free survival (PFS) of 96% and 94% at 5 and 10 years, respectively. Just 1.5% of patients developed a local recurrence, with no distant metastasis, far from the site of the previous tumorecto-

my. Gill et al. demonstrated that LPN was a viable alternative for treating selected renal tumour patients (3).

Moreover, in last decades, indications for LPN have progressively extended to tumors of greater diameter and stage (pT1b) (4).

For these reasons, many preoperative score systems have been proposed in order to estimate the pre-operative risk, based on computed tomography (CT) scan and magnetic resonance imaging (MRI). Most commonly used are the PADUA (5) score and the RENAL system (6) score.

Both trans and retro peritoneal approach are commonly used by surgeons with the comparable surgical and functional outcomes (7), although the retro peritoneal access, on the one hand guarantees a more restricted working space and a worse exposure of the medial kidney facia, on the other, it allows an immediate access to the renal vessels and reduces the risk of injury to the intra peritoneal organs.

The increasingly extreme use of partial nephrectomy is in terms of the size of the treated masses and of the comorbidity of the patients subjected to this procedure (solitary kidney, synchronous bilateral tumors, etc.) justifies the attention to the oncological and functional result, also in consideration of learning curves. Surgical results were evaluated using MIC-criteria (margin, ischaemia and complications) (8) that anticipated the Trifecta-criteria (9). The only difference between the two score-systems is the length of ischaemia time (20 vs 25 minutes). Herein, we report on postoperative outcomes of a single surgeon, single centre series of retroperitoneal LPN, in order to assess the correlation between preoperative parameters, including the individual nephrometric PADUA score, and post-operative outcomes, including MIC score, in order to provide an evaluation for surgical risk evaluation also related to the surgeon experience.

PATIENTS

AND METHODS

We designed a monocentric, single surgeon retrospective nonrandomized study. A total of 147 patients, who underwent retroperitoneal LPN for malignancy from March 2014 to April 2018, were enrolled. All the anonymously collected data have been retrospectively evaluated. All procedures were performed by a single surgeon with a

No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2020; 92, 3

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C. Sciorio, P.P. Prontera, S. Scuzzarella, P. Verze, L. Spirito, L. Romano, A. Trinchieri

previous long-lasting experience in renal laparoscopy.

Exclusion criteria were as follows: a) distant metastases at the time of the diagnosis; b) previous retroperitoneal surgery. Informed consent was administered and preoperative abdominal CT scan and/or MRI were performed for all patients in order to assess maximum lesion diameter and clinical TNM staging (10). Preoperative PADUA score (5) for each patient was calculated after the CT scan or MRI evaluation performed by two different radiologists, considering the site of the lesion (polar or nonpolar), the extension (exophytic/endophytic), the location at the equator (lateral/medial), the involvement of the renal hilum and the excretory pathway. Tumours were stratified in low (PADUA score: 6-7), medium (PADUA score: 1-2) and high risk (PADUA score: =/>10).

Age, gender, body mass index (BMI), American Society of Anesthesiologists (ASA) score, comorbidities (such as diabetes and hypertension), blood loss, operative time (trocars-in to trocars-out), warm ischemia time, conversion rate to open surgery, pathological stage, tumour histotype according to the classification of the World Health Organization (WHO), nuclear grading according to Fuhrman's classification (11) and surgical margins involvement have been evaluated. Peri and post-operative complications (within the first 30 days) have also been recorded and classified in minor and major according to the Clavien-Dindo system (12) (grade 1-2 and 34 respectively). The surgeon's experience was assessed by dividing surgical procedures into 6 chronological groups according to his learning curve.

Finally, the successful rate for each procedure was estimated using validate M.I.C. system (8) (which considers ischemia time less than 20 minutes, absence of surgical margins involvement and no major post-operative complication). According to this trifecta system, each patient has received from 1 to 3 points.

A descriptive statistical analysis of emerged data was performed. The continuous variables were reported as mean values and standard deviation while the categorical variables were reported as the number of cases (n°) and percentage (%) and their differences were correlated with the Pearson x².

Multiple linear logistic regression was used to evaluate the predict effect of a set of pre-operative parameters (age, gender, BMI, ASA, tumour size, TNM stage, PADUA score and surgeon’s experience) on different surgical outcomes as MIC, blood loss, transfusion rate, operative time, warm ischemia time and length of hospitalization.

All data were analysed using SPSS software and a p-value < 0.05 was defined as statistically significant.

RESULTS A total of 147 patients (101 male and 46 female), who underwent retroperitoneal LPN from 2014 to 2018, were retrospectively enrolled Mean age was 63 years (range 37-74).

Table 1 shows the baseline cohort characteristics and preoperative data.The assessed mean diameter of renal lesions at pre-operative CT scan was 3.55 cm +/-1.65. Application of PADUA score system allow to stratify the surgical risk as follows: 79 (54% of the population) as low risk, 51 as

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Archivio Italiano di Urologia e Andrologia 2020; 92, 3

Table 1.

Baseline cohort characteristics and preoperative evaluations (147 pts).

Median age, years M/F ratio (pts) BMI (kg/m2) Right/left side (pts) Average volume of lesions (radiological evaluation) PADUA score - Low - Intermediate - High Tumor site (polar/not polar) Tumor site (exophytic/not exophytic/completely endophytic) Tumor site (lateral/medial) Renal sinus involvement (yes/no) Excretory system involvement (yes/no)

63 (37. 64) 101/46 25.9 ± 3.2 83 (57%)/64 (43%) 3.55 ± 1.65 cm 6-7: 79 pts (54%) 8-9: 51 pts (35%) ≥ 10: 17 pts (11%) 99 pts. (67%)/48 pts. (33%) 82 pts (56%)/56 pts (38%)/9 pts (6%) 90 pts (61%)/57 pts (39%) 8 pts (5%)/139 pts (95%) 6 pts (4%)/141 pts (96%)

Table 2.

Intraoperative parameters of the cohort (147 pts).

Average operative time (min) Warm ischemia (pts) - no ischemia - < 20 minutes - 20–29 minutes - > 30 minutes Average time of warm ischemia (min) Average blood loss (ml) Average hospital stay (day) Average n° of transfusions per patient Percentage of transfused patients Percentage of major complications

118 ± 35 82 (56%) 51 (35%) 10 (7%) 3 (2%) 6.84 ± 8.74 236 ± 186 6.01 ± 5.43 0.16 ± 0.65 7.5% (11/147) 1.4% (2/147)

intermediate risk (35%) and 17 as high risk (11%).

Intraoperative and postoperative results are shown in Table 2. In 82 cases (56%) no ischemia was performed, whereas 64 patients received some warm ischemia time.

In detail, 51 patients (35%) underwent less than 20 minutes warm ischemia, 10 (7%) from 20 to 29 minutes and 3 (2%) more than 30 minutes of warm ischemia.

The global mean time of warm ischemia was 6.84 +/8.74 minutes. Peri-operative complication rate was 1.4% and there was no case of conversion to open surgery.

Average hospitalization time was 6.01 +/- 5.43 days.

Pathological analysis of the lesions shows a prevalence of pT1a stage tumours (64%), followed by pT1b (19.7%).

Pathological stages pT2 and pT3 all together represent 2.7% of the cohort and 20 lesions (13.6%) appear to be no-clear cells tumours (CCT). No positive surgical margin was observed.

In our purpose, the success of the treatment was defined

by MIC = 3, and it was obtained in 134 patients (91.1%).

At multiple linear logistic regression PADUA score, TNM stage (Table 4), tumour size by pre-operative CT, BMI, ASA and surgeon’s experience predicted the effect of MIC success (p = 0.034), operative time (p = 0.000), warm ischemia time (p = 0.000), blood loss (p = 0.000) and length of hospitalization (p = 0.002). Coefficient of determination R2 explain 10.7%, 34.7%, 26.7%, 23.4% and 16.2% of the variability of MIC success, operative time,

Surgical outcomes of RPN

Table 3.

Patient characteristics with and without MIC success (defined as MIC = 3).

Patients characteristics MIC success (134 pts) MIC failure (13 pts) Average volume of lesions (radiological evaluation) 3.38 ± 1.58 5.30 ± 1.34 PADUA score Pts: Pts: - 6-7 75 4 - 8-9 47 4 - ≥ 10 12 5 Tumor site Pts: Pts: - Exophytic 80 2 - Not exophytic 47 9 - Completely endophytic 7 2 pTNM Pts: Pts: - pT1a 90 4 - pT1b 20 9 - pT2 2 0 - pT3 2 0 - Others 20 0 Tumor size (histopathological evaluation) 3.08 ± 1.5 cm 4.97 ± 1.47 cm Average time of warm ischemia (min) 5.16 ± 6.96 24.07 ± 6.14 Average operative time (min) 115 ± 32 151 ± 51 Blood loss (ml) 222 ± 155 385 ± 360

P-value 0.000 0.006

0.007

0.000

0.000 0.000 0.000 0.002

Table 4.

Correlation between surgical outcomes and pathological stage. pT1a pT1b pT2 pT3 Others P-value Mean PADUA score 7.41 ± 1.42 8.48 ± 1.7 9.50 ± 3.53 8 ± 0.0 7.35 ± 1.38 0.000 Average time of ischemia 6.01 ± 7.71 11.62 ± 11.45 0 9.5 ± 13.43 4.25 ± 6.4 0.011 Pathological tumor size (cm) 2.78 ± 1.07 4.71 ± 1.66 5.25 ± 5.3 5.75 ± 4.59 2.88 ± 1.24 0.000 MIC=3 (pts) 90/94 20/29 2/2 2/2 20/20 0.000

warm ischemia time, blood loss and length of hospitalization. When the statistical significance of each of the independent variables was tested, surgeon’s experience added statistical significance to the prediction of operative time (p = 0.000), warm ischemia time (p = 0.000) and blood loss (p = 0.000); tumour size (p = 0.046) to the prediction MIC (p = 0.010), operative time (p = 0.000), warm ischemia time (p = 0.003) and blood loss (p = 0.010); ASA score to the length of hospitalization (p = 0.009).

For 13 patients (8.9%) with MIC < 3, failure was associated in a statistically significant way to lesion diameter (p = 0.000), TNM classification >/= pT1b (72.7% vs 95.7%) (p = 0.000), high risk calculated by PADUA score system (p = 0.006) (Table 3). Moreover, for all patients with MIC < 3 we registered significantly longer times of warm ischemia (p = 0.000), longer operating times (p = 0.000) and greater blood loss (p = 0.002). For all no-CCT MIC was 3, with a successful rate of 100%.

DISCUSSION The main goal of the present study was to evaluate the MIC score rate in our series of patients treated by retroperitoneal LPN. Secondary endpoints were the assessment of the correlation between pre-operative parameters, as PADUA score,

and perioperative and postoperative outcomes.

The successful rate obtained was elevate (MIC = 3 was obtained in 91,1% of patients), comparable to that of Gill's group (13) and to that of other robotic case studies (14).

Evaluation of some recent series excluded patients who had not undergone ischemia. By applying this criterion, our success rate would drop, although it should be underlined that in our series ischemia was not used even in many cases with high PADUA score and large diameter tumors. The exclusion of these patients from the study would be penalizing for the evaluation of our results. On the other hand, the MIC evaluation resulted in a “flattening” of the results range upwards. For this reason, in our opinion, the indicators of surgical success should be more stratified, for example by rewarding the absence of ischemia or very low ischemia times (< 10 minutes).

It is interesting to note that the learning curve for the examined procedure is long even for an experienced surgeon. In fact, the results obtained by a single surgeon, already an expert at the beginning of this experience, show a specific trend, with a significant improvement in perioperative and postoperative outcomes during the study period. However, the results in terms of MIC are not significantly related to the experience of the surgeon, who, when he has sufficient initial experience in renal laparoscopy, is able to ensure the surgical success of the procedure even with longer operating times and a higher blood loss and transfusion rate.

On the other hand, in the initial phase of the experience the surgeon tends to select cases with lower PADUA score (6-7), while in the continuation of the study were then considered more complex cases with higher PADUA score (> 10). More studies are needed to better investigate these relationships and provide the surgeon, both expert and on learning curve, with effective predictive tools to obtain the best results in terms of operative and oncological outcomes.

The use of the traditional laparoscopic technique for partial retroperitoneal nephrectomy has disadvantages and advantages over the robot-assisted technique. Numerous studies have compared the results of traditional laparoscopic partial nephrectomy (LPN) with those of roboticassisted partial nephrectomy (RAPN). Transperitoneal and retroperitoneal RAPN are equally effective and safe in terms of warm ischemia time, estimated blood loss, rate of conversion and complications and positive surgical margins (15). In particular, retroperitoneal RALPN proved to be an excellent option for posterior and lateral tumors with reduced operational times and shortened lenghts of stay (16).

Some Authors reported that RAPN has short operating and ischemia times and less blood loss compared with LPN (17, 18), although other studies have shown no differences in terms of operative time, warm ischemia time, estimated blood loss and lenght of hospital stay (19, 20).

A meta-analysis showed equivalent peri-operative outcomes of LPN and RAPN, which added the advantage of a shorter warm ischaemia time (21).

On the other hand, LPN implies lower healthcare costs and use of sutureless technique can reduce warm ischemia and operative time (22, 23).

At the moment, the two techniques represent excellent Archivio Italiano di Urologia e Andrologia 2020; 92, 3

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C. Sciorio, P.P. Prontera, S. Scuzzarella, P. Verze, L. Spirito, L. Romano, A. Trinchieri

alternatives to the in the management of moderate to complex renal tumours with high PADUA scores.

CONCLUSIONS Retroperitoneal LPN represents an adequate and safe technique for the treatment of T1 renal cancer. Optimal MIC success rate can be achieved, although intraoperative outcomes tend to progressively improve during the learning curve even in a very experienced surgeon.

Length of hospitalization depends on general health condition.

REFERENCES 1. de Castro Abreu AL, Cacciamani G, Gill IS. Partial Nephrectomy.

In: Sotelo R., Arriaga J, Aron M. (eds) Complications in Robotic Urologic Surgery. Springer, 2018; pp. 163-173.

2. Carini M, Minervini A, Masieri L, et al. Simple enucleation for the treatment of PT1a renal cell carcinoma: our 20-year experience.

Eur Urol. 2006; 50:1263-8.

3. Gill IS, Desai MM, Kaouk JH, et al. Laparoscopic partial nephrectomy for renal tumor: duplicating open surgical techniques. J Urol.

2002; 167:469-7.

4. Ljungberg B, Albiges L, Bensalah K, et al. EAU Guidelines for Renal Cell Carcinoma. Edn. presented at the EAU Annual Congress Copenhagen 2019. ISBN 978-94-92671-04-2.

5. Ficarra V, Novara G, Secco S, et al. Preoperative aspects and dimensions used for an anatomical (PADUA) classification of renal tumors in patients who are candidates for nephron-sparing surgery.

Eur Urol, 2009; 56:786-793.

6. Kutikov A, Uzzo RG. The R.E.N.A.L. nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth. J Urol. 2009; 182:844-53.

15. Xia L, Zhang X, Wang X, et al. Transperitoneal versus retroperitoneal robot-assisted partial nephrectomy: A systematic review and meta-analysis. Int J Surg. 2016; 30:109-15.

16. Laviana AA, Tan HJ, Hu JC, et al. Retroperitoneal versus transperitoneal robotic-assisted laparoscopic partial nephrectomy: a matched-pair, bicenter analysis with cost comparison using timedriven activity-based costing. Curr Opin Urol. 2018; 28:108-114.

17. Pierorazio PM, Patel HD, Feng T, et al. Robotic-assisted versus traditional laparoscopic partial nephrectomy: comparison of outcomes and evaluation of learning curve. Urology. 2011; 78:813-9.

18. Wang Y, Ma X, Huang Q, et al. Comparison of robot-assisted and laparoscopic partial nephrectomy for complex renal tumours with a RENAL nephrometry score ≥7: peri-operative and oncological outcomes. BJU Int. 2016; 117:126-30.

19. Masson-Lecomte A, Bensalah K, Seringe E, et al. A prospective comparison of surgical and pathological outcomes obtained after robot-assisted or pure laparoscopic partial nephrectomy in moderate to complex renal tumours: results from a French multicentre collaborative study. BJU Int. 2013; 111:256-63.

20. Simsek A, Yavuzsan AH, Colakoglu Y, et al. Comparison of robotic and laparoscopic partial nephrectomy for small renal tumours. Arch Ital Urol Androl. 2017; 89:93-96.

21. Zhang X, Shen Z, Zhong S, et al. Comparison of peri-operative outcomes of robot-assisted vs laparoscopic partial nephrectomy: a meta-analysis. BJU Int. 2013; 112:1133-42.

22. Corongiu E, Grande P, Di Santo A, et al. Safety and efficacy of retroperitoneal sutureless zero ischemia laparoscopic partial nephrectomy for low nephrometry score masses. Arch Ital Urol Androl. 2019; 91:157-162.

23. Tiscione D, Cai T, Luciani LG, et al. Sutureless laparoscopic partial nephrectomy using fibrin gel reduces ischemia time while preserving renal function. Arch Ital Urol Androl. 2019; 91:30-34.

7. Marszalek M, Chromecki T, Al-Ali BM, et al. Laparoscopic partial nephrectomy: a matched-pair comparison of the transperitoneal versus the retroperitoneal approach. Urology. 2011; 77:109-13.

8. TNM classification of malignant tumors. UICC International Union Against Cancer. 7th ed. Brierley J.D., Gospodariwicz M., Wittekind C. (eds). Wiley-Blackwell, 2009.

9. Buffi N, Lista G, Larcher A, et al. Margin, ischemia and complications (MIC) score in partial nephrectomy: a new system for evaluating achievement of optimal outcomes in nephron-sparing surgery.

End Urol. 2012; 62:617-8.

10. Hung AJ, Cai J, Simmons MN et al. “Trifecta” in partial nephrectomy. J Urol. 2013; 189:36-42.

11. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol.

1982; 6:655-63.

12. 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.

13. Hung AJ, Cai J, Simmons MN, Gill IS. "Trifecta" in partial nephrectomy. J Urol. 2013; 189:36-42.

14. Bianchi L, Schiavina R, Borghesi M, et al. Which patients with clinical localized renal mass would achieve the trifecta after partial nephrectomy? The impact of surgical technique. Minerva Urol Nefrol. 2019 Oct 10. doi: 10.23736/S0393-2249.19.03485-4.

[Epub ahead of print]

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Correspondence Carmine Sciorio, MD (Corresponding Author) carmine.sciorio@gmail.com Salvatore Scuzzarella, MD s.scuzzarella@libero.it ASST “A. Manzoni” Hospital - Lecco (Italy Pier Paolo Prontera, MD pierpaolo.prontera@virgilio.it ASL-TA “S:S. Annunziata Hospital - Taranto (Italy) Paolo Verze, MD pverze@gmail.com Lorenzo Spirito, MD lorenzospirito@msn.com Lorenzo Romano, MD loryromano@hotmail.it Università Federico II - Napoli (Italy) Alberto Trinchieri, MD alberto.trinchieri@gmail.com Urology Department, IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano (Italy)

DOI: 10.4081/aiua.2020.3.169

ORIGINAL PAPER

Comparison of GreenLight 180-W XPS laser vaporization versus transurethral resection of the prostate: Outcomes of a single regional center Daniele Mattevi, Lorenzo Luciani, Rosa Spina, Claudio Divan, Stefania Cicuto, Tommaso Cai, Valentino Vattovani, Marco Puglisi, Stefano Chiodini, Gianni Malossini Department of Urology, Santa Chiara Hospital, Trento, Italy.

Background: To evaluate the intermediate perioperative outcomes, rate of complications and functional data after XPS 180-W Greenlight photoselective laser vaporization (PVP) compared with transurethral resection of the prostate (TURP) in a prospective non-randomized single centre study.

Methods: We analyzed a prospectively-maintained database collecting data on 100 patients undergoing surgical treatment of BPH (50 consecutive PVP and 50 consecutive TURP).

All complications, recorded and graduated according to the Clavien Dindo system and the clinical, operative, perioperative variables were compared. The functional outcomes, International Prostate Symptom Score (IPSS), max flow rate (Qmax) and Prostate Specific Antigen (PSA), were recorded preoperatively and at 1 year of follow up.

Results: Age, prostate volume, use of anticoagulants or antiplatelets, ASA score and operative time were comparable in the two groups. The reduction in the hemoglobin levels (0.46 vs 1.8 g/dL), the catheterization time (1.2 vs 3.2 days), the hospital stay (1.7 vs 3.8 days) and rate of transfused patients (0 vs 8%), were significantly lower for PVP. Transient re-catherization (6 vs 26%) was significantly lower for PVP. The IPSS and Qmax at 1 year showed no significant difference.

The rate of repeat TURP/PVP was higher in the TURP group (0 vs 10%). Reduction of PSA, that reflects the major reduction of prostate volume, was statistically greater in PVP group respect TURP group (p = 0.001).

Conclusions: PVP has advantages in terms of perioperative safety and major complications than TURP. Functional outcomes at 1 year of follow-up were comparable.

nique has complications (5, 6), such as the transurethral resection syndrome secondary to irrigation fluid absorption, which presents risk factors including bleeding, operative times and large prostatic volume (7, 8). Laser treatment of the prostate is acquiring a role as a minimally invasive treatment of BPH. Potassium tytanyl phosphate (KTP) laser for the treatment of BPH was first used

by Watson in 1995 (9). Over the years the GreenLight laser has evolved starting from a power of 80 W, passing through a system to 120 W (GL-HPS) up to the 180 W XPS (GL-XPS) in 2011. The increase in power has made it is also necessary to introduce new laser fibers for an efficient ablation of prostate tissue (10). The light beam KTP 532 nm is selectively absorbed by oxyhemoglobin, facilitating coagulation and vaporization of tissues. After its introduction, the technique was confirmed as effective and safe in the short and medium term (11, 12).

Furthermore, it has been shown that the procedure does not require the anticoagulant suspension because the procedure is almost bloodless, making the procedure optimal in high-risk patients (13).

In the present study, we report our experience with photoselective vaporization of the prostate (PVP) and TURP regarding complications and functional results with a follow up to 1 year.

KEY WORDS: GreenLight; TURP; Photoselective vaporization; Laser; Benign prostatic hyperplasia.

We analyzed a prospectively-maintained database collecting data on 100 patients undergoing surgical treatment of BPH (50 consecutive PVP and 50 consecutive TURP) from March 2015 to March 2016 at the Department of Urology of Trento, Italy. The clinical, operative, perioperative, variables are shown in Table 1. All complications that occurred within 30 days of discharge and within 1 year have been recorded, defined and graduated according to the Clavien Dindo system (14) (Table 2). Comorbidities were evaluated according to preoperative risk assessment by the American Society of Anesthesiologist (ASA score).

The functional results were summarized in Table 3: International Prostate Symptom Score (IPSS); max flow rate (Qmax) and Prostate Specific Antigen (PSA). This data were recorded preoperatively and at 1 year of follow up.

Informed consent was obtained from all individual participants included in the study.

Summary

Submitted 22 April 2020; Accepted 31 May 2020

INTRODUCTION Benign prostatic hyperplasia (BPH) is a very common disease among elderly men. This pathology leads the patient to have symptoms of the lower urinary tract (LUTS) and lowers the quality of life (1). Medical therapy is usually the first-line treatment (2). Thus, more invasive treatment options have to be considered as the disease progresses. Transurethral resection of the prostate (TURP) is still considered the gold standard for the treatment of LUTS (3), which improves the urinary flow rate and reduces the voiding symptoms (4). However, this tech-

MATERIAL

AND METHODS

No conflict of interest declared.

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Surgical technique The TURP was performed by two urologists and the PVP was performed by two other urologists. TURP was performed with a 26-F resectoscope; at the end, a bladder catheter 22 Ch was placed with continuous bladder washing. The PVP was performed using the GreenLight XPS 180-W laser that uses a lithium tribal crystal instead of the KTP crystal, to produce a more collimated and powerful 532 nm laser beam than 80 W. This results in an intervention faster and greater ability to penetrate into prostate tissue (15). From the veru montanum to the bladder neck, the median and lateral lobes were vaporized with a final result similar to a TURP. Statistical analysis Distribution of continuous variables are reported as mean and standard deviation. Categorical variables are presented as numbers and percentages. The comparison between subgroups (surgical approach) was performed using Student t test or Mann-Whitney U test for continuous variables. Qualitative data were compared by the χ2 test or Spearman correlation. P values were considered significant when less than or equal to 0.05. All analyses were performed using the SPSS software (IBM Corp., Armonk, NY).

RESULTS 100 consecutive patients underwent endoscopic surgical treatment of BPH from March 2015 to March 2016: 50 in the PVP and 50 in the TURP groups. Demographic, preoperative, operative and postoperative characteristics are summarized in Table 1: Age, prostate volume, use of anticoagulants or antiplatelets, and ASA score were comparable between groups. Also, the mean operative time was comparable in the two groups. Compared to preoperative values, there was a significant reduction in the hemoglobin levels at the end of TURP procedure as compared to PVP. The average duration of catheterization was 1.2 ± 0.5 days for PVP and 3.1 ± 3.4 days for TURP group (p < 0.001) and also the definitive catheter removal was in favor of PVP (1.4 ± 0.8 vs 5.6 ± 6.6; p < 0.001). Hospital stay was also statistically shorter in the PVP as compared to TURP (2 days less). During PVP no blood transfusions were necessary whereas 4 patients (8%) undergoing TURP were transfused due to a significant bleeding (2 intraoperative and 2 postoperative) (p = 0.04).

Early (< 30 days) and late complications are presented in Table 2. Transient recatherization was performed for urinary retention at catheter removal in 13 (26%) of patients undergoing TURP and in 3 (6%) undergoing PVP (p = 0.01). Five patients (10%) with bladder neck sclerosis or prostate tissue regrowth requiring reTURP were found in the TURP group; none were found in the PVP group (p = 0.02). Two cases of mild incontinence were found in TURP group. The complications were graduated according to the classification of ClavienDindo and subdivided in minor and major complications. No major complications were found in PVP group, while 7 occurred in TURP group (p = 0.01). Overall complications were comparable in two groups.

Efficacy in terms of IPSS, Qmax and reduction of PSA are shown in Table 3. At 1 years, the outcome for both pro-

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Table 1.

Preoperative, and early postoperative outcomes in the two study groups.

Age (years) Prostate volume (cc) Anticoagulans/antiplatelet (n) ASA Score 3 (n) Operative time (min) Catheterization time (days) Definitive catheter removal (days) Tranfused patients (n) Hospital stay (days) Haemoglobin (g/L) preoperative first day hemoglobine reduction

TURP (n = 50) 68.8 ± 11.1 48.1 ± 14.5 18 11 61.6 ±27.9 3.1 ± 3.4 5.6 ± 6.6 4 3.8 ± 2.6

PVP(n = 50) 71.6 ± 7.4 53.3 ± 14.7 19 17 63 ± 15.1 1.2 ± 0.5 1.4 ± 0.8 0 1.7 ± 0.8

14.4 ± 1.3 12.6 ± 1.9 1.8 ± 1.2

p value 0.14 0.08 0.83 0.18 0.8 0.001 0.001 0.04 0.001

13.7 ± 1.4 13 ± 1.9 0.46 ± 0.42

0.01

Table 2.

Early and late postoperative complications.

TURP (n = 50) Early postoperative complications (<30 days) Clot retention (n) Dysuria/urge (n) Late postoperative complications redo TURP/VLP (n) incontinence (n) Complications based on Clavien-Dindo classification minor complications (n) major complications (n) overall complications (n)

PVP(n = 50) p value

13 8

3 16

0.01 0.06

5 2

0 0

0.02 0.15

13 7 20

11 0 11

0.7 0.01 0.06

Table 3.

Functional results and PSA at 12 months.

TURP (n = 50) Qmax (ml/s) preoperative 1 year Δ Qmax IPSS score preoperative 1 year Δ IPSS PSA (ng/mL) preoperative 1 year Δ PSA

PVP (n = 50)

p value

7.6 ± 3 15.6 ± 6.4 8.2 ± 7.2

8.4 ± 1.7 17 ± 3 9.7 ± 2.1

0.14 0.15 0.16

20.1 ± 5.4 8.7 ± 5.1 10.7 ± 6.8

22.2 ± 5.8 9.3 ± 3 12.9 ± 4.1

0.06 0.58 0.052

2.29 ± 2.19 1.9 ± 2.8 0.59 ± 0.6

4.41 ± 2.31 2.97 ± 1.8 1.73 ± 1.4

0.001 0.03 0.001

cedures was similar and there were no statistically significant differences between the groups for the primary outcome functional parameters except for PSA degrees.

The 1 year postoperative mean improvement in IPSS was 9.3 ± 3 in the PVP group and 8.7 ± 5.1 in the TURP group, and was not statistically different between the two groups (p = 0.58) and this reflected in the Qmax score.

Reduction of PSA, that reflects the major reduction of prostate volume, was statistically major in VLP group respect TURP group (p = 0.001)

Outcomes of comparison GreenLight 180-W XPS vs TURP

DISCUSSION For many years, TURP has been considered the gold standard for the treatment of LUTS secondary to benign prostatic hyperplasia. Very often, however, TURP is characterized by numerous post-operative complications. PVP was then introduced to minimize intra and post-operative complications with minimally invasive intent. The KTP 80-W laser is a light wavelength of 532 nm, which is strongly absorbed by hemoglobin. The GreenLight XPS 180-W laser provides the same wavelength of 532 nm with similar intrinsic absorption characteristics (15).

As a result, laser prostate ablation has been developed to minimize the risk of bleeding complications. The reduction of complications then becomes particularly important in the older and fragile population that frequently carries coronary stents or who suffers from atrial fibrillation, coronary artery disease, valvular cardiopathies or deep vein thrombosis. These conditions are mainly managed through use of oral anticoagulants or antithrombotic agents (16). Laser light vaporizes the prostatic tissues layer by layer; the thickness of each layer is 1-2 mm. At the same time, capillary vessels are coagulated to stop bleeding. This explains why the occurrence of intraoperative bleeding and blood transfusion is hardly seen in PVP treatment. In our study, the rate of transfusions and the reduction of hemoglobin is statistically lower in the PVP group as well and this is associated with a lower hospital stay and catheterization time (17).The catheterization and hospital time are important factors affecting patientâ&#x20AC;&#x2122;s quality of life, so this result indicates a major advantage of PVP. Considering complications the clot retention was the most frequent early complication in the TURP group (26%) and this may occur as a consequence as well as premature termination of procedure, with consequent inadequate relief of obstruction: only 3 patients (6%) experienced a recatheterization after PVP. Large non randomised studies have reported a more favorable safety profile for green light than TURP regarding major complications (18) accordingly to our results (7 vs 0; p < 0,001). In our study the reintervention rate was higher in the TURP group as respect to the PVP group and it was caused by bladder neck sclerosis or prostate tissue regrowth; another cause may be secondary to the reduced amount of tissue resected in patients undergoing TURP, which is underlined by the minor reduction of the postoperative PSA. One-year functional results showed dramatic improvement in both groups regarding reduction of IPSS and improvement of Qmax with no significant difference between both groups. Only greater urgency in the PVP group should be reported in the immediate postoperative period.

This study reveals that PVP offers more advantages than TURP in terms of clot retention, blood transfusion and lower incidence rate of major complications.

Furthermore, compared to the TURP group, patients undergoing PVP have a shorter duration of catheterization, less blood loss and shorter hospital stays, which may explain the broad acceptance of PVP surgery from patients with secondary LUT to BPH, as confirmed by metanalysis (18-20). The benefits of laser-based prostat-

ic surgery are reflected in its increasing use in daily clinical practice. The BPO rate treated with lasers increased from 6% in 2000 to 45% in 2011 (21). Since its introduction in 1995, for example, green lasers now account for about 23% of BPH surgeries in France (22). Also, it is important to point out that there is a growing interest to improve the use of laser in order to preserve the antegrade ejaculation (23).

Our study has some limitations. First, this is a non-randomized study comparing different surgical approaches.

However, many patients are unwilling to be randomly assigned to a particular surgical treatment and are usually attracted by the most modern surgical procedure or chose a procedure based on personal preferences for a specific surgeon. Second, our study involved a relatively low number of patients with inherent biases related to data collection. In this case, selection biases were partially limited by the inclusion criteria: the last consecutive 50 interventions for each surgical technique were included. Also, indications to surgery, operative techniques and perioperative management, and data collection should be relatively homogeneous in a single center.

Furthermore, age, prostate volume, used of anticoagulants or antiplatelets, and ASA score were comparable between groups.

CONCLUSIONS PVP has advantages in terms of perioperative safety and rate of major complications than TURP. Functional outcomes at 1 year of follow-up were comparable.

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11. Bouchier-Hayes DM, Van Appledorn S, Bugeja P, et al. A randomized trial of photoselective vaporization of the prostate using the 80-W potassium-titanylphosphate laser vs transurethral prostatectomy, with a 1-year followup. BJU Int. 2010; 105:964-969.

12. Thomas JA, Tubaro A, Barber N, et al. A multicenter randomized non-inferiority trial comparing GreenLight-XPS laser vaporization of the prostate and transurethral resection of the prostate for the treatment of benign prostatic obstruction: two-yr outcomes of the goliath study. Eur Urol. 2016; 69:94-102.

13. Reich O, Bachmann A, Siebels M, et al. High power (80 W) potassium-titanyl-phosphate laser vaporization of the prostate in 66 high risk patients. J Urol. 2005; 173:158-160.

14. Dindo D, Demartines N, Clavien P.A. Classification of Surgical Complications: a new proposal with evaluation in a cohort of 6336 Patients and results of a survey. Ann Surg. 2004; 240:2.

15. Malek RS, Kang HW, Peng YS, et al. Photoselective vaporization prostatectomy: experience with a novel 180 W 532 nm lithium triborate laser and fiber delivery system in living dogs. J Urol. 2011; 185:712-8.

16. Whitlock EP, Burda BU, Williams SB, et al. Bleeding risks with

Correspondence Daniele Mattevi, MD, FEBU (Corresponding author) danielemattevi85@gmail.com Lorenzo Giuseppe Luciani, MD lorenzo_luciani@hotmail.com Rosa Spina, MD rosa.spina@apss.tn.it Claudio Divan, MD claudio.divan@apss.tn.it Stefania Cicuto, MD stefania.cicuto@apss.tn.it Tommaso Cai, MD tommaso.cai@apss.tn.it Valentino Vattovani, MD valentino.vattovani@apss.tn.it Marco Puglisi, MD marco.puglisi@apss.tn.it Chiodini Stefano, MD Gianni Malossini, MD gianni.malossini@apss.tn.it Department of Urology, Santa Chiara Hospital Largo Medaglie d’oro 9, 38122, Trento, Italy

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aspirin use for primary prevention in adults: a systematic review for the U.S. preventive services task force. Ann Intern Med. 2016; 164:826.

17. Van Cleynenbreugel B, Srirangam SJ, Van Poppel H. Highperformance system GreenLight laser: indications and outcomes. Curr Opin Urol. 2009; 19:33-37.

18. Teng J, Zhang D, Li Y, et al. Photoselective vaporization with the green light laser vs transurethral resection of the prostate for treating benign prostate hyperplasia: a systematic review and metaanalysis. BJU Int. 2013; 111:312-323.

19. Ding H, Du W, Lu ZP, et al. Photoselective green-light laser vaporization vs. TURP for BPH: meta-analysis. Asian J Androl.

2012; 14:720-5.

20. Thangasamy IA, Chalasani V, Bachmann A, Woo HH. Photoselective vaporization of the prostate using 80-W and 120-W laser versus transurethral resection of the prostate for benign prostatic hyperplasia: a systematic review with metaanalysis from 2002 to 2012. Eur Urol. 2012; 62:315-23.

21. Chughtai BI, Simma-Chiang V, Lee R,, et al. Trends and utilization of laser prostatectomy in ambulatory surgical procedures for the treatment of benign prostatic hyperplasia in New York state (2000- 2011). J Endourol. 2015; 29:700-706.

22. Peyronnet B, Cornu J-N, Rouprêt M, et al. Trends in the use of the GreenLight laser in the surgical management of benign prostatic obstruction in France over the past 10 years. Eur Urol. 2015; 67:1193-1195.

23. Leonardi R. The LEST technique: Treatment of prostatic obstruction preserving antegrade ejaculation in patients with benign prostatic hyperplasia. Arch Ital Urol Androl. 2019; 91:35-42.

DOI: 10.4081/aiua.2020.3.173

ORIGINAL PAPER

Tamsulosin plus a new complementary and alternative medicine in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: Results from a retrospective comparative study Ferdinando Fusco, Massimiliano Creta, Francesco Trama, Fabio Esposito, Felice Crocetto, Achille Aveta, Francesco Mangiapia, Ciro Imbimbo, Marco Capece, Roberto La Rocca, Vincenzo Mirone, Nicola Longo Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II. Naples, Italy.

Background: We aimed to compare the efficacy of tamsulosin 0.4 mg once a day alone and the combination therapy involving tamsulosin 0.4 mg once a day plus the complementary and alternative medicine consisting of vitamins (C and D), herbal products (Cucurbita maxima, Capsicum annum, Polygonum capsicatum) and amino acid L-Glutamine bid in patients with lower urinary tract symptoms related to benign prostatic hyperplasia (LUTS/BPH).

Methods: We performed a retrospective matched paired comparison. The clinical records of LUTS/BPH patients who underwent medical therapy with tamsulosin 0.4 mg/day plus the complementary and alternative medicine consisting of vitamins (C and D), herbal products (Cucurbita maxima, Capsicum annum, Polygonum capsicatum) and amino acid L-Glutamine bid between January 2019 to September 2019 were reviewed (Group 1). These patients were compared in a 1:1 fashion with LUTS/BPH patients who underwent therapy with tamsulosin 0.4 mg/day alone (Group 2). Total, storage, voiding and Quality of Life (QoL) international prostate symptom (IPSS) score, as well as overactive bladder (OAB)-v8 score and treatment-related adverse events recorded at 40 days follow-up in both groups were compared.

Results: At 40 days follow-up mean total, storage, voiding and QoL IPSS sub-scores as well as OAB-v8 score significantly improved in both groups. Intergroup comparison showed statistically significant lower mean total IPSS score (11.6 vs 12.4, p = 0.04) mean storage IPSS sub-score (6.5 vs 7.5, p = 0.01), and mean OAB v8 score (16.7 vs 18.8, p = 0.03) in patients in the Group 1.

Conclusions: The combination of tamsulosin 0.4 mg/die plus the complementary and alternative medicine consisting of vitamins (C and D), herbal products (Cucurbita maxima, Capsicum annum, Polygonum capsicatum) and amino acid LGlutamine bid provides statistically significant advantages in terms of storage LUTS improvements in patients with LUTS/BPH compared to tamsulosin 0.4 mg/day alone.

These findings are preliminary and further prospective studies on a greater number of patients are needed to confirm it.

Summary

KEY WORDS: Benign prostatic hyperplasia; Combination therapy; Lower urinary tract symptoms; Phytotherapy.

Submitted 20 February 2020; Accepted 13 March 2020

everyday urological practice and their prevalence increases with ageing (1-3). In the EPIC study, Riboli et al. reported an incidence of storage and voiding LUTS of about 51% and 26% of men evaluated, respectively (3). Interestingly, approximately 18% of men reported the coexistence of storage and voiding symptoms (4, 5). The European Association of Urology (EAU) guidelines strongly recommend a1-adrenoceptor antagonists as first-line therapeutic option in patients with moderate to severe symptoms as they significantly improve urinary symptoms and maxim urinary flow (Qmax) (6). In men with moderate-to-severe LUTS who mainly have bladder storage symptoms EAU Guidelines strongly recommend muscarinic receptor antagonists (strong recommendation) or beta-3 agonists (weak recommendation) (7). However, a number of concerns have been reported with the prescription of these drugs. Antimuscarinics might theoretically decrease bladder strength, thus increasing post-void residual volume (PVR) urine and causing urinary retention. Moreover, not all antimuscarinics have been evaluated in elderly men, and long-term studies on their efficacy in men of any age with LUTS are not yet available. Furthermore, antimuscarinics are contraindicated in patients with angle-closure glaucoma, gastrointestinal obstruction, paralytic ileus, myasthenia gravis, severe heart disease (8, 9). On the other hand, mirabegron has been evaluated mainly in female patients (8, 9). In recent years the prescription of phytotherapeutic compounds in patients with LUTS/BPH has gained growing interest (10). These agents represent a heterogeneous group and may contain differing concentrations of active ingredients. The complementary and alternative medicine Kubiker (Naturmed, Italy), consisting of vitamins (C and D), herbal products (Cucurbita maxima, Capsicum annum, Polygonum capsicatum) and amino acid LGlutamine, has been proposed in the treatment of overactive bladder syndrome (OAB) (11). We aimed to compare the efficacy of the combination therapy involving tamsulosin 0.4 mg once a day plus Kubiker bid and therapy with tamsulosin 0.4 mg alone in patients with LUTS/BPH.

INTRODUCTION

MATERIALS

Lower urinary tract symptoms related to benign prostatic hyperplasia (LUTS/BPH) represent a common complaint in

We performed a retrospective comparative study. The clinical records of LUTS/BPH patients who underwent

AND METHODS

No conflict of interest declared.

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medical therapy with tamsulosin 0.4 mg/day plus Kubiker bid between January 2019 to September 2019 were reviewed (Group 1). These patients were compared in a 1:1 fashion with LUTS/BPH patients who underwent therapy with tamsulosin 0.4 mg/day alone (Group 2). The followings were considered exclusion criteria: post-void residual volume (PVR) > 150 ml, prostate specific antigen (PSA) > 10 ng/ml, concomitant therapy with 5-alpha reductase inhibitors and/or phosphodiesterase type 5 inhibitors and/or muscarinic receptor antagonists or beta3 agonists, presence of neurological disorders, previous pelvic surgery, diabetes, urinary tract infections, history of acute urinary retention. The matched-pair comparison was based on the following criteria: PSA, prostate volume (PV), Qmax, PVR, total international prostate symptom score (IPSS), and 8-item overactive bladder questionnaire 8 (OAB-v8) score. Total, storage, voiding and Quality of Life (QoL) IPSS scores, as well as OAB-v8 score and treatment-related adverse events recorded at 40 days followup in both groups were compared. Descriptive data of continuous variables were expressed as mean ± standard deviation (SD) and compared using the Student’s t tests.

The analyses were considered significant for a p-value < 0.05. All statistical analyses were performed with SPSS version 16.0 software.

The study was performed in accordance with the ethical standards laid down in the Declaration of Helsinki. Verbal informed consent was obtained from subjects.

RESULTS Overall, 36 eligible patients who underwent medical therapy with tamsulosin 0.4 mg/day plus Kubiker were identified and compared to 36 patients who underwent therapy with tamsulosin 0.4 mg/day alone. Baseline patients’ characteristics in both groups are reported in Table 1. At 40 days follow-up mean total, storage, voiding and QoL IPSS sub-scores significantly improved in both groups (Table 2). Similarly, a statistically significant improvement in terms of OAB v8 score and Qmax was observed in both groups (Table 2).

Intergroup comparison showed statistically significant lower mean total IPSS score, mean storage IPSS sub-score,

Table 1.

Baseline patients’ characteristics in both groups.

Age, years, mean (SD) Prostate volume, mL, mean (SD) PSA, ng/mL, mean (SD) PVR, mL, mean (SD) Qmax, mL/sec, mean (SD) IPSS total, mean (SD) IPSS voiding, mean (SD) IPSS storage, mean (SD) IPSS QoL, mean (SD) OAB v8, mean (SD)

Group 1 (n = 36) Group 2 (n = 36) 65.3 (9.6) 63.4 (8.5) 44.1 (24.4) 46.1 (22.7) 2.9 (0.8) 3.2 (0.4) 37.0 (11.2) 39.0 (10.8) 11.2 (0.7) 12.5 (0.8) 17.9 (0.9) 18.0 (0.8) 8.5 (2.2) 9.1 (1.3) 9.3 (2.0) 8.8 (1.2) 2.9 (0.3) 3.2 (0.4) 19.6 (0.8) 20.1 (0.9)

p 0.32 0.73 0.91 0.26 0.18 0.59 0.15 0.18 0.23 0.29

IPSS: International Prostate Symptom Score; QoL: Quality of Life; OAB v8: 8-item overactive bladder questionnaire; PSA: Prostate Specific Antigen; PVR: Post-void residua volume; Qmax: maximum urinary flow; SD: Standard Deviation.

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Table 2.

IPSS and OAB v8 scores in both groups at 40-day follow-up.

IPSS total, mean (SD) IPSS voiding, mean (SD) IPSS storage, mean (SD) IPSS QoL, mean (SD) OAB v8, mean (SD) Qmax mL/sec, mean (SD) PVR, mL, mean (SD)

Group 1 (n = 36) Group 2 (n = 36) 11.6 (1.7) * 12.4 (1.5) * 5.1 (2.1) 4.8 (1.1) 6.5 (1.9) * 7.5 (1.6) * 2.1 (0.8) 2.4 (0.8) 16.7 (0.5) * 18.8 (0.8) * 13.6 (0.8) 14.1 (0.7) 28.0 (10.2) 32.0 (8.8)

p 0.04 0.58 0.01 0.20 0.03 0.20 0.42

IPSS: International Prostate Symptom Score; OAB v8: 8-item overactive bladder questionnaire; PVR: Post-void residua volume; Qmax: maximum urinary flow; QoL: Quality of Life; SD: Standard Deviation. *: p < 0.05 with respect to baseline.

and mean OAB v8 scores in patients in the Group 1.

Not statistically significant differences in terms of voiding IPSS sub-score, Qmax and PVR emerged from intergroup analysis. Not clinically significant treatment-related adverse events were recorded in both groups.

DISCUSSION Benign prostatic obstruction has been reported to cause morpho-functional alterations involving the detrusor muscle. Clinically, these alterations can impair bladder contractility and cause detrusor overactivity, decreasing bladder compliance, and onset of storage LUTS characterized by an altered bladder sensation, increased daytime frequency, nocturia, urgency and urgency incontinence (121). Experimental models have shown that bladder outlet obstruction causes detrusor smooth muscle cells hypertrophy and hyperplasia as well as extracellular matrix alterations that may lead, over time, to detrusor overactivity and, later, to reduced bladder contractility (13-15). As reported in the EpiLUTS study, 45.7% of the 14.139 men evaluated had storage LUTS (16). a1-blockers act by inhibiting the effect of endogenously released noradrenaline on smooth muscle cells in the prostate thus reducing prostate tone and bladder outlet obstruction (17). These drugs can reduce both storage and voiding LUTS and are considered the first-line drug treatment for male LUTS due to their good efficacy, and low rate and severity of adverse events. LUTS/BPH patients with mainly bladder storage symptoms represent a difficult to treat subset of patients. Indeed, therapy with a1-blockers may be suboptimal. On the other hand, both muscarinic receptor antagonists and beta-3 agonists should be prescribed with cautions and adherence to treatments with these drugs is often inadequate.

Herbal treatments are an increasingly popular alternative for treating storage LUTS (18). To the best of our knowledge, we compared, for the first time, the clinical efficacy of the combination of tamsulosin 0.4 mg/day plus Kubiker and tamsulosin 0.4 mg/day alone in patients with LUTS/BPH. We found that the combination therapy provided statistically significant advantages in terms of storage LUTS as demonstrated by lower IPSS storage sub-scores as well as lower OAB-v8 score. A number of evidences exist about the potential beneficial effects provided by the compounds contained in the food supple-

Complementary and alternative medicine

ment Kubiker. Cucurbita maxima, contained in pumpkin seeds, has been reported to provide benefits in both preclinical and clinical models of lower urinary tract dysfunction (19-25). Pre-clinical studies have shown that pumpkin seeds have antioxidant and inflammatory properties and inhibit lipid peroxidation (20). Pumpkin seeds administered to rats affected by overactive bladder (OAB) syndrome showed to cause an increase of the production of nitric oxide (NO) via the NO/arginine pathway (22). Independently of the acetylcholin/adrenaline system, this pathway generated the relaxation of the bladder detrusorial musculature (23). Pumpkin seeds were also shown to modulate prostate growth. Abdel Rahman et al. found that rats fed with high amounts of pumpkin seeds in the diet had smaller prostate sizes as compared to untreated rats (24). Furthermore, Tsai and co-workers showed that rats receiving subcutaneous testosterone to induce an increase in prostate size and subsequently treated with pumpkin seeds for 14 days, presented a smaller prostate gland compared to the control group treated only with prazosin (25). Nishimura et al. observed that the administration of pumpkin seed extract for 12 weeks significantly reduced the symptoms of OAB with no side effects (19). Polygonum capsicatum has a strong antioxidant activity, which has been observed in vitro (26). Capsaicin is the first vanilloid investigated for therapeutic purposes and evidence exists demonstrating its efficacy in the treatment of LUTS (11).

The capsaicin has been used for the treatment of OAB syndrome due to its ability to desensitize the transient receptor potential vanilloid 1 receptor (27). Evidence exists demonstrating that vitamin C from food and beverages can modulate voiding symptoms (11). However, the knowledge of the exact mechanism of action deserves further investigations. Vitamin D is essential for the proper functioning of the pelvic floor. It has been widely reported that a vitamin deficiency can predispose patients to a high risk of developing LUTS and incontinence (28, 29). To date, the role of glutamine in patients with LUTS is widely under-investigated and deserves careful investigations. Overall, although preliminary, results from the present study have relevant clinical implications and pose the basis for further investigations.

The combination of a1-adrenoceptor antagonists and phytotherapeutic agents containing a mixture of compounds that can interfere with the pathophysiology of bladder dysfunction at multiple levels like Kubiker may represent a strategy to discuss in patients with prevalent storage LUTS/BPH for which therapy with a1-adrenoceptor antagonists alone is suboptimal and medical treatments with muscarinic receptor antagonists or beta-3 agonists are not recommended or not tolerated.

The main limits of the present study are the retrospective design, the small sample size, and the short follow-up.

Moreover, the specific role of the various components of Kubiker could not be assessed. Therefore, results from the present study should be considered preliminary and further studied are needed to confirm the efficacy and safety of the combination of tamsulosin and the food supplement Kubiker in LUTS/BPH patients and to identify the subset of patients that can benefit most from this approach.

The role of Kubiker in women with storage LUTS represents a further area of interest (11, 30).

CONCLUSIONS The combination of tamsulosin 0.4mg/die plus Kubiker bid provides statistically significant advantages in terms of storage LUTS improvements in patients with LUTS/BPH compared to tamsulosin 0.4 mg/day alone.

These findings are preliminary and further prospective studies on a greater number of patients are needed to confirm it.

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Correspondence Ferdinando Fusco, MD ferdinando-fusco@libero.it Massimiliano Creta, MD max.creta@gmail.com Francesco Trama, MD (Corresponding Author) francescotrama@gmail.com Fabio Esposito, MD fabioesposito025@gmail.com Felice Crocetto, MD felice.crocetto@gmail.com Achille Aveta, MD achille-aveta@hotmail.it Francesco Mangiapia, MD mangiapippo@libero.it Ciro Imbimbo, MD imbimbo@unina.it Marco Capece, MD Roberto La Rocca, MD robertolarocca87@gmail.com Vincenzo Mirone, MD mirone@unina.it Nicola Longo, MD Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II Via Sergio Pansini 5, Napoli (Italy)

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DOI: 10.4081/aiua.2020.3.177

ORIGINAL PAPER

The role of Protopine associated with Nuciferine in controlling adverse events during hyperthermic intravesical chemotherapy instillations. A nutraceutical approach to control adverse event during intravesical instillations Francesco Chiancone, Maurizio Carrino, Maurizio Fedelini, Marco Fabiano, Francesco Persico, Clemente Meccariello, Paolo Fedelini Department of Urology, A. Cardarelli Hospital, Naples, Italy.

Objectives: The aim of this study was to analyse the role of two alkaloid, Protopine and Nuciferine, in the prevention and the treatment of the low and mild grade adverse events related to the use of HIVEC® (Hyperthermic IntraVEsical Chemotherapy) instillations.

Materials and methods: From September 2017 to September 2019, 100 patients were prospectively randomized into two groups: Group A = Protopine and Nuciferine syrup, 10 ml, once a day, for 8 weeks; Group B = placebo (flavoured coloured water), 10 ml, once a day, for 8 weeks. The primary endpoint was the evaluation of the efficacy of the therapy with Protopine and Nuciferine in controlling of the irritative symptoms. The secondary endpoint was the evaluation of the influences of the treatment on the uroflowmetric parameters.

Results: The patients of Group A showed a better International Prostatic Symptoms Score (IPSS) score, a better control of urgency symptoms (PPIUS) and tolerate well the pain (VAS score). The treatment doesn’t modify Uroflow-Qmax and seems to improve the Uroflow-Voided Volume (ml) without influencing the Uroflow-Post Void Residual volume (PVR).

Moreover, the treatment with Protopine and Nuciferine has been proven to be effective in the treatment of overactive bladder (OAB) symptoms. Patients’ evaluation of the two different treatments assessed with Patient Global Impression of Improvement questionnaire (PGI-I), demonstrated improvements in the Group A, while the Group B showed a lower satisfaction.

Conclusions: Protopine and Nuciferine can be interesting nutraceutical compounds useful to control irritative and pain related symptoms of intravesical chemo/immunotherapy.

Summary

KEY WORDS: Complementary medicine; Bladder cancer; LUTS; Chemotherapy; Overactive bladder; Urodynamics.

Submitted 6 January 2020; Accepted 13 March 2020

INTRODUCTION In recent times, Hyperthermic IntraVesical Chemotherapy (HIVEC®) instillations has been added to the existing regimens as adjuvant and neoadjuvant treatment of bladder cancer (1). Most of the side effects were low grade and 97% of patients completed the HIVEC® protocol (2). In a population of 55 BCG (Bacillus CalmetteGuérin) unresponsive non-muscle invasive bladder cancer

(NMIBC) patients, 5% of the patients did not complete at least 5 HIVEC® instillations because of facial swelling, urticaria and urinary tract pain Grade 3 according to Common Terminology Criteria for Adverse Events (CTCAE). Despite this, 7% of patients reported CTCAE Grade 1 bladder spams, 11% CTCAE Grade 1 urinary frequency/urgency, 24% CTCAE Grade 2 urinary frequency/urgency, 4% CTCAE Grade 1 urinary tract pain, 9% CTCAE Grade 2 urinary tract pain and 2% CTCAE Grade 3 urinary tract pain (3).

Despite the low number of adverse events, the patients treated with HIVEC® were significantly more likely to develop urinary frequency, haematuria and bladder spasm than passive mitomycin-C (4).

The aim of this study was to analyse the role of two alkaloid, Protopine and Nuciferinein the prevention and the treatment of the low and mild grade adverse events related to the use of HIVEC® instillations.

MATERIALS

AND METHODS

From September 2017 to September 2019, 100 patients with Bacillus of Calmette Guerin (BCG)-failure (including BCG-refractory tumour, BCG-relapsing tumour and BCG unresponsive tumour) NMIBC whose underwent HIVEC® Chemotherapy were prospectively enrolled in this study.

The patients (pts) were randomized into two groups using block randomization in order to obtain two groups of equal sample size. In group A, we enrolled 50 patients who received Protoves M1® (Protopine and Nuciferine) syrup, 10 ml, once a day, for 8 weeks. In group B, we enrolled 50 patients who received placebo (flavoured coloured water), 10 ml, once a day, for 8 weeks.

They started the therapy two weeks before the beginning of HIVEC® treatment. Inclusion criteria covered all the patients with intermediate-and high-risk NMIBC patients who were planned to receive HIVEC® treatment. Patients with uncontrolled underlying diseases (ASA III or IV), post void residual urine ≥ 100 ml, bleeding tendency, drug abuse, chronic pelvic pain, urinary tract infection, neurological disease, bladder lithiasis, renal or liver failure, tachycardia and heart failure were

No conflict of interest declared.

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excluded from the study. Male patients with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH) were not excluded from the study if they had normal values of uroflowmetry and they did not assume any medical treatment for BPH. At the baseline, data on demographic and anthropometric features (age, weight, height, BMI [body mass index]), lifestyle characteristics (smoke, alcohol), any comorbidities (hypertension, diabetes mellitus, etc.) were collected. All patients underwent a clinical evaluation (comprised general, genital and urologic examination). Before starting the treatment, the following measurements were collected: prostate volume by transrectal ultrasound, prostate specific antigen (PSA), uroflowmetry parameters (Uroflow-Qmax, UroflowVoided Volume, Uroflow-PVR [Post-Void Residual]), International Prostatic Symptoms Score (IPSS) questionnaire, OverActive Bladder questionnaire-short form (OABqSF) 6 and 13, patient perception of intensity of urgency scale (PPIUS), and visual analogue scale (VAS). PSA and IPSS were investigated only in male pts. In addition, the patient impression of improvement was assessed.

Improvement was evaluated with the Patient Global Impression of Improvement questionnaire (PGI-I), a validated tool to estimate the improvement or the deterioration associated to the treatment. The primary endpoint was the evaluation of the efficacy of the therapy with Protopine and Nuciferine in controlling irritative symptoms, including nocturia, urinary frequency, bladder pain, urgency and urge incontinence related to the chemo-hypertermia treatment. The secondary endpoint we evaluated was the influence of the treatment on the uroflowmetric parameters. Evaluation was performed after 1 week and after 6 weeks of therapy. Statistical analyses were conducted using SAS version 9.3 software (SAS Institute, Inc., NC). Mean values with standard deviations (± SD) were computed and reported for all items.

Statistical significance was achieved if p-value was ≤ 0.05 (two-sides).

RESULTS Table 1 depicts patients’ demographics and baseline characteristics. The two groups showed no difference in terms of patients’ demographics as well as tumour characteristics in all variables.

Of all 100 patients enrolled, 2/50 (4%) of group B withdrew the study for adverse events of HIVEC treatment.

In Table 2 and 3 we show a comparison of uroflowmetric parameters and questionnaires from baseline and one and six weeks follow up of treatment in the cases (group A) and in the controls (group B). The uroflow parameters (Uroflow-Qmax, Uroflow-Voided Volume, Uroflow-PVR) did not show statistical significant difference from baseline in the group A and one and six weeks follow-up. Otherwise IPSS total significantly increase at one week from baseline (p < 0.001), but this difference was not significant at six weeks when IPSS total was not significantly worse from baseline (p = 0.09). In group A the quality of life showed a significant worsening from baseline after one week and six weeks of treatment in all parameters and questionnaires analyzed (OAB-q SF6, OAB-q SF13, PPIUS, VAS Scale) but after six weeks of treatment a significant-

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Table 1.

Demographics and baseline characteristics of the 50 cases and 50 controls.

Variable N° (%) Males Females Smokers Non-smokers Diabetes (Yes) Diabetes (No) C.I.S. (Yes) C.I.S. (No) Mean ± SD Age at surgery (years) BMI (kg/m2) T.U.R.B. (N°) Tumors (last T.U.R.B.) (N°) PSA (ng/ml) Prostate volume (cc) Uroflow-Qmax (ml/s) Uroflow-Voided Volume (ml) Uroflow-PVR (ml) IPSS total QOL score OAB-q SF 6 OAB-q SF 13 PPIUS VAS scale

Value (cases)

Value (controls)

p

40 (80%) 10 (20%) 12 (24%) 38 (76%) 5 (10%) 45 (90%) 11 (22%) 39 (78%)

39 (78%) 11 (22%) 11 (22%) 39 (78%) 7 (14%) 43 (86%) 8 (16%) 42 (84%)

p = 0.8061 p = 0.8061 p = 0.8122 p = 0.8122 p = 0.5383 p = 0.5383 p = 0.4444 p = 0.4444

58.52 ± 5.28 26.754 ± 1.96 1.86 ± 1.18 3.5 ± 2.44 2.33 ± 0.95 42.43 ± 13.39 17.49 ± 2.39 250.6 ± 39.8 15.4 ± 10.6 7.05 ± 3.88 2.22 ± 1.23 11.48 ± 5.18 25.12 ± 11.50 0.94 ± 0.79 0.08 ± 0.27

57.64 ± 5.38 26.916 ± 1.91 2.08 ± 1.16 4.08 ± 2.25 2.13 ± 0.95 41.38 ± 13.56 17.39 ± 2.21 242.2 ± 41.2 14.9 ± 10.1 7.79 ± 4.55 2.34 ± 1.26 11.92 ± 5.30 26.02 ± 11.39 0.96 ± 0.78 0.18 ± 0.87

p = 0.4138 p = 0.6764 p = 0.3495 p = 0.2195 p = 0.2951 p = 0.6977 p = 0.8285 p = 0.3023 p = 0.8097 p = 0.3837 p = 0.6310 p = 0,6755 p = 0.6950 p = 0.8989 p = 0.4395

CIS: In Situ Carcinoma; BMI: Body Max Index; TURB: Trans Urethral Bladder Resection; PSA: Prostate Specific Antigen; PVR: post-void residual; IPSS: International Prostatic Symptoms Score; QOL: quality of life; OAB: overactive bladder; PPIUS: patient perception of intensity of urgency scale; VAS: visual analogue scale.

Table 2.

Comparison of uroflowmetry parameters and questionnaires from baseline and between one and six weeks of treatment (cases).

Variable Uroflow-Qmax (ml/s) p (from baseline) Variable Uroflow-Voided Volume (ml) p (from baseline) p (from 1 and 6 weeks) Uroflow-PVR (ml) p (from baseline) p (from 1 and 6 weeks) IPSS total p (from baseline) p (from 1 and 6 weeks) OAB-q SF 6 p (from baseline) p (from 1 and 6 weeks) OAB-q SF 13 p (from baseline) p (from 1 and 6 weeks) PPIUS p (from baseline) p (from 1 and 6 weeks) PGI-I p (from baseline) p (from 1 and 6 weeks) VAS scale p (from baseline) p (from 1 and 6 weeks)

Value (baseline) 17.49 ± 2.39 Value (baseline) 250.6 ± 39.8 15.4 ± 10.6 7.05 ± 3.88 11.48 ± 5.18 25.12 ± 11.50 0.94 ± 0.79 4±0 0.08 ± 0.27

Value (one-week) Value (six-weeks) 16.99 ± 2.55 16.62 ± 2.43 p = 0.3142 p = 0.0742 Value (one-week) Value (six-weeks) 239.7 ± 40.10 250.9 ± 39.22 p = 0.1756 p = 0.9698 p = 0.1611 18.18 ± 12.46 19.7 ± 12.01 p = 0.2324 p = 0.0606 p = 0.5360 11.18 ± 4.84 8.35 ± 3.81 p < 0.001 p = 0.0941 p = 0.0016 17.16 ± 4.82 14.46 ± 5.60 p < 0.001 p = 0.0069 p = 0.0112 36.42 ± 10.67 31.16 ± 11.57 p < 0.001 p = 0.0102 p = 0.0201 2.26 ± 0.88 1.66 ± 0.66 p < 0.001 p < 0.001 p = 0.0002 4.2 ± 0.60 2.46 ± 0.86 p = 0.1161 p < 0.001 p < 0.001 3.38 ± 1.35 2.34 ± 0.96 p < 0.001 p < 0.001 p < 0.001

PVR: post-void residual; IPSS:International Prostatic Symptoms Score; OAB: overactive bladder; PPIUS: patient perception of intensity of urgency scale; PGI-I: Patient Global Impression of Improvement questionnaire; VAS: visual analogue scale.

Protopine and nuciferin for hyperthermic intravesical chemotherapy

Table 3.

Comparison of uroflowmetry parameters and questionnaires from baseline and between one and six weeks of treatment (controls).

Variable Uroflow-Qmax (ml/s) p (from baseline) p (from 1 and 6 weeks) Uroflow-Voided Volume (ml) p (from baseline) p (from 1 and 6 weeks) Uroflow-PVR (ml) p (from baseline) p (from 1 and 6 weeks) IPSS total p (from baseline) p (from 1 and 6 weeks) OAB-q SF 6 p (from baseline) p (from 1 and 6 weeks) OAB-q SF 13 p (from baseline) p (from 1 and 6 weeks) PPIUS p (from baseline) p (from 1 and 6 weeks) PGI-I p (from baseline) p (from 1 and 6 weeks) VAS scale p (from baseline) p (from 1 and 6 weeks)

Value (baseline) 17.39 ± 2.21

242.2 ± 41.22

14.9 ± 10.13

7.79 ± 4.55

11.92 ± 5.3

26.02 ± 11.39

0.96 ± 0.78

4±0

0.08 ± 0.27

Value (one-week) Value (six-weeks) 17.06 ± 2.25 17.02 ± 2.15 p = 0.4611 p = 0.3982 p = 0.9278 220.4 ± 43.66 218.8 ± 43.21 p = 0.0118 p = 0.0067 p = 0.8543 13.8 ± 10.08 15.9 ± 9.98 p = 0.5875 p = 0.6201 p = 0.2977 13.64 ± 5.71 14.62 ± 5.92 p < 0.001 p < 0.001 p = 0.4016 20.58 ± 6.29 24.34 ± 6.3 p < 0.001 p < 0.001 p = 0.0036 43.78 ± 13.02 49.44 ± 12.65 p < 0.001 p < 0.001 p = 0.0298 2.12 ± 0.69 2.54 ± 0.64 p < 0.001 p < 0.001 p = 0.0021 4.82 ± 0.96 5.22 ± 1.02 p < 0.001 p = 0.0462 p = 0.2719 3.68 ± 1.88 3.92 ± 1.93 p < 0.001 p < 0.001 p = 0.5302

PVR: post-void residual; IPSS:International Prostatic Symptoms Score; OAB: overactive bladder; PPIUS: patient perception of intensity of urgency scale; PGI-I: Patient Global Impression of Improvement questionnaire; VAS: visual analogue scale.

(p < 0.001). In this group the quality of life showed a significant worsening after one week and six weeks of treatment from baseline in all parameters and questionnaires analyzed (OAB-q SF6, OAB-q SF13, PPIUS, VAS Scale).

At six weeks follow-up a significantly worsening of quality of life was demonstrated from the values at one week.

PGI-1 showed a significantly increase from baseline at one and six weeks of follow-up with a worse perception of the response to the therapy. VAS scale also showed a significantly increase from baseline at one and six weeks of follow-up. In both cases an increase of values was seen from the one and six weeks of follow-up without reaching a significant difference.

Table 4 shows a comparison of uroflowmetric parameters and results of questionnaires between cases and controls at one and six weeks. No differences were seen in the Uroflow-Qmax and in the Uroflow-PVR at one (p = 0.8846) and six weeks (0.3951) while the UroflowVoided Volume was significantly reduced in the controls at one (p = 0.0234) and six (p = 0.0002) weeks followup. The IPSS questionnaire significantly get worse in the group B instead of group A at one (p = 0.0222) and six (p < 0.001) weeks of treatment. Group A showed a significantly better OAB-q SF 6 and OAB-q SF 13 at one and six weeks of follow-up, while the PPIUS and the VAS scale were significantly worse in the group B only at six weeks. PGI-1 showed a worst perception of the condition post-therapy in the group B both after one and six weeks of treatment. No adverse events were reported in both groups.

DISCUSSION Several clinical trials have demonstrated a benefit for chemo-hyperthermia over intravesical chemotherapy alone for treating NMIBC (5-6). Neoadjuvant HIVEC consisted of intravesical chemotherapy with Mitomycin-C (MMC) combined with bladder hyperthermia, which was achieved in our cases with the Bladder Recirculation System (BRS) system from Combat Medical. The Combat BRS device is an external device that heats fluid (MMC in this case) in a sterile disposable bag and recirculates it to the urinary bladder at a constant and controllable temperature and flow rate through a three-way Foley catheter. Hyperthermia increases drug uptake into the cancer cells, Table 4. affects drug metabolism, and Comparison of uroflowmetry parameters and results of questionnaires between cases impairs cellular DNA repair mechaand controls at one and six weeks. nisms that normally counteract Variable Value (Group A Value (Group B p Value (Group A Value (Group B p drug effect (7-9).

1-week) 1-week) 6-week) 6-week) This treatment might be a feasible Uroflow-Qmax (ml/s) 16.99 ± 2.55 17.06 ± 2.25 0.8846 16.62 ± 2.43 17.02 ± 2.15 0.3951 option in BCG unresponsive NMIBC Uroflow-Voided Volume (ml) 239.7 ± 40.10 220.4 ± 43.66 0.0234 250.9 ± 39.22 218.8 ± 43.21 0.0002 patients, potentially avoiding or Uroflow-PVR (ml) 18.18 ± 12.46 13.8 ± 10.08 0.0562 19.7 ± 12.01 15.9 ± 9.98 0.0611 postponing the need for radical surIPSS total 11.18 ± 4.84 13.64 ± 5.71 0.0222 8.35 ± 3.81 14.62 ± 5.92 < 0.001 gery in a proportion of these patients OAB-q SF 6 17.16 ± 4.82 20.58 ± 6.29 0.0029 14.46 ± 5.60 24.34 ± 6.3 < 0.001 (3, 10, 11).

OAB-q SF 13 36.42 ± 10.67 43.78 ± 13.02 0.0026 31.16 ± 11.57 49.44 ± 12.65 < 0.001 Nevertheless, this treatment can PPIUS 2.26 ± 0.88 2.12 ± 0.69 0.3782 1.66 ± 0.66 2.54 ± 0.64 < 0.001 increase the rate of local adverse PGI-I 4.2 ± 0.60 4.82 ± 0.96 0.0002 2.46 ± 0.86 5.22 ± 1.02 < 0.001 events than passive mitomycin-C VAS scale 3.38 ± 1.35 3.68 ± 1.88 0.3616 2.34 ± 0.96 3.92 ± 1.93 < 0.001 like urinary frequency, haematuria PVR: post-void residual; IPSS: International Prostatic Symptoms Score; OAB: overactive bladder; PPIUS: patient perception of intensity of urgency scale; and bladder spasm (4).

PGI: Patient Global Impression of Improvement questionnaire; VAS: visual analogue scale.

Protopine has a demonstrated antily improvement of quality of life was demonstrated with respect of the values at one week. PGI-1 did not significantly show any change at one week but showed a significant decrease at six weeks follow-up with a greater satisfaction for the treatment. In the group B the uroflow parameters did not show a statistical significant difference from baseline at one and six weeks follow-up except for a significant reduction of Uroflow-Voided Volume (p = 0.0118) at one week. A significant worsening of IPSS score was seen at one and six weeks of follow-up

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cholinergic- antimuscarinic (11, 12) and GABAergic (1215) action and it is able to influence some neurological systems responsible of bladder functions. Moreover, its anti-acetylcholinesterase action give it an antiamnesic property that may hold significant therapeutic value in alleviating certain memory impairments observed in dementia (15, 16).

Protopine increase the p53-mediated transcriptional activity, resulting in stabilization of p53 protein. It exerts an antiproliferative activity and may have potential effect as a chemopreventive agent for human colon cancer (16, 17).

Nuciferin is a partial antagonist of D2-like receptor and has a demonstrated regulatory action on the dopaminergic system (responsible of urination onset (17, 18) and seems to reduce states of tension and anxiety on a psychological level (18-20). Nuciferine significantly inhibited the lipopolysaccharide (LPS)-induced inflammatory cytokine IL-6 and TNF-a production in RAW 264.7 cells having potential anti-inflammatory activities (20, 21).

Its use significantly decrease the expression of TLR4 in a dose-dependent manner and potently ameliorates LPSinduced mastitis by inhibition of the TLR4-NF-kB signaling pathway (21, 22). In addiction nuciferine alleviated fructose-induced inflammation by inhibiting TLR4/PI3K/NF-kB signaling and NLRP3 inflammasome activation in rat renal cortex and HK-2 cells, which may contribute to the improvement of renal injury (22, 23).

This molecule is an aporphine alkaloid of lotus leaf extract which can induce relaxation in contracted tracheal rings. It induce relaxation in tracheal rings mainly by inhibition of extracellular Ca2+ influx through the blockade of voltage-dependent L-type Ca2+ channels and/or nonselective cation channels, showing therapeutic effect on respiratory diseases associated with the aberrant contraction of airway smooth muscles and/or bronchospasm (23, 24).

In our experience the patients who underwent Protopine and Nuciferine syrup treatment, showed a better IPSS score, a better control of urgency symptoms (PPIUS) and tolerate well the pain related to the chemo-hyperthermia treatment (VAS score) compared to control group.

The treatment doesn’t modify Uroflow-Qmax at 1 and 6 weeks and seems to improve the Uroflow-Voided Volume (ml) withouth influence the Uroflow-PVR. Moreover Protopine and Nuciferine syrup treatment has been proven to be effective in the treatment of OAB symptoms with a significant reduction of the symptoms assessed with Overactive Bladder Symptoms Score questionnaire (OAB-q SF6, OAB-q SF13) after six weeks of treatment but not after one week of treatment. This underline the need to start the treatment with Protopine and Nuciferine as soon as possible in order to enhance the effect of the treatment.

Patients’ evaluation of the two different treatments (Protopine and Nuciferine vs Placebo) assessed with PGI-I, demonstrated improvements in the group of cases with a greater satisfaction expressed by patients at six weeks, while the control group showed a lower satisfaction at one and six weeks.

Moreover, the treatment with Protopine and Nuciferine syrup was well tolerated by all patients, none of them showing any side effect during the period study.

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The study is a double-blind randomized study but is limited by the small number of patients and monocentric nature.

CONCLUSIONS Protopine and Nuciferine syrup can be an interesting alternative to antinflammatory and antimuscarinic agents to treat irritative and pain related symptoms of intravesical chemo/immunotherapy.

More studies should be carried out to clarify the precise role of the active ingredients of Protopine and Nuciferine syrup and their interactions.

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3. de Jong JJ, Hendricksen K, Rosier M, et al. Hyperthermic Intravesical Chemotherapy for BCG Unresponsive Non-Muscle Invasive Bladder Cancer Patients. Bladder Cancer. 2018; 4:35-401.

4. Tan WS, Palou J , Kelly J. Safety and tolerability analysis of hyperthermic intravesical mitomycin to mitomycin alone in HIVEC I and HIVEC II: An interim analysis of 307 patients Eur Urol. 2017; 16;e1150.

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7. Ahmed K, Zaidi SF. Treating cancer with heat: Hyperthermia as promising strategy to enhance apoptosis. J Pak Med Assoc. 2013; 63:504-8.

8. Kampinga HH. Cell biological effects of hyperthermia alone or combined with radiation or drugs: A short introduction to newcomers in the field. Int J Hyperthermia. 2006; 22:191-6.

9. Hildebrandt B, Wust P, Ahlers O, et al. The cellular and molecular basis of hyperthermia. Crit Rev Oncol Hematol. 2002; 43:33-56.

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12. Ustunes L., Laekeman GM, Gözler B, et al. In vitro study of the anticholinergic and antihistaminic activities of Protopine and some derivatives. J Nat Prod. 1988; 51:1021-2 13. Kardos J, Blaskó G, Simonyi M. Enhancement of gammaaminobutyric acid receptor binding by protopine-type alkaloids.

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Protopine and nuciferin for hyperthermic intravesical chemotherapy

14. Fedurco MJ, Gregorová K, Šebrlová J, et al. Modulatory Effects of Eschscholzia californica Alkaloids on Recombinant GABAA Receptors. Biochem Res Int. 2015; 2015:617620.

15,Häberlein H, Tschiersch KP, Boonen G, et al. Chelidonium majus L.: components with in vitro affinity for the GABAA receptor.

Positive cooperation of alkaloids. Planta Med. 1996; 62:227-31.

16. Kim SR, Hwang SY, Jang YP, et al. Protopine from Corydalis ternata has anticholinesterase and antiamnesic activities. Planta Med. 1999; 65:218-21.

17. Son Y, An Y, Jung J, et al. Protopine isolated from Nandina domestica induces apoptosis and autophagy in colon cancer cells by stabilizing p53. Phytother Res. 2019; 33:1689-1696.

18. Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci. 2008; 9:453-466.

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Nelumbinis semen on rats under chronic mild stress induced depression-like symptoms. Am J Chin Med. 2005; 33:205-13.

20. Farrel MS, McCorvy JD, Huang XP, et al. In vitro and in vivo characterization of the alkaloid nuciferine. PLoS One. 2016; 11:e0150602.

21. Zhang C, Deng J, Liu D, et al. Nuciferine inhibits proinflammatory cytokines via the PPARs in LPS-induced RAW264.7 cells.

Molecules 2018;23: pii: E2723.

22. Chen X, Zheng X, Zhang M, et al. Nuciferine alleviates LPSinduced mastitis in mice via suppressing the TLR4-NF-kB signaling pathway. Inflamm Res. 2018; 67:903-911.

23. Wang MX, Zhao XJ, Chen TY, et al. Nuciferine alleviates renal injury by inhibiting inflammatory responses in fructose-fed rats. J Agric Food Chem. 2016; 64:7899-7910.

24. Yang X, Yu MF, Lei J, et al. Nuciferine Relaxes Tracheal Rings via the Blockade of VDLCC and NSCC Channels. Planta Med. 2018; 84:83-90.

Correspondence Francesco Chiancone, MD (Corresponding Author) francescok86@gmail.com Maurizio Carrino, MD Maurizio Fedelini, MD Marco Fabiano, MD Francesco Persico, MD Clemente Meccariello, MD Paolo Fedelini, MD Urology Department, A. Cardarelli Hospital, Via Antonio Cardarelli 9, 80131 - Napoli (Italy)

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DOI: 10.4081/aiua.2020.3.182

ORIGINAL PAPER

Prepuce-sparing corporoplasty as a safe alternative for patients with acquired penile curvature Aldo Franco De Rose 1, Francesca Ambrosini 1, Guglielmo Mantica 1, Enrico Zero 2, Riccardo Banchero 1, Carlo Terrone 1 1 Department 2 Department

of Urology, Policlinico San Martino Hospital, University of Genoa, Genoa, Italy; of Computer Science, Bioengineering, Robotics and Systems Engineering, University of Genoa, Genoa, Italy.

Objectives: penile curvature is a rare condition, classified as congenital or acquired (Peyronie’s disease) (PD). Surgical correction is the standard treatment. It’s common practice to associate circumcision with penile de-gloving to prevent complications. In this paper we evaluate the feasibility of penile surgery avoiding circumcision.

Materials and methods: patients presenting with penile curvature were treated using a modified Nesbit procedure. Patients were divided into group A if they opted for a prepuce-sparing surgery and the others into group B. Patients were evaluated pre and postoperatively and postoperative complications were assessed. The 5-item International Index of Erectile Function (IIEF-5) was administered before and 6 months after surgery and we compared the difference of mean value using T-Test.

Results: Group A and B were made of 53 and 16 patients respectively. Median age was 59 years [interquartile range (IQR) 12] in A and 62 (IQR 9) in B (p = 0.2). Median curvature was 40° (IQR 40°) in A and 40 ° (IQR 30°) in B (p = 0.62). Mean difference between pre- and post-operative IEFF was 1.9 ± 2 in A and 2.6 ± 2.1 in B (p = 0.36).

Conclusions: According to our experience, surgical correction of penile curvature without performing circumcision could be a safe and feasible strategy. We recommend performing circumcision only in patients who present with pre-operative phimosis.

Summary

MATERIALS

AND METHODS

Data were collected from patients presenting with Peyronie’s disease (PD) who underwent to a modified Nesbit procedure from January 2014 to January 2019 at a single academic tertiary hospital. Our Institution’s prospectively updated database that have been retrospectively evaluated. All the procedures were performed by the same experienced surgeon (A.F.D.R.).

INTRODUCTION

1. Preoperative assessment and follow-up All patients had a stable disease for at least three months and suffered from pain during erection or during sexual intercourse. All patients underwent a standard clinical assessment, routine blood sample, urinalysis, physical examination during erection (after intracavernous injection of vasoactive drugs or self-photography at orthogonal, frontal, and sagittal planes). Curvature degrees were measured using a goniometer. Both the prepuce and the degree of penile curvature were assessed before surgery.

We considered curvature of more than 30 °. Medical and sexual history of patients was taken focusing on any previous penile surgery. The 5-item International Index of Erectile Function (IIEF-5) was administered before and 6 months after the treatment. Degree of angulation was recorded at follow-up with self-photograph at orthogonal, frontal and sagittal planes.

Penile curvature can be considered a relatively uncommon condition, with an incidence of 0,4-0,6%. Estimated prevalence is about 0.5% but according to several Authors it may reach up to 10% due to misdiagnosis and low awareness of the disease (1, 2). While new promising therapies are developing and spreading (3-4), surgery is still indicated as primary management for many patients with penile curvatures, especially when the curvature does not allow a satisfactory intercourse (5-7). A common feature of the many different techniques of corporoplasty which were proposed over the last decades is to associate circumcision with penile degloving in order to prevent postoperative oedema, phimosis and necrosis of the prepuce (8, 9). However, few recent studies have shown that a prepuce-sparing surgery is feasible with a low rate of local complications (10, 11). We aim to evaluate the fea-

2. Sample definition and analysis The patients were divided into two different groups: group A, made by patients who opted for a prepucesparing surgery, and group B made by those who decided to be circumcised. Patients’ characteristics, intra-, post-operative and 6 months follow-up data were collected and analysed. Post-operative complications were assessed according to Clavien-Dindo (CD) classification (14). In the two groups, we assessed the difference of mean value of IIEF-5 score administered before and 6 months after the surgery by using T-Test. Data were entered into a Microsoft Excel (Version 14.0) database and then transferred to Sofastat TM 1.4.6 for Windows.

Descriptive statistics were calculated for all patients’ variables and reported as median (IQR), mean ± stan-

KEY WORDS: Erectile dysfunction; Foreskin; Male; Phimosis; Penile induration.

Submitted 23 February 2020; Accepted 2 April 2020

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sibility and the safety of prepuce-sparing corporoplasty on a single-institution series.

No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2020; 92, 3

Feasibility of prepuce sparing corporoplasty

dard deviation (SD) or as proportion. The homogeneity and data of the two groups were compared using the Kolmogorov-Smirnov, Chi-Square, Fisher Exact and the paired T-test. We set the level of significance to 0.05.

3. Surgical procedure and perioperative management In all cases a modified Nesbit technique has been performed. The procedure starts with a sub-coronal circumferential incision 1 cm below the coronal sulcus. Then the degloving is carried out following the avascular plane between the dartos and the Buck’s fascia. We accurately spare the dartos in order not to damage the blood supply to the prepuce. The neurovascular bundle is mobilized from the dorsum of the penis by incising Buck’s fascia laterally. Five micro-grams of prostaglandin E1 (PGE 1) are injected into the corpora cavernosa to obtain an artificial erection.

The tunica albuginea can be grasped with an Allis clamp or with suspension stitches and then it is excised sharply with a cold scalpel (Figure 1).

The albuginea continuous solution is closed with interrupted polyglycolic 3/0 suture. The result is assessed by inducing a final hydraulic erection. Buck’s fascia is reapproximated with an absorbable monofilament suture.

Finally, we perform an interrupted 4/0 suture to approximate the skin (Figure 2).

For patients among group B the surgical procedure was similar to the technique performed for group A except for the final step of the circumcision. The redundant prepuce is pulled upwards, the adhesions to the glans is released, and after skin excision, haemostasis is performed with an electrocautery. We approximate the skin and the mucosal borders with simple interrupted absorbable suture (polyglycolic 3/0).

A transurethral catheter is placed during surgery and left for 1-2 days. All patients were premedicated with third Figure 1.

The electric scalpel delimits the area of corporoplasty subsequently engraved with the cold knife.

Figure 2.

Sub-coronal suture with Vycril rapid 4/0 stitches without circumcision.

generation cephalosporins as prophylactic antibiotic before induction of anaesthesia (12, 13).

4. Ethics statement Our institution doesn’t require an Institutional review board approval for retrospective observational studies.

However, every patient at the admission had to give a written consent for the prospective collection and retrospective analysis of data.

RESULTS Group A and B were made of 53 and 16 patients, respectively. The median age was 59 years (IQR 12) in group A and 62 (IQR 9) in group B (p = 0.20). Median grade of penile curvature was 40° (IQR 40°) in group A and 40° (IQR 30°) in group B (p = 0.62). The two groups were similar in direction of curvature (Table 1). Median operating time was 90 minutes (IQR 6) in group A and 100 minutes (IQR 30) in group B (p = 0.03). Patients of both two groups had their urethral catheters removed at a median of 1 day (IQR group A 1 and IQR group B 0) after surgery (p = 0.23). Median length of stay was 2 day (IQR 1) in group A and 2 day (IQR 0) in group B. Twenty-one patients of group A were used to take phosphodiesterase type 5 inhibitor (PDE5 inhibitor) before surgery. After the treatment 19 (36%) of them continued to use PDE5 inhibitor while two of them started using intracavernous injections of vasoactive medication.

Table 1.

Summary table on the population of patients considered in the study.

Variable Number of patients Age (y), median (IQR) a Curvature (°), median (IQR) Direction of curvature, n (%) Dorsal Ventral Lateral IEFF-5 score, mean ± SD

Group A 53 59 (12)

Group B 16 62 (9)

P value 0.91 0.20

40° (40°) 18 (34) 16 (30) 19 (36) 19 ± 2

40° (30°) 7 (44) 5 (31) 4 (25) 17 ± 2

0.62 0.74 0.98 0.59 0.02

a IQR = interquartile range.

Table 2.

Summary table on the population of patients considered in the study.

Variable Operating time (minutes), median (IQR) Duration of catheterization (days), median (IQR) Hospital stay (d), median (IQR) Complications CD a Grade III CD Grade IV IIEF-5 score 6 months after, mean ± SD IIEF-5 pre-/post-op. difference Residual curvature at 6 months Straight < 15°

Group A 90 (6) 1 (1) 1 (1)

Group B 100 (30) 1 (0) 1 (0)

P value 0.03 0.23 0.24

4 0 21 ± 2 1.9 ± 2

0 0 20 ± 2 2.6 ± 2.1

0.11 0.36

51 2

16 0

a CD = Clavien Dindo.

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A.F. De Rose, F. Ambrosini, G. Mantica, E. Zero, R. Banchero, C. Terrone

In group B, three patients used PDE5 inhibitor before surgery and they continued the same therapy also after the surgery. Mean difference between pre- and postoperative IIEF was 1.9 ± 2 in group A and 2.6 ± 2.1 in group B (p = 0.36). Four patients (7.5%) among Group A experienced CD grade III postoperative complications (secondary circumcision due to post-operative paraphimosis/edema). No CD grade IV complications were reported in both groups. Two patients among group A reported recurrent curvature of more than 15 degrees, but in both cases no secondary surgery was required (Table 2).

DISCUSSION Penile curvature is a congenital or acquired deformity which results in sexually debilitating condition and significant psychological stress for patients and their partners (15). Once medical treatment is excluded or unuseful, surgery becomes the standard of choice (16).

Both shortening and lengthening procedures are good options for patients. The first technique to correct penile curvature was described by Nesbit (17). In the following years various modifications to Nesbit’s technique were suggested such as the Yachia corporoplasty technique with or without penile degloving. According to the literature the outcomes of the “degloving” and “without degloving” techniques are similar (18).

Regardless of the procedure performed, penile degloving is generally combined with circumcision to reduce risk of postoperative oedema of the prepuce, with subsequent phimosis and necrosis (19, 20). However, recent studies demonstrate that circumcision is not always necessary, particularly when patients present with no phimosis pre-operatively (10, 11). Alei et al. (21) described a new corporoplasty technique named as the ‘doublebreasted’ corporoplasty, with penoscrotal and infrapubic access not requiring circumcision. They reported no major complications nor neurovascular lesions or change in erectile function, low morbidity, low recurrence rate and excellent aesthetic results. Garaffa et al. (10) reviewed a series of 251 patients who underwent a Lue (86 patients) or a Nesbit procedure (162 patients) or a combination of both. They reported very few complications in the group of patients without pre-operatively phimosis that chose not to be circumcised. They could state that circumcision should not be considered as a routine part of penile surgery unless a significant phimosis is present. Similarly, Pavone et al. (11) reported a series of 147 patients treated with Nesbit's corporoplasty without circumcision and no major complication were described. The authors affirmed that circumcision must not be considered a mandatory time in Nesbit procedure if the anatomical structures are carefully respected, the number of artificial erections is reduced.

In this paper we analysed surgical outcomes of a group of patients treated with modified Nesbit procedure without circumcision comparing them with a similar group treated with the same technique but completed with circumcision. Pre and post-operative data were similar in both two groups and no major complications were reported.

Not performing circumcision in penile surgery could be

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Archivio Italiano di Urologia e Andrologia 2020; 92, 3

a safe strategy if some precautions are followed. We recommend minimizing trauma of tissues carefully isolating the plane between the dartos and the Buck’s fascia to avoid bleeding and ischaemia. In addition, the initial subcoronal circumferential incision 1 cm below the coronal sulcus allows to spare a sufficient prepuce vascularization.

In this way the risk of tissue retraction and consequently to phimosis and foreskin necrosis could be reduced.

Overall, regardless of prepuce sparing surgery, reported success rate with tunica albuginea plication procedures is about 85%, with a good erectile function (IIEF-5 > 21 in more than 85% of patients) (22).

In our analysis surgical correction of penile curvature has a good impact on erectile function (IIEF score improve in both two groups) and the comparison of the IIEF difference between the 2 groups didn’t show any statistically significant difference.

Thus, it seems that if circumcision is not performed sexual outcomes could not be negatively affected.

Many limitations exist in the current research beginning with the study design because of the retrospective nature of the study and the limited sample. However, the Institution’s database has been prospectively updated and the size of the sample, even if small, is comparable to that of other previous studies. Furthermore, the enrolment period is quite long.

Anyway, to the best of our knowledge, the literature on this topic is weak and we couldn’t find any study on this subject with a prospective design.

CONCLUSIONS In conclusion, according to our experience, surgical correction of penile curvature without performing circumcision could be a feasible and safety strategy with low rate of foreskin complications. Additional prospective studies with larger patient cohorts are required to draw stronger conclusion.

AKNOWLEDGMENTS The authors acknowledge the Clinical risk management, quality, accreditation and public relation Unit of their Hospital that actively participated to the development of the research.

REFERENCES 1. Yachia D, Beyar M, Aridogan IA, Dascalu S. The incidence of congenital penile curvature. J Urol. 1993; 150:1478-9.

2. Stuntz M, Perlaky A, Des Vignes F, et al. The prevalence of Peyronie's disease in the United States: A population-based study.

PLoS One. 2016; 11:e0150157.

3. Liu T, Shindel AW, Lin G, Lue TF. Cellular signaling pathways modulated by low-intensity extracorporeal shock wave therapy. Int J Impot Res. 2019; 31:170-176.

4. Cocci A, Cito G, Urzì D, et al. Sildenafil 25 mg ODT + Collagenase Clostridium hystoliticum vs Collagenase Clostridium hystoliticum alone for the management of Peyronie's disease: a matched-pair comparison analysis. J Sex Med. 2018; 15:1472-1477.

Feasibility of prepuce sparing corporoplasty

5. García-Gómez B, González-Padilla DA, Alonso-Isa M, et al.

Plication techniques in Peyronie's disease: new developments Int J Impot Res. 2020; 32:30-36.

6. Cosentino M, Kanashiro A, Vives A, et al. Surgical treatment of Peyronie's disease with small intestinal submucosa graft patch. Int J Impot Res. 2016; 28:106-109.

7. Hatzimouratidis K, Giuliano F, Moncada I, et al. EAU Guidelines on Erectile Dysfunction, Premature Ejaculation, Penile Curvature and Priapism. www.uroweb.org 2019.

8. Nyirady P, Kelemen Z, Banfi G, et al. Management of congenital penile curvature. J Urol. 2008; 179:1495-8.

9. Langston JP, Carson CC 3rd. Peyronie disease: plication or grafting. Urol Clin North Am. 2011; 38:207-16.

10. Garaffa G, Sacca A, Christopher AN, Ralph DJ. Circumcision is not mandatory in penile surgery. BJU Int. 2010; 105:222-4.

11. Pavone C, Abbadessa D, Usala M, et al. Circumcision in Nesbit corporoplasty: a mandatory time? Our experience on 158 patients.

Urologia. 2012; 79:44-8.

12. Van Der Horst C, Martinez Portillo FJ, Seif C, et al. Treatment of penile curvature with Essed-Schroder tunical plication: aspects of quality of life from the patients’ perspective. BJU Int. 2004; 93:105-8.

13. Mantovani F, Patelli E, Castelnuovo C, Nicola M. ‘Straighteningreinforcing’ technique for congenital curvature and Peyronie’s disease.

Urol Int. 2005; 75:201-3.

14. Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien-Dindo

classification of surgical complications: five-year experience. Ann Surg. 2009; 250:187-96.

15. De Rose AF, Mantica G, Maffezzini M, Terrone C. Dermal graft surgery for Peyronie's disease: Long term results at a 15 years follow-up. Arch Esp Urol. 2019; 72:415-421.

16. Sokolakis I, Schönbauer P, Mykoniatis I, et al. Long-term results after surgical treatment of congenital penile curvature using a modified Nesbit technique World J Mens Health. 2019; 4 [Online ahead of print] 17. Nesbit RM. Congenital curvature of the phallus: report of three cases with description of corrective operation. J Urol. 1965; 171:230-232.

18. Dell’Atti L, Polito M, Galosi A. B. Is degloving the best method to approach the penile corporoplasty with Yachia’s technique?

Urology. 2019; 126:204-208.

19. Kalsi JS, Christopher N, Ralph DJ, Minhas S. Plaque incision and fascia lata grafting in the surgical management of Peyronie’s disease. BJU Int 2006; 98:110-510.

20. Adeniyi AA, Goorney SR, Pryor JP, Ralph DJ. The Lue procedure: an analysis of the outcome in Peyronie’s disease. BJU Int. 2002; 89:404-8.

21. Alei G, Letizia P, Alei L, et al. New surgical technique for ventral penile curvature without circumcision. BJU Int. 2014; 113:968-74.

22. Savoca G, Scieri F, Pietropaolo F, et al. Straightening corporoplasty for Peyronie’s disease: a review of 218 patients with median follow-up of 89 months. Eur Urol. 2004; 46: 610-4.

Correspondence Aldo Franco De Rose, MD aldofdr@libero.it Francesca Ambrosini, MD (Corresponding Author) f.ambrosini1@gmail.com ORCID 0000-0003-2160-763X Guglielmo Mantica, MD guglielmo.mantica@gmail.com Riccardo Banchero, MD riccardo.banchero@hsanmartino.it Carlo Terrone, MD carlo.terrone@med.uniupo.it Department of Urology, Policlinico San Martino Hospital, University of Genoa Largo Rosanna Benzi, 10, 16132, Genoa, Italy Enrico Zero, MD zero.enrico@gmail.com Department of Computer Science, Bioengineering, Robotics and Systems Engineering, University of Genoa, Genoa, Italy

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DOI: 10.4081/aiua.2020.3.186

ORIGINAL PAPER

Penile-scrotal flap vaginoplasty versus inverted penile skin flap expanded with spatulated urethra: A multidisciplinary single-centre analysis Giorgio Gentile 1, Ardigò Martino 2, Daniela Nadalin 3, Martina Masetti 4, Brigida Lilia Marta 5, Franco Palmisano 1, Alessandro Franceschelli 1, Patrizia Stella 3, Anna Paola Sanfelici 3, Eugenio Brunocilla 4, Fulvio Colombo 1 1 Andrology

Unit, University Hospital S.Orsola-Malpighi, Bologna, Italy; for Integrated Health, Federal University of Mato Grosso Do Sul, Campo Grande MS, Brazil; 3 Health Centre Gender Dysphoria at Movement for Transsexual Identity – Agreement with Local Health care Unit, City of Bologna, Italy; 4 Department of Urology, University of Bologna, Bologna, Italy; 5 Department of Anthropology, Medical Anthropology Research Center, Rovira I Virgili University , Tarragona, Spain.

2 Institute

This study is aimed to compare outcomes of penile-scrotal flap vaginoplasty to inverted penile skin flap expanded with spatulated urethra as a singlecentre experience.

Data regarding vaginoplasty performed between May 2003 and January 2014 were reviewed. Subjects were divided into two groups according to the surgical technique performed: perineal-scrotal flap vaginoplasty (Group A), and inverted penile skin flap expanded with spatulated urethra vaginoplasty (Group B). All patients underwent to psychological analysis before surgery. Functional follow-up was based on a modified validated Female Sexual Function Index. Overall, 67 patients with a mean (SD) age of 34 (±9.38) years underwent to surgery. 41 patients were included into the Group A and 26 into the Group B. Mean operative time among Groups A and B was 316 (±101.65) and 594 (±89.06) minutes, respectively (p<0.0001). Longer postoperative hospitalization was shown in Group B (14 days ± 4,51) than in Group A (10 days ± 2,49); (p<0.0001). Group B patients showed a higher anemization rate requiring blood transfusion (p=0.00014) as well as compressive neuropathy (p=0.038). In addition to this, necrosis of the skin flap was reported in 8 patients of Group B (p<0.0001). Comprehensive functional follow-up data was included; spontaneous vaginal lubrication was not reported in 82.4% of Group A vs 12.5% cases of Group B (p=0.0085).

When compared to penile-scrotal flap vaginoplasty, inverted penile skin flap expanded with spatulated urethra technique shows an increased risk of complications with comparable satisfaction rates whereas a higher spontaneous vaginal lubrication is reported. Sexological support is of utmost importance in this setting.

Summary

KEY WORDS: Transgender; Penile inversion; Vaginoplasty; Techniques; Outcomes, Sexologist.

Submitted 2 March 2020; Accepted 16 March 2020

INTRODUCTION The concept of "gender identity" (GI) in Male-to-Female people refers to the individual's awareness of belonging to female rather than to male gender (1). In this context, Stoller postulated the existence of GI distinguishing it from the “role identity”, defined as the behavioral struc-

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ture of one gender rather than other within a specific social and cultural background (2-3).

The term GI disorder appeared in the DSM-IV in 1994 (4-5) and was renamed “gender dysphoria” (GD) in the 2013 DSM-V revised version (6), whereas biological sex ("feeling of being trapped in the wrong body") (7) is not perceived as wrong by patients but the gender assigned at birth. In the light of this, transsexualism treatment necessarily requires the change of the nominally assigned gender rather than sexual characters (6).

Besides being of utmost importance the psychological evaluation in GD diagnosis, patient should be managed in a multidisciplinary setting taking into account hormone replacement therapy, psychological support and, if required, sex reassignment surgery (SRS) (8).

Regarding the technical aspects of SRS, the principal surgical goal is the creation of aesthetically natural and functionally effective external female genitalia, with a sufficiently deep and compliant neovagina allowing normal sexual intercourse without anatomical hindrance (8).

In the 1950s, pioneers of SRS used invagination of the inverted penile skin sheath to form the neovagina, in order to maintain optimal vascularization (9).

Almost two decades later, Jones et al. described the principles of male-to-female (MTF) SRS using a double cutaneous flap obtained from penile, perineal and scrotal skin for the configuration of the neovagina (10).

This technique was the starting point for the development of several other procedures for MTF-SRS. Particularly, Perovic et al. proposed to use a cylinder sharped by inverted penile skin widened with spatulated urethra for the neo-vaginal cavity’s lining allowing an increased vaginal sensitivity with urethral secretionsrelated autonomous lubrication (11-12).

Since the comparison of the different techniques is still the subject of debate in relation to the different surgical outcomes particularly those related to complications and satisfaction rate, the aim to this study was to compare results of penile-scrotal flap vaginoplasty to inverted penile skin flap expanded with spatulated urethra as a single-centre experience.

No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2020; 92, 3

Vaginoplasty: surgical-sexological comparison of two techniques

PATIENTS

AND METHODS

In this retrospective cohort study we identified patients within the Department of Andrology of our Centre who underwent vaginoplasty between May 2003 and January 2014. Patients were divided into two groups according the surgical technique performed: perineal-scrotal flap vaginoplasty (Group A), and inverted penile skin flap expanded with spatulated urethra vaginoplasty (Group B). For both groups, we recorded intraoperative features including, if present, a modification of the technique proposed by our Center for the creation of the mons veneris and of the neoclitoris, introduced from May 2010.

Before surgery, all patients underwent to psychological analysis performed by consultants working within the Transsexual Identity Movement (MIT), an Italian non-profit association that offers counselling assistance to transsexuals; this Service was created in 1994 acknowledging Emilia Romagna Government’s financial support.

All patients were previously treated with estrogens and androgen antagonists and lived for at least two years in the role of a person belonging to the desired gender.

Psychological aspects were recorded, such as the type of followed pathway, the observation of real-life experience, the examination of areas of the individual’s global functioning such as the emotional, social and working areas and her defense mechanisms.

All patients underwent a detailed medical history intake, as well as a general physical and andrological examination. The procedure was performed by the same experienced surgical team.

Intraoperative and post-operative adverse events were recorded. Surgical complications were divided into three

groups: intraoperative complications; short-term complications, noticed during the post-operative hospital stay; and long-term complications, noticed during follow up after patient discharge. Long-term complications were further divided according their aesthetical and functional concern.

Functional follow-up based on a standard internal protocol consisted of a modified validated Female Sexual Function Index (13-15), the questionnaire was administered through interviews during outpatient visits or by telephone to all the patients with at least 6 months of post-operative revaluation. This questionnaire was modified according to psychoclinical/sexological indications (see also supplementary file).

R software was used for statistical analysis (R: A language and environment for statistical computing; R Core Team, 2014; R Foundation for Statistical Computing, Vienna, Austria).

Statistical significance for the tests was set at a < .05.

Descriptive statistics and test statistics were used to compare the 2 groups in terms of clinical variables. One-way Kolmogorov-Smirnov statistical tests were applied to assess the normality of variables. Continuous variables were presented as mean ± standard deviation (SD) and compared using Chi squared, Fisher’s exact and Wilcoxon tests, where normality could not to be assumed.

This retrospective study was conducted according to the guidelines and principles of the Declaration of Helsinki and standard ethical conduct for research involving humans; after approval of our Ethical Committee for Clinical Research, all patients signed an informed consent agreeing to supply their own anonymous data for this and future studies.

Table 1.

Surgical complications.

Intra operative complications Rectum’s injuries Anemization (calo di hb > 2 g) Bulbar urethra’s injuries Short-term post operative complications Hyperpyrexia (T > 38°C after the 4th postoperative day) Anemization Compressive neuropathy Urethro-neovaginal fistula * Prolonged urethral bleeding Infection of the surgical wound associated with hyperpyrexia Clitoral ischemic necrosis Necrosis of the skin flaps with dehiscence of the wound sutures

Group A 1 (2.4%) 5 (12.2%) 2 (4.9%) Group A 11 (26.8%) 12 (29.3%) 3 (7.3%) 1 (2.4%) 1 (2.4%) 3 (7.31%)

Resolution Simple suture Transfusion Simple suture Resolution Antibiotic therapy Transfusion Physiotherapy Urinary catheter kept for 3 weeks Surgical revision 1 Antibiotic therapy and 1 surgical revision to remove necrotic material — —

Group B 1 (3.9%) 14 (53.8%) — Group B 13 (50%) 20 (76.9%) 7 (26.9%) — —

Resolution Protective stoma recanalized after two months Transfusion — Resolution Antibiotic therapy Transfusion Physiotherapy — —

— 1 (3.9%) 8 (30.8%)

— Loss of clitoris Courettage and sutures

Group A

Resolution

Group B

Resolution

5 (12.2%) 4 (9.8%) 1 (2.4%) —

Later meatoplasty Enteric vaginoplasty (1/4 patients) Colpopexy —

1 (3.9%) 2 (7.7%) 1 (3.9%) 1 (3.9%)

Urinary catheter placed and maintained for two weeks Enteric vaginoplasty (1/2 patients) — —

— —

* Probably due to urethral necrosis.

Long-term postoperative complications FUNCTIONAL COMPLICATIONS Stenosis of the neo- urethral meatus Neovaginal atresia (reduction in vaginal depth up to less than 5 cm) Vaginal prolapse Recto-vaginal fistula **

** The patient had previously undergone left hemicolectomy due to colorectal cancer followed by pelvic radiotherapy.

AESTETHICAL COMPLICATIONS Reconfiguration of the labia majora due to asymmetries of them or to the presence of dog-ear residual.

Clitoroplasty for a clitoral hypertrophy Labia minora and/or clitoral hood’s reconfiguration Lower neo-vaginal commissure’s reconfiguration Scar tissues’ removal

Group A 2 (4.9%) 1 (2.4%) 3 (7.3%) 3 (7.3%) 2 (4.9%)

Group B _ 2 (7.7%) 1 (3.9%) 1 (3.9%) _

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G. Gentile, A. Martino, D. Nadalin, M. Masetti, B.L. Marta, F. Palmisano, A. Franceschelli, P. Stella, A.P. Sanfelici, E. Brunocilla, F. Colombo.

RESULTS Overall, 67 patients with a mean (SD) age of 34 (± 9.38) years underwent to surgery. According to the technique performed, 41 patients were included into the Group A and 26 into the Group B. Our modified technique was applied to 26 subjects of Group A whereas was performed in all patients of Group B. Mean (SD) operative time among Groups A and B was 316 (± 101.65) and 594 (± 89.06) minutes, respectively; this result was statistically significant (p < 0.0001).

Similarly, postoperative hospitalization revealed longer in Group B (14 days ± 4.51) than in Group A (10 days ± 2.49); (p < 0.0001). Surgical complications are reported in Table 1; Group B patients showed a higher blood transfusion rate (p = 0.00014) as well as compressive neuropathy (p = 0.038). In addition to this, necrosis of the skin flap was reported in 8 patients of Group B (p < 0.0001).

Functional questionnaire was administered in 19 subjects in Group A (46.3%) and 17 patients in Group B (65.4%); 46.3% of the whole cohort resulted unreachable or refused the questionnaire administration.

In terms of sexual orientation, 18 patients of Group A (94.7%) declared to be mainly attracted to men and 1 (5.3%) has defined herself as bisexual, while 14 (82.3%) cases of Group B were mainly attracted to men, 1 was mainly attracted to women (5.9%) and 2 were bisexual (11.8%).

All patients with a stable partner, 12 (68.4%) in Group A and 4 (23.5%) in Group B, resulted to be attracted to men, and all their partners resulted to be attracted to women. Among Group A subjects with a stable relationship, 6 (46.1%) reported to have sex once or twice a month, 6 (46.1%) several times a week and 1 patient (7,8%) daily.

Regarding Group B patients, 1 (25%) reported to have sexual intercourses once or twice per month while 3 having sex (75%) several times per week. Additionally, 61.5% of Group A (8) declared to be satisfied with their couple sexuality, 4 (30.8%) revealed moderately satisfied whilst 1 case (7.7%) demonstrated very dissatisfied with her couple sexuality.

Among Group B, 1 patient (25%) declared to be very satisfied while 75% of cases (3) reported to be moderately satisfied with couple's sex life.

In terms of emotional complicity with the partner during sexual intercourse, 10 patients of group A (76.9%) declared to be very satisfied and 3 patients (23.1%) showed themselves moderately satisfied, while all 4 cases in Group B declared to be very satisfied about the couple emotional complicity.

Functional questionnaire results concerning autoerotism, sexual intercourses and sex arousal are reported in Table 2. When asked how often they managed to have a spontaneous vaginal lubrication during sexual activity, 82.4% of Group A answered to be never or almost never able to lubricate; significantly higher than 2 (12.5%) cases of Group B (p = 0.0085). In addition to this, 62.5% of Group B patients claimed to be able to lubricate always or most of the time.

Summarizing the overall sexual satisfaction in Group A and B, patients defined as very satisfied in 10 and 11

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Archivio Italiano di Urologia e Andrologia 2020; 92, 3

Table 2.

Functional questionnaire investigating desire and sexual interest, frequency of sexual intercourses and masturbation, sex arousal.

Group A (n,%) Group B (n,%) How often do you masturbate?

Never 12 (63.1) 5 (29.4) Less than once a month 1 (5.3) 2 (11.8) One or two times a month 2 (10.5) 4 (23.5) Several times a week 3 (15.8) 6 (35.3) Daily 1 (5.3) How often do you have sexual intercourses?

Never 3 (15.8) 2 (11.8) Less than once a month 2 (11.8) One or two times a month 8 (42.1) 4 (23.5) Several times a week 7 (36.8) 9 (52.9) Daily 1 (5.3) Over the last 4 weeks how often have you felt sexual desire or sexual interest?

Always or almost always 2 (10.5) 3 (17.6) Often 3 (15.8) 7 (41.2) Sometimes 10 (52.6) 7 (41.2) Never or almost ever 4 (21.1) Over the past 4 weeks, how would you rate your level of sexual desire or interest?

Very high 5 (26.3) 4 (23.5) High 5 (26.3) 4 (23.5) Moderate 5 (26.3) 9 (53) Low 1 (5.3) Very low or none at all Over the past 4 weeks, how often did you feel sexually aroused ("turned on") during sexual activity or intercourse?

No sexual activity 2 (10.5) 5 (29.4) Almost always or always 8 (47.1) 8 (66.7) Most times (more than half the time) 5 (29.4) 3 (25) Sometimes (about half the time) 3 (17.6) 1 (8.3) A few times (less than half the time) Almost never or never 1 (5.9) How often did you reach orgasm through masturbation?

I don’t masturbate 5 (26.3) 3 (17.6) Almost always or always 5 (26.3) 10 (71.4) Most times (more than half the time) 1 (7.1) 1 (7.1) Sometimes (about half the time) 3 (21.4) A few times (less than half the time) 1 (7.1) Almost never or never 4 (28.6) 3 (21.5) How often did you reach orgasm through sexual intercourses?

I don’t have sexual intercourses 1 (5.3) 1 (5.9) Almost always or always Most times (more than half the time) 7 (38.9) 7 (43.8) Sometimes (about half the time) 2 (11.1) 4 (25) A few times (less than half the time) 5 (28.7) 2 (12.5) Almost never or never 4 (22.2) 3 (18.8) Did you notice a change in the orgasmic feeling between before and after surgery?

Yes 13 (81.3) 13 (92.9) No 3 (18.8) 1 (7.1) I haven’t had orgasm yet 3 (15.8) 3 (17.6) Over the past 4 weeks, how satisfied were you with your ability to reach orgasm during sexual activity or intercourse?

No sexual activity 2 (10.5) 1 (5.9) Very satisfied 10 (58.8) 12 (75) Moderately satisfied 5 (29.4) 1 (6.3) Moderately dissatisfied 1 (5.9) 1 (6.3) Very dissatisfied 1 (5.9) 2 (12.5)

(52.6% vs. 64.7%; p > 0.05) cases. Moreover 6 (31.6%) patients of Group A declared to be moderately satisfied while 1 (5.3%) was really dissatisfied, whereas in Group B 3 (17.6%) patients were neither satisfied nor dissatis-

Vaginoplasty: surgical-sexological comparison of two techniques

Figure 1.

Supplementary data about post-operative problems.

fied and 2 (11.8%) declared to be moderately satisfied.

Other post-operative problems revealed through questionnaire are reported in Figure 1.

DISCUSSION Vaginoplasty is often the final stage in the gender-confirming process for transgender women. Being gender affirmation surgery paramount in the treatment of gender dysphoria, vaginoplasty offers the opportunity for removal of masculine-appearing genitalia and replacement with a gender-congruent appearance (16).

The aim of our study was to compare two different techniques, from a surgical and functional point of view, in a cohort of transgender patients who underwent vaginoplasty, in the real-life setting. We found significant differences in terms of short-term adverse events with good aesthetic and functional results. In decades of experience at our Center, an original technical modification which involves the preservation of tunica albuginea below the neurovascular bundle was introduced in 2007, allowing a faster and safer clitoroplasty and providing a more natural aspect of mons veneris; this modification was adopted by Jones and subsequently by Perovic (17).

Outcomes of penile inversion vaginoplasty are generally in the form of large case series from high volume institutions.

Buncamper et. Al reported a retrospective series of 475 patients who underwent penile inversion vaginoplasty, of whom 85% required additional full-thickness skin grafts (18). The most frequently observed intraoperative complication was rectal injury (n = 11-2.3%) whereas short-term postoperative bleeding that required transfusion and/or reoperation was shown in 6.7% of the cohort. Among other vaginoplasty techniques, Salgado et al. reported a small case series of transwomen who underwent primary sigmoid vaginoplasty (19); among 12 patients, 2 major complications were reported (1 deep venous thrombosis, 1 suspected pulmonary embolism).

From an aesthetical and functional point of view, it is important to emphasize that imperfections are extremely subjective: women with minor imperfections may suffer

from issues in their sexual life to the point of requiring further surgery, whereas other patients with serious blemishes decide not to undergo re-intervention.

Clitoral dimensions are inevitably related to original gland size, since the necessity of saving the marginal portion of the gland for vascularization and innervation of the neo-clitoris (20-21).

Moreover, depending on the surgical technique, the morphology of the lower commissure varies: Jones technique results in a u-shaped commissure while the Perovic strategy results in a v-shaped commissure, which has a more natural aspect and can allow hinder penetration (8). In our experience, more patients within group A than group B were subjected to surgical reconfiguration of the lower commissure (7% Group A - 3% Group B): this may be dependent to an interindividual variability.

Concerning the sexual functionality and sensitivity evaluation, a different time lapse between two Groups should be taken into account. In fact, follow-up of the patients of Group A is longer than that of Group B, whereas the type B procedure has been performed in our Center only since 2010. This may significantly influence the quality of sexual life reported by patients: in fact, the capability of re-balancing personal sexuality on a different reproductive system and of reaching orgasm frequently requires a long period (22).

An important element which emerged from the questionnaire relates to the high ability to reach an autonomous vaginal lubrication after appropriate sexual stimulation in the patients of group B, due to the mucous secretions of the urethral flap that forms the neovaginal roof, confirming the data in Literature (11-12).

Stable partner was reported more commonly in Group A, this can be due to a longer follow-up, as well as by a quicker post-surgery recovery; in addition to this, the emerging trend in Group B concerning low sexual satisfaction may be related to the more challenging surgery and therefore to a longer process of integration of body parts with the symbolic expectations (23).

The widely shared results within two cohorts about the high emotional complicity of the couples during intercourse are likely motivated by issues due to stigma and prejudice as experienced by transsexual couples that, once overcome, tend to favor emotional sharing and lead to an increase of intimacy (24). Concerning the sexual desire levels, higher scores reported in the patient of Group B may be hypothetically due to their more consistent effort in post-surgery recovery phase and their interest into the expression of a sexual activity.

Neovaginal moisture is perceived by these patients as crucial, because it allows to be closer to a standard ideal of femininity, as it matches the symbolic component of Archivio Italiano di Urologia e Andrologia 2020; 92, 3

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G. Gentile, A. Martino, D. Nadalin, M. Masetti, B.L. Marta, F. Palmisano, A. Franceschelli, P. Stella, A.P. Sanfelici, E. Brunocilla, F. Colombo.

representation with anatomical reality also in its functioning (25). Independently of the well-known benefits of SRS on the patients general and sexual life-related quality of life, as well as on cosmesis and sexual functioning (26, 31), it is reasonable to offer sexologic consultation in order to favor the integration of physical and anatomical parts and to sustain and encourage the subject undergoing surgery to achieve a satisfying sexuality.

Several limitations to this study should be acknowledged, of which the single Institution design is probably the most evident. Another limitation of the present study lies in the fact that the two different types of intervention were performed by two different surgeons, and this may affect the data collected. On the other hand, this aspect is a good representation of a real-life situation in contrast to single surgeon series. In this context, regardless of the surgeon who performed surgery, it is important to consider that the longer duration of the surgical intervention, the longer post-surgery hospitalization and the higher rate of anemia and hyperpyrexia in the case of group B patients may be related to the greater technical complexity of this procedure, and to the fact that more vascularized tissues â&#x20AC;&#x201C; such as the urethra â&#x20AC;&#x201C; are handled. Moreover, the questionnaire used is not standardized; nevertheless, its essential purpose is to answer a purely surgical and clinical interest rather than to report objective measures of sexual satisfaction. In the light of this, there are more variables involved in sexual satisfaction compared to the biological subset, which is essentially linked to the type of surgery and its clinical consequences.

Therefore, the impact of body transformation on sexuality should be evaluated by qualitative methods, rather than quantitative, involving couples and not only individuals since that may interfere with subjective evaluation of surgery outcomes.

Lastly, it should be noted that this analysis focuses on an outdated case series; this is due to the fact that after 2014 the State funds destined for this setting were suspended; in this sense, we hope that this analysis will be a signal for the restoration of this public activity answering to a real need in the transgender community of our region.

CONCLUSIONS When compared to penile-scrotal flap vaginoplasty, inverted penile skin flap expanded with spatulated urethra technique shows an increased risk of complications with a higher spontaneous vaginal lubrication and comparable satisfaction rates.

REFERENCES 1. Stoller RJ. Sex and gender. Vol.2: The transsexual experiment.

London: Hogarth Press, 1975.

2. Stoller RJ. Presentations of gender. New Haven: Yale University Press, 1985.

3. Stoller RJ. The gender disorders. In: Rosen I, ed. Sexual deviations. Third Edition. Oxford: Oxford University Press, 1997.

4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: APA, 1965.

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5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition, Text revision (DSM-IVTR). Washington, 2000.

6. American Psychiatric Association, Diagnostic and statistical manual of mental disorders (5th ed.) Arlington, 2013 VA: American Psychiatric Publishing.

7. Prosser J. Second skins: The body narratives of transsexuality.

New York: Columbia University Press, 1998.

8. Belgrano E, Fabbris B, Trombetta C. Il Transessualismo, Identificazione di un Percorso Diagnostico e Terapeutico. Milano: ed.

Kurtis 1999; 9-125.

9. Goddard JC, Vickery RM, Terry TR. Development of feminizing genitoplasty for gender dysphoria. J Sex Med. 2007; 4:981-9.

10. Jones HWJ, Schirmer HKA, Hoopes JE. A sex convention operation for males with transsexualism. Am J Obstet Gynecol. 1968; 100:101-9.

11. Perovic SV, Stanojevic DS, Djordjevic ML. Vaginoplasty in male transsexuals using penile skin and a urethra flap. BJU International.

2000; 86:843-850.

12. Perovic SV, Djinovic R. Genitoplasty in male-to-female transsexuals. Curr Opin Urol. 2009; 19:571-576.

13. 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.

14. Stephenson KR, Toorabally N, Lyons L, M Meston C. Further validation of the female sexual function index: specificity and associations with clinical interview data. J Sex Marital Ther. 2016; 42:448-61.

15. Roisin Worsley, Robin J. Bell, Pragya Gartoulla, and Susan R. Davis, Prevalence and predictors of low sexual desire, sexually related personal distress, and hypoactive sexual desire dysfunction in a community-based sample of midlife Women J Sex Med. 2017; 14:675-686.

16. Pariser JJ, Kim N. Transgender vaginoplasty: techniques and outcomes. Transl Androl Urol. 2019; 8:241-247.

17. Soli M, Brunocilla E. Male to female gender reassignment: Modified Surgical Technique for creating the clitoris and Mons Veneris. J Sex Med. 2008; 5:210-216.

18. Buncamper ME, van der Sluis WB, van der Pas RSD, et al.

Surgical outcome after penile inversion vaginoplasty: a retrospective study of 475 transgender women. Plast Reconstr Surg. 2016; 138:999-1007.

19. Salgado CJ, Nugent A, Kuhn J, et al. Primary sigmoid vaginoplasty in transwomen: technique and outcomes. Biomed Res Int. 2018; 2018:4907208.

20. Giraldo F, Esteva I, Bergero T, et al. Corona glans clitoroplasty and urethropreputial vestibuloplasty in male-to-female transsexuals: the vulval aesthetic refinement by the Andalusia Gender Team.

Plast Reconstr Surg. 2004; 114:1543-50.

21. Cocci A, Rosi F, Frediani D, et al. Male-to-Female (MtoF) gender affirming surgery: Modified surgical approach for the glans reconfiguration in the neoclitoris (M-shape neoclitorolabioplasty).

Arch Ital Urol Androl. 2019; 91:119-124.

22. Bockting WO, Miner M, Robinson BE, et al. Transgender Identity Survey. 2005 Minneapolis, MN: University of Minnesota, Program in Human Sexuality.

Vaginoplasty: surgical-sexological comparison of two techniques

23. Feldman J, Safer J. Hormone therapy in adults: Suggested revisions to the sixth version of the standards of care. International Journal of Transgenderism. 2009; 11:146-182.

24. Van Trotsenburg MAA. Gynecological aspects of transgender healthcare. International Journal of Transgenderism. 2009; 11:238246.

25. Ruppin U, Pfäfflin F. Long-term follow-up of adults with gender identity disorder. Arch Sex Behav. 2015; 44:1321-1329.

26. De Cuypere G, T’Sjoen G, Beerten R, et al. Sexual and physical health after sex reassignment surgery. Arch Sex Behav. 2005; 34:679-690.

27. Gijs L, Brewaeys A. Surgical treatment of gender dysphoria in

adults and adolescents: recent developments, effectiveness, and challenges. Annual review of sex research. 2007; 18:178-184.

28. Klein C, Gorzalka B. Sexual functioning in Transsexuals following hormone therapy and genital surgery: a review. J Sex Med. 2009; 6:2922-2939.

29. Marecek J, Crawford M, Popp D. On the construction of gender, sex, and sexualities. The psychology of gender. 2004; 2:192-216.

30. Bevan TE. The Psychobiology of Transsexualism and Transgenderism: A new view based on scientific evidence. Santa Barbara, CA: Praeger, 2015, p. 257 pp, ISBN-13: 978-1440831263.

31. Epstein S. A queer encounter: Sociology and the study of sexuality. Sociological Theory. 1994; 12:188-202.

Correspondence Giorgio Gentile, MD Franco Palmisano, MD (Corresponding Author) franco.palmisano@hotmail.it Fulvio Colombo, MD Alessandro Franceschelli, MD Andrology Unit, University Hospital S.Orsola-Malpighi, via Pelagio Palagi 9, 40138 Bologna (Italy) Ardigò Martino, MD Institute for Integrated Health, Federal University of Mato Grosso Do Sul, Campo Grande MS (Brazil) Daniela Nadalin, MD Patrizia Stella, MD Anna Paola Sanfelici, MD Health Centre Gender Dysphoria at Movement for Transsexual Identity Agreement with Local Health care Unit, City of Bologna (Italy) Martina Masetti, MD Eugenio Brunocilla, MD Department of Urology, University of Bologna, Bologna (Italy) Brigida Lilia Marta, MD Department of Anthropology, Medical Anthropology Research Center, Rovira I Virgili University, Tarragona, (Spain)

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ORIGINAL PAPER

Diagnosis and treatment of penile injury: Ten years experience of an emergency department Paolo Panella, Pietro Pepe, Michele Pennisi Urology Unit, Cannizzaro Hospital, Catania, Italy.

Summary

Introduction: To evaluate the imaging accuracy in the diagnosis and clinical management of penile injury.

Materials and methods: From January 2010 to January 2020, 20 men (median age 40.2 years) were admitted to our Emergency Department with the diagnosis of penile injury; the penile trauma was related to sexual intercourse in 16 cases, masturbation in 3 cases and injury caused by the partner in 1 case. All the patients underwent accurate medical history, clinical examinations and diagnostic imaging. Color Doppler ultrasound (CDU) evaluation was performed by Logiq E9 ecograph (General Electric; Milwaukee, WI) supplied with a linear probe small (7.5-10 MHz); magnetic resonance image (MRI) examination was performed within 3-24 hours from the trauma using a 1.5 Tesla scanner, (ACHIEVA 3T; Philips Healthcare Best, the Netherlands) performing pre-contrast and post-contrast multi-planar turbo spin-echo T1 and T2-weighted sequences.

Results: 15/20 (75%) men with high suspicion of the tunica albuginea rupture underwent surgical exploration; conversely, 5/20 (25%) patients underwent conservative management.

CDU detected 11/15 (73%) fractures of the penis and in 8 of them the length of the rupture was underestimated (more than 5 millimeters). On the contrary, MRI diagnosed all the albuginea ruptures showed by surgical exploration, but underestimated the length of the lesions in 9/15 (60%) cases.

The IIEF-5 score administered six months later penile trauma demonstrated a good performance in all the patients.

Conclusions: In our series, all the patients with a tunica albuginea rupture < 5 mm. diagnosed by MRI were submitted to conservative management with a complete functional restitutio ad integrum.

tion. The pain and sound are made by a strain in the tunica albuginea that during erection become thin from 2 to 0.25-0.50 mm. reducing its elasticity and reaching, in case of rupture, an internal pressure of 1.500 mmHg (2). The lesions of tunica albuginea could be unilateral or bilateral involving the corpus spongiosum of the urethra (3, 4). The clinical presentation is characterized by the presence of gross hematoma of the penis that, in the majority of the cases, is deviated controlaterally to site of rupture. The presence of “butterfly hematoma” suggest the injury of the Buck fascia (4, 5).

The diagnosis is usually based on clinical history (the typical sound referred as “crack”) and clinical examination. In the presence of urethral injury the patient could refer urethral bleeding or hematuria combined with dysuria, urinary voiding symptoms and acute urinary retention. The diagnostic imaging is mandatory to evaluate the integrity of the tunica albuginea (site and length of the lesion) and the extension of the hematoma. Color doppler ultrasound (CDU) and magnetic resonance imaging (MRI) are highly recommended to evaluate the morphology of the penis to plan the best clinical management; CDU could underestimate the extension of corpora cavernosa lesion but it allow to easily evaluate the dorsal penis vascular complex. In this retrospective study, we report our experience regarding the role of imaging in the diagnosis and clinical management of patients with non-penetrating penile injury.

KEY WORDS: Penile injury; MRI; CDU; Imaging and penile trauma.

MATERIALS

Submitted 17 May 2020; Accepted 11 July 2020

INTRODUCTION The injury of corpora cavernosa is a very rare urological emergency with an estimated incidence of 1.02/100,000 male subjects per year in the United States (1, 2); the rupture of the penis is secondary to an abrupt deviation during erection to which follows sudden pain and a noise referred as “crack” with rapid loss of erection combined with subcutaneous hematoma. The fractures of the penis following non-penetrating trauma are most commonly sustained during sexual intercourse; rarely, the trauma could be induced by careless movement performed to stop the erection (manuever of Taghaandan) or masturba-

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AND METHODS

From January 2010 to January 2020, 20 men with median age of 40.2 years (range: 21-65) were admitted to our Emergency Hospital for non-penetrating penile injury.

The penile trauma was related to sexual intercourse in 16 cases, masturbation in 3 cases and injury caused by the partner in 1 case; the clinical presentation of the patients at hospital admission are listed in Table 1.

All the patients underwent clinical examination, CDU and MRI evaluation. Ultrasound examination was performed by a Logiq E9 ecograph (General Electric; Milwaukee, WI) supplied with a linear probe small (7.5-10 MHz) to evaluate the integrity of the tunica albuginea and dorsal vascular complex of the penis, the site and extension of the hematoma. All MRI examinations were performed within 3-24 hours from the trauma using a 1.5 Tesla scanner, (ACHIEVA 3T; Philips Healthcare Best, the Netherlands) No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2020; 92, 3

Imaging and penile injury

equipped with surface 32 channels phased-array coil placed around the pelvic area with the patient in the supine position. All patients were studied with pre-contrast and postcontrast multi-planar turbo spinecho T1- weighted and T2-weighted (T2W) sequences (Figure 1).

The 15/20 (75%) men with high suspicion of penis rupture underwent surgical exploration; conversely, 5/20 (25%) patients underwent conservative management. In all cases the length of the penis lesion was measured with a centimeter during surgery. All the patients underwent follow up 1, 3 and 6 months from the trauma performing clinical evaluation, CDU and, in selected cases, MRI of the penis; moreover, the International Index Erectile Function-5 score (IIEF-5) was administered to evaluate the sexual performance.

Figure 1.

Diagnostic flow-chart for selection of treatment of penile trauma.

Table 1.

Clinical presentation of the 20 men with non-penetrating penile injury at hospital admission.

Clinical picture Hematoma Edema Sound of “crack” Pain Deviation of the penis Urethrorrhagia

20 cases (overall) 20 (100%) 14 (70%) 12 (60%) 20 (100%) 12 (60%) 1 (5%)

15 (100%) ruptures of the tunica albuginea showed by surgical exploration (Figure 2), but underestimated the length of the lesions in 9/15 (60%) cases; conversely, in 6/15 (40%) cases the extension of the lesion was superimposable or overestimated. In addition, MRI detected 1/2 lesion (50%) of the corpus spongiosum (Figure 3); 15/20 (75%) underwent surgery within 24 (12 cases) or 36 hours (3 cases) from the trauma; in all the cases, a Figure 3.

Fracture of the penis with corpus spongiosum involvement.

RESULTS Overall, MRI and CDU diagnosed 20/20 (100%) and 12/20 (60%) fractures of the tunica albuginea, respectively. In detail, CDU detected 11/15 (73%) fractures of the penis and in 8 of them the length of the rupture was underestimated (more than 5 millimeter “mm”) if compared with surgical exploration. MRI diagnosed all the Figure 2.

Ventral fracture of the tunica albuginea.

T1 weighted sagittal image pre-contrast

T1 weighted coronal image post-contrast

Table 2.

Location and side of the tunica albuginea rupture in the 15 patients submitted to surgical exploration.

T2 weighted sagittal image pre-contrast

T1 weighted sagittal image post-contrast

Side of the trauma Latero-dorsal Latero-ventral Bilateral Distal Middle of the penis Proximal Urethral involvment

Number of patients 2 13 2 1 9 5 2

% 13.3 86.6 13.3 6.6 60 33.3 13.3

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P. Panella, P. Pepe, M. Pennisi

Table 3.

Imaging, surgical data, complications and functional results in the 15 patients submitted to surgery.

15 patients CDU (overall) n (%) cm Right side 6 40 1-2

n 6

MRI (%) cm 40 1.5-2

n 8

Surgery (%) cm 53.4 1-2.8

Left side Bilateral

7 46.7 0.5-2 2 13.3 2.5

6 2

40 1-2 13.3 2-2.5

5 2

33.3 1-2.5 13.3 2-3

Urethra

0

1

6.6

2

13.3 2-3

2

Complications n (%) 1 (6) recurvatum 30° 0 1 (6) coital pain 1 (6) coital pain

CDU: colordoppler ultrasound; MRI: magnetic imaging resonance; IIEF-5: International Index of Erectile Function.

Table 4.

Imaging, complications and functional results in the 5 patients submitted to conservative management.

5 patients (overall) Right side Left side

n 0 1

CDU (%) cm 20 0.5

n 1 4

MRI Complications (%) cm n (%) 20 1 0 80 0.5 0

IIEF-5 score 24 22

CDU: colordoppler ultrasound; MRI: magnetic imaging resonance; IIEF-5: International Index of Erectile Function.

Table 5.

Initial and post trauma sexual performance evaluated by the International Index Erectile Function-5 score (IIEF-5).

IIEF-5 score Normal (22-25) Minimal DE (17-21) Minimal-moderate DE (12-16) Moderate DE (8-11) Severe DE (5-7)

Before trauma (pts) 15 (75%) 3 (15%) 2 (10%) 0 0

After trauma (pts) 15 (75%) 3 (15%) 2 (10%) 1 (5%) 0

DE: erectile dysfunction; pts: patients.

large hematoma combined with edema of the penis was found. The site of the tunica albuginea injury is listed in Table 2; median length of the lesion was 19 mm. (range: 5-30) with urethral involvement in 2 cases (13.3%).

In 14/15 men (93.4%) the penis was deviated controlaterally to the site of rupture.

All the patients submitted to surgical exploration underwent subcoronal approach, evacuation of hematoma and repair of the tunica albuginea using PDS (polydioxanone) 2/0 in 5 cases e vicryl (polyglatin 910) 3/0 in 10 cases. At the end of surgery, an erection was induced to evaluate the presence of missed lesions and the absence of recurvatum.

The urethral lesions were repaired using a slow absorption monofilament (monocryl 4/0 poliglecaprone 25) (Table 3); moreover, all the patients underwent antibiotic prophylaxis (a third generation cephalosporin combined with teicoplanin) and 2.5 days (range: 2-5 days) from surgery were discharged; 3/15 (20%) men had minor complications following surgery: 1 case of hematoma treated conservatively, 1 case of pain during sexual activity and a case of penis recurvatum equal to 30°.

Five out of 20 patients (25%) were hospitalized 48/96 hours from the trauma (average hospital stay was 2.5 days, range 1-5 days), and underwent conservative management, because MRI and CDU showed a lesion of the tunica albuginea < 5 mm. in 5 (100%) and 1 (20%)

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IIEF-5 score 18 moderate ED 0 22 22

cases, respectively; moreover, a clinically significant hematoma was absent (Table 4).

MRI vs CDU demonstrated a diagnostic accuracy in the diagnosis of tunica albuginea rupture equal to 100 vs 50%; at the same time, MRI vs CDU underestimated the real lentht of the rupture in 9 (45%) and 12 (80%) cases, respectively. All the patients were encouraged to have sexual activity at least 6 weeks later the trauma; median follow up was 5.7 months (range: 3-9).

The IEFF-5 scores evaluated before and after the trauma of the penis are listed in Table 5.

DISCUSSION Literature data recommend early surgical exploration of penis in the presence of tunica albuginea rupture to improve a rapid resolution of pain and to reduce the risk of ED, corpora cavernosa fibrosis, symptomatic scars of the penis or recurvatum (5-9).

In the last years, the use of MRI has improved the diagnosis of penile injury; Saglam et al (10) reported in 122 patients a sensitivity and specificity of MRI equal to 100 with a positive (PPV) and negative predictive value (NPV) of 87.5 and 100%, respectively. At the same time, Sokolakis et al. (11) on 43 patients showed a MRI sensitivity, specificity, NPV and PPV equal 100, 77.8, 100 and 90.5%, respectively. Therefore, today, the use of MRI combined with dedicated protocols is strongly recommended in the clinical evaluation of penile injury (6-8) to plan the best therapeutic treatment for each patient (12-18). Despite the high accuracy, MRI is not always used in the evaluation of penile trauma because expensive and little available in emergency. On the other hand, although CDU allows an easy and repeatable morfological and functional evaluation of the penis its accuracy results lower in comparison with MRI (19).

In our series, MRI and CDU detected 100 (15/15 cases) vs 73% (9/15 cases) of the penile fractures submitted to surgical exploration; conversely, among the five (25%) patients who underwent conservative MRI and CDU diagnosed a lesion of the tunica albuginea < 5 mm. in 100 (5/5 cases) vs 20% (1/5 cases) of the patients, respectively. During the follow up nobody referred functional clinical complications; moreover, the IIEF-5 score was predictive of a normal sexual activity in the 75% of the cases resulting superimposable with the results obtained in men who underwent surgery.

Regarding our results some considerations should be done. First, our study is retrospective and refer to a limited number of patients. Secondly, we do not know the real extension of the tunica albuginea rupture in men submitted to conservative treatment. Third, our considerations are based upon a very low number of cases but could be expression of a greater number of minor penile trauma with good prognosis that in the “real life” could be missed because don’t come to observation of the specialist. Finally, multicentric and multidisciplinary studies should be encouraged to improve the use of MRI in case of penile injury.

In conclusion, in our series, all the patients with a tunica albuginea rupture < 5 mm. diagnosed by MRI and submit-

Imaging and penile injury

ted to conservative management had a complete functional restitutio ad integrum. Anyway, multicentric and multidisciplinary studies should be encouraged to improve the imaging accuracy in the evaluation of penile injury.

9. Al-Shaiji TF, Amann J, Brock GB. Fractured penis: diagnosis and management. J Sex Med. 2009; 6:3231-40.

REFERENCES

11. Sokolakis I, Schubert T, Oelschlaeger M, et al. The Role of Magnetic Resonance Imaging in the Diagnosis of Penile Fracture in Real-Life Emergency Settings: Comparative Analysis with Intraoperative Findings. J Urol. 2019; 202:552-57.

1. Rodriguez D, Li K, Apoj M, Munarriz R. Epidemiology of Penile Fractures in United States Emergency Departments: Access to Care Disparities May Lead to Suboptimal Outcomes. J Sex Med. 2019; 16:248-56.

2. De Luca F, Garaffa G, Falcone M, et al. Functional outcomes following immediate repair of penile fracture: a tertiary referral centre experience with 76 consecutive patients. Scand J Urol. 2017; 51:170-75.

3. Anastasiou I, Anastasiou A, Katafigiotis I, et al. Isolated corpus spongiosum injury after sexual intercourse. Arch Ital Urol Androl.

2019; 90:295-296.

10. Saglam E, Tarhan F, Hamarat MB, et al. Efficacy of magnetic resonance imaging for diagnosis of penile fracture: A controlled study. Investig Clin Urol. 2017; 58:255-60.

12. Cozzi D, Verrone GB, Agostini S, et al. Acute penile trauma: imaging features in the emergency setting. Radiol Med. 2019; 124:1270-80.

13. Esposito AA, Giannitto C, Muzzupappa C, et al. MRI of penile fracture: what should be a tailored protocol in emergency? Radiol Med. 2016; 121:711-18.

14. Guler I, Ödev K, Kalkan H, et al. The value of magnetic resonance imaging in the diagnosis of penile fracture. Int Braz J Urol.

2015; 41:325-28.

4. Kasaraneni P, Mylarappa P, Gowda RD, et al. Penile fracture with urethral injury: Our experience in a tertiary care hospital. Arch Ital Urol Androl. 2019; 90:283-287.

15. Rosi G, Fontanella P, Venzi G, et al. 3T MR-guided minimallyinvasive penile fracture repair. Arch Ital Urol Androl. 2016; 88:68-69.

5. Özorak A, Hoşcan MB, Oksay T, et al. Management and outcomes of penile fracture: 10 years' experience from a tertiary care center. Int Urol Nephrol. 2014; 46:519-22.

16. Koifman L, Barros R, Júnior RA, et al. Penile fracture: diagnosis, treatment and outcomes of 150 patients. Urology. 2010; 76:1488-92.

6. Salonia A, Bettocchi C, Carvalho, et al. Guidelines Associates: EAU Sexual and Reproductive Health Guidelines 2020.

17. Pepe P, Panella P, Candiano G, et al. Partial priapism secondary to idiophatic segmental thrombosis of corpora cavernosa. Arch Ital Urol Androl. 2012; 84:101-03.

7. Yamaçake KG, Tavares A, Padovani GP, et al. Long-term Treatment Outcomes Between Surgical Correction and Conservative Management for Penile Fracture: Retrospective Analysis. Korean J Urol. 2013; 54:472-76.

8. Gamal WM, Osman MM, Hammady A, et al. Penile fracture: long-term results of surgical and conservative management.

J Trauma. 2011; 71:491-93.

18. Pennisi M, Grasso Leanza F, Panella P, Pepe P. La rottura traumatica del pene. Caso clinico e revisione della letteratura.

Contraccezione Fertilità Sessualità. 1992; 19:327-29.

19. Dell'Atti L, Scarcella S, Argalia G, et al. Rupture of the cavernous body diagnosed by contrast-enhanced ultrasound: Presentation of a clinical case. Arch Ital Urol Androl. 2018; 90:143-144.

Correspondence Paolo Panella, MD (Corresponding Author) ppanella5@gmail.com Pietro Pepe, MD Michele Pennisi, MD Urology Unit - Cannizzaro Hospital Via Messina 829, Catania (Italy)

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CASE REPORT

Bone pain palliation outcomes and possibility of Radium-223 re-treatment in mCRPC Viviana Frantellizzi 1, Julia Lazri 2, Mariano Pontico 3, Arianna Pani 4, Giuseppe De Vincentis 2 1 Department

of Molecular Medicine, Sapienza University of Rome, Rome, Italy; of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza University of Rome, Rome, Italy; 3 Ph.D., Program in Morphogenesis & Tissue Engineering, “Sapienza” University of Rome, Rome, Italy; 4 Clinical Pharmacology and Toxicology, University of Milan, Milan, Italy.

2 Department

Objective. Bone secondary localizations from metastatic castration-resistant prostate cancer are associated with an increase in mortality and a reduction in the patient’s quality of life. Radium-223 is a targeted alpha-therapy approved for the treatment of mCRPC (metastatic castration resistant prostate cancer) patients with symptomatic bone metastases. To our knowledge, no previous study has been performed assessing the bone pain palliation outcomes following Radium-223 therapy.

Materials and Methods. A mCRPC patient with symptomatic bone localizations and relevant bone pain symptoms has been subjected to Radium-223 treatment. Pain was assessed over time from the first administration of Radium-223 to follow-up.

Results. After Radium-223 treatment, patient showed a significant BPI (Brief Pain Inventory) decline from 7 to 4 and a concomitant partial regression of multiple bone hot spots in the bone scan exam. Three months after the last infusion of Radium-223, further BPI decline (from 4 to 2) with bone scan depicting stable disease was observed. However, after 6 months from Radium-223 treatment end, BPI increased from 2 to 10.

Conclusions. Taking into account the effectiveness on bone pain relief and the low toxicity profile showed by Radium-223 treatment, we encourage further analysis on large cohort to investigate the clinical outcome after Radium-223 treatment, in terms of bone pain palliation, together with the possibility of Radium-223 re-treatment in selected patients..

Summary

KEY WORDS: Radium-223 dichloride; Bone pain; Palliative treatment; mCRPC. Submitted 28 January 2020; Accepted 18 February 2020

INTRODUCTION Prostate cancer (PCa) in men worldwide is the second most common cancer (1, 2). Most subjects with metastatic PCa, following a median of 18-24 months of endocrine therapy, no longer respond to traditional androgen deprivation therapy (ADT) (3, 4) and are categorized as castration-resistant prostate cancer (CRPC), leading to disease progression (5, 6). CRPC disease progression is characterized by the presence of pain-inducing bone metastases (90% of patients), with the increase in total alkaline phosphatase (tALP) and prostate-specific antigen (PSA) levels (7, 8). The development of bone metastases is associated with an increase in mortality and a reduction in the patient’s health-related quality of life (QoL) (9-11). Treatment options for metastatic CRPC

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(mCRPC) have recently and include cytotoxic therapy (e.g., docetaxel, cabazitaxel), immunotherapy, oral hormonal therapies targeting the androgen receptor axis (e.g., enzalutamide and abiraterone), bone health agents (e.g., denosumab and zoledronic acid) and targeted alpha-therapy (Radium-223 dichloride) (12-14). Radium223 has been approved for the treatment of patients with mCRPC with symptomatic bone metastases and no known visceral metastatic disease (15). This radiopharmaceutical have a dual mechanism of action, destroying bone-metastatic cancer cells and affecting tumor-induced pathological bone activity (16). Currently, Radium-223 is approved as monotherapy or in combination with a Luteinizing Hormone-Releasing Hormone (LHRH) analogue for the treatment of adult patients with mCRPC who are in progression after at least two prior lines of systemic therapy (other than LHRH analogues), or ineligible for any available systemic mCRPC treatment (17).

Pharmacovigilance Risk Assessment Committee (PRAC) of European Medicines Agency (EMA) carried out a review on Radium-223 after data from a clinical study suggested that patients treated with Radium-223 in combination with abiraterone and prednisone/prednisolone could be at risk of dying earlier and had more fractures than patients given placebo with abiraterone and prednisone/prednisolone (18). The above recommendations are based on the assessment of data resulting from a randomized, double-blind, placebo-controlled phase III trial (ERA-223), which showed an increased incidence of skeletal-related events (SRE) (28.6% vs 11.4%), a possible reduction in median overall survival (OS) (30.7 months vs 33.3 months, HR 1.195, p = 0.13) and an increased risk of radiological non-bone progression (HR 1.376, p = 0.07) among patients receiving Radium-223 in combination with abiraterone acetate plus prednisone/prednisolone (n = 401) compared to patients receiving placebo in combination with abiraterone acetate plus prednisone/prednisolone (n = 405) (19). Despite several clinical trials and prospective studies have been carried out aiming to investigate the outcomes of Radium-223 therapy in terms of OS, progression-free survival (PFS), SRE and multiple QoL parameters (20), to our knowledge, in the literature there are no studies assessing specifically the bone pain palliation outcomes, as an independent factor, following the end of Radium-223 treatment. The following study No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2020; 92, 3

Bone pain palliation and Radium-223 re-treatment

describes a mCRPC patient, presenting a significant reduction of bone pain during the therapy, followed by further bone pain palliation after the first 3 months following the end of Radium-223 therapy without modification of pain-relieving medications.

MATERIALS

showed progression in the 99mTc-HDP bone scan performed in October 2017, after 6 months from the end of the Radium-223 therapy (Figure 1C), with extension of the areas of pathological uptake previously reported.

Unfortunately, after 13 months of follow-up, the patient died for multi-organ failure.

AND METHODS

A 77 years-old man was diagnosed with PCa (Gleason score 9, 4+5) in February 2014. He began ADT with Triptorelin and Bicalutamide for 19 months. Furthermore, after 2 years from the diagnosis, he has been treated with external beam radiation therapy (EBRT) to secondary bone lesions on the right pelvis. He came to our attention in November 2016 with a PSA recurrence (PSA 168 ng/mL) despite ADT, his testosterone level was 0.34 ng/dL), therefore he was diagnosed with mCRPC. The patient presented positive 99mTc-HDP bone scan imaging with increased uptake in the cranium, in both scapulae, in the left humerus and radius, in multiple ribs and vertebrae, in the pelvis and in the left femur (Figure 1A). The CT scan was negative for visceral metastasis. He was defined as a poly-metastatic patient (6-20 metastatic foci). Therefore, we started Radium-223 treatment. The Brief Pain Inventory by Numeric Rating Scale (BPI) value was 7 in spite of nonsteroidal antiinflammatory drug (NSAID) (ketorolac) and acetaminophen treatment.

Figure 1A. Baseline 99mTc-HDP bone scan imaging.

Figure 1B. End-of treatment 99mTc-HDP bone scan imaging.

Figure 1C. 99mTc-HDP bone scan imaging at 6 months follow-up.

Figure 2.

BPI trend over time.

RESULTS After 6 cycles of Radium-223 treatment, BPI declined from 7 to 4 without modification of pain-relieving medications. The bone scan performed in April 2017 showed a partial regression of multiple bone hot spots (Figure 1B).

The patient reported further improvement with BPI that declined from 4 to 2 after 3 months from the last administration of Radium-223 treatment with stable disease resulting in the bone scan. Nevertheless, at 6 months follow-up BPI increased from 2 to 10 without modification of pain-relieving medications. Pain score measurements during and after the Radium-223 treatment are shown in Figure 2. The patient Archivio Italiano di Urologia e Andrologia 2020; 92, 3

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DISCUSSION In this study, we presented the case of an mCRPC patient treated with Radium-223, showing bone pain reduction during the therapy which continued with a further decline for the next 3 months after the end treatment.

Nevertheless, after 6 months from Radium-223 treatment, BPI suddenly increased from 2 to 10 with the radiological progression of disease described in several bone districts, revealed with bone scan.

The phase 3 trial ALSYMPCA showed a significant effect of Radium-223 on OS and a delay in median time to the first SRE (21). In the meantime, several retrospective studies reported a difference in median OS between patients who received 1 to 4 versus 5 to 6 injections, demonstrating that a higher number of Radium-223 injections was associated with prolonged OS (median OS of 6.2 months, versus 17.9 months) (22). ALSYMPCA show furthermore that Radium-223 patients reduced the risk of need for EBRT for bone pain and notably delayed the time to first use of opioids (23). This is associated with significant palliation of bone pain by the radiopharmaceutical.

However, ALSYMPCA was not planned to evaluate the effect of Radium-223 on pain; any response to pain observed or lack of it was not considered a reason to stop treatment with Radium-223. The effect of treatment on pain was not systematically documented as it was not one of the objectives of the study. Currently, patients receive up to six intravenous injections of Radium-223, 55 kBq/kg in 4-week intervals. There have been recent studies of retreatment with Radium-223 (24). One of these is the open-label, phase 1/2 study (NCT01934790) (25).

This study, including 44 patients with no disease progression in bone during the first treatment and presence of later progression, that received Radium-223 re-treatment, up to 6 additional Radium-223 injections, showed that retreatment with Radium-223 was well tolerated with favorable effects on disease progression. Another ongoing phase II study (NCT02023697) evaluated standard dose (55 kBq/kg every 4 weeks up to 6 injections) versus high dose (88 kBq/kg every 4 weeks up to 6 injections) and versus extended standard dose (55 kBq/kg every 4 weeks up to 12 injections) (26, 27). In literature has been already showed how Radium-223 could significantly extend OS, associated with a delay in median time to the first symptomatic SRE, meaningful improvement in QoL and bone pain palliation (23, 28). Several trials showed that Radium-223 is well tolerated and has a favorable hematologic safety profile (29), with a low incidence of myelosuppression (30). Such safety is confirmed from long-term safety ALSYMPCA analysis up to 3 years from first injection, which indicated that Radium-223 remained still well tolerated, with low myelosuppression incidence and no new safety concerns (31). It is possible to postulate that some patients after initial treatment may derive benefit from extended treatment with Radium-223.

The open-label, phase 1/2 NCT01934790 trial (25) showed that re-treatment with Radium-223 sustained benefit on disease and progression was well tolerated. In particular, it showed a low incidence of clinical events such as symptomatic SRE or radiographic bone progression.

Furthermore, in this study tALP declined from baseline values after re-treatment, suggesting a continuation of the

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biologic effects of Radium-223; moreover, the median OS increased to 24.4 months at the end of the 2-year active follow-up period. A further study focused on these patients confirms its safety in a 2-year active follow-up analysis, especially with regards to the minimal hematologic toxicity and efficacy outcome from 2-year follow-up of the retreatment with Radium-223. In view of these remarkable results and based on our wide experience, we could reasonably assume that this patient would have provided clinical benefits if he continued the Radium-223 therapy.

CONCLUSIONS Further analysis should be conducted on a large cohort to evaluate the clinical outcome in terms of bone pain palliation after Radium-223 treatment and the possibility, considering the low toxicity profile, of re-treatment in selected patients.

ETHICAL

APPROVAL

This study has been approved by the local ethical committee.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

INFORMED

CONSENT

Informed consent was obtained from all individual participants included in the study.

RESEARCH INVOLVING AND/OR ANIMALS

HUMAN PARTICIPANTS

This article does not contain any studies with animals performed by any of the authors.

REFERENCES 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016; 66:7-30.

2. Santer FR, Erb HH, McNeill RV. Therapy escape mechanisms in the malignant prostate. Semin Cancer Biol. 2015; 35:133-44.

3. Sciarra A, Gentilucci A, Silvestri I, et al. Androgen receptor variant 7 (AR-V7) in sequencing therapeutic agents for castratrion resistant prostate cancer: A critical review. Medicine (Baltimore) 2019; 98:e15608.

4. Ricci M, Frantellizzi V, Bulzonetti N, De Vincentis G. Reversibility of castration resistance status after Radium-223 dichloride treatment: clinical evidence and Review of the literature. Int J Radiat Biol.

2019; 95:554-561.

5. Cornford P, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG Guidelines on prostate cancer. Part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol. 2017; 71:630-42.

6. Lowrance WT, Roth BJ, Kirkby E, et al. Castration-resistant prostate cancer: AUA guideline amendment 2015. J Urol. 2016; 195:1444-52.

Bone pain palliation and Radium-223 re-treatment

7. Sathiakumar N, Delzell E, Morrisey MA, et al. Mortality following bone metastasis and skeletal-related events among men with prostate cancer: a population-based analysis of US Medicare beneficiaries, 1999-2006. Prostate Cancer Prostatic Dis. 2011; 14:177-83.

8. Som A, Tu SM, Liu, et al. Response in bone turnover markers during therapy predicts overall survival in patients with metastatic prostate cancer: analysis of three clinical trials. Br J Cancer. 2012; 107:1547-53.

9. Smith HS. Painful osseous metastases. Pain Physician 2011; 14:E373-403.

10. De Vincentis G, Frantellizzi V, Follacchio GA, et al. No evidence of association between psychological distress and pain relief in patients with bone metastases from castration-resistant prostate cancer treated with 223Radium. Eur J Cancer Care (Engl) 2019; 28:e13112.

11. De Vincentis G, Monari F, Baldari S, et al. Narrative medicine in metastatic prostate cancer reveals ways to improve patient awareness & quality of care. Future oncology (London, England) 2018; 14:2821-32.

12. Asselah J, Sperlich C. Post-docetaxel options for further survival benefit in metastatic castration-resistant prostate cancer: Questions of choice. Can Urol Assoc J. 2013; 7:S11-7.

13. Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014; 65:467-79.

14. De Vincentis G, Gerritsen W, Gschwend JE, et al. Advances in targeted alpha therapy for prostate cancer. Ann Oncol. 2019; 30:1728-1739.

15. Baldari S, Boni G, Bortolus R, et al. Management of metastatic castration-resistant prostate cancer: A focus on radium-223: Opinions and suggestions from an expert multidisciplinary panel.

Crit Rev Oncol Hematol. 2017; 113:43-51.

16. Henriksen G, Breistol K, Bruland OS, et al. Significant antitumor effect from bone-seeking, alpha-particle-emitting (223)Ra demonstrated in an experimental skeletal metastases model. Cancer Res. 2002; 62:3120-5.

17. Du Y, Carrio I, De Vincentis G, et al. Practical recommendations for radium-223 treatment of metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2017; 44:1671-8.

18. O'Sullivan JM, Heinrich D, James ND, et al. The case against the European Medicines Agency's change to the label for Radium223 for the treatment of metastatic castration-resistant prostate cancer. Eur Urol. 2019; 75:e51-e2.

19. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. Oncology. 2019; 20:408-19.

20. Saad F, Gillessen S, Heinrich D, et al. Disease characteristics and completion of treatment in patients with metastatic castrationresistant prostate cancer treated with Radium-223 in an international early access program. Clin Genitourin Cancer. 2019; 17:348355.e5 21. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter Radium223 and survival in metastatic prostate cancer. N Engl J Med. 2013; 369:213-23.

22. Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a

phase 3, double-blind, randomised trial. The Lancet. Oncology.

2014; 15:738-46.

23. Nilsson S, Cislo P, Sartor O, et al. Patient-reported quality-oflife analysis of radium-223 dichloride from the phase III ALSYMPCA study. Ann Oncol. 2016; 27:868-74.

24. Sartor AO, Heinrich D, Mariados N, et al. Radium-223 (Ra223) re-treatment (Re-tx): First experience from an international, multicenter, prospective study in patients (Pts) with castration-resistant prostate cancer and bone metastases (mCRPC). Journal of Clinical Oncology. 2016; 34(Suppl 2):197.

25. Sartor O, Heinrich D, Mariados N, et al. Re-treatment with radium-223: 2-year follow-up from an international, open-label, phase 1/2 study in patients with castration-resistant prostate cancer and bone metastases. Prostate. 2019; 79:1683-91.

26. Parker CC, Pascoe S, Chodacki A, et al. A randomized, doubleblind, dose-finding, multicenter, phase 2 study of radium chloride (Ra 223) in patients with bone metastases and castration-resistant prostate cancer. Eur Urol. 2013; 63:189-97.

27. NCT02023697. Radium-223 Dichloride 50 kBq/kg (55 kBq/kg After Implementation of NIST Update) Versus 80 kBq/kg (88 kBq/kg After Implementation of NIST Update), and Versus 50 kBq/kg (55 kBq/kg After Implementation of NIST Update) in an Extended Dosing Schedule in Subjects With Castration-resistant Prostate Cancer Metastatic to the Bone. https://clinicaltrials.gov/ct2/show/ results/NCT0202369.

28. Nilsson S, Larsen RH, Fossa SD, et al. First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res. 2005; 11:4451-9.

29. Prelaj A, Rebuzzi SE, Buzzacchino F, et al. Radium-223 in patients with metastatic castration-resistant prostate cancer: efficacy and safety in clinical practice. Oncol Lett. 2019; 17:1467-76.

30. De Vincentis G, Follacchio GA, Frantellizzi V, et al. 223Radichloride therapy in an elderly bone metastatic castration-resistant prostate cancer patient: a case report presentation and comparison with existing literature. Aging Clin Exp Res. 2018; 30:677-680.

31. Vogelzang NJ, Coleman RE, Michalski JM, et al. Hematologic Safety of Radium-223 Dichloride: Baseline Prognostic Factors Associated With Myelosuppression in the ALSYMPCA Trial. Clin Genitourin Cancer. 2017; 15:42-52.e8.

Correspondence Viviana Frantellizzi, MD, PhD Viviana.frantellizzi@uniroma1.it Department of Molecular Medicine, Sapienza University of Rome Viale Regina Elena 324, 00161 Rome (Italy) Julia Lazri, MD Julia.lazri@uniroma1.it Giuseppe De Vincentis, MD, PhD Giuseppe.devincentis@uniroma1.it Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza University of Rome, Viale Regina Elena 324, Rome (Italy) Mariano Pontico, MD Mariano.pontico@uniroma1.it Ph.D Program in Morphogenesis & Tissue Engineering, â&#x20AC;&#x153;Sapienzaâ&#x20AC;? University of Rome, Viale Regina Elena 324, Rome (Italy) Arianna Pani, MD Arianna.pani@gmail.com Clinical Pharmacology and Toxicology, University of Milan, L.go De Benedetti 1, Milan (Italy)

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DOI: 10.4081/aiua.2020.3.200

CASE REPORT

Gelatin sponge (Spongostan®) and N-butyl-2-cyanoacrylate: Utility on percutaneous treatment of persistent urinary leakage after partial nephrectomy.

Case report and review of the literature.

Bernardino de Concilio 1, Francesca Vedovo 1, 2, Maria Carmen Mir 3, Tommaso Silvestri 1, 2, Andrea Casarin 4, Antonio Celia 1 1 Department

of Urology, San Bassiano Hospital, Bassano del Grappa, Italy; of Urology, Azienda Sanitaria Universitaria Integrata di Trieste, Trieste, Italy; 3 Fundación Instituto Valenciano Oncologia, Valencia, Spain; 4 Department of Radiology, San Bassiano Hospital, Bassano del Grappa, Italy.

2 Department

Introduction: Percutaneous treatment of persistent urinary fistula after partial nephrectomy using N-butyl-2-cyanoacrylate and gelatin sponge (Spongostan®) is an effective and relatively non-invasive procedure that should be considered when a conservative approach fails. Three successful cases of percutaneous embolization by using N-butyl-2-cyanoacrylate have been reported in the literature. To our knowledge, the use of Spongostan for the treatment of urinary fistula after partial nephrectomy has not been previously described.

Case report: We present the case of an 82-year old man who underwent percutaneous closure of a urinary fistula following partial nephrectomy by using gelatin sponge (Spongostan®) and N-butyl-2-cyanoacrylate.

Conclusions: We encourage the use of this technique in selected cases. Collaboration amongst urologists and skilled interventional radiologist is strongly recommended.

Summary

KEY WORDS: Cyanoacrylates; Fibrin foam; Gelatin sponge; Urinary fistula.

Submitted 18 August 2020; Accepted 1 September 2020

INTRODUCTION Partial nephrectomy (PN) is gold standard for treatment of small renal masses. PN is not exempt of complications, urinary fistula (UF) is one of the most common.

Its incidence rates between 2 and 10%, depending on the complexity of the surgery. The vast majority of fistulas are self-limited within short-term. However, a small percent of urinary fistula may require active treatment, either by open repair or by percutaneous approach.

In the current case, we report the use of N-butyl-2cyanoacrylate and gelatin sponge (Spongostan®) in a persistent urinary fistula.

CASE

REPORT

An 82-year-old man was assessed for an incidentally detected left renal mass at our institution. A CT scan confirmed the presence of a 46 mm round partially, posterior, upper pole mass. (Figure 1) Patient’s significant past medical history included hypertension, pace-maker

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implantation and left hip replacement. A robotic assisted laparoscopic partial nephrectomy was performed.

The procedure required intraoperative conversion to open procedure due to sclerolipomatosis. Pathology report showed a pT1a Fuhrman 1-2 clear cell renal carcinoma with negative surgical margins. Patient’s postoperative course showed prove of urinary leakage on post-operative day 1 (POD1). A double-J catheter was inserted to improve urinary drainage. At retrograde pyelography, a leakage on the central calix was observed.

Patient was discharged on POD10 and readmitted one week after due to fevers and diarrhea. A CT scan revealed a left retroperitoneal urinoma 3 cm in diameter with actual drainage through the chest wall and skin (Figure 2). The double-J catheter was exchanged to a single-J 8 Ch for better drainage. Ten day after the exchange a CT scan showed persistent leakage. Fistula consisted in a large cavity opened to the perirenal tissue.

A percutaneous approach was used to have a direct way to the fistula. There absorbable gelatin sponge (Spongostan®) was applied to the fistulous cavity to reduce the volume. Five strips of approximately 5 mm x 50 mm were pushed through the introducer to create a scaffold into the renal breach. Then 1 mL of N-butyl-2cyanacrilate (Glubran 2®; GEM, Italy) was located over the leakage orifice above the gelatin sponge. The postprocedure retrograde pyelography showed a substantial reduction on the fistulous tract. A 6 Ch drainage pigtail tube outside the kidney in the urinoma as well as a single-J stent were placed at the end of the procedure.

(Figure 3). Patient was discharged home the day after the procedure. Follow-up CT scan performed within 30 days of procedure showed a decreased debit and complete reduction in urinoma size. Both catheters were removed after the control CT scan, 1 month after the procedure and patient never develop any relapse.

DISCUSSION

AND LITERATURE REVIEW

According to AUA and EAU Guidelines, PN is considered the standard treatment for T1a tumors and it No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2020; 92, 3

Gelatin sponge (Spongostan速) and N-butyl-2-cyanoacrylate

Figure 1.

CT scan confirmed the presence of a 46 mm round partially, posterior, upper pole mass.

Figure 2.

CT scan revealed a left retroperitoneal urinoma 3 cm in diameter with actual drainage through the chest wall and skin.

Figure 3.

The post-procedure retrograde showed a substantial reduction on the fistulous tract. A 6 Ch nephrostomy tube as well as a single-J stent were placed at the end of the procedure.

should be favored over radical nephrectomy in patients with T1b, whenever feasible. Controversial data has been published regarding oncological outcomes of small renal masses in surgical terms. Retrospective data by Van Poppel et al. and EORTC group supports the use of PN, however, the only prospective randomized trial comparing both techniques did not show large advantage for PN (1). It is well known that PN is not exempt of complications. Tumor size, blood loss, ischemia time and endophytic mass location are factors related to UF formation.

Several authors have described conservative and nonconservative approaches for UF management. Kundu et al. reported a conservative approach perinephric drainage (2). Ureteric stent placement is a widely accepted strategy in case of persistent urinary leak and a minimum of 30-45 days might be required for resolution.

Other authors have used endoscopic fulguration of the fistula for sealing. Hemostatic agents and tissue sealants are now being used commonly during laparoscopic and robotic (LPN or RPN). The use of fibrin glues may offer adequate hemostasis in patients undergoing LPN when the collecting system is not opened, but in case of entering, a sutured bolster is recommended. Nevertheless, in 2007, Porpiglia and coworkers published results to the contrary (3).

The use of surgical sealants and biologic agents like thrombin, fibrin and collagen glues can be considered when a persistent leakage is present after PN, and they have been successfully used for over one decade.

Percutaneous embolization of UF is a relatively novel technique that has been used in the last decade (4). More recently the application of cyanoacrylate glues has been reported in different branches of surgery for endoscopic treatment of refractory bile leaks, gastroenteric fistulae, intracranial vascular malformations and also for the management of urinary fistulas.

To our knowledge few cases in literature described the endoscopic utilization of cyanoacrylate in repairing UF after urological maneuvers and until now there are only 4 single cases reports of percutaneous successful utilization of cyanoacrylate glue in repairing UF after PN have been reported till date (5, 6). In addition, two clinical case series: one of 13 cases in 9 years by Muto et al that reported the use of cyanoacrylate glue in repairing endoscopic percutaneous and endovaginal urinary fistula of various etiologies with a high success rate and few complications (7). The second by Selli et al. described 5 patients presenting UF, but only 3 following PN treated with cyanoacrylate glue endoscopically (8). Our case describes the association and combination of Spongostan to the already approved N-butyl-2-cyanacrilate (Glubran 2速). N-butyl-2-cyanacrilate is composed of N-butyl-2cyanoacrylate monomer and metacryloxysulpholane monomer. This compound presents favorable properties such as a good biocompatibility and progressive reabsorption without causing foreign body granulomas.

The property of nearly instantaneous bonding makes cyanoacrylates an effective haemostatic agent and tissue adhesive. Its polymerization time is rather fast in a wet environment, specifically with weak bases, such as water and blood. The gluing of the catheter tip is a potential complication of the technique especially in case of no dilution of the cyanoacrylate. Moreover, accidental glue injection directly into the collecting system may cause urinary obstruction. A skilled interventional radiologist is required for these procedures. Spongostan速 is a dry artificial sterile sponge of fibrin prepared by clotting with thrombin a foam or solution of fibrinogen. It is used to provide effective local hemostasis in cases of venous oozing where traditional hemostasis has failed. Moreover, Spongostan速 serves as a scaffold for proteins or cells implanted into defects fulfilling its function as a cell scaffold (9). The combination of sealants in our case was critical to obtain a success of treatment with the purpose of decreasing the defects of parenchyma, filling in the cavity and avoiding a large contact with the urine that could compromise the polymerization of glue. Ishii K. et al. in a PN animal model study demonstrated that fibrin Archivio Italiano di Urologia e Andrologia 2020; 92, 3

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sealant plus the collagen or gelatin hemostat have a stronger hemostatic effect than fibrin sealant applied alone (10). The histological investigation showed that the fibrin sealant adhered well to kidney tissue when it was applied with the collagen or gelatin hemostat, showing the advantage of combining these two materials for achieving effective hemostasis and closure effect. In our case Spongostan sheets are not only important as a bolster at the site of glue application, but also because a new complex is formed at the fistula site when the two substances are used in combination. Finally, one critical factor for success in UF closure using cyanoacrylate is the ratio between the length and the diameter of the fistulous tract. Tissue losses greater than 1 cm are unlikely to be completely plugged, and urine may continue to flow around the cast. The fistula diameter to length ratio is the more relevant prognostic factor for success and the combination of two sealants in our cases was the key to obtain a complete resolution.

CONCLUSIONS In conclusion, minimally invasive techniques to solve urinary refractory leakage after PN is a safe option.

The application of gelatin sponge (Spongostan®) and Nbutyl-2-cyanoacrylate improves the outcome resolution, particularly in difficult and high volume UF, without implying increased risk of urinary obstruction.

We encourage the use of this technique in selected cases.

Collaboration amongst urologists and skilled interventional radiologist is strongly recommended.

Acknowledgments: the authors would like to thank Dr. Andrea Casarin whose expertise made this procedure possible.

Correspondence Bernardino de Concilio, MD Antonio Celia, MD Department of Urology, San Bassiano Hospital, Bassano del Grappa (Italy) Francesca Vedovo, MD (Corresponding Author) francesca.vedovo@gmail.com Tommaso Silvestri, MD Department of Urology, Azienda Sanitaria Universitaria Integrata di Trieste Strada di Fiume 447, 34149 Trieste (Italy) Department of Urology, San Bassiano Hospital, Bassano del Grappa (Italy) Maria Carmen Mir, MD Fundación Instituto Valenciano Oncologia, Valencia (Spain) Andrea Casarin, MD Department of Radiology, San Bassiano Hospital, Bassano del Grappa (Italy)

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REFERENCES 1. Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective randomized EORTC intergroup phase 3 study comparing the complications of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol 2007; 51:1606-15.

2. Kundu SD, Thompson RH, Kallingal GJ, et al. Urinary fistulae after partial nephrectomy. BJU Int. 2010; 106:1042-4.

3. Porpiglia F, Renard J, Billia M, et al. Biological glues and collagen fleece for hemostasis during laparoscopic partial nephrectomy: technique and results of prospective study. J Endourol. 2007; 21:423-8.

4. Tekin MI, Peskircioglu L, Boyvat F, Özkardes H. Practical approach to terminate urinary extravasation: Percutaneous fistula tract embolization with N-butyl cyanoacrylate in a case with partial nephrectomy. Tech Urol. 2001; 7:67-9.

5. Aslan G, Men S, Gülcü A, et al. Percutaneous embolization of persistent urinary fistula after partial nephrectomy using N-butyl-2cyanoacrylate. Int J Urol. 2005; 12:838-41.

6. Aning JJ, Stott MA, Watkinson AF. Glue ablation of a late-presentation urinary fistula after partial nephrectomy. Br J Radiol. 2009; 82:e246-8.

7. Muto G, D’Urso L, Castelli E, et al. Cyanoacrylic glue: A minimally invasive nonsurgical first line approach for the treatment of some urinary fistulas. J Urol. 2005; 174:2239-43.

8. Selli C, De Maria M, Manica M, et al. Minimally invasive treatment of urinary fistulas using N-butyl-2-cyanoacrylate: a valid first line option. BMC Urol. 2013; 13:55.

9. Singh I, Saran RN, Jain M. Does sealing of the tract with absorbable gelatin (Spongostan®) facilitate tubeless PCNL? A prospective study. J Endourol. 2008; 22:2485-93.

10. Ishii K, Kawashima H, Hayama T, et al. Combination of a liquid fibrin sealant with sheet-type hemostatic agents: experimental evaluation in partial nephrectomy animal model. Int J Urol. 2011; 18:478-82.

DOI: 10.4081/aiua.2020.3.203

CASE REPORT

Infected kidney stone progressing to perinephric abscess and thoracic empyema Antonio Tufano 1, Rocco Minelli 2, Giovanni Di Lascio 1, Giampaolo Delicato 3, Giulio Baffigo 3, Stefano Signore 3 1 Department

of Maternal-Child and Urological Sciences, Sapienza Rome University, Policlinico Umberto I Hospital, Rome, Italy; Life and Health “V. Tiberio”, University of Molise, Campobasso, Italy; 3 Department of Urology, Sant'Eugenio Hospital, Rome, Italy.

2 Department

A case is presented that demonstrates unusual long-term evolution of an infected calculi, culminating in the formation of a retroperitoneal abscess that fistulised to the pleural space, leading to a right pleural empyema.

Summary

KEY WORDS: Infected kidney stone; Perinephric abscess; Empyema.

Submitted 26 January 2020; Accepted 29 February 2020

INTRODUCTION Perinephric and renal abscesses are uncommon, but potentially lethal complications of urinary tract infection. A perinephric abscess is usually a complication of an urologic infection (1). A perinephric abscess affects the renal capsule and Gerota’s fascia. These abscesses can extend from the Gerota’s fascia into the psoas and transversalis muscles as well as the peritoneal cavity and the pelvis (2). Renal calculi may harbour infection and cause localized obstruction. Urinary tract obstruction is generally considered a predisposing factor to urinary tract infection (3). Ascending urological infections towards the pleura are rare and only few cases are reported (4).

Here we describe a case of a 63 year-old woman with infected staghorn calculi of the right kidney who developed a perinephric abscess that extended across the diaphragm to cause an empyema as well.

CASE

REPORT

A 63 year-old women with a known history of recurrent urinary tract infections, including right-sided pyelonephritis presented because of fever (39°C). She was normotensive but tachycardic (130/min) and in respiratory distress.

Clinical examination showed signs of a large right pleural effusion but no abdominal tenderness. There was marked peripheral leucocytosis associated with a raised C-reactive protein (CRP).

Imaging, including computed tomography (CT) of thorax and abdomen, showed extensive peri-bronchial thickening, right lower lobe consolidation and a complex right pleural effusion with thickened pleura (Figires 1, 2).

In the right subdiaphragmatic area, a small hypodense collection of about 3 centimeters in diameter was appreciated in contiguity with the diaphragmatic dome.

The right kidney presents multiple hypodense areas of probable cystic nature and stones in thr middle and lower calyces and in the renal pelvis. The right kidney also demonstrated atrophic calcification, likely related to previous infections (Figures 3, 4).

A 24F intercostal catheter was urgently inserted with removal of 500 mL of turbid and exudative fluid which was cultured with growth of Citrobacter koseri.

Subsequently a 8F nephrostomy catheter was placed in the right kidney with aspiration of purulent fluid positive for Citrobacter. Sensitivities to antibiotics were obtained and therapy with ceftazadime and meropenem was initiated obtaining a clinical improvement with reduction of fever and of the perirenal abscess size (2 cm). Evaluation of renal function by dynamic scintigraphy with 99mTc-DTPA showed right kidney failure.

An open right radical nephrectomy was then performed and subsequently cardiothoracic surgeons proceeded with Video Assisted Thorascopic Surgery (VATS) to prevent the formation of a fibrothorax.

CONCLUSIONS Perinephric abscesses can cause severe illness.

The severity of the disease depends on the extent of the infection and the comorbidities of the patient.

Infection of the renal and perinephric space continues to be a serious urological problem with high mortality rate.

A high index of suspicion, prompt diagnosis, appropriate antibiotics and surgical intervention may be effective in reducing mortality.

REFERENCES 1. Thorley JD, Jones SR, Sanford JP. Perinephric abscess. Medicine.

1974; 53441-451.

2. Sheinfeld J, Erturk E, Spataro RF, & Cockett ATK. Perinephric Abscess: Current Concepts. The Journal of Urology. 1987; 137:191194.

3. Bichler KH, Eipper E, Naber K, et al. Urinary Infection stones.

Int J Antimicrob Agents. 2002;19:488-98.

4. Stewart ZE, Shaker M, and David Baxter J. Urinary tract infection caused by Citrobacter koseri in a patient with spina bifida, an ileal conduit and renal calculi progressing to peri-nephric abscess and empyema. Urol. Case Rep. 2017; 11:22-24.

No conflict of interest declared.

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Figure 1-2.

Computed tomography of thorax and abdomen, showing extensive peribronchial thickening, right lower lobe consolidation and right pleural effusion with thickened pleura.

Correspondence Antonio Tufano, MD antonio.tufano91@gmail.com Giovanni Di Lascio, MD Department of Maternal-Child and Urological Sciences, Sapienza Rome University, Policlinico Umberto I Hospital Viale del Policlinico 155, 00161 Rome (Italy) Rocco Minelli, MD Department Life and Health â&#x20AC;&#x153;V. Tiberioâ&#x20AC;?, University of Molise, Via Francesco De Sanctis 1, Campobasso 86100 (Italy) Giampaolo Delicato, MD Giulio Baffigo, MD Stefano Signore, MD Department of Urology, Sant'Eugenio Hospital, Rome (Italy)

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Figure 3-4.

TC showing right kidney atrophy with calcifications.

DOI: 10.4081/aiua.2020.3.205

CASE REPORT

Non-secreting adrenal myelolipoma in a middle-aged male patient manifesting with sudden onset of severe lower back pain Carlo Introini 1, Fabio Campodonico 1, Marco Ennas 1, Antonia Di Domenico 1, Luca Foppiani 2 1 Urology, 2 Internal

Medicine, Galliera Hospital, Genoa, Italy.

Adrenal myelolipoma (AML) is a rare benign tumor, usually non-functioning and asymptomatic until it reaches large size. AML is mostly detected incidentally by imaging and is composed of adipose tissue and hematopoietic elements. Only symptomatic tumor needs surgical excision. We report the case of a large non-functioning adrenal tumor discovered by means of combined imaging techniques in a middle-aged male patient who complained the sudden onset of severe lower back pain; successful laparoscopic removal was performed, and AML was diagnosed at histopathology.

Summary

KEY WORDS: Adrenal myelolipoma; Tumor size; Laparoscopy.

Submitted 2 March 2020; Accepted 15 March 2020

INTRODUCTION Adrenal myelolipoma (AML) is a benign tumor composed of variable amounts of mature adipose tissue and bone marrow (hematopoietic) elements. AML has an overall prevalence at autopsy of 0.0.8-0.2%, affects patients in their fifth to seventh decades of life, and is usually asymptomatic and non-functioning (1).

With the widespread use of ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI), the finding of AML has reached up to 7-15% of adrenal incidentalomas (2, 3). Albeit mostly asymptomatic, huge AML may cause flank pain and abdominal discomfort/pain by causing pressure of surrounding structures and may present with rupture, haemorrhage, or hemorrhagic shock (1, 3). In patients with AML three distinct types of endocrine dysfunctions have been described: hormone secreting AML, AML occurring in patients with congenital adrenal hyperplasia (CAH) and AML occurring in association with a secreting adrenal co-lesion. The rare secreting AMLs display cortisol or aldosterone secretion; nevertheless, a few reports of catecholamine and androgen secretion have been described (1, 3).

We report the case of a large non-functioning AML which was discovered in a middle-aged male patient presenting with sudden lower back pain.

CASE

REPORT

A 47-year-old man was admitted to the emergency department for severe lower right back pain and vomiting. Physical examination was unremarkable, and blood pressure and blood tests were normal. Abdomen US

showed a large 9 Ă&#x2014; 6 cm hyperechoic curved lesion with regular edge localized in the right suprarenal region.

Contrast-enhanced CT confirmed a large 9 cm elliptical heterogeneous neoplasm with regular margins localized in the right adrenal gland, which featured a hypodense part interspersed with more dense component (Figure 1a), and proved suspicious for pheochromocytoma.

The patient was admitted to the urology ward. In view of surgical removal of the adrenal mass, hormonal array was carried out on both plasma (ACTH, cortisol, 17-hydroxyprogesterone, DHEAS, upright renin and aldosterone) and urine (24-h free cortisol, 24-h metanephrines and normetanephrines); all values proved unremarkable.

Laparoscopic adrenalectomy was performed by transperitoneal approach. In lumbotomic position four trocars were placed by configuring a diamond draw. This technique offers a wide visualization of the operative field ensuring minimal morbidity. The 12-mm port was inserted at the lateral border of the rectus abdominis muscle just above the level of the umbilicus to accommodate the camera. Two subcostal 5-mm ports were placed; one in the midclavicular line and the other in the lateral border of the rectus abdominis muscle.

The third 5-mm subcostal trocar was inserted in the anterior axillary line. The upper pole of the right kidney was mobilised and the huge adrenal lesion was found (Figure 1b, c). Once the mobilization of the lesion was completed, the tumor was removed en-bloc by enlarging the pararectal incision. On gross examination, a 9 x 6 cm reddish yellow colored and friable mass was observed.

Histology showed normally shaped mature adipocytes mixed with hematopoietic cells and surrounded by a capsule; these features were compatible with the diagnosis of myelolipoma. Postoperative course was uneventful and the patient was discharged after 5 days.

DISCUSSION AML is discovered incidentally in 2-5% of population during imaging analysis performed for other reasons.

Tumor size varies from several millimeters to more than 40 centimeters (1, 3). The fat component of AML is postulated to be derived by the mesenchymal stem cells harbouring in the vessel wall of stromal fat of adrenal cortex. The mature adipocytes become inflammatory and stimulate adrenal cortex tissue to release substances (likely granulocyte colony stimulating factor) that recruit

No conflict of interest declared.

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of view is consolidated that the organ most suitable for the laparoscopic approach is the adrenal gland; since it is deeply located in the retroperitoneum a large incision is required in case of open surgery. The right adrenalectomy, specifically in case of tumor diameter larger than 5 cm, can be more challenging due to the proximity with the inferior vena cava and the duodenum (6).

A recent study compared the results in two groups of patients who underwent single-site transumbilical laparoendoscopic adrenalectomy (LA) for adrenal tumors or standard multi-port LA. No difference in terms of operative time, blood loss, analgesic requirement, and hospital stay was found; however in the first group 85% of patients did not require drainage compared to 25% of patients in the second group, and resumed normal diet earlier (7).

Figure 1.

Contrast-enhanced computed tomography scan demonstrating a huge inhomogeneous right adrenal mass containing amount of low attenuation tissue of fatty density (a, arrow), a large well capsulated round mass was found at surgery (b), the adrenal gland was entirely dissected along the capsule (c).

circulating haematopoietic progenitors to anchor and differentiate (4). The diagnosis of AML is usually made by means of various imaging techniques (US, CT and MRI). CT is considered the most sensitive way to detect these lesions, since AMLs show low attenuation values (-10 to -30 Hounsfield units) and mixed density.

Although not diagnostic, the presence of fat density within the mass is a very useful feature to characterize a lesion as a myelolipoma (5).

A recent review on 420 cases of AML ascertained that the average size was 10 cm; CAH was present in 10% of patients, whereas cortisol or aldosterone secretion was found in 7.5% of cases (1). In our patient the size of the adrenal mass was in line with literature data and no hormonal secretion was ascertained.

Asymptomatic AMLs which measure less than 4 cm do not require further investigation (hormonal evaluation or follow-up imaging). Surgical treatment becomes necessary in those rare tumours which are functional or increase in size or become symptomatic. AMLs larger than 6 cm are at high risk of spontaneous rupture with haemorrhage leading to acute abdomen and shock and should be removed (1, 3).

In our patient, a large (9 cm) AML became symptomatic (severe back pain) and required surgery. However, the CT features of the right adrenal mass were initially deemed suggestive of pheochromocytoma: this tumor, in fact, may show homogeneous or variable enhancement as was found in our patient (5), and this may puzzle the diagnosis. Hormonal work-up was therefore carried-out.

The normality of 24-h urinary metanephrine and normetanephrine levels and blood pressure prompted us to exclude a pheochromocytoma. In addition, normal 17-hydroxyprogesterone levels ruled out CAH; finally, normal ACTH and cortisol levels together with the absence of Cushingoidâ&#x20AC;&#x2122;s features likely excluded a cortisol-secreting AML. The Clinical Practice Guidelines of European Society of Endocrinology do not recommend in AML the endocrine/metabolic work-up deemed mandatory in other adrenal incidentalomas (2).

However endocrine dysfunctions are reported in 7-10% of AML (1, 3). In our opinion, given the increasing number of AML reported as secreting hormones or occurring in association with either CAH or adrenal collision tumors (adrenal carcinoma, cortisol-secreting adenoma, aldosterone-secreting adenoma), endocrine work-up seems advisable at least in those patients with hypertension, diabetes, or bilateral AML. From a urological point

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CONCLUSIONS AML is a rare, benign, and usually asymptomatic tumor of adrenal gland. Hormonal work-up seems worthwhile at least in those patients at high metabolic risk or who are referred to surgery. In particular, rare catecholaminesecreting AMLs must be ruled out before surgery in order to prevent life-threatening hypertensive crisis during intraoperative tumor manipulation.

The AMLs which are symptomatic owing to hormonal secretion or more frequently to mass effect should undergo surgical excision. Laparoscopic adrenalectomy is nowadays the preferred and safe surgical option.

Informed consent was obtained from the patient.

REFERENCES 1. Decmann A, Perge P, TĂłth M, Igaz P. Adrenal myelolipoma: a comprehensive review. Endocrine. 2018; 59:7-15.

2. Fassnacht M, Arlt W, Bancos I, et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2016; 175:G1-G34.

3. Shenoy VG, Thota A, Shankar R, Desai MG. Adrenal myelolipoma: Controversies in its management. Indian J Urol. 2015; 31:94-101.

4. Feng C, Jiang H, Ding Q, Wen H. Adrenal myelolipoma: a mingle of progenitor cells? Med Hypotheses. 2013; 80:819-22.

5. Wale DJ, Wong KK, Viglianti BL, et al. Contemporary imaging of incidentally discovered adrenal masses. Biomed Pharmacother.

2017; 87:256-262.

6. Gunseren KO, Cicek MC, Vuruskan H, et al. Challenging risk factors for right and left laparoscopic adrenalectomy: a single centre experience with 272 case. Int Braz J Urol. 2019; 45:747-753.

7. Carvalho JA, Nunes PT, Antunes H, et al. Transumbilical laparoendoscopic single-site adrenalectomy: a feasible and safe alternative to standard laparoscopy. Arch Ital Urol Androl. 2019; 91:1-4.

Correspondence Carlo Introini, MD (Corresponding Author) - carlo.introini@galliera.it Fabio Campodonico, MD - fabio.campodonico@galliera.it Marco Ennas, MD - marco.ennas@galliera.it Antonia Di Domenico, MD - antonia.didomenico@galliera.it Urology, Galliera Hospital, Genova (Italy) Luca Foppiani, MD, PhD (Corresponding Author) - luca.foppiani@galliera.it Internal Medicine, Galliera Hospital Mura delle Cappuccine 14, 16128 Genova (Italy)

DOI: 10.4081/aiua.2020.3.207

CASE REPORT

Non-invasive removal of self-locking entrapped nephrostomy tubes Fabio Campodonico 1, Umberto Geremia Rossi 2, Marco Ennas 1, Alessandro Valdata 2, Antonia Di Domenico 1, Francesco Pinna 2, Carlo Introini 1 1 Urology

Unit, Ospedale Galliera, Genova, Italy; Radiology Unit, Ospedale Galliera, Genova Italy.

2 Interventional

Introduction: The removal of an encrusted nephrostomy tube can be a challenging maneuver. Urological literature is very bare in detailing techniques for removal of entrapped percutaneous catheters. We present a simple, safe and non-invasive technique of nephrostomy removal using a vascular introducer sheath, useful to manage complicated situations such as nephrostomies blocked for severe encrustations or disabled in their self-locking system.

Surgical technique: The nephrostomy tube is cut and the stump is passed with a suture needle. The suture is passed through the inner vascular introducer sheath tip, and the introducer is then removed. The introducer sheath is advanced over the nephrostomy until joining the pigtail segment, under fluoroscopy guidance. Thus the suture is pulled out with strenght to contrast the opposite stiffness of the encrusted coil, until the nephrostomy has safely come out.

Comment: The sheath exchange technique is quick, involves less manipulation through the perirenal fascia and kidney, and is suitable for different conditions of entrapped nephrostomies.

Summary

KEY WORDS: Nephrostomy tube; Encrustation; Vascular sheath; Percutaneous nephrostomy.

Submitted 2 March 2020; Accepted 15 March 2020

tube, the use of guidewire is worthless and the release system could be enabled by encrustations. In both conditions, a non-invasive technique of nephrostomy removal is possible using a safety technique. As a consequence of an 8 French malfunctioning nephrostomy, a vascular introducer sheath of 9 French diameter and 10 cm long (RadifocusÂŽ Introducer II, Terumo Europe, Leuven, Belgium) is used with the following steps. The stopcock of the tube is cut and the stump is passed with a needle of a 2/0 silk suture (Figure 1A). The silk suture is passed through the inner vascular introducer sheath tip (Figure 1B), and the introducer is then removed (Figure 1C).

The introducer sheath is advanced over the nephrostomy by threading the suture through the tube in order to maintain a straight position (Figure 1D).

The sheath is advanced progressively until joining the pigtail segment (Figure 1E), under fluoroscopy guidance, thus the suture is pulled out with strenght to contrast the opposite stiffness of the encrusted coil, until the nephrostomy is removed (Figure 1F). Once the encrusted nephrostomy is removed, the introducer sheath may be left in place acting as a guide for a new nephrostomy tube. Radiologic steps are summarized in Figure 2.

INTRODUCTION Nephrostomy tube is a common device used in several urological procedures during urgent or elective surgery.

However, a number of complications can occur to patients such as urinary infections, bleeding, nephrostomy malfunction due to displacement or tube encrustation. Moreover, the calcified tube disables the release system in case of a self-locking nephrostomy. Thus, the removal of an encrusted nephrostomy tube can be a challenging maneuver. Urological literature is very bare in detailing techniques for removal entrapped percutaneous catheters (1). We present a simple, non-invasive technique of nephrostomy removal, useful to manage complicated situations.

NOTES

OF SURGICAL TECHNIQUE

When nephrostomy tube substitution is impossible for severe encrustation, firstly a guidewire should be used tapping the tip through the tube, under fluoroscopy guidance. When the tube patency is not achieved, the rigid stump of the guidewire can be used in the same way. However, in case of a self-locking nephrostomy

DISCUSSION A few percutaneous techniques have been proposed in non-urological literature. Canby-Hagino et al. reported the intraluminal pneumatic lithotripsy. The lithotripsy probe is directly inserted through the nephrostomy encrusted lumen, acting like a mini-jackhammer (2).

A similar technique was reported by Mangera et al. by using a 1-mm Lithoclast probe. The lithotripsy is gently carried on by pulling the nephrostomy onto the Lithoclast. An intra and extraluminal fragmentation is done along the straight portion of the tube, under radiological control, to avoid a dangerous exit of the Lithoclast probe into the kidney (3). Baron and McClennan firstly reported the simple exchange of catheters using an angiographic catheter sheath. They suggest to leave the sheath on the nephrostomy next to the stopcock of the new pigtail catheter (4). Pollack reported on two methods to remove an encrusted nephrostomy.

The first permits to remove a tube encrusted along the external tract, but patent in transparietal and coiled segments. The second is similar to our technique, based on

No conflict of interest declared.

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Figure 1.

Steps of removal of entrapped nephrostomy.

A) The stopcock of the tube is cut and the stump is passed with a needle of a 2/0 silk suture; B) The silk suture is passed through the inner vascular introducer sheath tip; C) The introducer is removed; D) The introducer sheath is advanced over the nephrostomy by threading the suture through the tube; E) The sheath is advanced until joining the pigtail segment; F) The suture is pulled out with strenght until the nephrostomy is removed; G) The nephrostomy removed.

Figure 2.

Radiological steps.

REFERENCES 1. Alnadhari I, Alwan MA, Salah MA, Ghilan AM. Treatment of retained encrusted ureteral Double-J stent. Arch Ital Urol Androl.

2019; 18; 90:265-269.

2. Canby-Hagino ED, Caballero RD, Harmon WJ. Intraluminal pneumatic lithotripsy for the removal of encrusted urinary catheters.

J Urol. 1999; 162:2058-60.

3. Mangera A, Mehta S, Hastie KJ, et al. Lithoclast removal of an encrusted nephrostomy tube . Ann R Coll Surg Engl. 2010; 92:353-4.

the use of a vascular sheath (5). Farooq et al. depicted in details the technique employing the angiographic catheter sheath, however in an interventional radiology context (6).

Finally, studies using a similar technique are very few (46), and mainly refer to the expertise of interventional radiologists in materials and techniques they use for percutaneous retrieval of intravascular foreign bodies (7).

Our report, however, has two points to be highlighted: this is the first description appearing in urological literature and the nephrostomy tubes we used was a self-locking type, thus resulting in a complicated condition.

The technique depicted showed to be useful, simple and safe in the most difficult cases of occluded and entrapped nephrostomy tubes. As reported by Baron, â&#x20AC;&#x153;the sheath exchange method is quicker and involves less manipulation through the perirenal fascia and kidney, less fluoroscopy time, and ensures preservation on the tract for direct insertion of the new nephrostomy tubeâ&#x20AC;?. When non-invasive maneuvers of nephrostomy removal fail, choice of treatments can be extracorporeal shock wave lithotripsy, ureteroscopy, percutaneous or open surgery.

The management of nephrostomy tubes is a common urological task. The urologist should be confident with the different problems encountered, and the technique reported could implement the practical expertise.

AKNOWLEDGEMENT We wish to thank Carlo Oliveri and Lino Squillace for technical assistance.

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4. Baron RL, McClennan BL. Replacing the occluded percutaneous catheter. Radiology. 1981; 141:824.

5. Pollack Hl, Banner MP. Replacing blocked or dislodged percutaneous nephrostomy and ureteral stent catheters. Radiology. 1982; 145:203-5.

6. Farooq A, Agarwal S, Vaughan J. Safe removal of an ecrusted nephrostomy tube using a vascular sheath: a technique revisited.

Cardiovasc Intervent Radiol. 2013; 36:820-3.

7. Rossi UG, Rollandi GA, Ierardi AM, et al. Materials and techniques for percutaneous retrieval of intravascular foreign bodies. J Vasc Access. 2019; 20:87-94.

Correspondence Fabio Campodonico, MD (Corresponding Author) fabio.campodonico@galliera.it Marco Ennas, MD marco.ennas@galliera.it Antonia Di Domenico, MD antonia.didomenico@galliera.it Carlo Introini, MD carlo.introini@galliera.it Urology Unit, Ospedale Galliera Via Volta 8, 16128 Genova (Italy) Alessandro Valdata, MD alessandro.valdata@galliera.it Umberto Geremia Rossi, MD umberto.rossi@galliera.it Francesco Pinna, MD francesco.pinna@galliera.it Interventional Radiology Unit, Ospedale Galliera Via Volta 8, 16128 Genova (Italy)

DOI: 10.4081/aiua.2020.3.209

CASE REPORT

Expression of miR-132 and miR-212 in prostate cancer and metastatic lymph node: Case report and revision of the literature Michele Salemi 1, Angela Pettinato 2, Filippo Fraggetta 2, Aldo E. Calogero 3, Michele Pennisi 4, Ludovica Pepe 4, Pietro Pepe 4 1 Oasi

Research Institute-IRCCS, Troina (EN), Italy; Unit, Cannizzaro Hospital, Catania, Italy; 3 Section of Endocrinology, Andrology and Internal Medicine, Department of Clinical and Experimental Medicine, University of Catania, Italy; 4 Urology Unit, Cannizzaro Hospital, Catania, Italy.

2 Pathology

MicroRNAs (miRNAs) are a class of small, non-coding RNAs that act as key regulators in various physiological and pathological processes as prostate cancer (PCa). In this study we describe molecular evaluation of 132 and 212 miRNAs expression, by Real-time reverse-transcription PCR (qRT-PCR), in a Caucasian man 64-year-old with locally advanced PCa (PSA 160 ng/ml, Gleason score 4+3/ISUP Grade Group 3, clinical stage T3NXM0) who underwent radical retropubic prostatectomy plus extended pelvic lymphadenectomy (LAD) as first step of a multimodal therapeutic treatment. A normal prostate of a 67-year-old man removed by post mortem autopsy was used as a control in the study. The mRNA for this study was conducted on paraffined prostatic sections of: a) index case of PCa; b) metastatic lymph node of index case; c) normal prostate. MiRNA-132, miRNA212 and Glyceraldehyde 3-phosphate dehydrogenase (as reference gene) assays were obtained. Definitive specimen showed a pT3bN1R1 stage: acinar cells adenocarcinoma with involvement of the seminal vesicles, multifocal positive surgical margins, Gleason score 8 (4+4/ISUP Grade Group 4), metastases in 5/25 iliac lymph nodes.

An increased expression of miRNA-132 and miRNA-212 in index case of prostatic adenocarcinoma compared to normal prostate tissue was found; moreover, a lower expression of miR-132 and miR-212 in metastatic lymph node compared to primitive PCa and normal prostate tissue was demonstrated.

Although a greater number of patients should be evaluated, these data suggest that the biology of the primary PCa, in our clinical case, was different from metastatic lymph node.

Summary

KEY WORDS: Prostate cancer; miR-132; miR-132; qRT-PCR.

Although there is no consensus regarding the optimal treatment of men with high-risk or locally-advanced PCa, in the last years, the multi-modal therapy has demonstrated a clinical advantage for the patients (1) and new clinical trials are ongoing to evaluate the best clinical therapeutic approach for each patient. Therefore, there is the necessity to better understand the prognosis for each high risk PCa using new parameters (i.e., histological and molecular genetics patterns) (2, 3); in this respect, the new techniques of proteomics, RNA and DNA microarrays, have been used to identify and validate accurate diagnostic biomarkers in samples of prostate tissue (4).

MicroRNAs (miRNAs) were found aberrantly expressed in PCa (9); MiR-132 has a central role in the processes of cell adhesion, angiogenesis, and tumorigenesis (MIM 610016). Several studies have described a strong association between levels of miR-132 and high Gleason score PCa (10). MiR-212 and mir-132 belong to the same family and are transcribed from a stable gene intron noncoding for proteins (MIM 613487). MiR-212 regulates a sub-set of genes involved in tumor progression in several tumor cell types as PCa (5).

In this study we describe molecular evaluation of 132 and 212 miRNAs expression, by Real-time reverse-transcription PCR (qRT-PCR), in a men with locally-advanced PCa who underwent radical retropubic prostatectomy (RPP) plus extended pelvic lymphadenectomy (LAD) as first step of a multimodal therapeutic treatment.

Submitted 2 March 2020; Accepted 15 March 2020

CASE INTRODUCTION Prostate cancer (PCa) is the most frequently tumor diagnosed in men; although the screening protocols have increased the early diagnosis for organ-confined PCa, still today, a not negligible number of initial diagnosis is characterized by high risk or metastatic cancer. Patients with high-risk PCa are at an increased risk of PSA failure, need for secondary therapy, metastatic progression and death from PCa; nevertheless, not all high-risk PCa patients have uniformly poor prognosis after definitive therapy (radical prostatectomy or radiotherapy).

REPORT

A Caucasian 64-year-old man had a total PSA value of 160.0 ng/ml and positive digital rectal examination.

Transperineal extended prostatic biopsies (13) showed in all the cores (12/12) an adenocarcinoma with a Gleason score 7 (4+3/ISUP Grade Group 3) (14); the clinical stadiation performed by total body computed tomography and bone scan showed no presence of metastases (clinical stage pT3NXM0). In January 2019 informed consent was obtained from the patient who accepted to undergo RRP plus extended pelvic LAD as first step of a multimodal therapeutic treatment. Definitive specimen showed a

No conflict of interest declared.

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Figure 1.

Relative expression value of miR-132 and miR-212: Control 1 and 1 respectively (histogram with double scale); Prostate index case 179.7 and 55.5 respectively; Metastatic lymph node 0.267 and 0.319 respectively.

pT3bN1R1 stage: acinar cells adenocarcinoma with involvement of the seminal vesicles, multifocal positive surgical margins, Gleason score 8 (4+4/ISUP Grade Group 4), bilateral metastases in 5/25 iliac lymph nodes.

A normal prostate of a 67-year-old man removed by post mortem autopsy was used as a control in the study.

The mRNA for this study was conducted on paraffined prostatic sections of: a) index case of PCa; b) metastatic lymph node of index case; c) and normal prostate. MiR132, miR-212 and Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (as reference gene) assays were obtained from Applied Biosystems (Carlsbad, CA).

Real-time analysis was performed on Light Cycler 480 (Roche Diagnostics; Mannheim, Germany).

The amplified transcripts were quantified using the comparative CT method and relative quantification analysis data were played using the comparative â&#x2C6;&#x2020;â&#x2C6;&#x2020;Ct method included in the Software Version 1.5 supplied with the LightCycler 480.

An increased expression of miRNA-132 and miRNA-212 in index case of prostatic adenocarcinoma compared to normal prostate tissue was found; moreover, a lower expression of miR-132 and 212 in metastatic lymph node compared to primitive PCa and normal prostate tissue (Figure 1) was demonstrated.

Finally, the patient had not clinical complications from RPP; the PSA value was equal to 2.7 ng/ml 30 days from surgery and the patient underwent adjuvant radiotherapy and hormonal therapy (LHRH agonist).

DISCUSSION

AND CONCLUSIONS

MicroRNAs are short non-coding RNAs involved in several important biological processes through regulation of genes post-transcriptionally; carcinogenesis is one of the key biological processes where miRNAs play important role in the regulation of genes. The miRNAs elicit their

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effects by binding to the 3' untranslated region (3'UTR) of their target mRNAs, leading to the inhibition of translation or the degradation of the mRNA, depending on the degree of complementary base pairing.

The miRNAs are deregulated in a wide variety of human cancers; in detail, miR-212 and miR-132 regulate a subset of genes involved in PCa progression and lymph node metastasis.

Data obtained in our case report showed an abnormal over-expression of miR-132 and miR-212 in PCa compared to normal prostatic tissue; also we found a down-expression of miR132 and miR-212 in metastatic lymph node.

Although a greater number of patients should be evaluated, these data suggest that the biology of the primary PCa, in our clinical case, was different from metastatic lymph node.

REFERENCES 1. Malik ZI, Fenwick JD. Radiotherapy to the primary tumour for patients with metastatic prostate cancer: practice-changing results from STAMPEDE. Clin Oncol. (R Coll Radiol). 2020; pii: S09366555(19)30540-0.

2. D'Antonio A, Caputo A, Fraggetta F, et al. KPNA2/ERG Coexpression is associated with early recurrence in advanced prostate cancers. Appl Immunohistochem Mol Morphol. 2020; 28:62-66.

3. Pepe P, Fraggetta F, Candiano G, Aragona F. Does Ki-67 staining improve quantitative histology in preoperative prostate cancer staging? Arch Ital Urol Androl. 2012; 84:32-35.

4. Hassan O, Ahmad A, Sethi S, Sarkar FH. Recent updates on the role of microRNAs in prostate cancer. J Hematol Oncol. 2012; 5:9.

5. Formosa A, Lena AM, Markert EK, et al. DNA methylation silences miR-132 in prostate cancer. Oncogene 2012; 32:127-134.

Correspondence Michele Salemi, MD michelesalemi@hotmail.it Oasi Research Institute-IRCCS, Troina (EN) (Italy) Angela Pettinato, MD angelapettinato@hotmail.com Filippo Fraggetta, MD Pathology Unit, Cannizzaro Hospital, Catania (Italy) filippofra@hormail.com Aldo E. Calogero, MD acalogero@hotmail.com Section of Endocrinology, Andrology and Internal Medicine, Department of Clinical and Experimental Medicine, University of Catania, Catania (Italy) Michele Pennisi, MD michelepennisi2@virgilio.it Ludovica Pepe, MD ludovicapepe@hotmail.com Pietro Pepe, MD (Corresponding Author) piepepe@hotmail.com Urology Unit, Cannizzaro Hospital Via Messina 829, Catania (Italy)

DOI: 10.4081/aiua.2020.3.211

CASE REPORT

Primary small-cell neuroendocrine carcinoma of the bladder: Case report and literature review Valerio Olivieri 1, Valentina Fortunati 2, Luca Bellei 1, Massimo Massarelli 1, Gabriele Ruggiero 3, Danilo Abate 3, Nicoletta Serra 3, Daniele Griffa 1, 3, Flavio Forte 4, Emanuele Corongiu 4 1 Division

of Urology, Ivrea Hospital (ASL TO4), Ivrea (Turin), Italy; of Pathology, Hospital Policlinico of Tor Vergata, Rome, Italy; 3 Division of Urology, Ciriè Hospital (ASLTO4), Ciriè (Turin), Italy; 4 Division of Urology, Hospital “Madre Giuseppina Vannini”, Rome, Italy.

2 Division

Background: Neuroendocrine tumours (NET) are extremely rare and aggressive.

Although they commonly affect intestine, many organs may be involved such as pancreas, lung or urinary tract. Bladder is rarely involved. Actually, two main forms of bladder NET have been described: small-cell and large-cell. The first one is considered highly agressive since it shows poor oncologic outcomes being mainly diagnosed at advanced stage: the second one is extremely rare and equally aggressive.

Case report: A 78-years-old Caucasian male presented to our facility for lower urinary tract symptoms and gross hematuria recently occurred. He was a strong smoker since many years.

No familiarity for urothelial cancer was referred nor previous episodes of hematuria until that time. Citology was negative; outpatient ultrasound of the bladder revealed a 3 cm bladder thickening highly suspicious for bladder cancer; patient underwent TC scan that confirmed the bladder lesion.

A transurethral resection of the bladder (TURB) was performed. After 3 months total body TC showed multiple visceral metastases also involving brain and lymph nodes. Best supportive care was offered but the patient died 6 months later.

Results: Pathology revealed a mixed bladder tumor: 30% of the specimen resulted as an high-grade urothelial cancer (G3) and 70% as small-cell neuroendocrine variant.Microscopic muscle involvement was excluded.

Conclusions: Neuroendocrine tumors are uncommon entities which origin from cells of neuro-endocrine system and may potentially involve all human tissues. Neuroendocrine smallcell carcinoma of the bladder is a non-urothelial histotype: it is highly aggressive and diagnosed mainly at advanced stages.

Whenever considering the high risk of metastatic spread and the poor prognosis, a multimodal approach is highly suggested.

TURB alone is uneffective in disease control due to its aggressive nature. Unless metastatic, radical cystectomy and adjuvant chemotherapy represent the gold standard.

Summary

KEY WORDS: Neuroendocrine; Bladder cancer; Uro-oncology; Rare tumors; Oncology.

Submitted 2 March 2020; Accepted 15 March 2020

INTRODUCTION Neuroendocrine tumours (NET) are extremely rare (1) and aggressive. It has been valued the annual incidence is approximately 2.5-5.0 per 100.000.

They take origin from cells of nervous and endocrine systems differently expressed in human tissues. Although they commonly affect intestine, many organs may be involved such as pancreas, lung or urinary tract.

Bladder is rarely involved (2). To date two main forms of

bladder NET have been described: small-cell and largecell. The first one is considered highly aggressive since it shows poor oncologic outcomes being mainly diagnosed at advanced stage: the second one is extremely rare and equally aggressive. Data in literature are strongly limited.

Here we report the case of a small-cell neuroendocrine carcinoma of urinary bladder. While opportunely describing this case, we also reviewed the literature on PubMed about this pathological condition.

CASE

REPORT

A 78-years-old Caucasian male presented to our facility for lower urinary tract symptoms and gross hematuria recently occurred. He was a strong smoker since many years. No familiarity for urothelial cancer was referred nor previous episodes of haematuria until that time.

On past anamnesis he suffered from myocardial infarction and chronic fibrillation being actually on medication with acetilsalicilate plus edoxaban. Multiple coexisting systemic illness were reported such as hypertension, dyslipidemia and mild chronic renal failure.

Furthermore, he was also on medication with adrenergic a1-antagonist for a benign prostatic hyperplasia (BPH) condition: anyway, his last PSA was normal and digito-rectal exploration confirmed an enlarged soft gland. General and systemic examination was unremarkable: no asthenia, weight loss, abdominal palpable masses or acute urinary retention were present. Blood examination revealed a mild anaemia while renal function and white blood count were unremarkable. Urinalysis confirmed haematuria but cytology was negative. Ambulatory ultrasound revealed a 3 cm bladder wall thickening highly suspicious for bladder cancer; the patient subsequently underwent to contrastenhanced CT. The examination confirmed the bladder lesion (Figure 1) totally excluding bilateral hydronephrosis, visceral metastases or lymph nodes involvement.

A trans urethral resection (TURB) of the mass was offered.

Pathology report revealed a mixed bladder tumour: 30% of specimen resulted as an high-grade urothelial cancer (G3) while 70% as small-cell neuroendocrine variant (Figure 2). Microscopic muscle involvement was excluded.

In order to better characterize the neuroendocrine differentiation, further evaluation using immunohistochemistry was mandatory: cytokeratin, synaptophysin and

No conflict of interest declared.

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Figure 1.

Abdominal contrast enhanced CT showing a right wall bladder lesion.

Figure 2.

Microscopic finding showing small cell neuroendocrine bladder cancer reacting to synaptophysin (original magnification x 400).

Figure 3-4.

Whole body contrast enhanced CT showing brain and liver multiple metastases in small cell neuroendocrine carcinoma of the bladder (SCCB).

were not suggested: radical cystectomy was also offered but patient refused that option. He simply underwent follow up. After 3 months total body TC showed multiple visceral metastases (Figures 3-4) also involving brain and lymph nodes: best supportive care was offered but the patient died 6 months later.

CONCLUSIONS Neuroendocrine tumours are uncommon entities1 which origin from cells of neuro-endocrine system and may potentially involve all human tissues.

Gastrointestinal localization is quite common while genitourinary is rare. Neuroendocrine small-cell carcinoma of the bladder is a non-urothelial histotype: it is highly aggressive and diagnosed mainly at advanced stages.

It’s considered as an aggressive tumor being characterized by poor prognosis and limited life expectancy. Small-cell carcinoma is a type of bladder NET along with large-cell variant. To date no treatment has shown established efficacy. Whenever considering the high risk of metastatic spread and the poor prognosis, a multimodal approach is highly suggested. TURB alone is uneffective in disease control due to its aggressive nature.

Unless metastatic, radical cystectomy and adjuvant chemotherapy represent the gold standard. Immunotherapy has been proposed but still under debate. Given its rarity and the absence of randomized trials, the therapeutic management of this tumor remains difficult and finding useful resources for physicians is troublesome yet.

REFERENCES Ki-67 were used as molecular markers. Urothelial histotype resulted positive for cytokeratine but negative for synaptophysin while the neuroendocrine variant was positive for both of them. Ki-67, a molecular marker as expression of proliferation rate, was 90% totally suggesting an aggressive bladder cancer, in fact NET are histologically graded according to mitotic count and markers of cellular proliferation (Ki-67 index) rather than cellular polymorphism: a mitotic count > 20 per 10 HPF and a Ki-67 index > 20% defines the high-grade. Due to its non-urothelial origins, it was also classified as a highest risk tumour.

Treatments, in these cases, depends on many factors; several issues such as anatomic location, tumour differentiation, staging, metastases, lymph node involvement and symptoms may help to define the best therapeutic approach. The high-grade forms should be managed by active treatment which may be multimodal. Unless metastatic, radical cystectomy and chemotherapy (either neoadjuvant or adjuvant) must be offered (3) since TURB alone seems to be an inadequate method of disease control.

Recently, some authors noted molecular abnormalities in small cell neuroendocrine bladder cancer also raising the question of using target therapies: targeting angiogenesis would be the most promising. Anyway, to date immunotherapy still remains under debate. In our case, we evaluated the patient in a multidisciplinary tumour board in order to offer the best disease management. According to Karnofsky performance status, comorbidities and iatrogenic bleeding risk, adjuvant chemotherapy and radiation

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1. Al-Ahmadie H, Iyer G. Updates on the genetics and molecular subtypes of urothelial carcinoma and select variants. Surg Pathol Clin. 2018; 11:713-723.

2. Cramer SF, Aikawa M, Cebelin M. Neurosecretory granules in small cell invasive carcinoma of the urinary bladder. Cancer. 1981; 47:724-30.

3. Siefker-Radtke AO, Dinney CP, Abrahams NA, et al. Evidence supporting preoperative chemotherapy for small cell carcinoma of the bladder: a retrospective review of the M.D. Anderson cancer experience. J Urol. 2004; 172:481-484.

Correspondence Valerio Olivieri, MD valerio.olivieri@uniroma1.it Luca Bellei, MD Massimo Massarelli, MD Gabriele Ruggiero, MD Division of Urology, Ivrea Civil Hospital (ASL TO4), Ivrea (Turin) (Italy) Daniele Griffa, MD Danilo Abate, MD Nicoletta Serra, MD Division of Urology, Ciriè Hospital (ASLTO4), Ciriè (Turin) (Italy) Valentina Fortunati, MD valerio.olivieri@uniroma1.it Division of Pathology, Hospital “Policlinico of Tor Vergata”, Rome (Italy) Emanuele Corongiu, MD (Corresponding Author) emanuele.corongiu@libero.it Flavio Forte, MD flavioforte@hotmail.com Division of Urology, Hospital “Madre Giuseppina Vannini”, Rome (Italy)

DOI: 10.4081/aiua.2020.3.213

CASE REPORT

Fatal infections in andrology.

Atypical clinical presentation of a Fournier’s disease Valerio Olivieri 1, Gabriele Ruggiero 1, 2, Danilo Abate 2, Nicoletta Serra 2, Valentina Fortunati 3, Daniele Griffa 1, 2, Flavio Forte 4, Emanuele Corongiu 4 1 Division

of Urology, Ivrea civil Hospital (ASL TO4), Ivrea (Turin), Italy; of Urology, Ciriè Hospital (ASLTO4), Ciriè (Turin), Italy; 3 Division of Pathology, Hospital “Policlinico of Tor Vergata”, Rome, Italy; 4 Division of Urology, Hospital “Madre Giuseppina Vannini”, Rome, Italy.

2 Division

Background: Fournier disease (FD) is a worrisome infection of genital area caused by a polimicrobial infection and characterized by a rapid progression to necrosis. Scrotum, perineum and lower abdomen represent the primary sites of origin. Clinical presentation and laboratory strongly suggest FD, but if not precociously diagnosed, it may quickly evolve into septic syndrome and patient’s death.

Case report: A 62 years old Caucasian male presented for fever and penile gross oedema recently occurred. No history of previous urinary tract infection, hematuria or genital trauma was referred. He did not complain any storage or voiding low urinary tract symptom (LUTS); no foci of infection in genitoperineal area was observed nor urethral discharge.

The ultrasound (US) revealed a disomogeneous broad thickening of subcutaneous tissues with increased vascularity on Color-Doppler. When the penis was manipulated in order to reduce oedema, retract foreskin and evaluate the glans, clinical parametres rapidly worsened and the patient developed a septic shock with blood pressure falling down, dyspnoea and tachyarrhythmia, and he was fastly sent to Intensive Care Unit where it has been hemodynamically stabilized and subjected to antibiotic therapy. Considering the clinical absence of gangrene’s foci, we opted for a conservative treatment by maintaining bladder catheter and drug therapy.

Summary

KEY WORDS: Andrology; Fournier’s disease; Atypical clinical presentation; Sepsis.

Submitted 2 March 2020; Accepted 15 March 2020

INTRODUCTION Fournier’s disease (FD) is a worrisome of genital area caused by a polimicrobial infection and characterized by a rapid progression to necrosis (1). It is a rare clinical condition accounting for 1.6 cases per 100.000 and represent the 0.01% to 0.06% of all the urological emergency (2).

Elderly and defeated patients are usually involved.

Scrotum, perineum and lower abdomen represent the primary sites of origin. It is characterized by a high rate of mortality since it quickly evolves into septic shock and patient’s death. Hence, whenever misdiagnosed or not promptly treated, it may result in a fatal infection. Clinical presentation and laboratory strongly suggest FD. Atypical presentation has been also described in literature1: if not precociously diagnosed, it may quickly evolve into septic syndrome and patient’s death. We report the case of an adult male with uncommon clinical presentation. While

opportunely describing this case, we also reviewed the literature about atypical FD.

CASE

REPORT

A 62 years old Caucasian male presented for fever and penile gross oedema recently occurred. He was a smoker but familiarity for penile cancer was ruled out on anamnesis. No history of previous urinary tract infection, haematuria or genital trauma was referred. Additionally, he denied any sexual intercourse in the last four weeks. He was affected by metabolic syndrome and diabetes mellitus actually on medication with oral hypoglycemic agents.

Dipstick urine confirmed glycosuria but was negative for urinary infection. Blood examinations were not available.

He did not complain any storage or voiding low urinary tract symptom (LUTS); no foci of infection in genitoperineal area was observed nor urethral discharge. On physical examination the patient was febrile. On local examination inguinal lymph nodes were negative; there was no erythema of the scrotum and the testis were normal. Rectal exploration was unremarkable too with a soft enlarged painless prostate. However, the penis presented with an asymptomatic massive oedema extended from pubis to foreskin (Figure 1); it was also warm but painless and with a normal skin appearance. The ultrasound examination of the abdomen and pelvis was normal while penile fast sonography revealed an inhomogeneous broad thickening of subcutaneous tissues with increased vascularity on Color-Doppler. Hence, as the penis was further manipulated in order to reduce oedema, retract foreskin and evaluate the glans, clinical parameters rapidly worsened and the patient developed a septic shock with blood pressure falling down, dyspnoea and tachyarrhythmia. He was hospitalized and quickly sent to Intensive Care Unit. During hospitalization, the patient presented with severe hypoxia, acute respiratory distress, marked hypotension and septic shock signs: no impairment of neurological function was present. On general examination it showed bluish colour of the skin at the level of the fingers totally according to intense cyanosis as an expression of severe hypoxia and peripheral vasoconstriction. Blood gas analysis (BGA) both confirmed hypoxia and metabolic acidosis with high lactate levels. Severe leucocytosis, high levels of procalcitonin

No conflict of interest declared.

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Figure 1.

Uncommon clinical presentation of Fournier’s gangrene of the penis.

and C-reactive protein were also confirmed on blood examination. Urine and blood culture sampling were mandatory. A bladder catheter (BC) was placed in order to check diuresis as a marker of septic evolution. Hence, respiratory and haemodynamic support in combination with a broad-spectrum antibiotic therapy were immediately offered according to guidelines for septic shock treatment.

Concerning of drugs, we opted for a combination of tazobactam/piperacillin and levofloxacin. However, by persisting severe anuria and hypoxia as a sign of poor response to resuscitation therapy, vasoactive drugs (noradrenaline) were mandatory. Clinical parameters progressively improved while patient started to show a response to drug therapy. Computed tomography (CT) scanning was subsequently performed: it ruled out abscess or any masses altering venous drainage. Urine and blood culture were positive for Enterobacteriaceae (Enterococcus fæcalis). Moreover, three days after hospitalization urethral discharge manifested: samples analysis confirmed Enterococcus too. In order to better evaluate penile anatomy and disease extent, Magnetic resonance (MR) was offered. It revealed an abscess at the right cavernosal body with a secundary fistula in the urethra (Figure 2). Furthermore, it appeared as dishomogeneous and hypervascularized with a severe thickening of surrounding soft tissues, as it usually happens in extended panniculitis. Signs of necrosis at the level of Buck´s fascia and gas in both cavernosal body and soft tissues were also reported strongly suggesting an uncommon isolated Fournier´s disease of the penis. The combined approach “drug therapy/surgery” actually represents the gold standard and may be also combined with vacuum assisted closure (VAC) or hyperbaric oxygen (HBO) therapy. Immediate surgical debridement must be performed as the infection is worsening despite drug therapy: it aims to avoid a fast spread of necrotic tissues and the development towards septic shock. It may be feasible as gangrene clinically manifests but becomes harder in early manifestation since no clear foci of infection are surgically treatable. The main procedure performed is the necrosectomy through the extended and radical demolition of necrotic surgery. Wound cloFigure 2.

Right cavernosal body involvement and secondary urethral fistula.

sure is achieved by different strategies: skin grafting, delayed primary closure and healing by secondary intention. VAC therapy and HBO may be combined with drugs and surgery since they act as synergic therapies and speed up wound healing. Vacuum-assisted closure has been also proposed but the use is controversial (3). Reconstructive surgery may be considered once the clinical resolution has been obtained. In our patient, considering the clinical absence of gangrene’s foci, we opted for a conservative treatment: we performed a urinary diversion by a suprapubic cystostomy and we continued with drug therapy.

Subsequently we sent the patient to a reference center for andrology, where they proceeded to the implantation of penile prosthesis.

CONCLUSIONS Fournier’s disease is an aggressive synergistic genitoperineal fasciitis quickly evolving into sepsis and death.

Polymicrobial infection actually represents the suggested mechanism. Elderly and patients with multiple comorbidities are at high risk to develop. Clinical presentation may be variable, strongly conditioning diagnosis and treatment: the later diagnosis, the faster evolution, the higher death. Uncommon clinical presentation may lead to a missed diagnosis. Antibiotics and extensive surgical debridement represent the gold standard. Mortality still remains high. Fever and leucocytosis associated to atypical penile swelling should be always evaluated for an uncommon form of Fournier’s gangrene.

REFERENCES 1. Anchi T, Tamura K, Inoue K, et al. Localized Fournier’s gangrene of the penis: A case report. Hinyokika Kiyo 2009; 55.

2. Chawla S, Gallop C, Mydlo J. Fournier’s gangrene: an analysis of repeated surgical debridement. Eur Urol. 2003; 43:572-575.

3. Yanaral F, Balci C, Ozgor F, et al. Comparison of conventional dressings and vacuum-assisted closure in the wound therapy of Fournier's gangrene. Arch Ital Urol Androl. 2017; 89:208-211.

Correspondence Valerio Olivieri, MD valerio.olivieri@uniroma1.it Division of Urology, Ivrea Civil Hospital (ASL TO4), Ivrea (Turin), Italy Gabriele Ruggiero, MD Daniele Griffa, MD Division of Urology, Ivrea Civil Hospital (ASL TO4), Ivrea (Turin), Italy Danilo Abate, MD Nicoletta Serra, MD Division of Urology, Ciriè Hospital (ASLTO4), Ciriè (Turin), Italy Valentina Fortunati, MD valerio.olivieri@uniroma1.it Division of Pathology, Hospital “Policlinico of Tor Vergata”, Rome, Italy Flavio Forte, MD flavioforte@hotmail.com Emanuele Corongiu, MD emanuele.corongiu@libero.it Division of Urology, Hospital “Madre Giuseppina Vannini”, Rome, Italy

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DOI: 10.4081/aiua.2020.3.215

CASE REPORT

Management of complications in penile prosthesis reimplantation: A case report Camilla Capretti 1, Antonio Avolio 2, Alberto Florio 2, Silvia Giovannozzi 2, Domenico De Carolis 2 1 Department 2 Department

of Urology, "Ospedali Riuniti" University Hospital and Marche Polythecnic University, Ancona, Italy; of Urology, Mazzoni Hospital, Ascoli Piceno, Italy.

A 74-years-old patient, without comorbidity, underwent malleable penile prosthesis (MPP) implantation in 2007. In 2015, after a perineal trauma, he experienced stress urinary incontinence, medial extrusion of the left prosthetic cylinder and an urethrocavernous fistula.

The cylinder was removed and an artificial urinary sphincter (AUS) implanted, together with a three-component inflatable penile prosthesis (IPP). The left corpus cavernosum (CC) was significantly shorter than the right one due to fibrosis.

After 8 months, partial lateral extrusion of the right prosthetic cylinder prompted a replacement with a shorter extensor. Six months after, a new diastasis of the ruptured area occurred due to a further CC shortening. The extensor was removed and the cylinder shortened, with a dermal graft applied to the area. Long-term patient satisfaction was high.

Summary

KEY WORDS: Erectile dysfunction; Penile prosthesis complications; Reimplantation.

Submitted 2 March 2020; Accepted 15 March 2020

INTRODUCTION Managing the complications of penile prosthesis reimplantation is one of the biggest challenges in urology.

Patients can develop corpus cavernosum (CC) scarring, with potential complications and penile shortening. In this study we present a patient with malleable penile prosthesis (MMP) who, after a perineal trauma, underwent inflatable penile prosthesis (IPP) implantation.

CASE

REPORT

We present the case of a 74-years-old patient with no comorbidities, who underwent radical prostatectomy in 2005. Due to an erectile dysfunction not responding to less invasive methods, in 2007 a MPP (Subrini) was implanted. In 2015, due to an accident, the patient had a perineal trauma with symphysis pubis diastasis, resulting in stress urinary incontinence and medial extrusion of the left prosthetic cylinder at the level of the navicular fossa.

This was due to the thinning and erosion of the tunica albuginea and the creation of an urethrocavernous fistula.

Thus, the decision was taken to remove the cylinder and wait 6 months for a second surgery, to allow for scar tissue formation. The urethrography before the second surgery revealed a complete spontaneous healing of the fistula (Figure 1).

Consequently, the patient underwent the implantation of

an artificial urinary sphincter (AUS) (Advance) and a three-component IPP (AMS 700-CX). During surgery, performed with penoscrotal approach, it occurred that the left CC was significantly shorter (18 cm) than the right one (22 cm), due to scarring and fibrosis.

The cylinders were implanted, a pump positioned in the scrotum and a 65 ml reservoir inserted in the retro-pubic space. The prosthesis was activated intraoperatively.

After 8 months, due to its partial lateral extrusion, the right prosthetic cylinder (which was 18 + 4 cm long) was extracted. The CC was now 19 cm long, compared to the previous 22 cm. The 4 cm-long extensor was substituted with a 1 cm-long one and the cylinder replaced.

The prosthesis was activated intraoperatively, without pressure on the sutured area.

After 6 months, a new diastasis of the previous rupture area occurred, with lateral extrusion of the cylinder due to a further CC shortening by 2 cm (17 cm compared to the previous 19 cm). The extensor 1 cm was removed and the cylinder shortened by 1.5 cm and re-positioned, with a total length gain of minus 2.5 cm. Since the tunica albuginea was inadequate to cover parts of the cylinder, a graft of bovine dermal collagen (XENFORM) was applied with semi-continuous 2-0 absorbable monofilament (Vicryl) sutures to reinforce the area (Figure 2), restoring tunica albuginea continuity.

The patient had an uneventful postoperative course with no complications.

In 2019, a long-term, telephone-based follow-up showed a IIEF-5 score of 25 and no need for disposable incontinence products.

DISCUSSION In this case report, an intense fibrotic reaction occurred after removing the MPP right cylinder, leading to the shortening of the CC. When a MPP is removed and an IPP implanted, a further CC shortening occurs after surgery. While a MPP would always be active, the IPP may not be sufficiently activated by the patient, thus prompting further CC tissue rearrangement.

Therefore, it is advisable to encourage patients to inflate their prosthesis daily.

Implementing downsized prosthesis cylinders could also be a possible solution. If patients are uncomfortable with penile shortening, the conversion to standard cylinders (1), is usually possible within 8-12 months. According

No conflict of interest declared.

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Figure 1.

A. Urethrography performed after the perineal trauma shows the urethrocavernous fistula (yellow circle); B. Urethrography repeated before the surgery shows the complete healing of the fistula (green square).

A.

B. Figure 2.

Schematic representation of the graft of bovine dermal collagen (in red) applied to reinforce the tunica albuginea (in blu are represented the prosthetics cylinders).

to literature, the combination of AUS and PPI does not adversely affect perioperative complications or device survival in relation to the device placement (2).

The use of grafts proved to be a safe option, resulting in no infections, rejections or discomfort for the patient.

Moreover, long-term patient satisfaction proved to be high.

In literature, there is no statistically significant difference in patient satisfaction between those undergoing PPI for the first time and those undergoing reimplantation (3).

3. Lledó-García E, Jara-Rascón J, Moncada Iribarren I, et al. Penile prosthesis first and replacement surgeries: analysis of patient and partner satisfaction. J Sex Med. 2015; 12:1646-1653. Available at: http://dx.doi.org/10.1111/jsm.12932.

CONCLUSIONS Patients should always be informed of reimplantation risks and complications and encouraged to undergo surgery. The degree of CC fibrosis should always be taken in consideration. Graft implementation might be necessary, especially when transitioning from a MPP to an IPP. However, long-term patient satisfaction remains high.

REFERENCES 1. Wilson SK. Reimplantation of inflatable penile prosthesis into scarred corporeal bodies. Int J Impot Res. 2003; 15(Suppl 5):S125-8.

2. Boysen WR, Cohen AJ, Kuchta K, et al. Combined placement of artificial urinary sphincter and inflatable penile prosthesis does not increase risk of perioperative complications or impact long-term device survival. Urology. 2019; 124:264-270. Available at: https://doi.org/10.1016/j.urology.2018.10.033.

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Correspondence Camilla Capretti, MD camilla.capretti2@gmail.com Department of Urology, "Ospedali Riuniti" University Hospital and Marche Polythecnic University, Ancona, (Italy) Antonio Avolio, MD antonio.avolio@gmail.com Alberto Florio, MD a.florio1960@gmail.com Silvia Giovannozzi, MD silvia.giovannozzi@alice.it Domenico De Carolis, MD dodecalis@gmail.com Department of Urology, Mazzoni Hospital, Ascoli Piceno (Italy)

DOI: 10.4081/aiua.2020.3.217

CASE REPORT

Clear Cell carcinoma of the urinary bladder, A case report: Surgical and oncological management Emanuele Corongiu 1, Pietro Grande 2, Emanuele Liberati 1, Roberto Iacovelli 3, Mostafà Amini 4, Paola Mascioli 4, Giorgio Pagliarella 1, Stefano Squillacciotti 1, Angelo Di Santo 1, Flavio Forte 1, Valerio Olivieri 5 1 Division

of Urology, Hospital “Madre Giuseppina Vannini”, Rome, Italy; Université, Assistance Publique-Hôpitaux de Paris, Pitié Salpétière, Urology department, Paris, France; 3 Oncologia Medica, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy; 4 Division of Histopathology, BIOS Spa, Roma, Italy; 5 Division of Urology, Ivrea Hospital (ASL TO4), Ivrea (Turin), Italy.

2 Sorbonne

Introduction: Bladder cancer is a condition characterized by a broad spectrum of histological variants and clinical courses. The morphological description of histological variants is becoming increasingly important. The 75% of cases of these cancers are classified as pure urothelial carcinoma, while the remaining 25% is represented by other histological variants. The clear cell carcinoma is part of urothelial group and is a very rare entity.

Oncological outcomes of this variant are still uncertain, but seems to be worst than for patiens with pure urothelial carcinoma. Moreover it seems to metastasize more easily to the lymph nodes.

Case report: We present a case of a Caucasian 73 year old woman who, after an episode of gross hematuria, underwent an ultrasound of the urinary system, a cystoscopy and a total body computed tomography (CT) which confirmed the presence of a bladder neoformation. A transurethral resection of the bladder (TURB) was performed: the result of the histological examination was "poorly differentiated clear cell carcinoma". Given the rarity of histological characterization, we required a PET CT scan for more accurate staging, at which a suspected right pelvic lymph node was detected. We proposed a radical cystectomy with hysteroannessiectomy and extended lymphadenectomy. During the pre-hospitalization process, the patient developed anuria, with acute renal failure and bilateral hydronephrosis, which required the placement of bilateral nephrostomies; we performed the planned surgical procedure and the histological exam confirmed: high grade urothelial carcinoma with a high percentage (more than 70%) of clear cell carcinoma, with a strong local aggression and lymphnode metastates. We referred the patient to the oncologist who suggested a treatment plan within an immunotherapy based clinical trial and cisplatin.

Conclusions: The morphological description of histological variants in bladder cancer is gaining increasing importance, especially for infiltrating and aggressive forms. The clear cell carcinoma is a very rare entity part of the urothelial group; they would seem more aggressive forms with an early lymph node involvement. This evidence is confirmed by the clinical case described, in which we have seen a large local aggression with an involvement of the lymph nodes of the right side of the pelvis of the pre-sacral ones. In these cases, the multimodal approach is crucial.

Summary

KEY WORDS: Bladder cancer; Oncology; Uro-oncology; Rare tumors; Cistectomy.

Submitted 2 March 2020; Accepted 15 March 2020

INTRODUCTION Bladder cancer is a condition characterized by a broad spectrum of histological variants and clinical courses.

Indicatively 75% of cases of these cancers are classified as pure urothelial carcinoma, while the remaining 25% is represented by other histological variants (1).

The morphological description of histological variants is becoming increasingly important as underlined by the WHO 2016 classification (2), which introduced a particular category: “invasive urothelial carcinoma with divergent differentiation” for tumours showing a component of urothelial carcinoma combined with other morphologies (2-3). The real clinical importance of the histological variant is still under discussion, in fact the data are still insufficient to demonstrate a different clinical course compared to the conventional urothelial bladder carcinoma of the same stage and grade (2). Currently we can distinguish the histological viariants in two large subgroups: urothelial and non-urothelial. The clear cell carcinoma is part of urothelial group and is a very rare entity, characterized by a glycogen-rich cytoplasmic pattern with tubulocystic, papillary, or diffuse growth patterns.

This histological pattern must be distinguished from clear cell adenocarcinoma of the urethra or bladder, or metastatic carcinoma originating from the kidney, prostate, or female genital tract; oncological outcomes of this variant are still uncertain, both for the rarity and for the short follow-up period, but seems to be worst than for patients with pure urothelial carcinoma (3-5).

Moreover it is also one of the variants (together with the micropapillary histotype) that seems to metastasize more easily to the lymph nodes, suggesting theses variants are associated with lymphatic spread (6).

CASE

REPORT

We present a case of a Caucasian 73 year old woman with a history of breast cancer, treated with left mastectomy and subsequent chemotherapy, diabetes mellitus and high blood pressure on medical therapy. She reported an episode of macrohematuria for which she underwent ultrasound of the urinary tract, which showed a thickening of the posterior wall of the bladder. It was therefore decided to perform a cystoscopy, which showed a large

No conflict of interest declared.

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E. Corongiu, P. Grande, E. Liberati, R. Iacovelli, M. Amini, P. Mascioli, G. Pagliarella, S. Squillacciotti, A. Di Santo, F. Forte, V. Olivieri

Figure 1.

Image of pre-operative cistoscopy.

solid-looking outward bending of the bladder that involved the posterior wall towards the trigone (Figure 1).

A transurethral resection of the bladder (TURB) was scheduled, and a pre-operatory total body computed tomography (CT) scan with contrast was required.

The CT scan did not show hydroureteronephrosis and any enlargement of the regional lymphnodes, but only a thickening of the posterior wall of the bladder without a clear cleavage plan between bladder and uterus.

The TURB was performed: the ureteral openings did not seem included in the neoformation, but the cutting surface seemed solid and it was not possible to identify healthy muscle tissue. The result of the histological examination was "poorly differentiated clear cell carcinoma". Given the rarity of histological characterization, we required a PET CT scan for more accurate staging, at which a suspected right pelvic lymph node was detected but no distant lesions were found. After discussing the case within the uro-oncology team we proposed a radical cystectomy with hysteronannessiectomy and extended lymphadenectomy with ileal conduit urinary diversion (Bricker conduit). During the pre-hospitalization process, the patient developed anuria, with acute renal failure and bilateral hydronephrosis, which required the placement of bilateral nephrostomies; this clinical condition was due to the involvement of the bladder trine by the neoplasm.We performed the planned surgical procedure, finding significant adhesions during lymphadenectomy from the right side. The post-operative course was regular and the patient was discharged on the fifth day. Post-operative blood tests showed a progressive recovery of renal function, up to obtaining values of creatinine and GFR in the normal range.

The result of the histological exam confirmed: high grade urothelial carcinoma with a high percentage (more than 70%) of clear cell carcinoma (Figure 2), infiltrating the full thickness of bladder wall, uterus, both ovaries and vagina; metastases were present in the obturator and iliac lymph nodes of the right side and in the presacral ones; both ureteral stumps were infiltrated, with negative proximal margin, pTNM pT4a N2; immunohistochemistry revealed immunopositivity of pan cytokeratin (CK), GATA3, P40, CK. On the basis of this finding, we referred the patient to the oncologist who suggested a treatment plan within an immunoFigure 2.

The microscopic finding showing clear cell carcinoma of the bladder (original magnification x 400).

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therapy based clinical trial and cisplatin; unfortunately the patient rapidly worsened developing loss of appetite, constipation and pain in her right side. She underwent a total body CT scan that showed disease recurrence at the peritoneum, pelvis and ileal conduit which determined intestinal sub-occlusion and right hydroureteronephrosis.

The clinical picture further worsened and the patient died almost four months after surgery.

CONCLUSIONS The morphological description of histological variants in bladder cancer is gaining increasing importance, especially for infiltrating and aggressive forms. The role of this more accurate histological characterization in clinical practice is still under discussion. The clear cell carcinoma is a very rare entity part of the urothelial group, the oncological outcomes of this histotype are still uncertain, but they would seem more aggressive forms with an early lymph node involvement; this evidence is confirmed by the clinical case described, in which we have seen a large local aggression (with a rapid involvement of the ureteral hosts, the uterine cervix and the annexes) with an involvement of the lymph nodes of the right side of the pelvis of the pre-sacral ones. We have also witnessed a rapid recurrence of disease which quickly led to patient’s death. In these cases, the multimodal approach could be fundamental to improve the prognosis.

REFERENCES 1. Cai T, et al. Concordance and clinical significance of uncommon variants of bladder urothelial carcinoma in transurethral resection and radical cystectomy specimens. Urology. 2014; 84:1141-1146.

2. Ulbright TM, Reuter VE. The 2016 WHO classification of tumours of the urinary system and male genital organs-part B: prostate and bladder tumours. Eur Urol. 2016; 70:106-119.

3. Moschini M, D'Andrea D, Korn S, et al. Characteristics and clinical significance of histological variants of bladder cancer. Nat Rev Urol. 2017; 14:651-668.

4. Sefik E, Celik S, Basmaci I, et al. Effect of variant histology presence and squamous differentiation on oncological results and patient's survival after radical cystectomy. Arch Ital Urol Androl.

2018; 90:172-175.

5. Rice KR, et al. Lymph node metastases in patients with urothelial carcinoma variants: influence of the specific variant on nodal histology. Urol. Oncol. 2015; 33:20.e23-20.e29.

Correspondence Emanuele Corongiu, MD (Corresponding Author) - emanuele.corongiu@libero.it Emanuele Liberati, MD - emanuele.liberati@libero.it Flavio Forte, MD - flavioforte@hotmail.com Giorgio Pagliarella, MD - giorgiopagliarella@hotmail.com Stefano Squillacciotti, MD - stefanosquillacciotti@gmail.com Angelo Di Santo, MD - adisanto1978@gmail.com Division of Urology, Hospital “Madre Giuseppina Vannini”, Rome (Italy) Pietro Grande, MD - grandepietro@gmail.com Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Pitié Salpétière, Urology department, Paris (France) Roberto Iacovelli, MD - roberto.iacovelli@policlinicogemelli.it Oncologia Medica, Fondazione Policlinico Universitario Gemelli IRCCS, Rome (Italy) Mostafà Amini, MD - mostamini@gmail.com Paola Mascioli, MD - paola.mascioli@tiscali.it Division of Histopathology, BIOS Spa, Roma (Italy) Valerio Olivieri, MD - valerio.oliveri@uniroma1.it Division of Urology, Ivrea Hospital (ASL TO4), Ivrea (Turin) (Italy)

DOI: 10.4081/aiua.2020.3.219

ORIGINAL PAPER

A global snapshot of endourology residency training Asad Ullah Aslam 1, 2, Joseph Philipraj 1,3, Sayed Jaffrey 1,4, Noor Buchholz 1 1 U-merge

Ltd. (Urology for emerging countries), London, UK*; of Urology, Letterkenny University Hospital, Saolta Healthcare Group, Ireland; 3 Department of Urology, Mahatma Ghandi Medical College & Research Institute, Sri Balaji Vidyapeeth, Pondicherry, India; 4 Dept. of Urology, University College Hospital, Galway Clinic and Bons Secours Hospital, Galway, Ireland.

2 Dept.

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

Summary

Background: Urology has become more complex over the last decades with surgical sophisticated technologies such as endoscopy, laparoscopy and robotic surgery. As these minimally invasive methods gain popularity throughout the world, this has led in some countries to a serious training gap as compared to other countries, and between generations of surgeons within national training systems. There is a huge heterogeneity in urological training between countries, whether developed or developing. This paper attempts to shed some light onto global urological training, comparing a significant number of various national systems, and to outline global tendencies in urological training.

It will enable interested readers to see where their own system stands in international comparison, and hopefully enable them to identify training needs to achieve global quality standards.

Materials & methods: This is a questionnaire-based assessment which was sent to 240 members of U-merge from 62 countries. In addition, there is ample literature on the requirements of structured training programs and assessments, and we have tried to briefly outline the key points in this paper.

Results: We received responses from 32 countries Urology residency training is hugely heterogenous between countries.

Only 44% of nations use a structured training program with assessments. Others use the Halstedian apprenticeship approach. Notably, some developing countries do use modern teaching and assessment methods, whereas some developed countries still use the outmoded apprenticeship model. For the interested reader, results have been tabled in detail, and training systems described country by country.

Conclusions: Our results have shown a huge heterogeneity in quality urology training between countries and within continents. In systems without national structure of training, it can be assumed that such differences exist even between hospitals/ training institutions. There is no doubt in times of globalization with resident and doctor migration and exchanges that training needs structure and standardization. The still huge gap in developing countries to catch up and be able to afford latest surgical and learning technologies need to be addressed with the help of responsible outreach programs.

KEY WORDS: Surgical training; Urology; Endourology; Performance assessment; DOPS; Dry lab; Wet lab; Simulator training; Global education.

Submitted 2 March 2020; Accepted 15 March 2020

INTRODUCTION

An estimated 5 billion people lack access to any surgical care. This despite surgical diseases accounting for 11-

30% of the global health care burden (1). This implies an urgent need to quality-train more surgeons in all specialties globally.

Historically, surgical training, and urological training as a surgical sub-specialty as well, followed the Halstedian tradition of defined apprenticeship. This includes basically observation, modelling and graded participation in surgical activities. This model of training is characterized through long working hours, poorly defined training goals, and a lack of focus on research and evidence-based best practice. In this traditional system, assessment and evaluation of the traineesâ&#x20AC;&#x2122; performance is outmoded, significantly subjective, with standards ill-defined and not uniformly applied (2). The optimal method to monitor and assess trainees, for example in endoscopy, has not been formally determined (3). Urology has become more complex over the last decades with increasing medical and surgical sophisticated technologies such as endoscopy, laparoscopy and robotic surgery. As these minimally invasive methods gain popularity throughout the world, this has led in some countries to a serious training gap as compared to other countries (4), and between generations of surgeons within national training systems. There is a huge heterogeneity in urological training between countries, whether developed or developing (5, 6). Most countries have a urological training duration of around 5 years, but this may include rotations in nephrology, pediatric surgery, gynecology, general surgery, anesthesia, pathology and others (4). Numerous recent studies have shown that trainees remain dissatisfied with their training in urology in many countries (7-12). The educational landscape in urology training is changing and adapting to modern learning methods. Globalization of demands and services also means there clearly is a need for a standardized and structured urological training for global use.

This must also include competency-based assessment, certification and re-certification (3). Naturally, these changes are adopted by various countries in various ways and speeds. This has led at the current time to a wide variation of training quality between countries and training systems.

U-merge is a urological educational platform. Its members are active in international teaching & training in many countries globally. Therefore, the authors have seen firsthand huge differences in structures and quality of urological training programs. Programs may vary from the old-

No conflict of interest declared.

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fashioned apprenticeship model with a see one, do one, teach one approach, to highly structured, sometimes nationalized training programs using modern technologies such as virtual, simulated and telemedical training.

This paper attempts to shed some light onto global urological training, comparing a significant number of various national systems, and to outline global tendencies in urological training. We focus on endourology and pediatric endourology training as representative for recent technological changes in urology.

This paper will enable interested readers to see where their own system stands in international comparison, and hopefully enable them to identify training needs to achieve global quality standards.

MATERIALS

AND METHODS

This paper is based on a questionnaire which was sent in 2015 to 240 members of U-merge from 62 countries (Appendix 1). U-merge members are consultant level academic urologists in their respective countries.

The questionnaire addressed • Structure and duration of the urology training program • Training in basic urology and endourology (if any) • Sub-specialty training in pediatric urology • Assessment structure • Availability of simulated training options.

No funding has been obtained to conduct this study.

RESULTS Cumulative results Of 240 questionnaires emailed to U-merge members in 60 countries, we received 37 (15.4%) responses from 32 countries. Twenty-one (56%) of these have no structured training program. Urology training follows an apprenticeship model. The other 16 have a structured training program. Endourology training can be integrated into the mainstream residency training or have its own defined training period. Duration of training within structured programs varies from 0.5 to 6 years. In 7 (18%) countries, urology residency training can be completed without gaining competency in endourology. 8 (21%) do not require URS, 17 (46%) do not require fURS/RIRS, and 18 (48%) do not require PCNL competency. 3 (8%) countries require endourology training in children (Table 1).

As per specific endourological procedures, 22 (59%) of countries require their trainees to be independently competent in URS, 5 (13%) to be competent with assistance, and 2 (5%) require mere exposure during training. In 10 (27%) URS training has not been specified.

For fURS/RIRS, the numbers are 9 (24%), 10 (27%), 6 (16%), and 13 (35%), respectively. For PCNL the numbers are 6 (16%), 13 (35%), 9 (24%), and 12 (32%), respectively. For endourological procedures in children, independent competency is usually not required to complete urology residency. 4 (11%) of countries require

Table 1.

Structured urology training programs and endourology components by country.

Country Algeria Austria Australia Bangladesh Brazil Bulgaria Canada China Colombia Egypt El Salvador France Germany Greece India Iran Iraq Ireland 1Italy Kenya Kurdistan Moldova Morocco Nepal Oman Pakistan Panama Romania Serbia South Africa Spain Sweden Syria Tunisia UAE UK Ukraine

220

Structured endourology training No No Yes No Yes Yes No No No No No No Yes No Yes Yes Yes Yes no Yes Yes No Yes Yes No Yes No No No No No Yes No Yes No Yes No

Duration endourology training program (years) Not applicable Not applicable 6 Not applicable 0,5 1 Not applicable Not applicable Not applicable Not applicable Not applicable Not applicable 5 Not applicable 5 2 3 6 Not applicable 4 1 Not applicable 5 3 Not applicable 6 Not applicable Not applicable Not applicable Not applicable Not applicable 5 Not applicable 2 Not applicable 5 Not applicable

Completion of training without competence in endouro procedures Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes No Yes Yes No Yes Yes No Yes Yes Yes Yes Yes No Yes Yes Yes No Yes No Yes

Archivio Italiano di Urologia e Andrologia 2020; 92, 3

Completion of training without competence in URS No No No Yes No No No No No No Yes No No No No No Yes No Yes No No No Yes No Yes No No No No No Yes No No No Yes No No

Completion of training without competence in fURS/RIRS No No No Yes Yes No No No Yes Yes Yes No Yes Yes Yes Yes Yes No Yes No No Yes Yes No Yes No No No No No Yes No Yes No Yes No No

Completion of training without competence in PCNL No No No Yes No No Yes Yes Yes No Yes No Yes Yes Yes Yes Yes No Yes No No Yes Yes No Yes No No No Yes No Yes No Yes No Yes No No

Completion of training without competence in EndoUro in Children Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes No Yes Yes Yes No Yes Yes Yes

Global urology training

Table 2.

Core competencies required in endourology by country.

URS Perform independently

Country

Algeria Austria Australia Bangladesh Brazil Bulgaria Canada China Colombia Egypt El Salvador France Germany Greece India Iran Iraq Ireland Italy Kenya Kurdistan Moldova Morocco Nepal Oman Pakistan Panama Romania Serbia South Africa Spain Sweden Syria Tunisia UAE UK Ukraine

URS perform with assistance

URS exposure

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

Yes

URS Lwarn URS not fURS/RIRS fURS/RIRS fURS/RIRS fURS/RIRS fURS/RIRS PCNL PCNL perform at specialist specified Perform perform with exposure Learn at not specified Perform with fellowship level independently assistance specialist independently assistance fellowship level Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

Yes

Yes Yes

Yes

Yes

Yes

Yes Yes

Yes Yes Yes

Yes Yes Yes

Yes Yes Yes Yes Yes

Yes Yes Yes Yes

Yes

Yes

Yes

Yes

Yes Yes yes

Yes

Yes Yes Yes

Yes Yes

Yes Yes

Results by country As mentioned before, twenty-one (56%) countries have no

Yes Yes Yes

Yes Yes Yes

Yes

competency with assistance by trainers, and 3 (8%) require some exposure during training. Some countries offer post-residency training on a fellowship level: 3 (8%) for fURS/RIRS, 6 (16%) for PCNL, and 6 (16%) for pediatric procedures, respectively (Table 2). Twenty-one (56%) countries have defined a minimum procedure number for endourology training: 20 (54%) for URS, 13 (35%) for fURS/RIRS, 18 (48%) for PCNL, and 7 (19%) for pediatric endourological procedures. Indicative numbers vary widely: 10-450 for URS, 10-100 for fURS/RIRS, 6-250 for PCNL, and 2-300 for pediatric procedures, respectively (Table 3). Twenty-six (70%) countries have no structured performance assessment during training in place. 19 (51%) rely on a general assessment, 12 (32%) perform regular audit, 9 (24%) use examinations as a tool of assessment, and 14 (38%) apply formal Direct Observation of Procedural Skills (DOPS) (Table 4).

Regarding simulated surgical skills training, 7 (19%) have a “dry lab” facility for URS at their disposal, another 7 (19%) have a “wet lab” training option for URS. 6 (16%) have these as a compulsory training part in their programs. Each 6 (16%) countries offer either for fURS/ RIRS training, and 6 (16%) offer “dry lab” and 5 (13%) “wet lab” training for PCNL. Each 3 (8%) use these as compulsory part of training (Table 5).

Yes Yes Yes

Yes

Yes Yes

Yes Yes

Yes

Yes

Yes Yes

Endourol in children not specified

Yes Yes

Yes

Yes

Endourol in children Learn at specialist fellowship level Yes Yes

Yes Yes Yes Yes

Endourol in children exposure

Yes Yes

Yes

Yes Yes

Yes

Endourol in children perform with assistance

Yes

Yes Yes Yes

Endourol in children Perform independently

Yes

Yes Yes Yes Yes

PCNL not specified

Yes

Yes

Yes

Yes

PCNL Learn at specialist fellowship level

Yes

Yes

Yes Yes Yes

PCNL exposure

Yes

Yes Yes Yes Yes

structured training program (Figure 1). Urology training follows an apprenticeship model. Another 16 have a structured training program of varying duration and performance assessments (Figure 2). In the following we present a short summary for the urological training in all responder countries in alphabetical order.

The following 21 countries have NO structured training program: 1. Algeria The completion of urological training includes competence in URS (semi-rigid ureteroscopy), fURS/RIRS (flexible ureteroscopy/retrograde intrarenal surgery) and PCNL (percutaneous nephrolithotomy), with exception of endourological procedures in children. Trainees are expected to perform a minimum of 10 cases each of URS and fURS/RIRS. In addition, fifteen PCNL with trainer assistance is a requirement. There is compulsory wet lab training on animal models for URS, fURS/RIRS and PCNL. No structured method of performance assessment has been specified.

2. Austria For endourological procedures (URS, fURS/RIRS, PCNL) a combined minimum case load of 150 procedures is required. There is no specified level of competence for these endourologal procedures in children. There is no Archivio Italiano di Urologia e Andrologia 2020; 92, 3

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Table 3.

Minimum endourology procedure numbers required by country.

Country Algeria Austria Australia Bangladesh Brazil Bulgaria Canada China Colombia Egypt El Salvador France Germany Greece India Iran Iraq Ireland Italy Kenya Kurdistan Moldova Morocco Nepal Oman Pakistan Panama Romania Serbia South Africa Spain Sweden Syria Tunisia UAE UK Ukraine

Min No. of case load Yes Yes Yes No Yes Yes No No No Yes No No No No Yes Yes Yes Yes no Yes Yes No No Yes

URS Min No. of Case Load Yes Yes Yes No Yes Yes No No No Yes No Yes Yes No Yes Yes Yes Yes No Yes Yes No No Yes

URS indicative number 10 Not mentioned 100 0 12 50 Not mentioned Not mentioned

fURS/RIRS indicative numbers 10 Not mentioned 75 0 No 10 Not mentioned Not mentioned

60 No 50 50 No 20 70 450 50

fURS/RIRS min no. of caseload Yes Yes Yes No No Yes No No No Yes No Yes No No Yes No Yes Yes

PCNL indicative numbers 15 Not mentioned 15 0 6 10 Not mentioned Not mentioned

20 No 50 No No 20 No 30 50

PCNL min no. of caseload Yes Yes Yes No Yes Yes No No No Yes No Yes No No Yes Yes Yes Yes

Endourology in children indicative numbers 0 Not mentioned 0 0 No No Not mentioned Not mentioned

30 No 20 No No 5 50 60 10

Endourology in chilidren min no. of caseload No Yes No No No No No No No Yes No No No No Yes Yes Yes No

50 200

Yes Yes

50 100

No 200

No Yes

Yes No Yes Yes No No No No Yes No Yes No

Yes

400

Yes Yes No No No No Yes No Yes No

All 4 procedures Not combined case numbers specified Not mentioned 150 Not mentioned No

10 No No No No 2 10 300 No

Not mentioned Not mentioned Not mentioned Not mentioned Not mentioned Not mentioned Not mentioned Not mentioned Not mentioned Not mentioned Not mentioned Not mentioned Not mentioned

Yes Yes

30 250

No Yes

No 20

Not mentioned Not mentioned

No 25

No Yes

No 100

No No

No Not mentioned

Not mentioned Not mentioned

No

No

Yes

250

No

No

Not mentioned

20 50 No No No No Not mentioned

No No No No No No No

No No No No No No No

Yes No No No No No Yes

20 No No No No No 20

No No No No No No No

No No No No No No No

Not mentioned Not mentioned Not mentioned Not mentioned Not mentioned Not mentioned Not mentioned

50 No

Yes No

50 No

Yes No

10 No

Yes No

10 No

Not mentioned Not mentioned

Yes Yes Yes Yes

Yes

Table 4.

Performance assessments by country.

Country Algeria Austria Australia Bangladesh Brazil Bulgaria Canada China Colombia Egypt El Salvador France Germany Greece India Iran Iraq Ireland Italy Kenya Kurdistan Moldova Morocco Nepal Oman Pakistan Panama Romania Serbia South Africa Spain Sweden Syria Tunisia UAE UK Ukraine

222

General assessment of performance No Yes Yes No No Not mentioned Not mentioned No Not mentioned Yes No Yes No Yes Yes Yes Yes Yes

Audit No Yes Yes No No Not mentioned Not mentioned Yes Not mentioned No No Yes No No No Yes Yes Yes

Formal examination/viva No Yes Yes No No Not mentioned Not mentioned No Not mentioned Yes No Yes No No No No Yes No

Direct Obs of Procedure Skills (DOPS) No No Yes No No Not mentioned Not mentioned Yes Not mentioned Yes No Yes No Yes No Yes Yes Yes

Several of above assessments No Yes Yes No No Yes Yes Yes Yes Yes No Yes No Yes No Yes Yes Yes

No specific assessment Yes No No Yes Yes No No Yes Yes Yes No Yes No Yes Yes Yes Yes Yes

Yes Yes No Yes Yes

Yes Yes No No Yes

Yes No No No Yes

Yes Yes No No No

Yes Yes No No Yes

Yes No No Yes Yes No No Not mentioned Yes

Yes No No No No No No Not mentioned Yes

Yes No No No No No No Not mentioned No

No No No No Yes No Yes Not mentioned Yes

Yes No No No Yes No No Yes Yes

Yes Yes No Yes Yes No Yes No No Yes Yes No Yes Yes Yes

Yes Yes

No No

Yes No

Yes No

Yes No

Yes Yes

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Global urology training

Table 5.

Availability and integration of dry & wet lab model training into the training program by country.

Country Algeria Austria Australia Bangladesh Brazil Bulgaria Canada China Colombia Egypt El Salvador France Germany Greece India Iran Iraq Ireland Italy Kenya Kurdistan Moldova Morocco Nepal Oman Pakistan Panama Romania Serbia South Africa Spain Sweden Syria Tunisia UAE UK Ukraine

URS DryLab No No No No NS Yes No Yes No No No Yes No No Yes No No No No

URS WetLab Yes No No No NS No No No No No No Yes Yes No No No Yes No No

No

Yes

No

No

URS Compulsory Yes No No No No Yes No No No No No No Yes No No No Yes No No No No Yes No No

Yes No No Yes No Yes

Yes No No Yes No No

No No No No No No No No Yes

No No

No No

No No

FURS DryLab No No No No NS Yes No Yes No No No Yes No No Yes No No No No

FURS WetLab Yes No No No NS No No Yes No No No Yes No No No No Yes No No

No

No

No

No

FURS Compulsory Yes No No No No Yes No No No No No No No No No No Yes No No No No No No No

Yes No No Yes No No No No

compulsory dry or wet lab training. The assessment is via general assessment of performance, audit and formal examination with viva by the trainers.

3. Bangladesh Trainees can achieve completion of training without proven competence in fURS/RIRS, PCNL and endourological surgery in children. They are required to perform some URS and PCNL with trainer assistance.

Endourology in children is later taught at fellowship level. Indicative numbers of procedure and performance assessment methods are not specified.

4. Canada URS and fURS/RIRS are a requirement for completion of training with candidates expected to perform these procedures independently. Endourology in children and PCNL is taught at fellowship level post-residency. Model training is not compulsory. Various method of assessment of performance are in place.

5. China For completion of training, URS with trainer assistance is required. However, trainees are expected to have had exposure to fURS and PCNL. There is no specified endourology training in children. There is dry lab training for URS and wet lab training for fURS and PCNL, albeit not compulsory. Audit and DOPS are used for assessment.

6. Colombia URS is mandatory and trainees are expected to perform it

PCNL DryLab No No No No NS Yes No Yes No No No Yes No No Yes No No No No

FURS WetLab Yes No No No NS No No Yes No No No Yes No No No No Yes No No

No

No

No

No

Yes No No Yes No Yes

No No No No No No No No No

Yes No No No No Yes

Yes No No No No No

No No

No No

No No

No No

FURS Compulsory Yes No No No No No No No No No No No No No No No Yes No No No No No No No no info No No No No No No No No Yes no info No No

independently. fURS and PCNL with trainer assistance are required. Endourology in children is not regulated. There is no model training and no specific assessment structure in place.

7. Egypt Trainees can complete their training without gaining independent level competence in fURS/RIRS and endourological procedures in children. Twenty and 10 assisted or observed cases in fURS and paediatric endourology, respectively, are indicative, albeit not mandatory. URS and PCNL procedures are compulsory for the trainee to perform independently, with indicative numbers of 60 and 30, respectively. There is no compulsory model training.

Assessment of performance is via formal examination with viva and DOPS. 8. El Salvador There is no specified mandatory requirement for any endourological procedures. Indicative numbers, provision of model training, or assessment methods are not specified.

9. France There is no structured endourology training program.

However, it is mandatory to achieve competence in URS, fURS/RIRS and PCNL. Endourological procedures in children is not a mandatory requirement. Fifty cases each for URS and fURS/RIRS, and 20 cases of PCNL are indicative, with numbers unspecified for paediatric endourology.

There are dry and wet labs for each of these procedures.

However, model training is not compulsory.

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Figure 1.

Countries with no structured (endourology) training and indicative numbers of procedures (empty bars indicate no minimum number specified).

Figure 2. ountries with structured (endourology) training programs: duration of training.

224

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Global urology training

Assessment of performance is via several methods including audit, general assessment, formal examination and viva with DOPS. 10. Greece URS is a mandatory requirement with no specified indicative numbers. Completion of training is possible without further competence in endourology.

There is no provision of model training. Assessment of performance is via general assessment and DOPS. 11. Italy There are no competence requirements for endourology.

Indicative numbers are unspecified. There is no provision of model training. Assessment methods are not specified.

12. Moldova Trainees are expected to gain independent level competence in URS for completion of training with unspecified indicative numbers. There is compulsory URS wet lab on animal models. The performance assessment method is unspecified.

13. Oman Endourology is not a mandatory requirement for completion of training. There are no specified indicative numbers, model training or assessment methods.

14. Panama URS, fURS/RIRS and PCNL are mandatory requirements for completion of training, however indicative numbers are not specified. Dry and wet labs are not available, and there is no specified method of assessment.

15. Romania Although there is lack of structured endourology training, for completion of training it is mandatory to achieve competence in URS, fURS/RIRS and PCNL. URS and PCNL are expected to be performed independently, fURS with trainer assistance. Twenty cases for URS are indicative. Dry and wet labs are not compulsory, and assessment of competency is not specified.

16. Serbia URS and fURS/RIRS are mandatory requirements to complete training with 50 cases for URS as indicative number. Dry and wet labs for each of these procedures are accessible by trainees, but not compulsory.

Competency is assessed by general assessment.

17. South Africa It is mandatory to achieve competence in endourology for completion of training. Trainees are required to gain competence in all procedures (URS, fURS/RIRS, PCNL and paediatric endourology). Level of competence is not specified with no indicative numbers. There are no dry or wet labs. Assessment of performance is via general assessment and DOPS. 18. Spain Trainees are not required to gain competence in endourology to complete training. There are no specified indicative numbers, lab provisions or assessment methods.

19. Syria Trainees are required to gain independent level competence in URS with exposure to PCNL and assistance in paediatric endourology. fURS training is not specified.

There are no minimum case numbers and model training. Assessment of performance is not specified.

20. United Arab Emirates There is no specific training program.

21. Ukraine URS, fURS/RIRS and PCNL are mandatory for completion of training, however core competency, indicative numbers and lab provision are not specified. There is a general assessment of competency.

The following 16 countries do have a structured training program (Figure 3): 1. Australia The training program runs for 6 years. It is mandatory to achieve competence in endourology for completion of training such as independent level competence in URS and fURS/RIRS. Performance of PCNL with assistance is a requirement. Paediatric endourology is learned at fellowship level. Indicative numbers include 100 URS, 75 fURS/RIRS, and 15 PCNL with no specified numbers for paediatric endourology. Dry and wet labs are not provisioned. Assessment of performance is via several methods including audit, general assessment, formal examination and viva with DOPS. 2. Brazil A 6 month endourology program is in existence with mandatory expertise in URS. PCNL with assistance and exposure to fURS/RIRS is deemed satisfactory. Twelve URS and 6 PCNL are indicative for completion of training. There are no specified numbers for paediatric endourology. Lab training is not provisioned and there is no specified method of assessment of competence.

3. Bulgaria An endourology program of 1-year duration exists with trainees expected to perform URS independently and PCNL with assistance. Exposure to fURS/RIRS is mandatory. Paediatric endourology is learned at fellowship level. Indicative numbers for each of these procedures are 50 URS, 10 each fURS/RIRS and PCNL. A dry lab is compulsory for each category, with the exception of endourology in children. Assessment of performance is via several methods including audit, general assessment, formal examination and viva with DOPS. 4. Germany A 5-year urology training program is in place. Endourology training comprises of mandatory URS. fURS/RIRS, PCNL and endourology in children is not specified. Fifty URS procedures are indicative. Wet lab for URS is compulsory.

Assessment of performance is via several methods.

5. India Expertise in URS is mandatory as part of a 5-year uroArchivio Italiano di Urologia e Andrologia 2020; 92, 3

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Figure 3.

Countries with structured endourology training and indicative numbers of procedures required (empty bars indicate no number specified).

logical training program. fURS/RIRS and PCNL are accepted to be performed with assistance. Paediatric endourology is not specified. Indicative numbers include 20 for URS, 20 for fURS/RIRS, 5 for PCNL and 2 in paediatric endourology.

There is a provision of dry lab for each of these procedures, albeit not compulsory. Assessment of performance is via general assessment.

6. Iran An endourology program runs for 2 years with independent expertise in URS being mandatory. PCNL and paediatric endourology exposure is necessary, whereas fURS/RIRS is not specified. Seventy URS, 50 PCNL and 10 paediatric endourology cases are indicative. There is no provision of dry and wet labs. Assessment of performance is via several methods including audit, general assessment and DOPS.

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7. Iraq Endourology training for 3 years is mandatory, however trainees can finish training without gaining independent level competence in either of the endourology procedures with exception being URS. A minimum of 450 cases of URS, 30 of fURS/RIRS, 60 of PCNL and 300 of paediatric endourology are indicative. There is provision of dry and wet labs for each of these procedures which are compulsory. Assessment of performance is via several methods including audit, general assessment, formal examination and viva with DOPS. 8. Ireland A 6-year training program exists, with a structured endourology training. URS, fURS/RIRS and PCNL are mandatory, with paediatric endourology learned at fellowship level. Trainees are required to gain independent level competence in URS and fURS/RIRS, with PCNL

Global urology training

performed with trainer assistance. Indicative numbers 50 URS, 50 fURS, and 10 PCNL. There is no provision of lab training. Assessment of performance is via several methods including audit, general assessment, formal examination and viva with DOPS. 9. Kenya URS, fURS/RIRS and PCNL are mandatory to achieve competence in endourology for completion of a 4-year training program. Paediatric endourology is performed at fellowship level hence not a requirement for completion of training. Trainees are expected to perform URS and fURS/RIRS independently, and PCNL with assistance. Fifty cases each for URS and fURS/RIRS, and 30 cases of PCNL are indicative. Lab is not provisioned.

Assessment of performance is via several methods including audit, general assessment, formal examination and viva with DOPS. 10. Kurdistan A one-year structured endourology training program makes it mandatory for trainees to be independently proficient to perform URS and fURS/RIRS, and PCNL to be performed with assistance. There is no specified paediatric endourology training. Two hundred cases for URS, 100 for fURS/RIRS, 250 cases of PCNL, and 20 paediatric endourology cases are indicative. There is no provision of lab training. Several methods such as general assessment, audit and DOPS are used for assessment.

11. Morocco The training program comprises endourology training and runs for 5 years. Trainees are required to gain exposure to URS, fURS/RIRS and PCNL in order to complete their training. Endourological procedures in children are not a mandatory requirement. There are no specified indicative numbers, and no lab training. General assessment of performance exists to assess competency.

12. Nepal It is mandatory to achieve competence in endourology for completion of training of a 3-year training. Trainees are required to gain independent level competence in URS, with fURS/RIRS and PCNL to be performed with trainer assistance. Endourological procedures in children are not a mandatory requirement. Two hundred cases for URS, 25 for fURS/RIRS, and 100 cases of PCNL are indicative, with no particularly specified numbers for paediatric endourology. There is no provision of lab training. Audit, general assessment, formal examination and viva are in place to assess competency of training.

13. Pakistan A 5-year program exists with mandatory endourology training. Trainees are required to gain independent level competence in URS, with fURS/RIRS and PCNL performed with trainer assistance. Endourological procedures in children are not a mandatory requirement. Four hundred cases for URS and 250 cases of PCNL are indicative, with no particularly specified numbers for fURS/RIRS and paediatric endourology. There is no provision of dry and wet labs for each of these procedures. Several methods

exist including audit, general assessment, formal examination and viva to assess competency.

14. Sweden It is a mandatory requirement to achieve competence in endourology for completion of a 5-year training program. Trainees are required to gain independent level competence in URS, fURS/RIRS and PCNL in order to complete their training. Endourological procedures in children and indicative numbers are not specified. There are dry and wet labs for URS and fURS/RIRS, which are however not compulsory. Assessment is via DOPS. 15. Tunisia A 2-year training program exists comprising of endourology training in URS and fURS/RIRS. PCNL is learned at fellowship level. Paediatric endourology is not specified.

Trainees are required to gain independent level competence in URS. Twenty PCNL performed with assistance are indicative. A compulsory dry lab for URS and PCNL exists with optional fURS wet lab. Assessment is via audit, general assessment, formal examination and DOPS. 16. United Kingdom The UK training program runs for 5 years with mandatory competence in URS, fURS/RIRS and PCNL. Endourological procedures in children are not a mandatory requirement. Trainees are required to perform URS and fURS/RIRS independently, with PCNL exposure, and no specified paediatric endourology. Fifty cases each for URS and fURS/RIRS, and 10 cases of PCNL, as well as 10 cases of paediatric endourology as indicative.

There is no compulsory lab training. Competency assessment is via several methods including audit, general assessment, formal examination, viva and DOPS.

DISCUSSION

Our results have shown that there is a huge heterogeneity between training systems in various countries.

This has previously been confirmed by others (5,6).

Urological training, although embracing modern learning technologies in many countries, is far from ideal in most places. Inevitably, that will lead to huge differences in the training quality as well.

In Europe, there is a general lack of standardized training curricula. Great differences exist between training requirements in different countries. Trainees complain about a lack of confidence when performing major surgical procedures, non-compliance with European working hour regulations, a worrisome risk of burn-out and a negative impact on their work-life balance (6). Irish residents complain mainly about a lack of operative experience (7). In Spain, trainees find their training inadequate because of a lack of supervision, trainers completing their own training needs first, and a lack of operative experience (10). In Germany, 45% of trainees feel unprepared for their future roles. 85% complain about a lack in structured training, evaluations, and transparency.

Another complaint is economic constraints during training (8). Throughout South America, training, accreditation and re-certification are highly heterogenous and far Archivio Italiano di Urologia e Andrologia 2020; 92, 3

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from being standardized. In addition, academic activities are not properly valued (5).

Turkish residents report a lack of surgical exposure, and of encouragement for any academic activities (11). In Tunisia, most trainees in urology were dissatisfied with their training (9).

Training is further compromised by reduced working hours for training as well as an increasing threat of litigation (12).

All these studies confirm that there is a dire need to improve training quality in urology internationally. Not only may patient safety be compromised, but even the trainees themselves will face a future that they do not feel ready for, and that they are not adequately trained for.

So how could one achieve a meaningful improvement?

It appears that a well-structured training approach is key to ensure a surgeon’s professional growth in the safest way for the patients (4).

Structured training is in place in some countries who may serve as a model for others. Structuring the training may start with the right candidate selection. A surgeon needs compassion, communication skills, and should be perceptive and dedicated, besides manually skilled (2).

Structuring this crucial initial step of training, recruitment should be at least regional, if not national.

Candidates must undergo a validated assessment by objective, well-trained and experienced assessors. The process should be overseen by national authorities such as colleges or deaneries. This way each candidate will have the same chances and will undergo the same assessment, decreasing the chance of subjective bias. The UK system may serve here as an example (13).

The next step to structure would be the training program itself. Most modern training programs have already moved from a “see one, do one, teach one” approach to a structured learning – at least in minimally invasive treatment options –, and from e-learning to skills labs and modulated training settings (14). A structured training program will encompass a better definition of training goals and skills, specialization, structured evaluation, standardization of exams and include research (8).

Simulation-based training can indeed address many concerns of the old apprenticeship model, such as patient safety, efficient acquisition of complex surgical skills, overcoming the learning curve, and cost-effectiveness (4, 15). Improved structured training should include structured scheduling of activities, use of peer training, elearning, access to simulation training on high fidelity models and/ or animals, trainee information on all available resources, effective tutoring, research, and evidence based practice learning (2, 9, 16,17).

A consensus has been reached on markers defining the quality of a surgical training program (18): - Trainer – trainee relationship - Operative exposure - Supervision - Feed back - Structures and organization of training - Structured teaching programs No training is effective without assessment of the competency and proficiency achieved by the trainee.

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However, assessments are often perceived as haphazard, subjective and non-transparent (5, 8).

In structured simulation training programs, the most commonly used tools for objective assessment are (15): - Technical skills assessment - global rating scale of performance rating scores - questionnaires and post-training surveys - structured assessment by use of video recording - motion tracking software.

Another established, effective and valuable tool in surgical training assessment is the Direct Observation of Procedural Skills (DOPS) (19, 20).

In any case, trainee assessment has to move away from the mere measure of the number of surgical procedures to mediation of competencies and skills as markers of competency (21, 22).

A consensus statement has been reached on the quality markers of training assessment (18): - trainee feedback - trainer feedback - timetable structure - trainee improvement.

However, there are also barriers to effective training assessment which we must bear in mind. These are uncertainty on what to document, concern of a negative impact on faculty popularity amongst trainees, lack of clear standards, and lack of effective remediation options (23) According with the mission of Urology for emerging countries (U-merge), the authors looked at a wide array of urological training in various countries. It is notable that structured training programs do not only exist in developed countries, and old-fashioned apprenticeship models do still prevail in some developed countries although modern learning options are readily available there, albeit not implemented.

Especially but not only in the developing world, urological training is marred by inconsistency, lack of structure, and lack of focus on research and evidence-based practice (2). This is where an international and/or global training approach comes into play. More affluent countries could afford to help less fortunate countries to establish sustainable, capacity-building educational collaborations that are essential to address the global burden of global disease. International collaboration can lead the way towards competency-based training, assessment of technical skills by international standards, longterm trainer proficiency, and community-specific quality initiatives (24). Established tools for this purpose are an online curriculum, visiting educator trips, expert surgeon involvement, trainee competency tracking and identification of local outreach partners (25).

However, any collaboration towards standardized and structured training needs to be responsible, meaning responding to locally identified needs, training projects according to local contexts, and a general working towards self-sufficiency of the trainees (26).

Our results have shown a huge heterogeneity in quality urology training between countries and within continents. In systems without national structure of training it

Global urology training

can be assumed that such differences exist even between hospitals/training institutions. There is no doubt in times of globalization with resident and doctor migration and exchanges that training needs structure and standardization. The still huge gap in developing countries to catch up and be able to afford latest surgical and learning technologies need to be addressed with the help of responsible outreach programs.

There is ample literature on the requirements of structured training programs and assessments, and we have tried to briefly outline the key points in this paper.

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18. Siau K, Dunckley P, Valori R,, et al. Joint Advisory Group on Gastrointestinal Endoscopy. Changes in scoring of direct observation of procedural skills (DOPS) forms and the impact on competence assessment. Endoscopy. 2018; 50:770-778.

19. Khanghahi M, Azar EF. Direct observation of procedural skills (DOPS) evaluation method: Systematic review of evidence. Med J Islam Repub Iran. 2018; 32:45.

20. Heidenreich A, Salem J, Paffenholz P, Pfister D. Interdisciplinary education in urology: innovations for better training. Urologe A. 2019; 58:870-876.

1. Campain NJ, Kailavasan M, Chlawe M, et al. An Evaluation of the role of simulation training for teaching surgical skills in subsaharan Africa. World J Surg. 2018, 42:923-929.

21. Forbes N, Mohamed R, Raman M. Learning curve for endoscopy training: Is it all about numbers? Best Pract Res Clin Gastroenterol.

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2. Ather MH, Siddiqui T. Urology training in the developing world: The trainerâ&#x20AC;&#x2122;s perspective. Arab J Urol. 2013. http://dx.doi.org/ 10.1016/j.aju.2013.07.001

22. Singh P, Aggarwal R, Zevin B, et al. A global Delphi consensus study on defining and measuring quality in surgical training. J Am Coll Surg. 2014; 219:346-353.

3. Anderson JT. Assessments and skills improvement for endoscopists. Best Pract Res Clin Gastroenterol. 2016, 30:453-471.

23. Sanfey H. Assessment of surgical training. Surgeon. 2014; 12:350-356.

4. Sarikaya S, Meneses AD, Cacciamani GE, Rivas JG. Future of urology training. Arch Esp Urol. 2018; 71:158-163.

24.Wagner JP, Schroeder AD, Espinoza JC, et al. Global outreach using a systematic, competency-based training paradigm for inguinal hernioplasty. JAMA Surg. 2017; 152:66-73.

5. Angulo JC, Figueroa C, Gomez R, et al. Current status of urological training in South America. Arch Esp Urol. 2018; 71:23-33.

6. Carrion DM, Gomez Rivas J, Esperto F, et al. Current status of urological training in Europe. Arch Esp Urol. 2018; 71:11-17.

7. Oâ&#x20AC;&#x2122;Sullivan KE, Byrne KS, Walsh TN. Basic surgical training in Ireland: the impact of operative experience, training, program allocation and mentorship on trainee satisfaction. Ir J Med Sci. 2013; 182:687-692.

25. Sue GR, CovingtonWC, Chang J. The ReSurg global training program: a model for surgical training and capacity building in global reconstructive surgery. Ann Plast Surg. 2018; 81:250-256.

26. Macpherson L, Collins M. Training responsibly to improve global surgical and anaesthesia capacity through institutional health partnerships: a case study. Trop Doct. 2017; 47:73-77.

8. Struck JP, Cebulla A, Ralla B, Koenig J. Structured training curriculum for urological residents: chances and limits. Urologe A. 2019; 58:109-113.

9. Naouar S, Binous MY, Braiek S, El Kamel R. Training of Tunisian future urologists: how to improve it. Tunis Med. 2018; 96:401-404.

10. Soria F, Villacampa F, Serrano A, et al. Training program in endourological surgery. Future perspectives. Arch Esp Urol. 71:89-96.

11. Sarikaya S. Needs, realities and expectations for urology training: Questionnaire-based study. Arch Esp Urol. 2018; 71:18-22.

12. Lovegrove CE, Abe T, Aydin A, et al. Simulation training in upper tract endourology: myth or reality? Minerva Urol Nefrol.

2017; 69:579-588.

13. NHS health education England: Training and development (urology) https://www.healthcareers.nhs.uk/explore-roles/doctors/ roles-doctors/surgery/urology/training-and-development. Accessed 29.11.2019.

14. Van der Poel H, Brinkman W, van Cleynenbreugel B, et al.

Training in minimally invasive surgery in urology: European Association of Urology/ International Consultation of Urological Diseases consultation. BJU Int. 2016; 117:515-530.

15. Atesok K, Satava RM, Marsh JL, Hurwitz SR. Measuring surgical skills in simulation-based training. J Am Acad Orthp Surg. 2017; 25:665-672.

16. De Vries AH, van Luijk SJ, Scherpbier AJ, et al. High acceptability of a newly developed urological practical skills training program. BMC Urol. 2015; 15:93.

Correspondence Asad Ullah Aslam, MD asadullahaslam@gmail.com Dept. of Urology, Letterkenny University Hospital, Saolta Healthcare Group (Ireland) Joseph Philipraj, MD josephphilipraj@gmail.com Department of Urology, Mahatma Ghandi Medical College & Research Institute Sri Balaji Vidyapeeth, Pondicherry (India) Sayed Jaffrey, MD jaffry@urology.ie Dept. of Urology, University College Hospital, Galway Clinic and Bons Secours Hospital, Galway (Ireland) Noor Buchholz, MD (Corresponding Author) scientific-office@u-merge.com U-merge scientific office Athens/Greece

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DOI: 10.4081/aiua.2020.3.230

ORIGINAL PAPER

Transperitoneal and retroperitoneal approach in laparoscopic partial nephrectomy for posterior cT1 renal tumors: A retrospective, two-centers, comparative study Nikolaos Ferakis 1, Antonios Katsimantas 1, Nikolaos Charalampogiannis 2, Spyridon Paparidis 1, Jens Jochen Rassweiler 2, Ali Serdar Gözen 2 1 Department 2 Department

of Urology, Korgialenio-Benakio Hellenic Red Cross Hospital, Athens, Greece; of Urology, SLK-Kliniken Heilbronn, University of Heidelberg, Heilbronn, Germany.

Summary

Objectives: To compare perioperative, oncological and functional outcomes of Laparoscopic Transperitoneal Partial Nephrectomy (LTPN) and Retroperitoneal Laparoscopic Partial Nephrectomy (LRPN) for posterior, cT1 renal masses (RMs).

Materials and methods: Databases of two urologic institutions applying different laparoscopic surgical approaches on posterior cT1 RMs between June 2016 and November 2018 were retrospectively evaluated. Data on patient demographics, perioperative data and tumor histology were collected and further analyzed statistically.

Results: Each group consisted of 15 patients. Baseline characteristics were comparable in each group. When compared to LTPN, LRPN was associated with significantly shorter operative time (OT) (115 min versus 199 min, p < 0.05). No significant differences were detected in the other outcomes.

Conclusions: LRPN is associated with a significantly shorter OT compared to LTPN for posterior cT1 RMs. Both surgical approaches are safe, feasible and credible, demonstrating optimal results.

KEY WORDS: Laparoscopy; Partial nephrectomy; Transperitoneal; Retroperitoneal; Renal tumor.

Submitted 2 March 2020; Accepted 15 March 2020

INTRODUCTION

Partial nephrectomy (PN) is as a valid surgical approach for cT1 renal masses (RMs) and is strongly recommended whenever technically feasible (1-6). It can equally be performed by open (OPN), pure laparoscopic (LPN) or robot-assisted laparoscopic approach (3, 7-9).

A wide variety of endoscopic instruments and the steadily increasing laparoscopic experience rendered LPN a feasible treatment modality for cT1 RMs (1, 7, 10-11).

Both routes, either transperitoneal (TP) or retroperitoneal (RP), can be equally advocated (1, 7, 11-15).

A benefit of retroperitoneal LPN (LRPN) is the direct, rapid access to the posterior hilar structures and to posterior RMs allowing for less kidney’s mobilization and rotation (1, 7, 12-18). LRPN avoids bowel mobilization, need for lysis of adhesions in patients with prior abdominal surgery and peritoneal cavity irritation through contamination of blood and urine (1, 3, 7, 11, 14, 15).

Moreover, the RP space may tamponade a possible postoperative bleeding and avoids peritonitis caused by a

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possible postoperative urinary fistula (5, 16). The presence of abundant RP fat (e.g. in obese patient) or the case of a large or anteriorly located tumor may render LRPN challenging (6, 10, 15, 16). In addition, LRPN is technically demanding, with a steep learning curve (19).

TP route offers better spatial orientation due to the presence of more familiar anatomic landmarks (1, 7, 11, 14, 15, 19). Ease in port placement due to larger skin surface, increased working space allowing for wider angulations and enhanced maneuverability are in favor of transperitoneal LPN (LTPN) (1, 3, 7, 11, 14, 15, 19).

Major drawbacks of the LTPN are the difficulty in dissection of posterior RMs and subsequent reconstructive suturing, which may guide surgeon’s decision to perform OPN instead of minimal invasive procedure, if he is not familiar with the steps for creating RP space (15, 17, 18).

The aim of the present study is to analyze and present comprehensively the perioperative, oncological and functional outcomes of LTPN and LRPN for posterior cT1 RMs in two urologic centers.

MATERIALS

AND

METHODS

Following institutional review board approval, we reviewed prospectively collected data of two centers to evaluate consecutive patients who underwent LTPN or LRPN for posterior, cT1 RM from June 2016 to November 2018. All TP procedures (Group A) were performed by one experienced surgeon (NF) at a single institution in Greece, where LTPN is the standard operative technique for cT1 RMs. All RP procedures (Group B) were performed by two experienced surgeons (JJR, ASG) at a large German academic center, where LRPN is the usual operative technique for posterior RMs. Intraoperative findings were recorded systematically on surgical and video files and evaluated retrospectively.

Inclusion and exclusion criteria are listed in Table 1.

We excluded patients who underwent ETHOS chairassisted LRPN, as it was demonstrated that it significantly improves intraoperative parameters (16).

Preoperatively, all patients underwent routine laboratory testing, chest x-Ray, cardiological evaluation and abdominal Computed Tomography scan or Magnetic Resonance Imaging. Informed consent was obtained by each patient.

No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2020; 92, 3

Transperitoneal vs retroperitoneal LPN

Table 1.

Inclusion and exclusion criteria.

Inclusion • Single, unilateral, contrast-enhanced cT1N0M0 renal mass • Localization of the tumor in the posterior renal surface • Resection of the mass via transperitoneal or retroperitoneal laparoscopic partial nephrectomy Exclusion • Conversion to open partial or radical nephrectomy • LRPN using the ETHOS chair • Missing data

Our database included information on patient’s age, gender, body mass index (BMI), American Society of Anesthesiologists (ASA) score, tumor characteristics, preand post-operative serum hemoglobin (Hb) value, preand post-operative estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Renal Disease, tumor complexity evaluated by Preoperative Aspects and Dimensions Used for an Anatomical Classification (PADUA) score, operative time (OT), warm ischemia time (WIT), length of hospital stay (LOS), TNM stage and histology, surgical margins (SM) status [positive SM (PSM) defined as the presence of cancer cells at the level of the inked parenchymal excision surface] and intra-/post-operative complications (according to the modified Clavien-Dindo classification scale).

The technique of LRPN has been described previously (16). In brief, under general anesthesia and in a full flank position, a RP space is created through a 16-18 mm transverse incision below the tip of the 12th rib in the ‘musclefree’ Petit’s triangle. The RP space is entered bluntly by using the index finger and developed by using an optical dilatation balloon. A 12 mm trocar is placed with the guidance of index finger inside the RP space for the right hand and a 5 mm trocar for the left hand. Optionally, another 5 mm trocar is placed under view medially to the rim of peritoneum when a retraction of the kidney and Gerota’s fascia (GF) is needed. GF is incised horizontally parallel to the psoas muscle and the renal hilum is accessed for the dissection of the renal artery. The entire kidney is isolated from perirenal fat (except from the fat overlying the tumor) to localize the RM. The kidney is mobilized and the incision line around the tumor is scored with bipolar forceps. We clamp the renal artery with a bulldog clamp and we proceed to tumor’s excision according to the principles of enucleo-resection, preserving a 5-mm rim of normal renal tissue. The tumor is placed in an endoscopic specimen bag. Subsequently, we perform inner renorrhaphy by continuous suturing with a barbed suture (V-LocTM, Covidien, SH, 20 cm) preloaded with an absorbable LAPRA-TY® clip supported by a Vicryl patch or Durapatch, which is stitched out on the contralateral side of the resection wound and fixed with a LAPRA-TY® clip. Renal parenchyma is closed with a continuous suture secured at every loop using LAPRA-TY® clips, the bulldog clamp is removed and the suturing line is covered with perirenal fat. Finally, the specimen bag is removed through the optic trocar incision and is grossly inspected, a drain (24 Fr) is placed via 12 mm port incision and port incisions are closed.

Regarding LTPN, the patient is fixed in the lateral flank position with the table half flexed, under general anesthesia. We use open Hasson technique to place the first trocar (12 mm) for the 30° laparoscope 2 fingerbreadths above and 8-10 cm lateral to the umbilicus. We place the rest of trocars (one 12 mm and one 5 mm at the midclavicular line according to the triangulation principle, serving as surgeon’s working channels, and one 12 mm 3 fingerbreadths medial to the superior anterior iliac spine and one 5 mm 8 cm lateral to the camera trocar for the first assistant) under direct vision. On the right side, we may place another 5 mm subxyphoid trocar to retract liver. We release colon’s lateral attachments, to deflect it medially, and splenorenal or hepatorenal ligaments.

On the right side, we mobilize duodenum (Kocher maneuver) medially, until we clearly visualize vena cava.

GF is opened, the genital vessels, the proximal ureter, the psoas muscle and the renal pedicle are located and the kidney is defatted down to the renal capsule (preserving the fat overlying the tumor) and is mobilized. After locating the tumor, the margin of resection is marked with electrocautery. We use Rummel Tourniquet (RT) technique on renal artery in order to achieve WI, similarly to the technique described by Shefler et al. (20). We create our tourniquet by using a 30 cm long 2 mm thick vessel loop, a 2 cm cylinder sheath prepared from a 16 Fr Levin tube and a large Hem-o-Lock clip.

The tumor is excised [(enucleo)-resection] using cold scissors at 5 mm from the tumor’s edge. Subsequently, we perform inner renorrhaphy using a 15 cm 3-0 V-Loc running suture, we release RT (early unclamping technique) and we complete renorrhaphy using a 13 cm 1/0 polyglycolic acid running suture. We secure our running sutures using a large Hem-o-Loc clip at each exit point.

We reapproximate perirenal fat over the cutting surface, the tumor is removed via a 12 mm port using an endoscopic specimen bag and is grossly inspected, a drain (16Fr) is placed via a port incision and port incisions are closed.

In both techniques, 2-Dimensional High Definition (HD) cameras were used, pneumo (retro) peritoneum was maintained at 12 mmHg and mannitol iv was administered prior to clamping the renal artery. In both departments, we apply similar perioperative protocols: bowel preparation is applied preoperatively, no antiemetic or opioid drugs are routinely administered postoperatively, nasogastric tube is removed immediately postoperatively, patients receive liquid diet and are mobilized and Foley catheter is removed on the 1st postoperative day.

The patients are discharged following drain’s removal and when they are medically stable, full ambulatory without assistance and need for intravenous analgesia and capable to tolerate a light diet. Patients with malignant pathology are scheduled for 6-month imaging follow-up.

All statistical analyses were performed using an SPSS25 statistical program. Data were less than 35 (A = 15, B = 15), so standard normality assumptions did not meet.

Thus, non-parametric statistical tests were conducted.

Quantitative characteristics were compared using MannWhitney test and qualitative characteristics were compared using 2-tailed chi-square test. A p value < 0.05 was considered statistically significant. Median values and Archivio Italiano di Urologia e Andrologia 2020; 92, 3

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range were calculated for quantitative continuous variables and proportions for nominal variables.

RESULTS

Following exclusion, each cohort consisted of 15 patients.

Preoperative characteristics of both groups (demographic data and tumors’ characteristics) were comparable (Table 2).

Peri-operative data of both groups are summarized on Table 3. Variation of serum Hb value pre- and 10 hours post-operatively was comparable in both groups.

However, 4 patients were transfused intra-operatively (1 unit of packed red blood cells each), being all of them from group A (3 pT1a, 1pT1b, 1 with no ischemia), although the difference between cohorts was not statistically significant. OT was shorter in group B (p < 0.05).

Three patients of group A (1 pT1a, 2 pT1b) and 5 patients of group B (3 pT1a, 2 pT1b) underwent clampless LPN. Regarding postoperative complications, both groups were comparable. There were 5 patients of group A with minor postoperative complications (fever and bleeding which was managed conservatively with transfusion). One patient of group B presented prolonged drain excretion of serum fluid (biochemically confirmed). One patient of group A with a medical history of acute myocardial infarction died on the 4th postoperative day, following an episode of orthostatic hypotension, which resulted in fall on the ground, head injury and heart attack. No patient needed antiemetic drugs postoperatively or readmission following discharge.

Oncological data are demonstrated on Table 4. PSM rate was 13.3% in each cohort. There was solitary, focal, microscopic invasion of the tumor pseudocapsule in 3 cases [Group A: 2 cases of cT1b, clear-cell Renal Cell Carcinoma (ccRCC), Fuhrman Grade (FG) 2 and 3, Group B: 1 case of cT1b, ccRCC, FG 2]. In addition, there was a case of pT1a, papillary type 2 RCC in group B with equivocal SM status (focally), which was interpreted as positive. PSMs were detected only in cases of clampless PN. There was no local or distant recurrence during the follow-up period.

Gendera - Male/female Sidea - Right/left Ageb (years) BMIb (kg/m2) ASA scoreb Preop. Hbb (g/dl) Preop. eGFRb (ml/min/1.73m2) PADUA scoreb Tumor sizeb (cm)

p 0.09 0.07 p 0.95 0.05 0.140 0.201 0.458 0.798 0.271

LTPN/LRPN: Laparoscopic Transperitoneal/Retroperitoneal Partial Nephrectomy; BMI: Body Mass Index; ASA score: American Society of Anesthesiologists score; Preop.: Preoperative, Hb: Hemoglobin; eGFR: estimated glomerular filtration rate; PADUA score: Preoperative Aspects and Dimensions Used for an Anatomical Classification score. a x2 test, Fisher’s test; b Mann-Whitney test, 2-sided Fisher exact test.

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Hb postop.a (g/dl) Variation of Hb pre- and postop.a (g/dl) Variation of eGFR preop. and at dischargea (ml/min/1.73m2) Operative timea (minutes) WITa (minutes) Length of Hospital Staya (days) WIb Intraoperative transfusionb Postop. complicationsb Minor complications (grade 1 & 2)b Postop. fever (%) Postop. bleeding-transfusion (%) Prolonged drain excretion (%) Major complications (≥ grade 3)b

LTPN (nA = 15) LRPN (nB = 15) Median (25th-75th centile) 11.8 (11.3–13.5) 11.1 (10.5–13.3) 1.4 (0.8–3.4) 1.35 (0.675–1.925)

6.8 (0.0–14.1) 0.0 (-5.0–13.8) 199 (150.0–220.0) 115 (100.0–180.0) 16 (14.0–20.0)* 23 (20.0–28.5)** 5 (4–7) 6 (5–6) Number Yes/No 12/3 10/5 Yes/No 4/11 0/15 Yes/No 6/9 1/14 Yes/No 5/10 1/14 2 (13.3) (-) 3 (20) (-) (-) 1 (6.7) Yes/No 1/14 0/15 Death (%) 1 (-)

p 0.256 0.646 0.352 < 0.05 0.160 0.233 p 0.68 0.10 0.06 0.17

0.31

LTPN/LRPN: Laparoscopic Transperitoneal/Retroperitoneal Partial Nephrectomy; Hb: Hemoglobin; eGFR: estimated glomerular filtration rate; WI(T): Warm Ischaemia (Time). a Mann-Whitney test; 2-sided Fisher exact test; b x2 test, Fisher’s test.

Table 4.

Oncological data of the two groups.

LTPN (nA = 15) LRPN (nB = 15) Median (25th-75th centile) Tumor’s sizea (cm) 3.5 (2.5–3.8) 4.5 (2.2–5.0) Follow-up perioda (months) 23.0 (19.8–22.3) 17.0 (15.0–24.3) Number Malignancyb Yes/No 12/3 14/1 SMb Neg./Pos. 13/2 13/2 Number Benign lesions Oncocytoma 3 (20) 1 (6.7) Malignant lesions ccRCC 9 (60) 9 (60) FG 1 (-) 5 (55.6) FG 2 6 (66.7) 4 (44.4) FG 3 2 (22.2) (-) FG 4 1 (11.1) (-) pRCC type 2 1 (6.7) 4 (26.7) chRCC 2 (13.3) 1 (6.7) T stage pT1a 8 (66.7) 7 (50) pT1b 3 (25) 7 (50) pT3a 1 (8.3) (-)

p 0.271 0.137 p 0.28 1.00 p

LTPN/LRPN: Laparoscopic Transperitoneal/Retroperitoneal Partial Nephrectomy; SM: Surgical Margins, RCC: Renal Cell Carcinoma; FG: Fuhrman Grade; Neg./Pos.: Negative/Positive; ccRCC: clear cell RCC; pRCC: papillary RCC; chRCC: chromophobe RCC. a Mann-Whitney test; 2-sided Fisher exact test; b x2 test, Fisher’s test.

Table 2.

Baseline characteristics of the two groups.

LTPN (nA = 15) LRPN (nB = 15) Number 9/6 13/2 5/10 10/5 Median (25th-75th centile) 70 (62–73) 68 (53–75) 25.0 (24.2–27.3) 28.1 (26.1–30.8) 2.0 (1.0–2.0) 2.0 (2.0–3.0) 14.4 (12.7–15.1) 13.0 (11.8–14.4) 76.3 (69.7–85.1) 68.0 (63.8–87.8) 7.5 (6.8–9.0) 7.0 (6.0–10.0) 3.5 (2.5–3.8) 4.5 (2.2–5.0)

Table 3.

Perioperative data of the two groups.

DISCUSSION

In previous studies, the surgeon’s decision to perform TP or RP approach was usually influenced by tumor’s characteristics, patient’s history of previous intraperitoneal operations and by his discretion and experience (1, 3, 1113, 15, 17, 18). Previous studies demonstrated that both approaches have comparable outcomes or that LRPN outperforms LTPN in several parameters (1, 3, 7, 11-15, 17, 18). However, to the best of our knowledge, this is the first comparative study of TP and RP approach on pure LPN, exclusively for posterior, cT1 RMs of similar complexity, in patients with similar demographic data.

Transperitoneal vs retroperitoneal LPN

In our study, LRPN was associated with shorter OT. The difference in OT is probably due to the rapid access of LRPN to the tumor, avoiding bowel and extensive kidney mobilization, and due to the need for lysis of adhesions in the first cohort (1, 3, 7, 11-18). It is worth-mentioning that we noticed intrabdominal adhesions in more patients of the group A than anticipated by the history of previous intraperitoneal operation and this might prolong OT. Commonly, WI is applied during PN in order to control bleeding, facilitating tumor excision and renorrhaphy and avoiding complications (9, 17, 21-23). WIT below 20-25 minutes is generally considered safe (9). Efforts to minimize WIT resulted in the introduction of terms such as early unclamping technique, selective renal artery clamping technique, clampless PN and selective renal parenchymal ischemia (9, 16, 22, 23). We commonly occlude renal artery without occluding renal vein in both centers. Although the occlusion of both renal vessels reduces bleeding from the tumor bed and offers better visualization by preventing venous backflow, animal studies revealed that selective renal artery clamping is superior in preserving renal function postoperatively, as it allows the retrograde irrigation of the normal renal parenchyma by venous blood at lower oxygen tension (23). We used different techniques in order to achieve WI. As expected, group A (early unclamping technique) had shorter median WIT than group B. However, the difference was not statistically significant.

In cases where we met favorable conditions intraoperatively, we proceeded in clampless PN in order to complete resection and renal reconstruction. HD view and increased intrabdominal pressure due to pneumoperitoneum in laparoscopy facilitate clampless PN offering higher control of bleeding (2, 9). Solitary kidney model demonstrated lower incidence of Acute Kidney Injury and Chronic Kidney Disease when ischemia is not applied, although comparison of long-term results on renal function following on-clamp or off-clamp LPN did not demonstrate any benefit in favor of clampless technique in the case of normal contralateral renal function preoperatively (21, 23). In fact, all patients who underwent clampless LPN had no change in eGFR postoperatively.

In any case, the possible benefit of clampless PN has to be balanced against the risk of intraoperative bleeding, which may affect the oncological outcome and the complication rate (9). Any other techniques except conventional WI are technically challenging and should not be popularized (5).

Transient vascular occlusion exposes the remnant kidney to WI-reperfusion injury, mitigating the renoprotective character of PN (9, 10, 21-23). In addition, postoperative renal function is determined by the preoperative renal function, the volume of the resected RM and the suturing in order to perform renorrhaphy (22).

The variation of eGFR preoperatively and at discharge in each cohort results from the patients who received WI, as patients who underwent clampless LPN demonstrated no change in eGFR. However, we did not notice any benefit in favor of early unclamping technique. As tumor size and complexity are comparable between the two groups, this result may be due to the quality of renorrhaphy of each

approach in posterior tumors or due to the quality of remaining parenchyma in each group (24, 25).

Usual intraoperative complications of LPN are bleeding and injuries of adjacent viscera (10). Bleeding (postoperative or delayed) and urine leak are the most common postoperative complications (10). Previous studies demonstrated that LRPN is related to lower intraoperative blood loss, as it provides excellent hilar control and demands lesser extent of dissection (1, 11, 15).

The intraoperative transfusion rate of group A and the fact that preoperative serum Hb value and variation of serum Hb value pre- and post-operatively were similar may confirm the result of previous studies. Nevertheless, this may be due to differences in clamping technique between cohorts (1). The majority of our complications were minor, while the only death was unrelated to the operation. An advantage of LRPN is the avoidance of peritoneal entry and bowel mobilization, resulting in earlier bowel recovery postoperatively (1, 7, 15, 19).

We did not observe any complications or readmissions related to bowel dysfunction in both cohorts, no patient needed antiemetic drugs postoperatively and we applied similar feeding protocols. In any case, intrabdominal adhesions following LTPN are usually of minor clinical importance (1, 14).

We did not notice difference in LOS, although previous studies favored LRPN (1, 3, 7, 12, 14, 15, 17).

This result may be due to the application of similar perioperative care and discharge criteria, although different hospital settings and postoperative complications may affect outcome (11).

PSM rate was similar between approaches. PSM status was noticed only in patients who underwent clampless LPN and there may be a relationship between them. Our PSM rate is relatively high compared to previous studies, but this may be affected by the small sample size (4, 8, 9, 14, 23). PSMs may increase the likelihood of recurrence, although their role in natural history of RCC is still under investigation and tumorâ&#x20AC;&#x2122;s multifocality, grade and stage may be more important factors than PSM on the development of local recurrence (4). Nevertheless, microscopic PSMs do not seem to influence survival (4, 8).

Although our follow-up period is relatively short, none of the patients presented recurrence. In the cases of PSM, we schedule our patients in shorter follow-up time intervals, in order to manage a possible recurrence on time (8).

Our research has several limitations. The statistical power of the sample size is possibly capable to detect only the largest differences between cohorts. It was a retrospective study and patients were not randomly allocated to treatment groups. However, we believe that it is difficult to design randomized, prospective studies with larger sample to compare LTPN and LRPN exclusively for posterior RMs in order to draw definitive conclusions, as there are already a lot of approaches and there is a rapid progress in technology and surgical equipment.

Our results reflect the experience of high-volume laparoscopic surgeons and it may be difficult to replicate them in a different setting. Moreover, differences in hospital settings may affect outcomes. Finally, longer follow-up period is required for our functional and oncological results to mature.

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CONCLUSIONS

LRPN is associated with shorter OT compared to LTPN for patients with posterior cT1 RMs. Ultimately, good results can be achieved with either approach in experienced hands and the choice should be based on surgeon’s experience and judgment in order to achieve the optimum outcome for the patient.

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1. Ren T, Liu Y, Zhao X, et al. Transperitoneal approach versus retroperitoneal approach: a meta-analysis of laparoscopic partial nephrectomy for renal cell carcinoma. PLoS One. 2014; 9:e91978.

2. Porpiglia F, Mari A, Bertolo R, et al. Partial nephrectomy in clinical T1b renal tumors: Multicenter Comparative Study of Open, Laparoscopic and Robot-assisted Approach (the RECORd Project).

Urology. 2016; 89:45-51.

3. Ouzaid I, Xylinas E, Pignot G, et al. Laparoscopic partial nephrectomy: is it worth still performing the retroperitoneal route? Adv Urol.

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4. Minervini A, Campi R, Sessa F, et al. Positive surgical margins and local recurrence after simple enucleation and standard partial nephrectomy for malignant renal tumors: systematic review of the literature and meta-analysis of prevalence. Minerva Urol Nefrol.

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16. Rassweiler JJ, Klein J, Tschada A, Gözen AS. Laparoscopic retroperitoneal partial nephrectomy using an ergonomic chair: demonstration of technique and matched-pair analysis. BJU Int. 2017; 119:349-357.

17. Ng CS, Gill IS, Ramani AP, et al. Transperitoneal versus retroperitoneal laparoscopic partial nephrectomy: patient selection and perioperative outcomes. J Urol. 2005; 174:846-849.

18. Kieran K, Montgomery JS, Daignault S, et al. Comparison of intraoperative parameters and perioperative complications of retroperitoneal and transperitoneal approaches to laparoscopic partial nephrectomy: Support for a retroperitoneal approach in selected patients. J Endourol. 2007; 21:754-9.

19. Klap J, Butow Z, Champy CM, et al. 1,000 retroperitoneoscopic procedures of the upper urinary tract: analysis of complications.

Urol Int. 2019; 102:406-412.

20. Shefler A, Ghazi A, Zimmermann R, Janetschek G. Renal hilus clamping with tourniquet during laparoscopic partial nephrectomy.

BJU Int. 2011; 107:1688-93.

21. Shah PH, George AK, Moreira DM, et al. To clamp or not to clamp? Long-term functional outcomes for elective off-clamp laparoscopic partial nephrectomy. BJU Int. 2016; 117:293-9.

22. Bagheri F, Puztai C, Farkas L, et al. Impact of parenchymal loss on renal function after laparoscopic partial nephrectomy under warm ischemia. World J Urol. 2016; 34:1629-1634.

5. Marconi L, Challacombe B. Robotic partial nephrectomy for posterior renal tumours: retro or transperitoneal approach? Eur Urol Focus. 2018; 4:632-635.

23. Ng AM, Shah PH, Kavoussi LR. Laparoscopic partial nephrectomy: a narrative review and comparison with open and robotic partial nephrectomy. J Endourol. 2017; 31:976-984.

6. Paulucci DJ, Beksac AT, Porter J, et al. A multi-institutional propensity score matched comparison of transperitoneal and retroperitoneal partial nephrectomy for cT1 posterior tumors. J Laparoendosc Adv Surg Tech A. 2019; 29:29-34.

24. Corongiu E, Grande P, Di Santo A, et al. Safety and efficacy of retroperitoneal sutureless zero ischemia laparoscopic partial nephrectomy for low nephrometry score masses. Arch Ital Urol Androl. 2019;91:157-162.

7. Fu J, Ye S, Ye HJ. Retroperitoneal versus transperitoneal laparoscopic partial nephrectomy: a systematic review and meta-analysis.

Chin Med Sci J. 2015; 30:239-44.

25. Tiscione D, Cai T, Luciani LG, et al. Sutureless laparoscopic partial nephrectomy using fibrin gel reduces ischemia time while preserving renal function. Arch Ital Urol Androl. 2019; 91:30-34.

8. Vartolomei MD, Foerster B, Kimura S, et al. Oncologic outcomes after minimally invasive surgery for cT1 renal masses: a comprehensive review. Curr Opin Urol. 2018;28:132-138.

9. Mearini L, Nunzi E, Vianello A,et al. Margin and complication rates in clampless partial nephrectomy: a comparison of open, laparoscopic and robotic surgeries. J Robotic Surg. 2016; 10:135-44.

10. Zhao PT, Richstone L, Kavoussi LR. Laparoscopic partial nephrectomy. Int J Surg. 2016; 36:548-553.

11. Gin GE, Maschino AC, Spaliviero M, et al. Comparison of perioperative outcomes of retroperitoneal and transperitoneal minimally invasive partial nephrectomy after adjusting for tumor complexity. Urology. 2014; 84:1355-1360.

12. Fan X, Xu K, Lin T, et al. Comparison of transperitoneal and retroperitoneal laparoscopic nephrectomy for renal cell carcinoma: a systematic review and meta-analysis. BJU Int. 2013; 111:611-621.

13. Muñoj-Rodriguez J, Prera A, Dominguez A, et al. Laparoscopic partial nephrectomy: comparative study of the transperitoneal pathway and the retroperitoneal pathway. Actas Urol Esp. 2018; 42:273-279.

14. Marszalek M, Chromecki T, Al-Ali BM, et al. Laparoscopic partial nephrectomy: a matched-pair comparison of the transperitoneal versus the retroperitoneal approach. Urology. 2011; 77:109-13.

15. Wright JL, Porter JR. Laparoscopic partial nephrectomy: comparison of transperitoneal and retroperitoneal approaches. J Urol.

2005; 174: 841-845.

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Correspondence Nikolaos Ferakis, MD ferakis@otenet.gr Antonios Katsimantas, MD antonioskatsimantas@gmail.com Spyridon Paparidis, MD sppap1986@gmail.com Department of Urology, Korgialenio-Benakio Hellenic Red Cross Hospital, Athens (Greece) Nikolaos Charalampogiannis, MD nickharas@yahoo.gr Jens Rassweiler, MD jens.rassweiler@slk-kliniken.de Ali S Gozen, MD (Corresponding Author) asgozen@yahoo.com Department of Urology, SLK-Kliniken Heilbronn, University of Heidelberg, Heilbronn, Germany

DOI: 10.4081/aiua.2020.3.235

ORIGINAL PAPER

Prostate cancer with cribriform pattern: Exclusion criterion for active surveillance?

Rui Miguel Bernardino 1, Rita Carvalho 2, Luis Severo 1, Marta Alves 3, Ana Luisa Papoila 3, Luis Campos Pinheiro 1 1 Urology

Department, Central Lisbon Hospital Center, Lisbon, Portugal; Department, Central Lisbon Hospital Center, Lisbon, Portugal; 3 Epidemiology and Statistics Unit, Research Center, Central Lisbon Hospital Center, Lisbon, Portugal.

2 Pathology

Summary

Introduction: Following the 2014 International Society of Urological Pathology meeting, a rapidly growing body of evidence by several researchers has been demonstrating a poor prognosis in association with cribriform morphology. The aim of our study was to describe the presence of cribriform foci in specimens of radical prostatectomies and to evaluate whether demographic and clinical characteristics are associated with the presence of cribriform pattern.

Materials and methods: This cohort study was based on 70 radical retropubic prostatectomies specimens collected between 2012 and 2016 and evaluated for the association of the cribriform pattern with age, prostate-specific antigen at surgery day, Gleason on biopsy, Gleason after radical prostatectomy, extracapsular extension, vesicles invasion, margins, multiparametric magnetic resonance imaging, and post-operative radiotherapy.

Results; From the univariable analysis, biochemical prostatespecific antigen recurrence (p = 0.001), extracapsular extension (p = 0.003), pre-operative prostate-specific antigen (p = 0.017), vesicles invasion, (p = 0.038) and post-operative radiotherapy (p < 0.001) showed an association with the presence of cribriform pattern. There was also a significant difference of cribriform pattern and Gleason 7 in needle biopsy (p = 0.020) and cribriform pattern and Gleason 8 or 9 in radical prostatectomy specimen (p = 0.036).

Conclusions: In our study, the increase in preoperative prostate-specific antigen had a high association with cribriform pattern. Further evidence is needed to discriminate preoperative prostate specific antigen values that might potentially be associated with the presence of cribriform pattern.

Raising our knowledge about the cribriform pattern can be an excellent opportunity to correctly identify and treat patients who will eventually die from prostate cancer, sparing treatment in those who will not.

KEY WORDS: Cribriform pattern; Prostate cancer; Radical prostatectomy.

Submitted 2 March 2020; Accepted 15 March 2020

INTRODUCTION

The Gleason pattern (GP) 4 has been assigned to most cribriform patterns, because of the understanding that invasive cribriform carcinoma is relatively aggressive (1).

Cribriform is characterized by a "solid proliferation with multiple, punched out lumina without intervening stroma" (2).

Following the 2014 International Society of Urological Pathology (ISUP) meeting, a rapidly growing body of evi-

dence by several researchers has been demonstrating a poor prognosis in association with cribriform morphology (3).

Dong et al. (4) showed that, after 10 years of follow-up, 13% of patients with cribriform architecture morphology at radical prostatectomy (RP) developed metastasis compared to 2.6% with GP 4 without cribriform morphology. Other studies supported the information that the presence of any cribriform was associated with higher biochemical recurrence (5-6). Cribriform lesions in their pure form on RP specimens were found to be poorly visible on multi-parametric magnetic resonance imaging (mpMRI), namely only 17% of foci were visible (7).

Sarbay et al. (8) demonstrate that diagnosing all cribriform patterns, at least GP 4, would significantly affect further therapeutic options and prognosis.

The aim of our study is to access the cribriform foci on the RP specimens, and to evaluate whether demographic and clinical characteristics are associated with the presence of cribriform pattern (CP).

MATERIALS

AND METHODS

This cohort study was based in 70 radical retropubic prostatectomies specimens collected between 2012 and 2016 in our Department. All the patients had a mpMRI pre-operatively. The study was approved by institutional ethics committee, and informed consent was obtained from all patients. Patients treated with cryotherapy, radiotherapy, or androgen deprivation pre-operatively were excluded.

The prostate-specific antigen (PSA) was measured at the day of the surgery and in the last consultation before the beginning of the study. A postoperative serum PSA above 0.2 ng/mL was considered as a biochemical prostate-specific antigen recurrence (BPR) (9).

Each prostate was sampled according to the standardized laboratory's protocol by the original reporting pathologist: specimens fixed in 10% neutral buffered formalin for at least 24h, serial sectioning into 0.3 mm thick sections of the whole prostate, paraffin embedding and 4 Îźm thick sections stained with H&E. All the specimens were evaluated by the same pathologist with the aim of identifying the presence of a cribriform pattern. This pattern was considered to be present

No conflict of interest declared.

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R.Miguel Bernardino, R. Carvalho, L. Severo, M. Alves, A.Luisa Papoila, L. Campos Pinheiro

Figure 1.

Confluent epithelial proliferations with multiple lumina and no intervening stroma.

Figure 2.

Cribriform formation attached to only one edge of the gland, resulting in the less common glomeruloid pattern.

when confluent epithelial proliferations with multiple lumina and no intervening stroma were observed (Figure 1), and also when the cribriform formation was attached to only one edge of the gland, resulting in the less common glomeruloid pattern (Figure 2).

Cases with comedonecrosis were not observed. For some cases with cribriform areas with smooth contours, immunohistochemistry (p63 and CK34be12) was applied to distinguish from high-grade prostate intraepithelial neoplasia (PIN) and intraductal carcinoma.

Statistical analysis Characteristics of study patients were described using the median and interquartile range (IQR: 25th percentile75th percentile) for continuous variables and frequencies (percentages) for categorical variables.

To study the association between cribriform foci and clinical and demographic variables, logistic regression models were used. Odd ratios were estimated with corresponding 95% confidence intervals (CI).

The following variables were considered in the univariable analysis: age, PSA at surgery day, Gleason on biopsy, Gleason after radical prostatectomy, extracapsular extension, vesicles invasion, margins, mpMRI, and postoperative radiotherapy.

Those variables attaining a p-value < 25 in the univariable analysis were selected as candidates for the multivariable model.

Discriminative ability and calibration of the model were assessed by the area under the receiver-operating characteristic curve (AUC) and the Hosmer-Lemeshow test (Figure 3), respectively.

The level of significance a = 0.05 was considered. All data were analyzed using the Statistical Package for the Social Sciences for Windows 22.0 (IBM Corp. Released 2013.

IBM SPSS Statistics for Windows. Armonk, NY: IBM Corp.).

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RESULTS

Out of 70 specimens of patients with radical retropubic prostatectomy included in the study, 23 (32.9%) had a cribriform pattern. The median age at diagnosis was 66 years (range 60-70) for patients with cribriform pattern and 65 years (range 60-68) for patients who do not have cribriform pattern at radical prostatectomy specimen.

The pathologic characteristics of the study sample are presented in Table 1. The grade group distribution of the 70 specimens was as follow: 14 (20%), 27 (38.6%), 14 (20%), 5 (7.1%), 6 (8.6%), 3 (4.3%) and 1 (1.4%) were Gleason 3+3, 3+4, 4+3, 4+4, 4+5, 5+4 and 3+5, respectively.

Furthermore, for cases with CP, 14 (60.9%), 12 (52.2%) and 5 (21.7%) had extraprostatic extension (EPE), surgical margin (SM) and vesicles invasion, respectively.

On the other hand, for cases without CP, 11 (23.4%), 15 (31.9%) and 2 (4.3%) had EPE, SM and vesicles invasion, respectively. By previous definition of PSA failure, 7 (30.4%) of the patients with CP and only 1 (2.2%) without CP showed BPR. Of those who had BPR, 7 (87.5%) had cribriform pattern, while from those who did not had BPR, only 16 (26.2%) had cribriform pattern. Concerning radiotherapy, 16 (69.6%) of the patients with CP have done adjuvant radiotherapy, while only 7 (30.4%) with CP have not been submitted to RT. From the univariable analysis, BPR (p = 0.001), EPE (p = 0.003), pre-operative PSA (p = 0.017), vesicles invasion (p = 0.038) and RT (p < 0.001) showed an association with the presence of cribriform pattern (Table 2).

There was no statistically significant difference between the presence of CP and positive margins (p = 0.105), mpMRI PIRADS 4 (p = 0.609) and 5 (p = 0.254), Gleason Score 7 in RP Specimen (p = 0.131) or Gleason score 8 or 9 in needle biopsy (p = 0.429). On the other hand, there was a significant difference with CP pattern and Gleason 7 in needle biopsy (p = 0.020) and with CP and Gleason 8 or 9 in RP specimen (p = 0.036) (Table 2).

Figure 3.

Good discriminative ability to distinguish between patients with and without cribriform pattern with an AUC = 0.79 (95% CI: 0.67-0.91).

Prostate cancer with cribriform pattern

Table 1.

Clinical characteristics of the patients by group.

Preop PSA (per ng/dL)* EPE, n (%) Positive Negative BPR, n (%) Yes No RT, n (%) Yes No SM, n (%) Positive Negative Vesicles Invasion, n (%) Positive Negative

With cribriform pattern n = 23 9.10 (6.04-15.44)

Without cribriform pattern 6.04 (4.86-8.45)

14 (60.9) 9 (39.1)

11 (23.4) 36 (76.6)

7 (30.4) 16 (69.6)

1 (2.2) 45 (97.8)

16 (69.6) 7 (30.4)

11 (23.9) 35 (76.1)

12 (52.2) 11 (47.8)

15 (31.9) 32 (68.1)

5 (21.7) 18 (78.3)

2 (4.3) 45 (95.7)

* Values are expressed as median (interquartile range); BPR, biochemical prostate-specific antigen recurrence; EPE, extraprostatic extension; SM, surgical margin; PSA, prostate specific antigen.

Table 2.

Univariable regression analysis, dependent variable: cribriform pattern.

Variables Age (years)* Preop PSA Gleason in needle biopsy** 7 8 or 9 Gleason in RP Specimen** 7 8 or 9 EPE Vesicle invasion Margins mpMRI*** 4 5 Adjuvant RT

Odds ratio estimates 1.01 1.14

95% CI 0.93 1.10 1.02 1.27

p-value 0.811 0.017

3.82 2.17

1.24 0.32

11.80 14.71

0.020 0.429

3.50 7.00 5.09 6.25 2.33

0.69 1.14 1.74 1.11 0.84

17.76 42.97 14.93 35.20 6.47

0.131 0.036 0.003 0.038 0.105

1.40 2.80 7.27

0.39 2.59 2.38

5.08

0.609 0.254 < 0.001

22.23

* For each one-year increase of age; ** Reference category: 6; *** Reference category: 2 or 3; CI, Confidence Interval; EPE, Extracapsular extension; PSA, Prostate Specific Antigen; RT, Radiotherapy; p-values obtained by logistic regression models.

Results of multivariable model showed that for each unit increase in pre-operative PSA, there was a 14.2% increase (OR-estimate = 1.14; 95% CI: 1.01-1.29; p = 0.033) in the odds of cribriform pattern. It was also observed that patients with extracapsular extension have a 5-fold increase in the odds of having cribriform pattern (OR-estimate = 5.35; 95% CI: 1.68-17.02; p = 0.005).

The multivariable model showed a good discriminative ability to distinguish between patients with and without cribriform pattern with an AUC = 0.79 (95% CI: 0.670.91) (Figure 3). The Hosmer-Lemeshow goodness-of-fit test showed a good calibration (p = 0.377).

DISCUSSION

Cribriform tumours are now recognized as highly aggressive and with worse prognosis compared to other

morphologies. This means that enhancing the understanding of cribriform cancer biology is of the utmost importance to precisely identify and treat men that will eventually die of prostate cancer, while sparing treatment in those who will not (10).

What could be the implication of a cribriform pattern in clinical practice? In a study by Kenneth et al. (11) that involved 153 men who underwent RP, 76 with PSA failure (> 0.2 ng/mL) were matched to 77 men without failure. In high-grade pattern frequencies, 54.9% showed a CP. This pattern was also present in 61% of PSA failure cases. According to the multivariable analysis, the CP had the highest odds ratio for PSA failure.

In another study, 241 consecutive RP specimens were reviewed. The presence of poorly formed glands, fused glands, and CP was recorded for each case. The types of architectural patterns presented were associated with patient outcome. Twenty-two of 165 patients (13.3%) with CP adenocarcinoma develop metastasis, whereas 2 of 76 (2.6%) without a CP developed metastasis at a median postoperative follow-up of 10.0 years. They concluded that the presence of a CP was an independent predictor for BPR as well as metastasis after RP (12).

In the present study, we investigated the association of age, preoperative PSA, Gleason on biopsy, Gleason after RP, EPE, vesicles invasion, positive margins, BPR, mpMRI and post-operative radiotherapy with the presence of CP. In the univariable analysis, EPE, vesicles invasion, preoperative PSA and adjuvant RT showed significant association in the presence of CP. There was also a statistical significance between CP and BPR. Of those who had BPR, 87.5% had CP, while those who did not had BPR, only 26.2% had CP. In the multivariable analysis, only EPE and pre-operative PSA revealed a statistically significant association with CP. Use of active surveillance in select favorable intermediate-risk patients (Gleason 3+4) has been proposed (13).

Some groups have argued that cribriform morphology itself outperforms the percentage of Gleason pattern 4 involvement for prognostication and should be used to determined candidates for active surveillance. In this context, CP might be a valuable additional parameter in selecting patients for active surveillance.

In this study, we found that RP specimens with CP had a significantly higher likelihood of seminal vesicle invasion and extraprostatic extension compared to specimens without CP. The presence of CP was also associated with an advanced pathological stage (Gleason 8 or 9) compared to those without CP. Presently, the only way accepted to identify the presence of the cribriform morphology is through tissue analysis.

Holemans et al., identified PSA as independent predictor (Odds Ratio 3.5; 95% Confidence Interval 1.2-9.4, P = 0.02) for cribriform architecture on radical prostatectomy (14).

In our study, the increase in preoperative PSA had a high association with CP. Further evidence is needed to discriminate preoperative PSA values that might potentially be associated with the presence of CP. We believe it is also worth to explore the value of prostate-specific membrane antigen ligands, to accurately detect the presence of the cribriform morphology and possibly treat it. Since tumors Archivio Italiano di Urologia e Andrologia 2020; 92, 3

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with CP are characterized by specific genetic and molecular alterations, it would be possible to define the molecular profile of the neoplasm either in the tissue or in liquid biopsies (urine or blood) (9). It is important to differentiate these patients that would otherwise be selected for active surveillance and abstained of immediate treatment.

CONCLUSIONS

According our study, we found that patients with CP had higher preoperative PSA levels, higher rate of EPE, Seminal Vesicles Invasion, positive SM in final pathology, higher rate of adjuvant radiation therapy and BCR in postoperative course.

The evidence for the distinct adverse prognostic impact of invasive cribriform cancer has increased rapidly in recent years, so it is really important to ask our pathologists to specifically report the presence of CP in the pathology report. Excessive treatment of non-lethal prostate cancer has been a critical area in the approach to prostate cancer treatment, so raising our knowledge about the cribriform pattern can be an excellent opportunity to correctly identify and treat patients who will eventually die from prostate cancer, sparing treatment in those who will not. It might be important to consider cribriform growth as an exclusion criterion for active surveillance in Gleason score 3+4 = 7 patients.

REFERENCES

1. Quian J, Jenkins RB, Bostwick DB, Detection of chromosomal anomalies and c-myc gene amplification in the cribriform pattern of prostatic intraepithelial neoplasia and carcinoma by fluorescence in situ hybridization, Mod. Pathol. 1997; 10:1113-1119.

2. Kweldam CF, Wildhagen MF, Steyerberg EW, et al. Cribriform growth is highly predictive pospostoperative metastasis and disease specific death in Gleason score 7 prostate cancer. Mod Pathol. 2015; 28:457-464.

3. Epstein JI, Egevad L, Amin MB, et al. The 2014 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma definition of grading pat-

Correspondence Rui Miguel Bernardino, MD (Corresponding Author) ruimmbernardino@gmail.com Luis Severo, MD Luis Campos Pinheiro, MD Urology Department, Central Lisbon Hospital Center, Lisbon (Portugal) Rita Carvalho, MD Pathology Department, Central Lisbon Hospital Center, Lisbon (Portugal) Marta Alves, MD Ana Luisa Papoila, MD Epidemiology and Statistics Unit, Research Center, Central Lisbon Hospital Center, Lisbon (Portugal)

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terns and proposal for a new grading system. Am J Surg Pathol.

2016; 40:244-252.

4. Dong F, Yang, Wang C, et al. Architectural heteroneneity and cribriform pattern predict adverse clinical outcome for Gleason grade 4 prostatic adenocarcinoma. AMJ Surg Pathol. 2013; 37:1855-1861.

5. Trudel D, Downes MR, Sykes J, et al. Prognostic impact of intraduztal carcinoma and large cribriform carcinoma architecture after prostatectomy in a contemporary cohort. Eur J Cancer. 2014; 50:1610-1616.

6. Kir G, Sarbay BC, Gumus E, Topal CS, The association of the cribriform pattern with outcome for prostatic adenocarcinomas.

Pathol Res Pract. 2014; 210:640-644.

7. Truong M, Feng C, Hollenberg G, et al. A comprehensive analysis of cribriform morphology on MR/US fusion biopsy correlated with radical prostatectomy specimens. J Urol. 2018; 199:106-113.

8. Sarbay BC, Kir G, Topal CS, et al. Significance of the cribriform pattern in prostatic adenocarcinomas. Pathol Res Pract. 2014; 210:554.557.

9. Moul JW: Prostate specific antigen only progression of prostate cancer. J Urol. 2000; 163:1632-1642 10. Montironi R, Cimadamore A, Gasparrini S, et al. Prostate cancer with cribriform morphology:diagnosis, aggressiveness, molecular pathology and possible relationships with intraductal carcinoma.

Expert Rev Anticancer Ther. 2018; 18:685-693.

11. Iczkowski KA, Torkko KC, Kotnis GR, et al., Digital quantification of five high-grade prostate cancer patterns, including the cribriform pattern, and their association with adverse outcome. Am J Clin Pathol. 2011; 136:98-107.

12. Dong F, Wang C, Farris B, et al., Impact on the clinical outcome of prostate cancer by the 2005 International society of urological pathology modified Gleason grading system. Am J Surg Pathol.

2012; 36:838-843.

13. Morlacco A, Cheville JC, Rangel LJ. Adverse disease features in Gleason score 3+4 "favourable intermediate-risk" prostate cancer: implications for active surveillance. Eur Urol. 2016; 72:442-447.

14. Hollemans E, Verhoef EI, Chris H, et al. Large cribriform growth pattern identifies ISUP grade 2 prostate cancer at high risk for recurrence and metastasis. Mod Path. 2019; 32:139-146.

DOI: 10.4081/aiua.2020.3.239

ORIGINAL PAPER

The impact of tumor invasion to muscularis mucosaevascular plexus on patient outcome in pT1 bladder urothelial carcinoma Ahmet Sahan 1, Fatma Gerin 2, Asgar Garayev 3, Emine Bozkurtlar 2, Alkan Cubuk 1, Orkunt Ozkaptan 1, Kasım Ertas 4, Yıloren Tanidir 3, Haydar Kamil Cam 3, Ilker Tinay 3 1 Kartal

Dr. Lutfi Kirdar Training and Research Hospital, Department of Urology, Istanbul, Turkey; University, Department of Pathology, Istanbul, Turkey; 3 Marmara University, Department of Urology, Istanbul, Turkey; 4 Yuzuncu Yıl University, Department of Urology, Van, Turkey.

2 Marmara

Summary

Objectives: T1 bladder cancer has a wide range of tumor behavior and lamina propria invasion depth has a high potential risk of disease progression. To evaluate the patient outcome according to the tumor invasion to the muscularis mucosae-vascular plexus (MM-VP) in pT1 bladder urothelial carcinoma (BUC).

Materials and methods: This study is a retrospective analysis of patients consecutively recorded from 2007 to 2013. A total of 93 patients with a history of primary pT1 BUC and complete follow-up were included. We used a pathological substaging system according to the tumor invasion regarding the MM-VP: pT1a (invasion above MM-VP) and pT1b (MM-VP invasion). We evaluated recurrence-free survival (RFS), progression-free survival (PFS), disease-specific-survival (DSS) based on this sub-staging system.

Results: Pathological evaluation regarding the MM-VP invasion revealed 53 patients (57%) as pT1a BUC and 40 patients (43%) as pT1b BUC. The mean follow-up was 78.8 months.

During the follow-up period; 60 patients (64.5%) had tumor recurrences, 32 patients (34.4%) had progression to invasive disease, 18 patients (19.4 %) died during follow-up related to the BUC. In 29 (54.7%) of pT1a and in 31(77.5%) of pT1b tumors, the recurrent disease was recorded during the followup period (p = 0.023). DSS rates at 5 years for pT1a and pT1b were 80.2% and 60.8%, respectively. PFS, RFS, and DSS rates were similar for pT1a/pT1b and did not reach statistical significance (p > 0.05).

Conclusions: Sub-staging of pT1 BUC according to the MM-VP invasion showed a limited impact on the outcome in our patient cohort. However, the presence of pT1b disease caused a significantly higher rate of recurrence.

KEY WORDS: T1 bladder cancer; Survival; Sub staging; Muscularis mucosae; Lamina propria depth.

Submitted 2 March 2020; Accepted 15 March 2020

INTRODUCTION

Bladder urothelial carcinoma (BUC) with pathological T1 stage represents a complex clinical dilemma due to its high rate of recurrence and progression. In fact, T1 BUC comprises a wide spectrum of different cases causing a huge clinical variability. At presentation, 75% of cases are non-muscle invasive bladder cancer (NMIBC), and approximately 70 % of patients present as pTa, 20 % as pT1, and 10 % with carcinoma in situ (CIS) lesions (1).

In T1 high-grade tumors, 1 and 5 years of disease-progression rates are 11.4% and 19.8%, respectively, and recurrence rates are between 21% to 53% despite intravesical treatments (2-7). This wide range in the recurrence and progression rates indicates the immense clinical variation of pT1 patients. Therefore, the overall management of T1 tumors is a challenge for urologists. How to differentiate the clinically aggressive pT1 tumors and how to provide the appropriate treatment strategy i.e. early cystectomy remains a difficult issue.

Tumor grade, stage, size of the tumor, multiplicity, and presence of CIS are known risk factors for recurrence and progression (1). Pathologic features like tumor growth pattern (papillary vs solid), tumor invasion pattern (broad vs trabecular vs infiltrative vs nested), and lymphovascular invasion were investigated to identify the variability of tumor behavior (3, 8, 9). Factors dependent on surgery i.e. re-TUR has shown the benefit of recurrence and progression-free survival (10).

However, no strict criteria to predict prognosis in pT1 BUC have not been defined.

Due to a wide range of tumor behavior, there were many studies related to subclassification/sub-staging of T1 BUC since 1990 (11). These sub-staging systems were made according to the invasion of the muscularis mucosae-vascular plexus and invasion depth to lamina propria (11-13). Sub-staging according to MM-VP has been reported to be more superior than the invasion depth to lamina propria (14). However, the World Health Organization (WHO) (2004)/International Society of Urological Pathology (ISUP) and clinical guidelines do not recommend the sub-staging of T1 bladder cancer for the current daily practice (15, 16). Some reports showed that sub-staging is useful and predictive for progression of pT1 BUC (2, 12, 17, 18).

On the other hand, sub-staging is technically difficult and so far does not yield a clear prognostically significant separation on T1 bladder tumor (19, 20).

Therefore, new clinical series are required to evaluate the clinical utility of sub-staging in pT1 BUC. In the present study, we evaluated the impact of the invasion of the muscularis mucosae-vascular plexus (MMVP) on the clinical outcome of T1 BUC.

No conflict of interest declared.

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PATIENTS

AND METHODS

We evaluated a total of 140 patients, who were referred to our center or diagnosed in our center with primary and pathologically reported pT1 BUC between 2007 to 2013. Data of the patients were recorded prospectively in our electronic database and reviewed retrospectively for the study. The study protocol was approved by the local ethics committee (Number: 27-2014). Due to the retrospective nature of the study, only written consent was obtained from the patients.

The original pathology slides of all pT1 bladder tumors were re-evaluated by two uropathologists (EB/FG) for stage and grade. We used the World Health Organization 2004 classifications to review grade. After this re-evaluation, initial pathological staging was confirmed in 82% of patients.

We further excluded patients with a history of previous bladder cancer diagnosis, an absence of muscular layer, an absence of a repeated transurethral resection (Re-TUR) after 3 to 6 weeks, the presence of concomitant CIS and with upstaged/downstaged tumors based on this pathological re-evaluation. A total of 14 patients were lost to follow-up and as a result, 93 patients were eligible for final analysis.

All patients received intravesical BCG treatment with at least 1 year duration. The follow-up cystoscopies and imaging of the upper urinary tract are planned according to the recommendation of EAU 15. Recurrences were defined as pTa, pT1 and CIS tumors and progression was defined as pT2 or higher stage and/or development of metastasis. We used a pathological sub-staging system Figure 1.

Microscopic apperarnece.

Table 1.

Characteristics of the patients based on the two sub-staging systems.

Gender (M/F) Age (year) Tumor size (< 3 cm/> 3 cm) < 3 cm > 3 cm Tumor number Solitary Multiple Grade (Low/high) Low High Follow up time (month) Recurrence (n) Progression (n) Time to recurrence(month) Time to progression(month)

T1a (n: 53) 42/11 64.8 (10.7) 40 (75%) 13 (25%) 28 (53%) 25 (47%) 32 (60%) 21 (40%) 83.4 (61.7) 29 (55%) 8 (15%) 17.3 (29.1) 42.9 (49.8)

T1b (n: 40) 31/9 64.3 (12.1) 28 (70%) 12 (30%) 25 (62%) 15 (37%) 15 (37%) 25 (62%) 72.7 (46.7) 31 (77%) 10 (25%) 13.2 (14.2) 30.5 (38.4)

P value 0.839 0.834 0.556 0.351 0.029 0.359 0.023 0.231 0.491 0.440

according to the tumor invasion regarding the MM-VP: T1a (invasion above MM-VP), T1b (MM-VP invasion) bladder cancer 12. Whenever muscularis mucosae-vascular plexus were not identified the presence of large blood vessels in the upper one-half of the lamina propria coursing parallel to the mucosa was used as a morphologic landmark of the level of the MM (Figure 1) (12).

Statistical analyses were performed using the SPSS software version 20. The Chi-square test and Student t-test were used to compare in two groups. A p value of less than 0.05 was considered to show statistically significant results. For the multivariate analyses, the possible factors identified with univariate analyses were further entered into the logistic regression analyses to determine independent predictor of tumor recurrence.

Hosmer-Lemeshow goodness of fit statistics was used to access model fit. Survival rate was analyzed using the Kaplan-Meier method and compared between the 2 groups with the log-rank test.

RESULTS

In total 73 male and 20 female patients were included in the study. Mean age at initial diagnosis was 64.6 (+/-11.3) years and mean follow up time was 78.8 (+/58.4) months. Overall, radical cystectomy was performed in 14 patients (15.0%), and a total of 4 patients (4.3%) refused radical cystectomy due to surgical and/or risks of the anesthesia. These patients received radiotherapy plus chemotherapy due to the progression to muscle-invasive disease during this follow-up. Mean recurrence time was 15.2 Âą 22.5 months and mean proTable 2.

Logistic regression analysis to determine the independent predictors of recurrence.

Risk factors Tumor number (solitary vs multiple) Tumor grade (Low vs high ) Substage (T1a vs T1b) Tumor size (< 3 cm vs > 3 cm)

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Sig.

Exp (B)

0.068 0.000 0.026 0.006

3.117 12.643 4.219 7.325

95% C.I. for EXP (B) Lower Upper 0.918 10.585 3.680 43.432 1.191 14.947 1.758 30.525

Substaging of T1 bladder cancer

gression time was 37.1 ± 44.5 months considering the all pT1 cases.

The results of the comparison of the sub-staging system are shown in Table 1. There were no statistically significant differences between the two groups according to age, gender, size, multiplicity, follow up time. The MMVP invasion was not detected in 53 tumors (56.9%) and patients were classified as pT1a. The MM-VP invasion was present in 40 patients (43.0%) that we classified as pT1b. 25 (47.1%) for T1a vs. 15(37.5%) for T1b had multiple tumors (p = 0.351) (Table-1). 40% and 62% of patients were high grade BUC in T1a and T1b, respectively. There was a statistically significant difference between sub-staging according to pT1a/pT1b and the WHO 2004 grade system (p = 0.003).

In 29 (54.7%) of pT1a and in 31(77.5%) of pT1b tumors, the recurrent disease was recorded during the follow-up period. This difference was statistically significant (p = 0.023). In total, 18 patients (19.3%) progressed to further stages, and 12 patients (14%) died of BUC. There was no statistically significant difference between the two groups based on progression (p: 0.231).

Stepwise multivariate regression analysis revealed that Figure 2.

Kaplan-Meier estimates of disease spesific survival according to invasion of MM-VP in primary T1 transitional cell carcinoma (TCC) of the bladder.

the grade of bladder cancer, the pathological sub-staging system according to the tumor invasion regarding the MM-VP, and tumor size were the prominent factors affecting the recurrence of bladder cancer (Table 2).

Mean recurrence and progression time based on pT1a/ pT1b was 17.3 ± 29.1/42.9 ± 49.8 months and 13.25 ± 14.2/30.5 ± 38.4 months, respectively. Although mean recurrence time and progression time longer in pT1a group than pT1b group, it did not reach statistically significant differences between groups because of the small sample size (p > 0.05). Disease-specific survival (DSS) rates at 5 year for pT1a and pT1b were 80.2% and 60.8%, respectively. Progression free survival (PFS), recurrence free survival (RFS) and DSS rates were similar for pT1a/pT1b and did not reached statistically significance (p > 0.05) (Figures 2-3).

DISCUSSION

In this study, sub-staging based on the invasion of MMVP has no effect on progression and recurrence-free survival rates in patients with pT1 BUC. However, patients with pT1b have experienced a higher rate of recurrence during follow-up compared to pT1a group. Disease-specific survival was relatively longer in T1a however there was no statistically significant difference in Kaplan-Meier survival estimate analyses.

The management of T1 bladder cancer is a great challenge for urologists because of its wide and unpredictable range of clinical behavior. Therefore, pT1 disease represents a spectrum of different patients with different tumor behavior. Because of that, investigations have been focused on how to classify and predict the prognosis. Tumor grade, size, multiplicity, the presence of CIS, Re-TUR, lymphovascular invasion, BCG treatment, age, histotype and histological variants, tumor growth pattern, 3rd-month cystoscopy results, time to relapse are known parameters that affect prognosis (16). According to TNM classification, pT1 tumors recurrence and progression are not homogeneous some of them very aggressive that require early radical cystectomy. Remaining cases should need to follow up with cystoscopies after intravesical therapy. In the contrary, some patients who are treated more aggressively, in fact, may receive overtreatment. However, some Figure 3.

Kaplan-Meier estimates of recurrence-free (A) and progression-free (B) survival according to invasion of MM-VP in primary T1 transitional cell carcinoma (TCC) of the bladder.

Whereas the recurrence-free interval and progression-free were similar for both groups.

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pT1 cases may progress to the inoperable stage under the conservative approach. So any improvement to the treatment strategy for the management of pT1 BUC is significant. This study proposes that invasion of MM-VP (pT1b) may be associated with a higher and earlier recurrence, although a statistical difference was not shown. Larger series with longer follow-up may show a remarkable distinction for pT1b sub-staging.

Different sub-staging systems have been studied in the literature recently (11, 13, 18). WHO (2004)/ISUP and clinical guidelines do not recommend the sub-staging of T1 bladder cancer yet (15, 16). Invasion of muscularis mucosae-vascular plexus invasion and depth and area to lamina propria invasion were most commonly applied sub-classification (12, 13). Orsola et al. substaged according to invasion superficial to, into or beyond the muscularis mucosae (13, 18). Holmang et al. substaged based on the absent or presence of MM-VP invasion (T1a/T1b) as in our study (21). Van Rhijn et al. investigated two substaging systems based on the extent of lamina propria involvement [T1-microinvasive (T1m) versus T1-extensive-invasive (T1e)] and invasion to MM-VP 12.

Amin et al. commented that the efficacy of the sub-staging of T1 bladder tumors is still controversial since lack of consensus to define the depth of invasion criteria and established clinical significance (22). The main problem may be the detection of MM-VP since it is not a constant layer, 6% to 75% of pathology specimen were not identified (23). Main studies of interest of MM invasion in T1 NMIBC with staging system and assessment rate were changes between 63% to 100% (22). In our study we planned to reclassify the T1 tumors based on presence or absence of MM-VP invasion and depth invasion to lamina propria: T1a (the tumor does not infiltrate the MMVP) and T1b (the tumor infiltrates and/or invades the [MM-VP]), and T1m (micro-invasive- a single focus of lamina propria invasion with a maximum diameter of 0.5 mm) and T1e (extensive-invasive, > 0.5 mm). If the MM-VP was not seen at the invasion front, we classify pT1a or pT1b according to the depth of invasion into the lamina propria by looking at the MM-VP in tumor-free areas in the same or other TUR slides (12). We classified as T1a/b all the patients and classification according to lamina propria invasion depth (T1m/e) < 0.5 mm or > 0.5 mm was not feasible result in our study. Since only 6 of the patients classified as T1m BCa and all the others reported as T1eBCa so we could able to analyze only the presence or absence of MM-VP invasion (T1a/T1b).

In literature the largest study was reported by RouprĂŞt et al. with 587 patients, that pT1a/b sub-staging based on the MM-VP invasion was very predictive of T1 NMIBC behavior as recurrence-free (p = 0.03) progression-free (p < 0.001) and cancer-specific survival (p = 0.02) in 35 months median follow up time (24). In our study, pT1a BUC a was a higher recurrence rate of 29(54.7%) than T1b 31(77.5%) (p: 0.023) but there were no statistically significant differences between two groups with Kaplan Meier analyses (log rank, p-value > 0.05) in 78.8 (58.4) months mean follow-up time.

Skoup et al. reported that T1 sub-staging was the indepented prognostic factors for tumour progression (p < 0.0001), cancer-specific survival (p = 0.0001) and over-

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all survival (p = 0.0002) (25). De-Marko et al. analyzed two sub-staging systems for T1 bladder cancers based on MM-VP invasion (T1a/b/c) and lamina propria invasion depth (T1m/e) two sub-staging system were not reached prognostic significance level for progression-free survival and disease-specific survival after 9.5 years of follow-up 20. Van Rhijn et al. evaluated MM-VP invasion depth as T1a/T1b/T1c and lamina propria invasion above or below to 0.5 mm (T1m/T1e), which show a higher predictive value for disease progression and disease-specific survival (12). Orsola et al. reported that sub-staging using depth of lamina propria invasion was significant for progression (13). In our study, there were no statistically significant differences between disease progression, recurrence and cancer-specific survival between the T1a/b sub-staging systems.

Patriarca et al. report that 1 mm invasion system predicted progression (p < 0.04) and Re-TUR increase the survival rate (26). They reclassified 1 mm sub-staging system in 100% of cases, the T1m/e in 100%, and the anatomy-based method (T1 a/b) in 72.3% of cases (26).

In our study, we detected only 6 cases with T1m groups based on 0.5 mm threshold, so 1 mm of invasion threshold might be more useful results clinically. Finally, although the EORTC and CUETO risk scores improve risk stratification by quantifying recurrence and progression possibilities, their performance remains imperfect.

These scoring systems may further improve with using this sub-staging system (27).

Our study has some limitations such as reporting the retrospective data of a relatively small patient group. Our results could not show statistically significant differences according to disease-specific survival and progressionfree survival because of the small sample size.

CONCLUSIONS

Based on the findings presented in this study, sub-staging of T1 BUC according to the muscularis mucosaeâ&#x20AC;&#x201C;vascular plexus invasion showed a limited impact on the outcome in our patient cohort. However, the presence of pT1b disease was found to be associated with significantly higher of recurrence.

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20. De Marco V, Cerruto MA, D'Elia C, et al. Prognostic role of substaging in T1G3 transitional cell carcinoma of the urinary bladder.

Mol Clin Oncol. 2014; 2:575-80.

21. Holmang S, Hedelin H, Anderstrom C, et al. The importance of the depth of invasion in stage T1 bladder carcinoma: a prospective cohort study. J Urol. 1997; 157:800-3 22. Amin MB, McKenney JK, Paner GP, et al. ICUD-EAU International Consultation on Bladder Cancer 2012: Pathology. Eur Urol. 2013; 63:16-35.

23. Ro JY, Ayala AG, el-Naggar A. Muscularis mucosa of urinary bladder. Importance for staging and treatment. Am J Surg Pathol.

1987; 11:668-73.

24. Roupret M, Seisen T, Comperat E, et al. Prognostic interest in discriminating muscularis mucosa invasion (T1a vs T1b) in nonmuscle invasive bladder carcinoma: French national multicenter study with central pathology review. J Urol. 2013; 189:2069-76.

25. Soukup V, Duskova J, Pesl M, et al. The prognostic value of T1 bladder cancer substaging: a single institution retrospective study.

Urol Int. 2014; 92:150-6.

26. Patriarca C, Hurle R, Moschini M, et al. Usefulness of pT1 substaging in papillary urothelial bladder carcinoma. Diagn Pathol.

2016; 11:6.

27. Gershman B, Boorjian SA, Hautmann RE. Management of T1 urothelial carcinoma of the bladder: what do we know and what do we need to know? Bladder Cancer 2015; 2:1-14.

Correspondence Ahmet Sahan, MD Alkan Cubuk, MD (Corresponding Author) alkancubuk@hotmail.com Orkunt Ozkaptan, MD Kartal Dr. Lutfi Kirdar Training and Research Hospital, Department of Urology, Cevizli Mh Şemsi Denizer Cad. E-5 Karayolu Cevizli Mevkii, 34890 Kartal Istanbul (Turkey) Fatma Gerin, MD Emine Bozkurtlar, MD Marmara University, Department of Pathology, Istanbul (Turkey) Asgar Garayev, MD Yıloren Tanidir, MD Haydar Kamil Cam, MD Ilker TinaY, MD Marmara University, Department of Urology, !stanbul (Turkey) Kasım Ertas, MD Yuzuncu Yıl University, Department of Urology, Van (Turkey)

Archivio Italiano di Urologia e Andrologia 2020; 92, 3

243

ORIGINAL PAPER

DOI: 10.4081/aiua.2020.3.244

Non-invasive evaluation of obstruction after ureteroscopic stone removal: Role of renal resistive index assessment Bilal Eryildirim 1, Ahmet Sahan 1, Özlem Türkoğlu 2, Murat Tuncer 1, Övünç Kavukoğlu 1, Berkan Simsek 1, Alkan Cubuk 1, Kemal Sarıca 3 1 Health

Sciences University, Kartal Dr. Lutfi Kirdar Training and Research Hospital, Urology Clinic, Istanbul, Turkey; Sciences University, Sultan Abdulhamid Han Training and Research Hospital, Radiology Clinic, Istanbul, Turkey; 3 Biruni University, Medical School, Urology Clinic, Istanbul, Turkey.

2 Health

Summary

Objectives: The aim of this study is to evaluate prediction of postoperative ureteral obstruction needing ureteral stent insertion by evaluating the resistive index (RI) values and the grade of hydronephrosis.

Material and Methods: A total of 66 adult patients undergoing stentless endoscopic ureteral stone treatment (URS) between January 2018 and January 2019 were included in this prospective study. Preoperative patient and stone characteristics were noted. All patients were evaluated with renal Doppler ultrasonography study to assess degree of hydronephrosis and RI values. A renal Doppler ultrasonography was repeated at postoperative 1st, 3rd and 7th days. Changes in both RI and hydronephrosis levels before and after the procedures were noted. On the postoperative 7th day, patients were divided into two groups including obstructive and non-obstructive cases according to RI values assessed where a RI value of 0.7 was accepted as the cut-off for obstruction. The preoperative and perioperative characteristics of both groups were evaluated in a comparative manner.

Results: The mean patient age was 43.6 ± 1.72 years.

Significant improvements were noted in RI and grade of hydronephrosis after the operation. The grade of hydronephrosis and RI values were found to improve more significantly on postoperative 3rd day when compared to the postoperative 7th day (p < 0.01 and p < 0.01). A significant correlation was detected between the grade of hydronephrosis (>grade 2) and obstructive RI values (> 0.7) in each postoperative visits (p: 0.001). RI values (> 0.7) at postoperative seventh days were correlated with larger mean stone size, increased ureteral wall thickness, increased diameter of the ureter proximal to the stone, and longer duration of the operation. Preoperative high-grade hydronephrosis indicated obstructive RI values at postoperative seventh day (p = 0.001) Conclusion: Changes in RI values on Doppler sonography and the grade of hydronephrosis may be a guiding parameter in assessing postoperative ureteral obstruction.

KEY WORDS: Ureteral obstruction; Resistive index; Renal Doppler ultrasonography.

Submitted 2 March 2020; Accepted 15 March 2020

INTRODUCTION

Urolithiasis is a common disease that affects 5-10% of the general population (1). Of all the stones diagnosed ureteral calculi sizing larger than 5 mm may cause obstruction and colic pain requiring immediate management. Early intervention on this aspect, not only protects renal morphological and functional integrity but

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also enables the patient to return to normal life quickly (2, 3). Ureteroscopic procedures have an important place not only in the diagnosis but especially in the treatment of ureteral stones. Although the procedure is accepted as a minimally invasive approach; some certain complications and procedure-related complaints could be noted in a certain percent of the cases. Persistence of the obstruction after ureteroscopic procedures secondary to the edema formation, presence of coagulum, and residual stone fragments is a major problem after this modality. Follow-up of the ureteral obstruction in a non-invasive manner constitutes a dilemma both during preoperative and also postoperative periods.

Renal Doppler ultrasonography (USG) may be one of the non-invasive diagnostic methods to help us in evaluating the degree as well as the course of the ureteral obstruction following endoscopic ureteral stone treatment. It has been well shown that changes in the degree of hydronephrosis and resistive index values (Δ%) after ureteroscopic stone removal could provide important information regarding the severity (grade) of obstruction (4, 5).

Insertion of an ureteral stent after ureteroscopic procedures can be a rational option to avoid postoperative obstruction. However, accumulated data so far have clearly shown that despite their protective effects, ureteral stents may certainly have some distressing problems which have been classified as stent-related symptoms (6, 7). Due to this fact, the insertion of a stent after these procedures is optional depending on the preference of the surgeon. On the other hand, again, there is no commonly accepted consensus with established certain criteria for the necessity of a ureteral stent after ureteroscopic procedures (8, 9). Studies have demonstrated that not all of the dilatation detected in the upper urinary tract after ureteral stone removal will reflect a true obstruction and residual dilation is a commonly observed scenario. Taking this fact into account again no reliable criteria with certain parameters have been reported to predict which patients will require ureteral DJ stent placement due to ureteral obstruction during follow-up after endoscopic ureteral stone surgery.

To fill this gap, in this present prospective study, we aimed to investigate the predict the presence of postoperative ureteral obstruction after ureteral stone removal by evaluating the resistive index values and the grade of hydronephrosis.

No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2020; 92, 3

Non-invasive evaluation of obstruction after ureteroscopic stone removal: Role of renal resistive index assessment

PATIENTS

AND METHODS

A total of 66 adult patients undergoing stentless endoscopic ureteral stone treatment for ureteral stones between January 2018 and January 2019 were included in the study. Patients with previous stone surgery including stent placement and auxiliary procedures, congenital anomalies, active urinary tract infection, pregnancy, renovascular disease, or renal insufficiency were all excluded from the program.

Approval for the study protocol was obtained from our Local Hospital Ethics Committee and all cases were well informed about the procedure from all aspects in detail and informed consent was obtained before the intervention (Local ethical approval no: 2017/514/115/2).

In addition to a detailed medical history; a careful physical examination was done and biochemical examinations including renal functional tests, urine analysis together with urine culture sensitivity tests were performed.

Although a non-contrast computed tomography (NCCT) was performed in all cases during a colic attack; sonography, plain X-ray of the kidney, ureter, and bladder (KUB) and excretory urography were done when necessary.

In addition to these evaluations, renal color doppler sonography was done preoperatively in all cases in the supine position using 3.5-5MHz transducer of MINDRAY® Realtime ultrasound machine Model DC-6 (ShenzhenMindrayBiomedical electronics, Nanshan, Shenzhen, China). The presence of hydronephrosis was evaluated in each case on Bmode and graded as described by Piazzese et al. (10).

Thereafter, the Doppler study (color and spectral) of the interlobar arteries was done to calculate the renal resistive index value as [(peak systolic velocity ± end-diastolic velocity)/peak systolic velocity] (11, 12).

Preoperative stone and patient-related parameters such as stone size and localization, the diameter of the ureter proximal to the stone, the ureteral wall thickness at the site of the ureteral stone (UWT), the grade of hydronephrosis and RI values were all assessed and recorded (3).

All ureteroscopic stone removal procedures were performed under general anesthesia by using a semirigid 8 Fr ureteroscope (Karl Storz, Tuttlingen, Germany). All cases received 1 gr of Cephazolin injection for prophylaxis before the procedure. Stone fragmentation was accomplished by using the holmium-YAG laser. Perioperative data including duration of operation, stone-free rate, and hospitalization time were recorded. The interval between initial colic pain and surgery was also recorded.

All patients were scheduled for a postoperative follow-up evaluation after 1st day, 3rd day and 7th day following the procedures. A Doppler USG was performed at each visit to assess the grade hydronephrosis and RI values.

Ultrasonography was carried out by the same senior radiologist. Changes in both RI and hydronephrosis levels before and after the procedures were given as “percentage of change” (Δ%) (Difference between a timely measurement with basal level/basal level x100) (10).

On the postoperative 7th day, patients were divided into two groups including obstructive and non-obstructive cases according to RI values assessed where a RI value of 0.7 was accepted as the cut-off for obstruction (10). The preoperative and perioperative characteristics of both groups were evaluated in a comparative manner.

Statistical analysis The IBM SPSS version 20.0 (IBM Co., Armonk, NY) was used for statistical analysis. Chi-square test was applied to evaluate categorical data and the two-sided P-value was used in inference, and p < 0.05 was accepted as significant. The variables were investigated using visual (histogram) and analytic methods (Kolmogorov-Smirnow) to determine normal distribution. Descriptive analyses were presented using means and standard deviation.

The ANOVA was used to compare normally distributed parameters.

RESULTS

Of all the 66 patients (40 men and 26 women) evaluated 36 cases had a stone on the right and 30 cases on the left side. The overall mean patient age was 43.6 ± 1.72 years with a mean BMI value of 26.3 ± 0.4 kg/m2. Changes in both the RI values and the grade of hydronephrosis before and after the ureterolithotripsy were significantly improved. The grade of hydronephrosis and RI values were found to improve more significantly on postoperative 3rd day when compared to the postoperative 7th day (Figures 1, 2). A comparison of hydronephrosis grade and resistive index values in conjunction with the timing of the follow-up period is being shown in Table 1.

A hydronephrosis grade of 2 and more were detected in 46 of the patients preoperatively. While 30 of these patients were diagnosed as on day 1, 18 patients were on postoperative day 3 and 10 patients on postoperative day 7. A significant correlation was detected between the grade of hydronephrosis (> grade 2) and obstructive RI values (> 0.7) (p: 0.001).

According to the resistive index value detected, 42 patients were found to have an obstructive pattern at preoperatively and 26 patients were found to have an obstructive pattern at postoperative day 7. Further evaluation of our findings clearly demonstrated that obstructive RI values > 0.7) at postoperative 7 days were well Figure 1.

Delta resistive index changes are shown below during the follow-up.

Figure 2.

Delta hydronephrosis grade changes are shown below during the follow-up.

Archivio Italiano di Urologia e Andrologia 2020; 92, 3

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Table 1.

Comparison of hydronephrosis and resistive index values among the days of the surgery.

Grade of hydronephrosis RI 0 0 2 0.680 1 18 0.664 2 38 0.729& 3 8 0.840*, &. + Total 66 0.723 pvalue 0.01

12 24 28 2 66

RI 1 0.611 0.662 0.725*, & 0.860*, & 0.686 0.01

Resistive index values RI 3 28 0.583 20 0.680* 18 0.757*, & 0 66 0.660 0.01

30 26 10 0 66

RI 7 0.562 0.695* 0.766*, & 0.645 0.01

* comparing to 0 p < 0.01; & comparing to 1 p < 0.01; + comparing to 2 p < 0.01.

Table 2.

Comparison of obstructive resistive index value based on RI 7th day value to pre-operative parameters.

Ureteral stone diameter Ureteral wall thickness (UWT) Diameter of theureter Duration of theoperation Stone localization (upper/lower) Preoperative grade of hydronephrosis

0 1 2 3

RI < 0.7 (n:40) RI > 0.7 (n:26) p value 6.8(1.6) 8.5(1.4) 0.01 3.3(1.2) 4.9(0.6) 0.01 9.2(3.2) 13.6(3.06) 0.01 36.2(7.1) 48.0(5.1) 0.01 10/30 10/16 0.245 2 0 14 0 0.001 24 8 0 18

correlated with larger mean stone size, increased UWT, increased diameter of the ureter proximal to the stone, and longer duration of the operation (Table 2).

Additionally, the presence of preoperative high-grade hydronephrosis seemed to increase the likelihood of postoperative obstruction according to resistive index values assessed at postoperative days 7 (p = 0.001).

DISCUSSION

Endourological procedures were introduced to the clinical practice in the 1980s and since then they have been used as widely accepted and reliable methods for ureteral stone treatment with limited complications (14). As a result of the technological improvements, ureterorenoscopes became thinner, and advanced visualization quality resulted in increased success and decreased complication rates. Despite a successful ureteroscopic procedure, however, published data have demonstrated that ipsilateral colic pain can be observed due to edema and coagulum formation, residual stone fragments which may cause a temporary urinary obstruction and lead to the symptoms similar to the preoperative period in these patients.

In light of these facts, it will be very useful to predict the possibility of postoperative obstruction during the preoperative evaluation period and plan to insert a ureteral stent after successful stone removal. On the other hand, evaluation and follow-up of possible obstructive status after such interventions with minimal or non-invasive means carry considerable importance for the involved cases. Renal Doppler USG and RI value assessment can be a useful tool in the non-invasive evaluation of upper urinary tract obstruction on this aspect (4, 15). Related with this issue,

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Archivio Italiano di Urologia e Andrologia 2020; 92, 3

Apoku et al reported that renal Doppler sonography is highly sensitive and specific for the diagnosis of obstructive uropathy. Increased resistive index of the obstructed kidney may be a useful diagnostic tool in situations where intravenous urography cannot be done or is contraindicated. Their findings indicated a sensitivity and specificity of 86.7% and 90% respectively following urinary obstruction, an increase in the pressure of the intrarenal collecting system will occur. The result of increased renovascular resistance will eventually cause a reduction in the renal blood flow. An increase in intra-renal vascular resistance diminishes diastolic blood flow velocity in intrarenal arteries which will subsequently cause an increase in the RI values noted (16). Similarly, Patti et al. have emphasized that RI is a good index of obstruction in children with unilateral hydronephrosis which has been found to be well correlated with the results of diuretic renography in such cases (12). Thus, all these findings indicate the possible and effective use of RI value assessment in the follow-up of upper tract obstruction.

In our current prospective study, we evaluated the presence and degree of obstruction in the upper urinary system with renal Doppler USG (RI values and grade of hydronephrosis) before and after (1, 3, and 7 days) ureterolithotripsy in cases with ureteric stones. We observed a gradual improvement in RI values and grade of hydronephrosis following the removal of ureteral calculi.

The change in RI values and grade of hydronephrosis after stone removal (Δ%) was found to be statistically significant. Furthermore, the improvement in RI values after intervention with significant decrease were well correlated with the decreasing grade of hydronephrotic status during the postoperative follow up period. Our current findings implicated that, the RI values and grade of hydronephrosis are convenient and useful parameters in the noninvasive follow-up of obstruction status after ureterolithotripsy.

Routine ureteral stent insertion is not recommended after an uncomplicated URS, as it both increases the cost and lowers the patients' quality of life. According to EUA guidelines, ureteral stents should be inserted in patients with any operative complication (bleeding, perforation, unsuccessful ureterolitotripsy, and ureteral injury) and in all doubtful situations to avoid the possible risk of postoperative complications (8, 9, 17, 18).

However finding the answer to outline these “doubtful cases as well as to avoid stressful emergencies” mentioned in the EAU urolithiasis guideline, we need to define some predictive parameters to assess such situations. It is a known fact that many patients may refer to the emergency department with colic flank pain after a successful endoscopic ureteral stone surgery. Possible causes of partial ureteral obstruction in such cases are edema formation in the ureteral wall or presence of a coagulum in the lumen of the ureter. Preoperative prediction of such factors (if possible) is highly important to decide on the placement of a ureteral stent following stone removal.

In the light of the RI values obtained, 26 patients (without ant stent in place) had obstructive patterns at postoperative day 7 in our study. Of these patients classified as “obstructed” according to the RI values; eight of them had grade 2 hydronephrosis and 18 patients had grade 3 hydronephrosis in the preoperative period.

Non-invasive evaluation of obstruction after ureteroscopic stone removal: Role of renal resistive index assessment

Based on our current findings, we can say that the grade of preoperative hydronephrosis may be associated with the postoperative obstructive pattern and ureteral stent placement might be more beneficial in these patients.

Additionally, patients with obstructive RI values at postoperative 7 days did also have increased mean stone size, UWT values, the diameter of the ureter proximal to the stone during preoperative evaluations along with longer mean operative duration. These data clearly indicate that postoperative restoration of the obstruction may take some more time if the stone burden, UWT value, the diameter of the ureter proximal to the stone is high and the operation time is longer. Our study has certain limitations. First of all the number of cases included in the study program is limited. Also, long-term follow-up data are lacking in the groups. However, taking the lack of publications regarding this issue and the first introduction of such parameters to assess the factors affecting postoperative ureteral obstruction; we believe that our current findings will certainly be contributive enough to the existing literature on this critical subject. Lastly, it would be interesting to compare cases with high RI > 0.7 and the ones with no or mild upper tract dilatation, to help the urologist to decide to place stent rather than wait for the obstruction to resolve by itself in these cases.

However, we were not able to make such a comparison due to the limited number of patients in our groups.

CONCLUSIONS

Based on our current findings we may state that the changes in RI values on Doppler sonography and the grade of hydronephrosis may be a guiding parameter in assessing whether obstruction is removed after endoscopic ureteral stone treatment. If the stone burden is high, operation time is long and the stone is impacted to the ureteric wall, postoperative restoration of obstruction may take longer than anticipated. We believe that in addition to changes in the degree of hydronephrosis outlined, the assessment of renal RI values may provide us further information to differentiate the obstructive pattern after ureteroscopic surgery prior to ureteral catheter placement.

A prospective randomized controlled trial. Kaohsiung J Med Sci. 2018; 34:695-9.

7. Tanidir Y, Mangir N, Sahan A, Sulukaya M. Turkish version of the Ureteral Stent Symptoms Questionnaire: linguistic and psychometric validation. World journal of urology. 2017; 35:1149-54.

8. Song T, Liao B, Zheng S, Wei Q. Meta-analysis of postoperatively stenting or not in patients underwent ureteroscopic lithotripsy.

Urol Res. 2012; 40:67-77.

9. Haleblian G, Kijvikai K, de la Rosette J, Preminger G. Ureteral stenting and urinary stone management: a systematic review. J Urol. 2008; 179:424-30.

10. Piazzese EM, Mazzeo GI, Galipo S, et al. The renal resistive index as a predictor of acute hydronephrosis in patients with renal colic. J Ultrasound. 2012; 15:239-46.

11. Norris CS, Pfeiffer JS, Rittgers SE, Barnes RW. Noninvasive evaluation of renal artery stenosis and renovascular resistance.

Experimental and clinical studies. J Vasc Surg. 1984; 1:192-201.

12. Patti G, Menghini ML, Todini AR, et al. The role of the renal resistive index ratio in diagnosing obstruction and in the follow-up of children with unilateral hydronephrosis. BJU Int. 2000; 85:308-12.

13. Tanidir Y, Sahan A, Asutay MK, et al. Differentiation of ureteral stones and phleboliths using Hounsfield units on computerized tomography: a new method without observer bias. Urolithiasis. 2017; 45:323-8.

14. Turk C, Petrik A, Sarica K, et al. EAU Guidelines on Diagnosis and Conservative Management of Urolithiasis. Eur Urol. 2016; 69:468-74.

15. Kilic S, Altinok MT, Ipek D, et al. Color Doppler sonography examination of partially obstructed kidneys associated with ureteropelvic junction stone before and after percutaneous nephrolithotripsy: preliminary report. Int J Urol. 2005; 12:429-35.

16. Klahr S, Pukerson ML. The pathophysiology of obstructive nephropathy: the role of vasoactive compounds in the hemodynamic and structural abnormalities of the obstructed kidney. Am J Kidney Dis. 1994; 23:219-23.

17. Seklehner S, Sievert KD, Lee R, et al. A cost analysis of stenting in uncomplicated semirigid ureteroscopic stone removal. Int Urol Nephrol. 2017; 49:753-61.

18. Ogreden E, Oguz U, Demirelli E, et al. The impact of ureteral Double-J stent insertion following ureterorenoscopy in patients with ureteral stones accompanied by perirenal fat stranding. Arch Ital Urol Androl. 2018; 90:15-19.

REFERENCES 1. Teichman JM. Clinical practice. Acute renal colic from ureteral calculus. N Engl J Med. 2004; 350:684-93.

2. Joshi HB, Obadeyi OO, Rao PN. A comparative analysis of nephrostomy, JJ stent and urgent in situ extracorporeal shock wave lithotripsy for obstructing ureteric stones. BJU Int. 1999; 84:264-9.

Correspondence

4. Apoku IN, Ayoola OO, Salako AA, Idowu BM. Ultrasound evaluation of obstructive uropathy and its hemodynamic responses in southwest Nigeria. Int Braz J Urol. 2015; 41:556-61.

Bilal Eryildirim, MD Ahmet Sahan, MD Özlem Türkoğlu, MD Murat Tuncer, MD Berkan Simsek, MD Alkan Cubuk, MD (Corresponding Author) alkancubuk@hotmail.com Kartal Dr. Lutfi Kirdar Training a nd Research Hospital, Department of Urology Cevizli Mh Şemsi Denizer Cad. E-5 Karayolu Cevizli Mevkii, 34890 Kartal Istanbul (Turkey)

5. Platt JF, Rubin JM, Ellis JH. Distinction between obstructive and nonobstructive pyelocaliectasis with duplex Doppler sonography.

AJR Am J Roentgenol. 1989; 153:997-1000.

Övünç Kavukoğlu, MD Health Sciences University, Kartal Dr. Lutfi Kirdar Training and Research Hospital, Urology Clinic, Istanbul (Turkey)

6. Cubuk A, Yanaral F, Ozgor F, et al. Comparison of 4.8 Fr and 6 Fr ureteral stents on stent related symptoms following ureterorenoscopy:

Kemal Sarıca, MD Biruni University, Medical School, Urology Clinic, Istanbul (Turkey)

3. Yencilek F, Sarica K, Erturhan S, et al. Treatment of ureteral calculi with semirigid ureteroscopy: where should we stop? Urol Int. 2010; 84:260-4.

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ORIGINAL PAPER

DOI: 10.4081/aiua.2020.3.248

Nephroureterostomy as a treatment of obstructive uropathy: A single center experience Muhammad Faisal Khan 1, Maira Saeed Babar 1, Georgios Tsampoukas 2, Soumya Misra 1 1 Urology 2 Urology

Department North Devon Hospital, Barnstaple, UK; Department Princess Alexandra Hospital, Harlow, UK.

Summary

Objective: To report the outcomes of percutaneous nephroureterostomies performed in a single center a period of ten years.

Materials and methods: We retrospectively collected and analyzed data for 52 nephroureterostomy procedures that were performed from September 2008 to August 2018.

We present patientâ&#x20AC;&#x2122;s demographics, indications for the procedure, type of anesthesia, technical difficulties, length of stay in hospital and complications.

Results: A total of 52 procedures including 13 bilateral nephroureterostomies were performed on 39 patients. Taking into account the need for replacement of nephroureterostomy procedures during the study period, total number of procedures was 168. Out of a total 39 patients, 32 (84%) of patients had advanced cancer. All procedures were performed as day cases using sedation and had no immediate or early complications. Ten patients or 16% (27 nephroureterostomies out of total 168 procedures) had minor complications.

Conclusions: To the best of authorâ&#x20AC;&#x2122;s knowledge, this is the largest case series reporting the outcome of percutaneous nephroureterostomies. We can therefore conclude that percutaneous nephroureterostomy is a useful palliative procedure to relieve ureteric obstruction, when other measures are not possible, and it has low incidence of complications. However, further studies are warranted to compare different procedures used to relieve ureteric obstruction.

KEY WORDS: Nephroureterostomy; Ostructive uropathy; Palliation; Nephrostomy; JJ stent.

Submitted 2 March 2020; Accepted 15 March 2020

INTRODUCTION

Ureteric obstruction is a well-known urological problem that has an overall incidence of 3.1% rising to 5.1% in people over age of 60 years (1). It can result in urinary tract obstruction and subsequently may lead to more serious consequences including, renal failure, sepsis or even death. The obstruction can be reversible or irreversible. The etiology of ureteric obstruction includes ureteric calculi, renal papillary necrosis, strictures, pregnancy, renal tract tumors or pelvic masses. In cases where it is not possible to reverse the etiology, methods such as permanent stents, nephrostomies, ureteric diversion and re-implantation or reconstruction become necessary. Some patients are not fit to undergo extensive surgery. This leaves them with options of either stenting, or external diversion of urine with nephrostomy tubes and urinary bag.

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Stents (Double J or JJ) and nephrostomies have their advantages and disadvantages. Stents are internalized tubes and hence avoid problems associated with external tubes and bags like wound infections, urine bypassing and leakage of urine, tubes falling out and physical/psychological impact of bags hanging out. Disadvantages include stent failure rate of 16-58% (2), stent irritation, pain, infections, hematuria, stent encrustations, stone formation and obstruction and blockage of stents.

Failure rate due to obstruction secondary to primary prostate, bladder and cervical cancer is high with success rates in the range of 15-21% (3). However, success rates are relatively higher at more than 50% (3) in cases of ureteric obstruction secondary to metastatic cancers.

Another challenge with stents is the requirement for frequent changes, which involves anesthesia (general or regional). To some extent, frequent changes can be avoided by inserting metallic stents. Theoretically, metallic stents by virtue of being metallic may help mitigating the need for replacement too frequently, however their complications in terms of stent blockage or stent migration have been reported to be around 18% (4).

Nephrostomies, on the other hand have low initial complication rate of up to 3% (5), and can potentially avoid the requirement for anesthesia and bladder infection, and other complications encountered with stents.

However, these can be difficult for patients to manage in community as these can frequently get blocked, bypass urine and can get easily pulled out or fall off requiring frequent unplanned visits to hospital. New et al. (5) in their systematic review reported that patients spend up to 50% of their remaining time in hospital, though it is not very clear if it is solely due to nephrostomy complications or contributed largely by primary disease and itâ&#x20AC;&#x2122;s related complications. Also for nephrostomy procedures, an experienced interventional radiologist is required which can be a resource issue. Nephrostomy is favoured for patients considered high risk American Society of Anesthesiologist classification (ASA) III + or where stent change is considered difficult. This is true in cases of significant involvement of the bladder by a prostatic or bladder malignancy. This also includes those cases where attempts to identify ureteral orifices fail due to gross haematuria or difficulty in reaching the bladder due to previous surgery or anatomic anomalies (6, 7).

Nephroureterostomy is a modification of the nephrostomy technique, where the internal drainage tube extends No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2020; 92, 3

Nephroureterostomy for obstructive uropathy

from the renal pelvis, down the ureter, into the bladder, therefore, obviating the need for an external bag to collect the urine in most cases. We describe a single center experience of this unique technique in the management of ureteric obstruction. The primary aim was to analyse and report the outcome including complications related to nephroureterostomy in the management of obstructive uropathy.

MATERIALS

AND METHODS

All patients who had the percutaneous nephroureterostomy at our hospital for either malignant or benign conditions causing obstructive uropathy from September 2008 till August 2018 were included in the study. We retrospectively reviewed the computerized record of patient’s admission and discharge, clinic letters, radiology reports, laboratory record and radiologist log of the procedure.

We recorded patient’s demographics, their disease characteristics and procedural details including indication, technical details, difficulty, and post procedure parameters including length of stay in hospital, and complications requiring unplanned hospital attendances.

We counted the initial procedure with follow up change of nephroureterostomy tubes, which brings the total number of procedures done during the above period to 168.

Selection criteria In patients who were being managed with stents, percutaneous nephroureterostomy was chosen as the final option if they were deemed high risk for general anaesthesia (ASA III and above) or if they had technically difficult stent changes. Patients were also considered for a nephroureterostomy as a palliative solution for life, where a nephrostomy had been initially inserted for renal failure or sepsis related to ureteric obstruction.

Brief overview of the technique In preparation for the procedure, we measured skin to renal pelvis distance from the CT imaging done prior to the procedure. Patients had 160 mg Gentamicin as prophylaxis. Lidocaine 1% 10 mls was used for local infiltration and Midazolam 0-5 mg and/or Fentanyl 0-50 mg was used for sedation. Patients were monitored throughout the procedure.

We used AccuStick™ II Introducer Systems (Boston Scientific) with radiopaque marker for easy detection under image intensifier screening. The procedure is as follows: 1. 21-Gauge diagnostic needle with a stylet is inserted into renal pelvis under ultrasound (USS) guidance.

Stylet reduces tissue trauma and bend of needle.

2. Stylet is withdrawn and urine is aspirated from the kidney.

3. This is followed by insertion of a 0.018" kink-resistant nitinol guide wire, which is designed to provide strength.

4. This is followed by a Coaxial sheath/dilator assembly with locking stiffening cannula designed for overthe-wire placement.

5. Dilator is removed and contrast injected into the renal pelvis to outline anatomy on image intensifier.

6. Once operator is satisfied with the positioning of sheath, nitinol guide wire can be exchanged with a working Bentson (Cook®) 0.35” guide wire, which can be advanced down to the bladder and the length of the ureter is measured.

7. If any doubt exists or it is a challenging case due to body mass index (BMI) of patient or any other reason, a second 0.018” guide wire can be passed alongside the first nitinol wire instead of removing it.

8. The Sheath is removed and “Cook®” dilators of 6 French (Fr) and 8 Fr diameter are used to dilate the tract from skin to renal pelvis.

9. This is followed by advancement of Cope nephroureterostomy stent (Cook®)” 8.5Fr, tapered end diameter of 0.038” and ureteric part of stent 22 to 28 cm long. The length of tube is selected as per measurements made with guide wire length needed to approach bladder from renal pelvis.

10. The external end is locked and closed with a stopper after aspiration of urine from the bladder and kidney and position confirmation with of nephroureterostomy with image intensifier.

The following techniques were used to overcome particular challenges.

Pelviureteric junction (PUJ) obstruction with dilated renal pelvis: • The above is procedure is altered at step 7 by aspirating urine from renal pelvis and thus reducing the space and encouraging the guide wire to pass through more easily into ureter.

• If the above step does not work then an TEMPOTM angiographic catheter 4Fr, 65 cm long and 0.038” in diameter with tapered and curved end is introduced over the wire to approach the PUJ and help wire slide through the narrow opening.

Tortuous ureter secondary to hydroureter: • This is again negotiated with the angiographic catheter. The slippery Terumo® angled or straight 0.035” and 150 cm long guide wire is advanced to the bend of ureter. Sliding angiographic catheter to the obstruction follows this. The guide wire is then maneuvered around the bend of ureter gradually until it reaches bladder.

Strictures in ureter: • The slippery Terumo® angled or straight 0.035” and 150 cm long guide wire is passed through the stricture.

If that is successful then Sterling over the wire balloon dilatation catheterTM (Boston Scientific) is negotiated through the stricture. It is 80 cm long with a balloon 100 mm long and 4 Fr (non dilated) to 12 Fr (dilated) in diameter. Once stretched the nephroureterostomy catheter is advanced into the bladder. This dilatation is not the permanent solution of stricture and hence the need for nephroureterostomy remains.

Vesicoureter junction stenosis: • If the above measures fail and it is a very tight stenosis, the distal end of nephroureterostomy is cut. The distal part of nephroureterostomy then remains in disArchivio Italiano di Urologia e Andrologia 2020; 92, 3

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tal ureter. It serves the purpose of anchor, providing extra length thus making it difficult for tube to be dislodged. The proximal end of tube is kept open and connected to bag for drainage.

Following the procedure patients are observed in radiology recovery ward for 4 hours and then sent home.

Change of nephroureterostomy is usually a straightforward procedure mostly without or with minimal sedation. The old tube is removed over a guide wire and a new one inserted over the same wire and position checked with image intensifier. However if tube is blocked than mostly insertion of Amplatz super stiff guide wireTM (Boston Scientific) 0.35â&#x20AC;? in diameter and 145 cm long, through the tube clears the blockage. If that does not work then the old tube is removed and the procedure is repeated as new.

RESULTS

A total of 52 nephroureterostomy procedures were done in 39 patients, with 13 patients having bilateral nephroureterostomy. The median age at the time of initial procedure were calculated as 74.7 years (range 39 to 86). The male to female ratio was 3.3:1.

Nephroureterostomy was not used as first line procedure but was reserved after stents or nephrostomy were not longer considered viable options. The aetiologies of the obstructive uropathy were divided into two broad groups: malignant and non-malignant. The vast majority were due to cancer (85%). In the group with cancer, prostate cancer was the most frequent primary cancer site (n = 17) followed by bladder cancer with 12 patients.

Remaining patients had other pelvic malignancies or metastatic disease in the pelvis. These results are summarised in Table 1.

The AP renal pelvic diameter varied from 11 mm to 56 mm (median 24.5 mm). The calculated skin renal pelvis distance ranged from 3.6 cm to 20.7 cm (median 9 cm).

From the point of view of this study, early complications Table 1.

A summary of aetiology of ureteric obstruction.

Reason for obstructive nephropathy Prostate cancer Bladder cancer Benign ureteric stricture Obstructing stone Endometrial cancer Retroperitoneal mass Colon cancer Posterior urethral valve Metastatic breast cancer

Total number (Percentage) 17 (43.5%) 12 (30.7%) 3 (7.6%) 2 (5.2%) 1 (2.6%) 1 (2.6%) 1 (2.6%) 1 (2.6%) 1 (2.6%)

Table 2.

A summary of late complications.

Total procedures 168

250

Pulled/ fallen 6 (3.5%)

Leaked/ bypass 5 (2.9%)

Blocked

Infection

Sepsis

6 (3.5%)

0

0

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Total complications 17 (9.9%)

were defined as ones occurring during or up to 72 hours after the procedure.

There were no early complications. All patients were discharged home the same day from the radiology department without the need for transfer to inpatient wards.

We recorded as late complications when patients attended hospital for advice or treatment in an unplanned way rather than for regular and planned change of nephroureterostomy. The total number of complications was 10 (16%) if measured per nephrostomy initially inserted. This number stands increases to 27 (19%) if all the follow-up procedures since initial insertion are counted. None of these complications were life threatening or critically significant requiring immediate pharmacological or interventional input. No patients were recorded as having reported pain as the main cause of concern or demanded regular analgesia or removal of nephroureterostomy as a result. There were no infection or sepsis related events. The main complications included pulled/fallen tube, leaked/bypass and blocked tube.

One case was an outlier in respect of number of related hospital attendances. He admitted to self-manipulating tubes as a means to seek medical attention. This led to an exceptionally high number of complications and contributing to 50% (6 out of total 12) of pulled/fallen tubes, 40% (3 out of total of 8) of leakage/bypass and 14% (1 out of total of 7) of blocked tube category. Once the social issues were sorted, the patient had no further problems or complications during the last three years of he study period. If we exclude the outlier from the analysis, the complication rate comes down to 9.9%. This is summarized in Table 2.

DISCUSSION

Our centre is one of the very few centres or perhaps the only centre in the UK performing this radiological-guided procedure for the past few years. It has mainly been performed as a palliative procedure for patients with cancer causing ureteric obstruction. However, it has also been used in our centre for benign conditions.

By conducting a review of the outcome of the procedure, the authors have not only attempted to measure the clinical effectiveness of the procedure for our local centre but also generated baseline data for future reference.

A detailed literature search revealed very few studies that particularly focused on percutaneous nephroureterostomy, and with small numbers, it makes it particularly difficult to compare studies and draw firm conclusions.

We have summarized studies that have captured nephroureterostomy, in Table 3.

This includes case reports (9, 13), insertion techniques (10-12), one short outcome analysis of cost and complications among nephroureterostomy and JJ stent (15), case series (16), and one abstract (17). We found one small study in ileal conduits mentioning complication rate of 16% which is comparable to our study (18).

Monsky et al compared complications for all three types of decompressive procedures but the evaluation was limited to up to 90 days (14) (summarized in Table 4).

Apart from the absence of long term follow up data, studies have also differed in the definition of complica-

Nephroureterostomy for obstructive uropathy

Table 3.

A comparative analysis of studies included.

Study with year of publication Type of study Gemender et al. 2017 (9) Case report Makramalla et al. 2011 (10) Techniques of ureteral catheters/tubes Taveres et al. 2008 (11) Technique of insertion in paediatric pyeloplasty Hadley 2009 (12) Technique of insertion in paediatric pyeloplasty

Type of tube Neproureterostomy Nephrostomy, nephroureterostomy, Stent Nephroureterostomy Nephroureterostomy (KISS catheter or kidney internal splint/stent)

Hatzidakis et al. 2014 (13) Monsky et al. 2013 (14)

Nephroureterostomy Nephrostomy, Nephroureterostomy and JJ stent for 90 days.

Nephroureterostomy and JJ stent

Case report for infected obstructed system by hernia Quality-of-Life assessment after palliative interventions to manage malignant ureteral obstruction Outcome analysis and cost comparison between externalized pyeloureteral and standard stents in 470 consecutive open pyeloplasties Percutaneous nephroureteral tube: a useful tool for management of intractable hematuria Palliative care intervention in oncology: a pictorial review for the inter- ventional radiologist and the palliative care physician

Braga L.H.P et al. 2008 (15)

Spradling et al. 2019 (16) Mahajan et al. (17)

Tal et al. 2003 (18)

External-internal nephro-uretero-ileal stents in patients with an ileal conduit: long-term results

Nephroureterostomy Esophageal, duodenal and colonic stenting, gastrostomy and feeding tubes, percutaneous biliary drainage and stenting, tunneled peritoneal catheters, nephrostomy and nephroureterostomy tubes.

Endobronchial stents, runneled pleural catheters.: Venous stenting for thoracic outlet obstruction, vascular access.

Nephroureterostomy

Table 4.

Monsky et al study elaborated further in this table.

Complications Dislodged Pain Infection

Nephrostomy (16) 7 4 3

Clogged Leak Fistula Total Quality of life (at 90 days)

4 1 0 20 Around 3

Nephroureterostomy (15) Stent (15) 1 1 2 1 1 1 2 2 0 8 Around 3

0 0 1 4 Around 3

Complications Tumour seeding from bladder to skin None discussed None discussed.

10 patients mean 13 days.

2 blocked and flushed, 1 pulled + infection and requiring JJ stent 1 Infection.

None * Short-term comparison. 8.3% complications with Urinoma 1, prolong drainage 5, infection 1 and recurrent obstruction 12 (comparable to JJ stent) Treatment of hematuria with Nephroureterostomy not responsive to cystoscopy management. (6 patients) None mentioned

1 out of 16 had recurrent blockages, 2 out of 16 recurrent infections, 3 had failed exchange

tions. Our complication rates compare favourably to those reported by Ali and Lee (19, 20) and Monsky et al.

(14) (Table 5).

Our study has some limitations. This is a retrospective study and the sample size is small. We were unable to measure the quality of life, as this was not recorded at the time. However we can indirectly infer from the data, that all the patients were able to tolerate nephroureterostomy.

None of the patients requested removal of nephroureterostomy. All the patients undergoing the procedure did not stay in hospital due to pain or discomfort again suggesting good tolerance to the procedure.

Table 5.

Comparison of different studies complications with our study.

Complications

Dislodged Infection/fever Sepsis Clogged Urinoma/extravasation/leak Other organs affected (ileus, pneumonia/atelectasis) Bleeding (requiring transfusion) Pain/Intolerance Total

Ali et al.

Complications of nephrostomy (%) 2.3 No Data 2% 5% 0.3%

Lee et al.

Complications of nephrostomy (%) 4.8% 13.6% 3.6% No Data 4.3%

Monsky et al.

Complications of nephroureterostomy (%) 6.7% 6.7%) 0% 13.3% 13.3%

Our Data Complications of nephroureterostomy (%) 3.5% 0% 0% 3.5% 2.9%

No Data 2.3% Not mentioned 11.9%

5.4% 2.4% Not mentioned 27.7%

0% 0% 13.3% 53.2%

0% 0% 0% 9.9%

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CONCLUSIONS

We have reported results of a large case series of percutaneous nephroureterostomy. This procedure appears safe and well tolerated and can be performed as day case using local anaesthetic/sedation.

Further studies are needed to clarify the position of nephroureterostomy amongst other procedures, which provide renal collecting system decompression.

ACKNOWLEDGMENTS

10. Makramalla A, Zuckerman D. Nephroureteral stents: principles and techniques. Semin Intervent Radiol. 2011; 28:367-379.

11. Taveres A, Manaboriboon N, Lorenzo A, Farhat W. Insertion of an internal-external nephroureteral stent during pediatric laparoscopic pyeloplasty: description of the technique. Urology. 2008; 71:1199-1202.

We acknowledge Dr. Jennifer Macpherson (consultant radiologist) who kindly provided the list of patients who had nephroureterostomy at our hospital.

12. Hadley D, Wicher C, Wallis M. Retrograde Percutaneous Access for Kidney Internal Splint Stent Catheter Placement in Pediatric Laparoscopic Pyeloplasty: Avoiding Stent Removal in the Operating Room. J Endourol. 2009; 23:1991-1994.

REFERENCES

13. Hatzidakis A, Kozana A, Glaritis D, Mamoulakis C. Right-sided Bochdalek hernia causing septic ureteric obstruction. Percutaneous treatment with placement of a nephroureteral double pigtail. BMJ Case Rep. 2014; 2014:bcr2014207247.

2. Wong LM, Cleeve LK, Milner AD, Pitman AG. Malignant ureteral obstruction: outcomes after intervention. Have things changed? J Urol. 2007; 178:178-83;

14. Monsky W, Molloy C, Jin B, et al. Quality-of-life assessment after palliative interventions to manage malignant ureteral obstruction. Cardiovasc Intervent Radiol. 2013; 36:1355-1363.

3. Kouba E, Wallen EM, Pruthi RS. Management of ureteral outcomes. J Urol. 2008; 180:444-50.

15. Braga L, Lorenzo A, Farhat W, et al. Outcome analysis and cost comparison between externalized pyeloureteral and standard stents in 470 consecutive open pyeloplasties. J Urol. 2008; 180:16931699.

1. Bell ET. Renal Diseases. 2nd ed. Philadelphia: Lea & Febiger.

1950:122-125.

4. Agarwal S, Brown CT, Bellamy EA, Kulkarni R. The thermoexpandable metallic ureteric stent: an 11-year follow-up. BJU Int. 2009; 103:372-6.

5. New F, Deverill S, Somani BK. Role of percutaneous nephrostomy in end of life prostate cancer patients: a systematic review of the literature. Cent European J Urol. 2018; 71:404-409.

6. Danilovic A, Antonopoulos IM, Mesquita JL, Lucon AM. Likelihood of retrograde double-J stenting according to ureteral obstructing pathology. Int Braz J Urol. 2005; 31:431-6.

7. Uthappa MC, Cowan NC. Retrograde or antegrade double-pigtail stent placement for malignant ureteric obstruction? Clin Radiol.

2005; 60:608-12.

16. Spradling K, Elliott C, Vo H, Reese J. Percutaneous nephroureteral tube: a useful tool for management of intractable hematuria. Urology. 2019; 126:232-235.

17. Mahajan A, Pugash R, Annamalai G, et al. Conference abstract only. International Symposium on Endovascular Therapy (ISET) 2013. JVIR ISET Abstracts 145.e25-145.e26 18. Tal R, Bachar G, Baniel J, Belenky A. External-internal nephrouretero-ileal stents in patients with an ileal conduit: long-term results. Urology. 2004; 63:438-441.

8. North Devon District Hospital leaflet for â&#x20AC;&#x153;Percutaneous Insertion of a Nephroureterostomy tubeâ&#x20AC;?.

19. Ali SM, Mehmood K, Faiq SM, et al. Frequency of complications in image guided percutaneous nephrostomy. J Pak Med Assoc. 2013; 63:816-20.

Available from: URL: https://www.northdevonhealth.nhs.uk/wpcontent/uploads/2015/05/percutaneous_insertion_nephroureterostomy_tube.pdf.

20. Lee WJ, Patel U, Patel S, Pillari GP. Emergency percutaneous nephrostomy: results and complications. J Vasc Interv Radiol. 1994; 5:135-9.

Correspondence Muhammad Faisal Khan, MD drfaisalkhan@gmail.com Maira Saeed Babar Soumya Misra Urology Department North Devon Hospital, Barnstaple, UK Georgios Tsampoukas, MD tsampoukasg@gmail.com Urology Department Princess Alexandra Hospital, Harlow, UK

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9. Gemender M, Rinzler E, Werder G, Trace A. Seeding of a highgrade papillary urothelial carcinoma of the bladder along a nephroureterostomy tract. Radiol Case Rep 2017; 12:542-545.

Archivio Italiano di Urologia e Andrologia 2020; 92, 3

DOI: 10.4081/aiua.2020.3.253

ORIGINAL PAPER

Intralesional injection of the calcium channel blocker Verapamil in Peyronie's disease: A critical review Murad Asali 1, Muhammad Asali 2 1 Assuta

Medical Center, Ben Gurion University of the Negev, Beer Sheva, Israel; School of Economics, Tbilisi, Georgia; IZA, Bonn, Germany; and School of International and Public Affairs, Columbia University, New York.

2 International

Objective: To assess the effectiveness of an intralesional injection of verapamil in men with Peyronie’s disease (PD).

Materials and Methods: The data provided in the current review are based on a thorough review of the available original articles on PD retrieved with a systematic literature search using PubMed- Medline, and the Cochrane Central Register of Controlled Trials, up to December 2019, to identify studies dealing with Peyronie’s disease and its treatment. Included were only original articles, that we thoroughly evaluated. We searched for the primary and secondary terms of: “Peyronie’s disease,” “Penile curvature,” “Erectile dysfunction,” “Verapamil and Peyronie’s disease,” “Calcium channel blocker,” and “Intralesional injection.”

Results: The initial search of the databases yielded a total of 1240 studies (PubMed: 1058; Cochrane: 182), as of December 2019. Seventy studies were removed due to duplication.

Further 986 studies were removed due to not being in English (except for one study by Arena F. for which we got a translation form Italian), being about animal experimentations, not being full-text, and not being clinical trials. Likewise, studies not referring at all to verapamil were excluded (148). From the remaining 36 full-text articles we focused on 13 studies which met the inclusion criteria, mainly being deemed relevant to the context of this study.

Conclusions: Calcium channel blockers have been shown in both in vitro and in vivo studies to inhibit the synthesis and secretion of extracellular matrix molecules, as well as to increase collagenase activity. Patients with localised plaque are the best candidates for intralesional injections of verapamil. The beneficial effects of intralesional verapamil are apparent within the first three months. For patients who respond to treatment, the injections should be continued for six months. Patients who fail to respond to intralesional verapamil or whose angulation is greater than 30° at presentation should be considered candidates for surgery. Injection of verapamil is clinically safe for patients with Peyronie’s disease, and it appears to induce a rapid, beneficial effect in patients for the reduction of plaque size. Intralesional verapamil injection for Peyronie’s disease could reduce pain, decrease penile curvature, and improve sexual function.

Summary

KEY WORDS: Peyronie’s disease, Verapamil, Calcium channel blocker, Penile curvature, Erectile dysfunction.

is 3.2% to 8.9% (2, 3). Although more than 260 years have elapsed since de la Peyronie's description, the disease is not yet well understood. No perfect treatment is available, and many surgical and non-surgical approaches have been suggested and used in practice. illiams and Thomas were the first to describe the natural course of the disease, and they claimed that all of the patients they followed maintained the same plaques, unchanged over time; therefore, they suggested that these patients should be followed and that there was no need for any treatment. When their data were examined later, however, it was found that there were not sufficient follow-up studies conducted and that the followup varied from patient to patient (4). Gelbard et al. and, later, Kadioglu et al. claimed that PD is a progressive disease in most cases and that only in a few cases is the disease ameliorated without treatment (5, 6). In a retrospective review of men with PD, at least one risk factor for systemic vascular disease was identified in 67.5% of patients, and hypercholesterolemia and diabetes were the most common. Patients with at least one risk factor were at a significantly higher risk for severe penile deformity. Their data showed that penile deformities were disabling (greater than 30°) in 62.5% of cases. Risk factors, such as serum lipid abnormalities, diabetes, and hypertension, seemed to have a significant impact on the severity of symptoms and on outcomes (6). Despite the lack of understanding of the aetiology and pathophysiology of the disease, there has been some success with non-surgical approaches, including with vitamin E (tocopherol) (7), colchicines (8), tamoxifen (9), and POTABA (potassium para- aminobinzoate) (10); similarly, different intracavernosal injections have been suggested, including collagenase (11), steroids (12), orgotein (13), interferon alpha 2B (14), and verapamil (a calcium channel blocker) (15-18), and other nonsurgical treatments have been attempted, including radiation (19) and extra-corporeal shockwave therapy (20). It should be noted that vitamin E, colchicine, and tamoxifen can provide some benefit, but there have been no large placebo-controlled trials of these agents (7-9).

Submitted 2 March 2020; Accepted 15 March 2020

MATERIALS

INTRODUCTION

Literature search We carried out a systematic search in PubMed and Medline and the Cochrane Central Register of Controlled Trials, up to December 2019, to identify studies dealing

Peyronie’s disease (PD) was described in the eighteenth century by de la Peyronie as an induration of the male sexual organ’s tunica layers (1). The estimated rate of the disease

AND METHODS

No conflict of interest declared.

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Figure 1.

PRISMA flow diagram.

with Peyronie’s disease and its treatment. Included were only original articles, that we thoroughly evaluated. We searched for the primary and secondary terms of: “Peyronie’s disease”, “Penile curvature”, “Erectile dysfunction”, “Verapamil and Peyronie’s disease”, “Calcium channel blocker” and “Intralesional injection”.

Figure 2.

Risk of Bias Analysis

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Studies selection and evaluation Only results from original studies were included.

The search further imposed the restrictions that: the articles being in English; the studies being performed on humans; that they exist as full-text studies; including clinical trials; referring to verapamil and focused on the

Verapamil in Peyronie’s disease

Table 1.

Modality and results of treatment of Peyronie's disease with verapamil.

Reference

No`

Dose (mg)

Di Stasi SM, et al. (12) Levine LA 1997 (15) Levine LA 1994 (16) Rehman J (17) Arena F (26) Greenfield JM, et al. (29)

47 38 14 7 39 23

5 + 8 mg Dex. 10 10 10-27 10 10

Treatments per week/ length of treatment (weeks) 4/6 2/24 2/24 1/24 2/24 2/12

I/T/E T+E I I I I E

% Pain resolved Yes 97 N/A 100 90.9 N/A

% Curvature improvement 57 76 42 29 50 65

Sexual function improvement % 51% Regained erectile activity 72% Improvement in sexual function 83% Plaque- related changes in erectile function 43% Quality of erection 23.1% Rigidity improvement 66% Erectile function satisfaction

“No`” is the number of patients treated with verapamil and completed the study; “I” stands for Injection; “T” for Transdermal; “E” for Electromotive Drug Administration; and “Dex.” for Dexamethasone.

treatment of this condition. Further, studies which were deemed irrelevant or repetitive were excluded. We used the revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool to assess the risk of bias (RoB) of the reviewed studies.

RESULTS The initial search of the databases yielded a total of 1240 studies (PubMed: 1058; Cochrane: 182), as of December 2019. Seventy studies were removed due to duplication.

Further 986 studies were removed due to not being in English (except for one study by Arena F. for which we got a translation form Italian), being about animal experimentations, not being full-text, and not being clinical trials. Likewise, studies not referring at all to verapamil were excluded (148).

From the remaining 36 full-text articles we focused on 13 studies which met the inclusion criteria, mainly being deemed relevant to the context of this study. Figure 1 presents a PRISMA flow diagram of the studies’ search and selection.

Figure 2 reports the RoB assessment for each of the individual studies, according to the QUADAS-2 tool. The distribution of RoB (low risk, unclear risk, high risk) is also outlined in Figure 2 across the four different domains of risk (patient selection, index test, reference standard, and flow and timing).

DISCUSSION Technique The physician should perform local anaesthesia using a penile block technique with 10 ml bupivacaine 0.5%, should feel and locate the patient’s penis plaque and should hold it between two fingers. At one entrance of the skin, the needle should then be passed into and out of the plaque. To prevent haematoma, the patient is asked to compress the penis over the puncture site.

The standard dosage is 10 mg of verapamil diluted in 10 ml of 0.9% saline, while the solution is distributed into the plaque using a 25-gauge needle. It should be noted that Levine et al. were the first authors to report that 10 mg verapamil resulted in the best overall response with no toxicity (16). The patient is asked to avoid sex for the 24 hours following each treatment (15, 16). Blood pressure and heart rate should be monitored throughout the procedure for the first 3 months and may be discontinued

later. To prevent incidental injury to the dorsal nerve fibres or dorsal arteries, the needle should be inserted into the dorsolateral or lateral side, depending on the location of the plaque. Precaution should be taken not to inject the drug into the corpus cavernosum. Slight, gentle pressure on the syringe is required for injection into the tunica albuginea, whereas injection into the corpus cavernosum does not require pressure (17). Treatment is recommended once every two weeks; once-a-week treatment can lead to inflammatory reactions (16). The recommended duration of treatment is six months, but if no response is achieved in three months, additional verapamil injections are not recommended (15).

Background, analysis, and findings The use of the calcium channel blocker verapamil began in the 1980s and has continued into the twentieth century because of its influence on the production of fibroblasts in the extracellular matrix. Kelly showed that exocytosis in the extracellular matrix, including of collagen, fibronectin, and glycosaminoglycan, is calcium iondependent (21). Askey et al. showed that verapamil inhibits fibroblast secretion (22). Experiments on animals have shown that verapamil decreases peritoneal adhesions (23). Other work has shown that verapamil has an effect on the expression of collagen by its excessive activity and that it actually changes the collagenase activity and extracellular matrix structure changes caused by burns (24). Anderson et al. investigated the influence of verapamil on fibroblasts derived from excised Peyronie’s plaques in a laboratory model, and they found that verapamil had the greatest effect on cell proliferation, compared to other agents, including colchicine, interferon alpha -2b, and prostaglandin E-1 (25). An intracellular balance of ingredients is important so that the production and destruction of fibroblasts play an important role in healing and creating a scar, and the importance of calcium blockers lies in their effect on different levels on fibroblast activity, including production, excretion, and destruction. Therefore, calcium blocker therapy could slow, stop, or even reverse the progression of PD. In 1994, Levine et al. published a series of the first cases with injections of verapamil into plaques in cases of PD. Of the cases reported in this series, there was a decrease in pain in 91%, an improvement in the curvature of the penis in 42%, and an improvement in erectile dysfunction in 58%. The injections were given every other week for six months at a dose of 10 mg per treatment (16). A year later, another series showed once again Archivio Italiano di Urologia e Andrologia 2020; 92, 3

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an improvement in penile curvature as a result of a verapamil injection once every other week for six months, but the improvement was not obvious in cases in which the duration of illness was more than one year (26).

Teloken, however, showed that there was no difference between steroids and verapamil injections but emphasised that the injections were near, and not into, the plaques (27). In 1998, Rehman et al. published their study, which was the first prospective, randomised study of PD. In that study, verapamil injections were administered into the plaques weekly for six months. According to their results, there was improvement in penile curvature but without statistical significance. Erectile dysfunction improved, penile girth increased, and there was a decrease in plaque volume. The authors concluded that the best results were observed in cases with penile curvature of less than 30 degrees (17).

Levine (1997), studying 46 cases that had been treated with injections of verapamil into the plaques, given every two weeks for six months, found that pain lessened in 97% of the cases, curvature improved in 54% of the cases, and erectile dysfunction improved in 72% of the cases (15). A study of a series of 156 cases with PD showed an improvement in penile curvature in 60% of the cases, an increase in penile girth in 83% of the cases, an improvement in rigidity distal to the plaque in 80% of the cases, and improvement in erectile dysfunction in 71% of the cases (18). Other researchers, due to pain at the injection sites and the fears of the patients, have used local verapamil as a gel (28); because of problems with absorption, however, they applied verapamil gel to the penile skin and simultaneously used a local electric current. In a double-blind, prospective study with a control group (Table 1), comparing verapamil to saline in two groups receiving electrical stimulation to improve the results, there was an improvement in penile curvature but no significant difference between the groups. The authors concluded that verapamil gel treatment with electric stimulation is a therapeutic option for patients with mild penile curvature who do not want to receive injections (29). In another prospective study (Table 1) assessing verapamil and steroid injections, using electrical stimulation at the same time, to improve penetration of the drug into the tunica, compared with lidocaine and electrical stimulation as a control, there was improvement in penile curvature and a decrease in plaque volumes (12). As mentioned before, the studies that examined POTABA, vitamin E, colchicine, tamoxifen, and acetyl-L carnitine failed to show consistent beneficial effects on PD, with the exception of POTABA, which may obtain a decrease of plaque size and curvature.

It may be better to use intralesional injection therapy for PD as a first-line therapy, along with oral medication (30). Abern et al. used a combination of penile traction, intralesional verapamil, and oral therapies for PD, showed that there was a trend toward measured curvature improvement and a significant gain in stretched penile length. This combination could be an acceptable nonsurgical treatment for PD (31).

A recent study using Penile traction therapy with the new device Penimaster PRO in a group of patients with stable PD, achieved good results including reduction in curva-

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ture, increased stretched penile length, and improvement in International Index of Erectile Function (IIEF-EF) score with minimal side effects (32). Penile stretching as a treatment for PD was reviewed by Cowper et al. who concluded that penile stretching is an effective therapy for PD (33). Rice et al. reviewed twelve studies with 1025 patients using plaque incision and grafting (PIG). They concluded that PIG is indicated for men with complex or severe penile curvature and, despite a multitude of incision types and grafting materials having been used, no individual technique has proven superiority (34). Barbosa et al. concluded that there is no consensus on which surgical technique achieves better results or fewer complications; therefore, the decision on which technique to use is a matter of surgeon preference. Studies comparing distinctive techniques and either opening or not opening the tunica albuginea should be performed to support surgical decision making (35). In a survey, which represents one of the largest studies on the management of PD, members of the European Society of Sexual Medicine and of various andrology and urology societies across Europe, with the majority (78%) being urologists, were contacted via email and newsletters and asked to fill in an online questionnaire. The survey comprised 56 items developed by an expert consensus of the educational committee of the European Society of Sexual Medicine. In the end, 401 participants responded to the entire survey. Primary treatment options were oral (65%), counseling (57%), and topical/local therapy (30%). Among oral drug users, tadalafil 5 mg was the most commonly used (57%), followed by vitamin E (40%). Regarding intralesional therapy, collagenase clostridium histolyticum was the leading drug (34%), followed by calcium channel blockers (17%). Considering surgical procedures, the original Nesbit technique was the preferred procedure (33%).

The conclusion in the study was that one third of experts and two thirds of patients were dissatisfied with the currently available PD treatment options (36). Vactosertib, a novel, orally bioavailable activin receptor-like Kinase 5 inhibitor, promotes regression of fibrotic plaques in a rat model of PD. Vactosertib induced significant regression of fibrotic plaques in PD rats in vivo through reduced infiltration of inflammatory cells and reduced expression of phospho-Smad2, which recovered erectile function.

Vactosertib also abrogated TGF-b1-induced enhancement of extracellular matrix protein production and hydroxyproline content in PD fibroblasts in vitro by hindering the TGF-b1-induced Smad2/3 phosphorylation and nuclear translocation, and fibroblast-to-myofibroblast trans-differentiation.

In view of the critical role of TGF-b and the Smad pathway in the pathogenesis of PD, inhibition of this pathway with an ALK5 inhibitor may represent a novel, targeted therapy for PD (37).

Dosage and complications The therapeutic level for cardiac arrhythmia or hypertension using a calcium channel blocker is between 0.01 and 0.2 micromoles; in contrast, the therapeutic level needed to affect collagen synthesis is 100 micromoles, so to affect collagen synthesis and avoid toxic levels in serum, there is a need in PD to inject the material into

Verapamil in Peyronie’s disease

the plaques (38). Levine and Goldman, in their 156-case series, reported overall complications in six cases (4%), nausea in three cases, and transient headaches, without any changes in blood pressure and without any cases of cardiac arrhythmia. Three cases noted pain for less than a week. In most cases, there was local ecchymosis with no clinical significance, and no treatment was needed.

There were no cardiovascular events (18). Additionally, in Rehman et al.’s series, in which the patients received a weekly intralesional injection, there were no long-term complications, neither local nor systemic, although there was some ecchymosis that disappeared a short time later (17).

REFERENCES 1. De La Peyronie F. Sur quelques obstacles qui s’opposent al’ejaculation naturelle de la semence. Mem de l’Acad Roy de Chir. 1743; 1:425-434.

2. Schwarzer U, Sommer F, Klotz T, et al. The prevalence of Peyronie’s disease: results of a large survey. BJU Int. 2001; 88:727-730.

3. Mulhall JP, Creech SD, Boorjian SA, et al. Subjective and objective analysis of the prevalence of Peyronie’s disease in a population of men presenting for prostate cancer screening. J Urol. 2004; 171:2350-2353.

4. Williams JL, Thomas GG. The natural history of Peyronie’s disease. J Urol. 1970; 103:75-76.

5. Gelbard MK, Dorey F, James K. The natural history of Peyronie’s disease. J Urol. 1990; 144:1376-1379.

CONCLUSIONS Peyronie’s disease can occur with different combinations of pain and curvature, depending on the levels of plaque in the tunica albuginea or in the dorsal side of the penis, and with erectile dysfunction. The treatment approach is still non-surgical during the first year of the disease.

Treatments include common agents, including vitamin E and POTABA, or drug injections into the tunica layers.

Treatments with steroids or orgotein are not recommended because there are no prospective studies with control groups. Verapamil treatment has been presented in prospective randomised study with a control group.

Verapamil injection into plaques in PD can affect the activity of fibroblasts on several levels, including the proliferation, synthesis, and secretion of proteins in the extracellular space. It also affects collagen breakdown.

These changes can slow, stop, or even reverse the progression of the disease.

Many studies investigating PD and the use of intralesional verapamil injections have shown decreased pain, improvement in penile curvature, improvement in erectile dysfunction, increased penile girth, and postponement of surgery. In cases that were treated with verapamil injections and that were submitted to surgery later, the use of verapamil injections did not compromise the surgical results. Treatment with oral medications has shown negligible improvement of the disease. Treatment with injections into the plaques with verapamil, collagenase or interferon have shown good results, and these injections are considered first-line treatments. For a better understanding of the pathophysiology of the disease, there is a need for more extensive studies on the subject.

It may be that the preferred future treatment lies in a combination of drugs.

Patients with localised plaque are the best candidates for intralesional injections of verapamil. The beneficial effects of intralesional verapamil are apparent within the first three months. For patients who respond to treatment, the injections should be continued for six months. Patients who fail to respond to intralesional verapamil or whose angulation is greater than 30° at presentation should be considered candidates for surgery. Injection of verapamil is clinically safe for patients with Peyronie’s disease, and it appears to induce a rapid, beneficial effect in patients for the reduction of plaque size. Intralesional verapamil injection for Peyronie’s disease could reduce pain, decrease penile curvature, and improve sexual function.

6. Kadioglu A, Tefekli A, Erol B, et al. A retrospective review of 307 men with Peyronie’s disease; results of a large survey. J Urol. 2002; 168:1075-1079.

7. Stojic M, Negrojevic M, Josic P, Stojic S. Conservative therapy of Peyronie’s disease using vitamin E. Med Pregl. 1987; 40:133-135.

8. Akkus E, Carrier S, Rehman J, et al. Is colchicine effective in Peyronie’s disease? A pilot study. Urology. 1994; 44:291-295.

9. Teloken C, Rhoden EL, Grazziotin TM, et al. Tamoxifen vs placebo in the treatment of Peyronie’s disease. J Urol. 1999; 162:2003-2005.

10. Carson CC. Potassium para-aminobenzoate for the treatment of Peyronie’s disease: is it effective? Tech Urol. 1997; 3:135-139.

11. Gelbard MK, James K, Riach P, Dorey F. Collagenase vs placebo in the treatment of Peyronie’s disease: a double-blind study. J Urol. 1993; 149:56-58.

12. Di Stasi SM, Giannantoni A, Stephen RL, et al. A prospective, randomized study using transdermal electromotive administration of verapamil and dexamethasone for Peyronie’s disease. J Urol.

2004; 171:1605-1608.

13. Primus G. Orgotein in the treatment of plastic induration of the penis (Peyronie’s disease). Int Urol Nephrol. 1993; 25:169-172.

14. Ahuja S, Bivalacqua TJ, Case J, et al. A pilot study demonstrating clinical benefit from intralesional interferon alpha 2B in the treatment of Peyronie’s disease. J Androl. 1999; 20:444-448.

15. Levine LA. Treatment of Peyronie’s disease with intralesional verapamil injection. J Urol. 1997; 158:1395-1399.

16. Levine LA, Merrick PF, Lee RC. Intralesional verapamil injection for the treatment of Peyronie’s disease. J Urol. 1994; 151:15221524.

17. Rehman J, Benet A, Melman A. Use of intralesional verapamil to dissolve Peyronie’s disease plaque: a long-term single-blind study.

Urology. 1998; 51:620-626.

18. Levine LA, Goldman KE. Updated experience with intralesional verapamil injection treatment for Peyronie’s disease. J Urol. 2000; 163:170, abstract 751.

19. Bittard H, Schraub S, Bittard M. Treatment of Peyronie’s disease by a combination of radiotherapy and surgery. Apropos of 51 cases. Ann Urol. 1988; 22:67-69.

20. Busetto GM. Extracorporeal shock wave therapy in the treatment of Peyronie's disease: Long- term results. Arch Ital Urol Androl. 2010; 82:128-33.

21. Kelly RB. Pathways of protein secretion in eukaryotes. Science.

1985; 230:25- 32.

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22. Askey DB, Miller EA, Holguin MA, Albertini D.F. The effect of weak electric fields and verapamil on exocytosis in human fibroblasts. J Cell Biology. 1988; 107:336a, abstract 1905.

23. Kappas AM, Barsoum GH, Ortiz JB, Keighley MR. Prevention of peritoneal adhesions in rats with verapamil, hydrocortisone sodium succinate, and phosphatidylcholine. Eur J Surg. 1992; 158:33-35.

24. Lee RC, Doong H, Jellema, AF. The response of burn scars to intralesional verapamil. Report of five cases. Arch Surg. 1994; 129:107-111.

25. Anderson MS, Shankey TV, Lubrano T, Mulhall JP. Inhibition of Peyronie’s plaque fibroblast proliferation by biologic agents. Int J Impot Res. 2000; 12(Suppl 3):S25 -S31.

26. Arena F. Clinical effects of verapamil in the treatment of Peyronie’s disease. Acta Biomed Ateneo Parmense. 1995; 66:269-272.

27. Teloken C. Objective evaluation of non-surgical approach for Peyronie’s disease. J Urol. 1996; 155:633A, abstract 1290.

28. Martin DJ, Badwan K, Parker M, Mulhall JP. Transdermal application of verapamil gel to the penile shaft fails to infiltrate the tunica albuginea. J Urol. 2002; 168:2483-2485.

29. Greenfield JM, Shah SJ, Levine LA. Verapamil versus saline in electromotive drug administration for Peyronie's disease: a doubleblind, placebo controlled trial. J Urol. 2007; 177:972-5.

30. Trost LW, Gur S, Hellstrom WJ. Pharmacological management of Peyronie's disease. Drugs. 2007; 67:527-45.

31. Abern MR, Larsen S, Levine LA. Combination of penile traction,

Correspondence Murad Asali, MD (Corresponding Author) muradasali@hotmail.com Assuta Medical Center, Ben Gurion University of the Negev Sokolov 26/99, Beer Sheva 8430905 (Israel) Muhammad Asali International School of Economics, Tbilisi (Georgia; IZA, Bonn (Germany); and School of International and Public Affairs, Columbia University, New York (United States)

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intralesional verapamil, and oral therapies for Peyronie's disease. J Sex Med. 2012; 9:288-95.

32. Moncada I, Krishnappa P, Romero J, et al. Penile traction therapy with the new device 'Penimaster PRO' is effective and safe in the stable phase of Peyronie's disease: a controlled multicentre study.

BJU Int. 2019; 123:694-702.

33. Cowper MG, Burkett CB, Le TV, et al. Penile stretching as a treatment for Peyronie's disease: A review. Sex Med Rev. 2019; 7:508-515.

34. Rice PG, Somani BK, Rees RW. Twenty years of plaque incision and grafting for Peyronie's disease: a review of literature. Sex Med. 2019; 7:115-128.

35. Barbosa ARG, Takemura LS, Cha JD, et al. Surgical Treatment of Peyronie's Disease: Systematic review of techniques involving or not tunica albuginea incision. Sex Med Rev. 2019; pii: S20500521(19)30082-4.

36. Porst H, Burri A; European Society for Sexual Medicine (ESSM) Educational Committee. Current strategies in the management of Peyronie's disease (PD)-Results of a survey of 401 sexual medicine experts across Europe. J Sex Med. 2019; 16:901-908.

37. Song KM, Chung DY, Choi MJ, et al. Vactosertib, a novel, orally bioavailable activin receptor-like kinase 5 inhibitor, promotes regression of fibrotic plaques in a rat model of Peyronie's disease.

World J Mens Health. 2019 Aug 27. doi: 10.5534/wjmh.190071.

[Epub ahead of print] 38. Lee RC, Ping JA. Calcium antagonists retard extracellular matrix production in connective tissue equivalent. J Surg Res. 1990; 49:463-466.

DOI: 10.4081/aiua.2020.3.259

ORIGINAL PAPER

Best time to wait for the improvement of the sperm parameter after varicocelectomy: 3 or 6 months?

Mohammad Ali Ghaed 1, Seyed Alireza Makkian 2, Asaad Moradi 1, Robab Maghsoudi 1, Alireza Gandomi-Mohammadabadi 3 1 Urology

Department, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran; University of Medical Sciences, Tehran, Iran; 3 Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.

2 Iran

Summary

Objective: To estimate the duration of time required following varicocelectomy to wait for the improvements of semen parameters. Therefore, we characterized the changes with the time in sperm parameters in men after varicocelectomy.

Materials and methods: In this prospective cohort study we included consecutively observed men who underwent varicocelectomy between September 2017 and September 2018 in a referral academic hospital. Clinical data of the patients, as well as their semen parameters, were measured before surgery and at 3 and 6 months afterward.

Results: In this study, a total of 100 men with average age of 29.5 Âą 6.2 years were included. Mean sperm concentration and sperm motility significantly improved by 3 (p < 0.05), but not by 6 months following varicocelectomy. The semen volume and sperm with normal morphology were the same before and after surgery (p > 0.05). There was no statistically significant difference in the improvement of semen parameters when comparing 6 months to 3 months postoperatively (p > 0.05).

Conclusions: Sperm parameters (concentration and motility) improve by 3 months after varicocelectomy without further improvements. Consequently, physicians should decide quickly after 3-month of varicocelectomy if surgery has been not helpful and then plan other therapies, like assisted reproductive technology (ART) for managing infertility in couples.

KEY WORDS: Varicocelectomy; Male infertility; Semen parameters; Time factors; ART. Submitted 2 March 2020; Accepted 15 March 2020

INTRODUCTION

Varicocele is the most common but correctable cause of infertility in men and is defined as dilated tortuous veins of the pampiniform plexus in the spermatic cord (1).

Its prevalence rate is 30% in men with primary infertility, up to 80% in men with secondary infertility and 15% in general adult male population (2). The pathophysiology of varicocele-associated infertility has not been well defined. It is thought to be related to the impairment of spermatogenesis induced by increased testicular blood flow, scrotal hyperthermia, reflux of renal and adrenal metabolites, hypoxia from venous stasis and endocrine dysfunction (3, 4).

In current practice, varicocelectomy, drug therapy and Assisted Reproductive Technology (ART) including intrauterine insemination (IUI), in vitro fertilization (IVF), or intracy-

toplasmic sperm injection (ICSI) are some modalities approved for men with varicocele-associated infertility (2).

To date, varicocelectomy is one of the most popular modality. There are various ways to perform varicocele repair, including surgical ligation (with or without microscopic approach), laparoscopic surgery and embolization (5-8).

The effectiveness of varicocelectomy on male fertility has remained in doubt (3, 9). Numerous studies including systematic reviews on clinical results of varicocelectomy have reported improvements in fertility rates and semen parameters (10-14). However, some studies have reported controversial results, consisting of an unstable improvement in fertility following surgery or even worsened semen parameter (15-17).

For both couples and physicians, it is important to know the time needed to wait after varicocelectomy for the best improvement in semen parameters. So they can assess better the changes in semen parameters and the need to plan on other therapies as invasive forms of ART (18). According to the report of the Practice Committee of American Society for Reproductive Medicine in 2014, time to improvement in semen parameters following varicocelectomy is usually 3 to 6 months (19). While this has become a common practice, there are only a few studies that assess the time needed to wait for the improvement of sperm parameters following varicocelectomy.

Therefore, this study was evaluated the time-dependent changes in semen parameters in men who underwent microsurgical inguinal varicocelectomy and had semen analyses at baseline, and 3 and 6 months following surgery to estimate the duration of time required to wait for improvement of semen parameters.

MATERIALS

AND METHODS

This prospective cohort study was conducted in consecutive men who underwent unilateral inguinal varicocelectomy. It was carried out in a referral academic hospital between September 2017 and September 2018 after approval of ethical committee of Iran University of Medical Sciences. All patients filled an informed written consent form. Inclusion criteria were infertile men who had a leftsided palpable varicocele (grade I/II/III) and were further documented with Doppler duplex ultrasound with at least

No conflict of interest declared.

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one or more abnormal semen parameter and also adolescents who had left palpable varicocele and objective evidence of reduced ipsilateral testicular size more than 20% is in comparison with the right testis (19). Infertility was defined as male partner who was unsuccessful to achieve successful fertility at least after 12 months of regular unprotected sexual intercourse or couples who had been able to get pregnant at least once, but now is unable with female partners normal in fertility re gynecologist.

The semen samples from infertile individuals were classified according to the WHO-2010, and samples with a sperm concentration < 15 million/ml (oligozoospermic) and/or progressive motility (a+b) < 32% (asthenozoospermic) and/or morphologically normal sperm < 4%( teratozoospermic) considered as abnormal.

The largest vein diameter and reversal blood flow of pampiniform plexus of veins were measured. Diagnosis of clinical varicocele was based on 2 criteria: 1) Left-sided venus diameter cut-point values of 2.5 mm in rest or 3 mm during Valsalva and 2) presence of retrograde flow (20).

Exclusion criteria were additional causes of infertility, significant medical diseases, leucocytospermia, azoospermia, patients with a history of probable sexually transmitted diseases and previous history of scrotal or inguinal trauma or surgery.

All patients’ information including demographic information (age, marriage, number of children) and smoking habits were obtained and entered into the checklist.

Then patients underwent microsurgical inguinal varicocelectomy by a single expert urologist.

Masturbation was used to collect semen samples following 3-day period of sexual abstinence. The samples were analyzed within 1 hour after collection to measure the ejaculation volume, sperm concentration, motility and morphology. To eliminate the effects of different test kits from different laboratories, three-stage trials of patients were conducted in a single laboratory. Based on the last guidelines of the World Health Organization (WHO) (2010), computer-aided sperm analysis (CASA) was used to assess sperm concentration, motility and morphology.

We documented any pregnancy that might occur during the study period. Semen analyses were obtained before, 3 and 6 months after surgery. We followed the participants for 6 months after the day of surgery.

The primary outcome measure was characterizing the time-dependent changes of each semen parameter during.

Secondary outcomes were determining spontaneous pregnancy rate after intervention during 6 months follow-up.

The provided data were analyzed by SPSS 18 (statistical package for social sciences, Chicago, IL). Continuous variables with normal distribution were described using

means ± SEM (standard error of mean). Paired t-test was used for comparison between the pre- and post-surgery.

Wilcoxon signed-ranks test was used for the parameters with a non-normal distribution. P-value less than 0.05 were considered statistically significant.

RESULTS

One-hundred patients (mean age = 29.5 ± 6.2 years; range: 17-46) with various grades of varicocele were enrolled in our study. All patients had a left-sided varicocele; six patients (6%) had grade 1 varicocele, 18 (18%) had grade 2, and 76 (76%) had grade 3. Among our patients, 65 patients were married: 39 of them had primary infertility and 26 of them had secondary infertility. The mean of vein dilatation was 3.62 ± 1.2 and the mean of reflux duration in pampiniform plexus of veins was 2.3 ± 1.8 seconds.

Sperm concentration among 78 patients was under 15 million/ml, progressive motility among 49 patients was under 32% and normal morphology among 7 patients was under 4%. Therefore, the 100 individuals with grades I, II & III varicocele were sub-grouped to oligoasthenoteratozoospermic (n = 2), oligoteratozoospermic (n = 5), oligoasthenozoospermic (n = 25) oligozoospermic (n = 46) and asthenozoospermic(n =22). Other demographic data are listed in Table 1.

Sperm concentration and motilities were significantly increased by 3 months but not by 6 months following surgical therapy compared with preoperative. No further significant improvement was found in sperm concentration or motility after 3 months up to 6 months after surgery.

Semen volume and the proportion of sperm with normal morphology did not significantly improve during the study. In Table 2 we summarized the findings of semen parameters analysis before,3 and 6 months after varicocelectomy. Also 24 of the 65 married patients’ wives (37%) Table 1.

Demographic and baseline characteristics of participants.

Characteristic Age (Y) Marriage, n (%) Married Single Smoking, n (%) Type of infertility, n (%) Primary Secondary Grade of varicocele, n(%) 1 2 3

Patients (n = 100) 29.5 ± 6.2 65 (65%) 35 (35%) 67 (67%) 39 (39%) 26 (26%) 6 (6%) 18 (18%) 76 (76%)

Table 2.

Changes in semen parameters at 3 and 6 months after surgery.

Parameters* Semen volume (mL) Sperm concentration (million/mL) Sperm morphology (% normal): Progressive motile sperm count (%)

Timing of semen analysis according to surgery Preoperative 3 Months 6 Months 2.91 ± 1.36 2.94 ± 1.22 2.93 ± 1.30 16.33 ± 20.41 19.36 ± 20.66 17.79 ± 15.36 50.01 ± 21.51 51.40 ± 19.57 49.79 ± 18.80 42.43 ± 22.04 47.98 ± 19.01 46.48 ± 21.58

* Data are expressed as means ± SEM (standard error of mean).

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Before vs. 3 Mo .272 .012 .229 .001

P-Value Before vs. 6 Mo .741 .120 .657 .075

3 Mo After vs. 6 Mo .852 .903 .192 .194

Best waiting time for improving sperm parameter

got pregnant, including 19 (49%) and 5 (19%) in patients with primary and secondary infertility, respectively.

DISCUSSION

The most common diagnosed cause of infertility in men is varicocele, and about 30% of infertile men with primary infertility have varicocele. Many factors such as altered venous pressure, hyperthermia, testicular blood flow, oxidative stress, hormonal imbalance, toxic substances, genetic factors, and lifestyle are among factors that are supposed to have a role in varicocele (21).

In this study, our patients underwent microsurgical varicocelectomy, which has been regarded as the gold standard in comparison with other surgical techniques and radiological management such as retrograde embolization in terms of the recurrence rate and the pregnancy rate (22, 23). While there are conflicting findings regarding the effects of varicocelectomy on fertility rates in couples with infertility, strong accepted evidence and reports suggest it has a positive effect on male reproduction because it upgrades semen parameters, reduces sperm DNA fragmentation, improves ART outcomes and increases spontaneous pregnancy rates (24).

Two meta-analysis by Agarwal et al. (3) and Marmar et al.

(25) in 2007 assessed the effects of varicocelectomy on semen parameters, and concluded that surgical varicocelectomy has a positive effect on all semen parameters in infertile men with a clinical varicocele. In this study, we reported significant increase in sperm concentration and motility at 3 months but not at 6 months after varicocelectomy. However, we did not observe significant improvement in other parameters including sperm morphology and semen volume.

Revised WHO manual (2010) has recommended CASA system as a selective means to analyze semen samples, that it has not been routinely used before 2010 for semen analysis. In this study, we performed semen analysis by using this new method based on the guidelines of the WHO (2010) and confirmed the varicocelectomy effect by a more accurate system. Ariagno et al. (26) also used CASA to assess semen parameters. However, improvement of all semen parameter was insignificant in contrast to our study.

This difference in the improvement of sperm parameters between different studies can be related to the type of male factor infertility, heterogeneity of intrasamples, type of surgery, sample sizes, type of semen assessment, etc.

In addition, varicocelectomy, a low-risk modality with minimal morbidity, has many advantages over the simple improvement of sperm parameters. It could improve other parameters of sperm quality that we do not assess in standard semen testing, such as sperm deoxyribonucleic acid fragmentation rates. Alargkof V, et al. (27), Zini et al. (28) and Smit et al. (29) found that there is a higher degree of DNA fragmentation in patients with varicocele and significantly improvements after varicocelectomy of semen parameters and DNA fragmentation rates in men with infertility.

Previously studies demonstrated varicocelectomy potentially improves semen parameters that lead to applying less invasive and expensive forms of ART or even natural pregnancy (30). In past years, several options other than

varicocelectomy such as IUI and IVF have been introduced to improve couplesâ&#x20AC;&#x2122; chance of conceiving (31).

Accordingly, it has become a common concern for couples to know the duration needed to wait for the improvement of semen parameters after varicocelectomy; since it is unacceptable for most couples, especially those with an elderly woman, to wait a long time for the outcome of varicocelectomy to become clear. Instead, they prefer to continue directly with IUI or IVF, resulting in missing the benefit of varicocelectomy.

Regarding these findings, in this study we retrospectively investigated the time-dependent changes in the semen parameters results in 100 men following varicocelectomy to estimate the time needed to note improvements in semen parameters. Improvements in the semen parameters after 3 months following surgery were not significant in our patients. Al Bakri et al. (32) and Fukuda et al. (24) reported similar findings to our study.

These findings suggest that up to 3 months after surgery, improvement in semen parameters could occur, and further improvement after that time in unexpected.

Therefore, varicocelectomy is an acceptable option for men with clinical varicocele, even for couples with advanced female age; because they could quickly proceed to ART if their semen parameters did not improve up to 3 months after the surgery.

In this study spontaneous pregnancy was achieved in 37% of couples during a 6-month period after varicocelectomy, and rate of pregnancy was higher in patients with primary infertility (49%) in comparison with secondary infertility (19%). Abdel-Meguid TA et al. (9) reported a pregnancy rate of 36.4% during a 12-month follow-up in patients who underwent surgery and concluded varicocelectomy increase odds of spontaneous pregnancy within 1 year of follow-up which is consistent with our results. Contrary to these findings, Nieschlag et al. (33), found no difference in the odds of pregnancy in varicocele-treated patients compared with no treatment, suggesting no benefit for varicocele treatment There are several limitations to this study. Initially, it had a relatively small sample size and was a non-randomized study without a control group. Therefore, the findings of this study need to be confirmed with a larger group to determine definite results. In addition, we followed our patients up to 6 months after surgery. As pregnancy is the ultimate goal for infertility due to this short duration of observation in patients, for efficient evaluation of pregnancy rate, we should consider at least 1-year follow-up, and compare results of intervention group with a control group. Finally, it is better to investigate the characteristics data of the female partner, as her age because of its impact on the decision-making process in couples.

CONCLUSIONS

Sperm parameters (concentration and motility) improve by 3 months following varicocelectomy and then do not improve further by 6 months. This finding could help couples and physicians evaluate better the outcome of surgery and then if required, plan on the use of other approaches, such as ART to manage infertility without prolonged delay.

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ACKNOWLEDGMENT

We would like to show our gratitude to the Rasoul Akram Hospital Clinical Research Development Center (RCRDC) for its technical and editorial assists.

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8. Al-Said S, Al-Naimi A, Al-Ansari A, et al. Varicocelectomy for male infertility: a comparative study of open, laparoscopic and microsurgical approaches. J Urol. 2008; 180:266-70.

9. Abdel-Meguid TA, Al-Sayyad A, Tayib A, Farsi HM. Does varicocele repair improve male infertility? An evidence-based perspective from a randomized, controlled trial. Eur Urol. 2011; 59:455-61.

10. Ghaed MA, Mahmoodi F, Alizadeh HR. Prognostic factors associated with bilateral, microsurgical vasovasostomy success. Middle East Fertility Society Journal. 2018; 23:373-6.

11. Goldstein M, Gilbert BR, Dicker AP, et al. Microsurgical inguinal varicocelectomy with delivery of the testis: an artery and lymphatic sparing technique. J Urol. 1992; 148:1808-11.

12. Kibar Y, Seckin B, Erduran D. The effects of subinguinal varicocelectomy on Kruger morphology and semen parameters. J Urol.

2002; 168:1071-4.

25. Marmar JL, Agarwal A, Prabakaran S, et al. Reassessing the value of varicocelectomy as a treatment for male subfertility with a new meta-analysis. Fertil Steril. 2007; 88:639-48.

26. Ariagno JI, Mendeluk GR, Furlan MJ, et al. Computer-aided sperm analysis: a useful tool to evaluate patient's response to varicocelectomy. Asian J Androl. 2017; 19:449-52.

27. Alargkof V, Kersten L, Stanislavov R, et al. Relationships between sperm DNA integrity and bulk semen parameters in Bulgarian patients with varicocele. Arch ItalUrol Androl. 2019; 91:125-129.

28. Zini A, Blumenfeld A, Libman J, Willis J. Beneficial effect of microsurgical varicocelectomy on human sperm DNA integrity.

Hum Reprod. 2005; 20:1018-21.

29. Smit M, Romijn JC, Wildhagen MF, et al. Decreased sperm DNA fragmentation after surgical varicocelectomy is associated with increased pregnancy rate. J Urol. 2013; 189(1 Suppl):S146-50.

30. Inci K, Hascicek M, Kara O, et al. Sperm retrieval and intracytoplasmic sperm injection in men with nonobstructive azoospermia, and treated and untreated varicocele. J Urol. 2009; 182:1500-5.

31. Tournaye H. Male factor infertility and ART. Asian J Androl.

2012; 14:103-8.

32. Al Bakri A, Lo K, Grober E, et al. Time for improvement in semen parameters after varicocelectomy. J Urol. 2012; 187:227-31.

13. Marmar JL, Kim Y. Subinguinal microsurgical varicocelectomy: a technical critique and statistical analysis of semen and pregnancy data. J Urol. 1994; 152:1127-32.

33. Nieschlag E, Hertle L, Fischedick A, et al. Update on treatment of varicocele: counselling as effective as occlusion of the vena spermatica. Hum Reprod. 1998; 13:2147-50.

14. Segenreich E, Shmuely H, Singer R, Servadio C. Andrological parameters in patients with varicocele and fertility disorders treated by high ligation of the left spermatic vein. Int J Fertil. 1986; 31:200-3.

Correspondence

15. Breznik R, Vlaisavljevic V, Borko E. Treatment of varicocele and male fertility. Arch Androl. 1993;30:157-60.

16. Krause W, Muller HH, Schafer H, Weidner W. Does treatment of varicocele improve male fertility? results of the 'Deutsche Varikozelenstudie', a multicentre study of 14 collaborating centres.

Andrologia. 2002; 34:164-71.

17. Rageth JC, Unger C, DaRugna D, et al. Long-term results of varicocelectomy. Urol Int. 1992; 48:327-31.

18. Masterson TA, Greer AB, Ramasamy R. Time to improvement in

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Mohammad Ali Ghaed, MD - ghaed1982@gmail.com Asaad Moradi, MD - Moradi.a@iums.ac.ir Robab Maghsoudi, MD - rmaghsudy@yahoo.com Urology Department, Firoozgar Hospital, Iran University of Medical Sciences, Tehran (Iran) Seyed Alireza Makkian, MD - alireza.makian@gmail.com Iran University of Medical Sciences, Tehran (Iran) Alireza Gandomi-Mohammadabadi, MD (Corresponding Author) A.gandomi.researcher@gmail.com Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

DOI: 10.4081/aiua.2020.3.263

ORIGINAL PAPER

L-carnitine as primary or adjuvant treatment in infertile patients with varicocele. A systematic review Georgios Tsampoukas 1, 4, Muhammad Faisal Khan 2, Antigoni Katsouri 3, Waseem Akhter 4, Mohamad Moussa 5, Konstantinos Deliveliotis 6, Athanasios Papatsoris 1, 6, Noor Buchholz 1 1 U-merge

Ltd. (Urology for emerging countries), London, UK*; of Urology, North Devon hospital, Barnstaple, UK; 3 Department of Pharmacy, University of Patras, Patras, Greece; 4 Department of Urology, Princess Alexandra Hospital, Harlow, UK; 5 Al Zahraa Hospital, University Medical Center, Lebanese University, Beirut, Lebanon; 6 2nd Department of Urology, University Hospital of Athens, Athens, Greece.

2 Department

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

Background: Varicocele has been found to impair the function of the epididymis resulting in subfertility whereas the varicocelectomy can resolve the phenomenon. L-carnitine is regarded as a biomarker for the function of the epididymis and has been found in reduced concentrations in infertile patients of various causes, including infertile men with varicocele. It seems that Lcarnitine and varicocele share clinical significance and the area of research looks promising.

Objective: To identify the role of L-carnitine in the treatment of varicocele.

Materials and methods: A systematic search was performed in Pubmed/Medline with the terms (L-carnitine) and (varicocele) and (L-carnitine) and (varicocelectomy). Inclusion criteria were studies reported outcomes of L-carnitine administration alone or in duet, as primary or adjuvant treatment to varicocele. Exclusion criteria were non-English language and animal studies. Studies using L-carnitine as part of a panel of therapeutic agents were avoided.

Results: Only four suitable studies were identified for discussion. In one randomized study, the combination of L-carnitine and cinnoxicam improved semen parameters in patients with non-high-grade varicocele compared to L-carnitine alone and had a favourable effect on pregnancy rates but the effect of grade is unknown. In another study, as an adjuvant treatment to varicocelectomy, L-carnitine showed no clear benefit.

Finally, in comparison to surgery, the results are inconclusive; two studies showed some benefit might be expected in low-grade or subclinical varicocele, but surgery appears superior.

Conclusions: The evidence regarding the role of L-carnitine as a primary or adjuvant treatment of varicocele is sparse.

The pathophysiological significance of L-carnitine implicates a potential role of the molecule in the management of varicocele, but the evidence so far is controversial for any recommendations. L-carnitine might be taken into consideration in selected cases; however, further search is needed in order the optimal role of L-carnitine in infertile patients with varicocele to be clarified.

Summary

KEY WORDS: Varicocele; Male infertility; L-carnitine; Antioxidants; Varicocelectomy.

Submitted 2 March 2020; Accepted 15 March 2020

INTRODUCTION -

BACKGROUND

Varicocele is considered one of the most common treatable causes of male infertility (1). The interventional or surgical approach is considered the standard of care for the condition in case of infertility due to favourable outcomes regarding improvement in semen parameters and pregnancy rates (2). In modern era, research has also focused on the varicocele-induced oxidative stress and reduction in antioxidant capacity which results in impaired spermatogenesis, broadening new horizons in the treatment of the condition (3, 4). Antioxidative treatment is well-established in idiopathic infertility and oligoasthenoteratospermia (OAT), albeit the results still conflicting and the optimal agents or combination still lacking (5). Among the investigated agents, L-carnitine (LC) has shown effectiveness on ameliorating oxidative stress, improving semen parameters in infertile patients (6-9). Additionally, the molecule has a significant physiological role and the measurement of seminal L-carnitine is used as biomarker for the assessment of epididymal function in patients with various fertility issues including varicocele (10, 11).

The measurement of L-carnitine in the semen is meaningful and clinical relevant as a positive correlation between seminal carnitine levels and several semen parameters including motility, concentration and DNA quality has been shown in infertile patients with varicocele (12). All the above render LC as a potent biomarker during the evaluation of infertile patients with varicocele and as a potential target in the treatment of such patients as well. In this review, we explore the role of LC in the potential management of varicocele.

MATERIALS

AND METHODS

We performed an systematic literature search using the advanced search engine in PubMed/Medline with the terms (L-carnitine) and (varicocele) and (L-carnitine) and (varicocelectomy).

The results were checked for duplicates in Mendeley. Our search targeted studies reporting conclusions relating to

No conflict of interest declared.

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G. Tsampoukas, M. Faisal Khan, A. Katsouri, W. Akhter, M. Moussa, K. Deliveliotis, A. Papatsoris, N. Buchholz

Figure 1.

PRISMA 2009 Flow Diagram.

the role of carnitine management of varicocele. Only studies using L-carnitine alone or in duet were included and studies reporting results with combination of multiple antioxidants were avoided.

Animal studies, case reports and articles in non-English language were excluded; reviews were also excluded from the literature search but were screened independently for the identification of other sources.

The flowchart of our strategy is presented on Figure 1.

The risk of bias assessment of the selected studies is illustrated on Figure 2.

Figure 2.

Risk of bias of the selected studies.

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RESULTS (Table 1) Performance of L-carnitine in infertile patients with varicocele as sole treatment One study was identified reporting the benefit of LC administration in semen parameters of infertile patients with varicocele-induced OAT. Cavallini et al. randomized patients into 3 groups, group 1 given placebo only, group 2 given oral LC (2 g/d)/acetyl-L-carnitine (1 g/d) and placebo suppository and group 3 given oral LC and suppository cinnoxicam 30 mg every 4 days; the medication were given for a total duration of 6 months whereas the varicocele was graded according to the severity of venous reflux into 5 grades, with grades 1-2 corresponding to subclinical varicocele and grades 3-5 corresponding to clinical grades I, II and III respectively (13). The authors observed that the combination group had significantly increased sperm parameters at 3 and 6 months compared to other groups in patients with grade 1 to 4 whereas the effect was durable as long as patients were on the medication; on the other hand, no treatment made any difference in grade 5 varicoceles. Thus, the authors concluded that the combination of LC and cinnoxicam suppositories proved a reliable treatment for lowgrade varicoceles in terms of semen parameters but not efficient for high grades; notably, the pregnancy rates were also raised in group 3 but there was no special comment regarding the varicocele grade contribution (13).

Performance of L-carnitine in comparison to varicocelectomy Two studies reported outcomes of varicocelectomy compared to administration of LC. In one study, Sofimajidpour et al allocated 62 patients with a mean age of 29 years and mean infertility duration of 3.3 years with clinical varicocele grade II or more into two groups; thirty-one patients were administrated an oral dose of 250 mg LC four times a day for six months and 31 patients underwent varicocelectomy (14). Both groups showed significant improvement in semen parameters including sperm count, motility, morphology and semen volume while no difference was observed between groups (14).

Notably, the study was not randomized and the groups differed significantly in terms of clinical grade (the 87.1% of the participants in the medicinal group had grade II varicocele in comparison to 25.8% of patients in the

L-carnitene and varicocele

Table 1.

Summarized data of the studies.

Scope Placebo vs LC alone vs LC and cinnoxicam on the improvement of semen parameters in infertile patients with idiopathic OAT and infertile patients with OAT and various grades of VC (including SV) Varicocelectomy vs LC alone on the improvement of semen parameters of infertile patients with varicocele of various clinical grades

Type of clinical trial Prospective/ randomized

Number of participants 195 patients into 3 groups *

Main outcome/conclusions Significant improvement in grades I-IV for drug combination but no treatment was effective in grade V

Comments The higher the grade, the lower the benefit of drug therapy; combination group had increased pregnancy rates, but the contribution of grade is unknown

Prospective/ non-randomized (patient preference)

62 patients into 2 groups

No significant difference between groups

JT Seo et al. (2008)

Observation vs varicocelectomy vs LC alone on infertile patients with SV

Retrospective

143 patients into 3 groups

Pourmand et al. (2014)

Varicocelectomy alone vs Varicocelectomy plus adjuvant LC on improvement of semen parameters and DNA in infertile patients with varicocele

Prospective/(block) Randomized

100 patients into 2 groups

Varicocelectomy outnumbered LC monotherapy and observation in both semen parameters and pregnancy rates No statistically significant improvement in terms of parameters and DNA damage

Imbalance of grade contribution between groups as most patients at medical group had grade II and most patients at surgical group had grade III varicocele LC administration was better vs observation in terms of pregnancy rates but inferior to varicocelectomy

Cavallini et al. (2004)

Sofimajidpour et al. (2016)

Lower dose than used in other studies; trend in improvement of DNA damage; longer follow-up might be required (> 6 months)

LC: L-carnitine; OAT: oligoasthenoazoospermia; VC: varicocele; SV: subclinical varicocele; * varicocele group.

surgery group); therefore, it seems that LC supplementation might be an alternative to surgery in infertile patients with grade II varicocele in terms of semen parameters (14). In a retrospective study of 143 infertile patients with left subclinical varicocele, the authors had allocated the participants into 3 groups according to their preference: a surgery group was treated with microsurgical varicocelectomy, a medical group with 3 g of LC orally for at least 6 months and an observation group including patients deciding no treatment (15). The operation increased the sperm count significantly whereas the pregnancy rate raised to 60%; on the contrary, the LC administration did not offer any benefit in terms of semen parameters but the pregnancy rate was 34.5% differing significantly to observation group (18.7%) (15).

Performance of L-carnitine as adjuvant treatment to varicocelectomy Pourmand et al randomized 100 infertile patients with clinical and subclinical varicocele and dyspermia into two groups; the first group underwent varicocelectomy alone whereas patients in the second group were given adjuvant 750-mg oral LC a day for 6 months (16).

The study failed to show any benefit of the adjuvant administration of the agent as neither the semen parameter improvement nor DNA damage reduction differed significantly in the patients underwent combined treatment in comparison to the surgery alone group; however, the slope of improvement for morphology and motility was better in the combination treatment group (16).

DISCUSSION We decided to investigate the role of LC in the management of varicocele for two main reasons. Firstly, the epi-

didymis is considered the main supply of LC to the semen, providing around the 95% of the total amount and this is why seminal LC has been proposed as a marker for the assessment of the functional capacity of the organ (17, 18). The finding is significant as LC acts as a co-factor for the mitochondrial transport and the subsequent oxidation of fatty acids and phospholipids which are used by the epididymal spermatozoa as a substantial source of energy (19). Subsequently, a positive correlation between seminal plasma total carnitine with total sperm count and morphology has been reported, findings suggesting that the determination of seminal carnitine levels may be a useful test in evaluation of male fertility (20), (21). Varicocele has been shown to impair the function of the accessory glands including the epididymis resulting in impaired semen quality (22). Such observations come in accordance with experimental data showing that the induction of varicocele causes impairment in the epididymal microenvironment resulting in reduced epididymal carnitine levels and subsequent hypoxia, increased apoptosis and possible subsequent infertility (23). Moreover, the beneficial effect of varicocelectomy on the epididymal function is reflected as an increase of epididymis-specific proteins such as alphaglucosidase along with the improvement in semen parameters (24). An intriguing point is that seminal Lcarnitine has been reported to be reduced in infertile patients with (low-grade) varicocele and normal semen parameters; the observation is meaningful as it shows that varicoceles might impair epididymal function and cause infertility even if this is not profound in conventional spermiogram, whereas LC could be used to unmask the underlying pathology and facilitate management (25). Secondly, the recent years the increased use of antioxidants as empirical treatment for several condiArchivio Italiano di Urologia e Andrologia 2020; 92, 3

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tions including male infertility has given birth to a phenomenon called â&#x20AC;&#x153;antioxidant paradoxâ&#x20AC;?, which is defined as the unresponsiveness of the body despite the administration of large doses of dietary antioxidants (26). This paradoxical phenomenon along with the possibility of increased toxicity due to excessive use of antioxidants and the harming results of reductive stress have raised concerns for more accurate therapies and specific guidelines in patients suffering from infertility (27). Therefore, we focused our search on LC alone or in dual combination as the molecule has physiological significance and we reviewed its clinical relevance as therapeutic agent.

The performance of LC in infertile patients with varicocele was reported in one randomized study and the authors concluded that the combination of the agent along with cinnoxicam was proven effective for subclinical and lowgrade varicoceles in comparison to LC alone in terms of semen parameters; however, no treatment was efficient for high grades (13). If the varicocele grade affects the outcome of conservative treatment should be a matter of future research as the evidence is sparse. In a doubleblind, placebo-controlled study, the combination of Lcarnitine, fumarate, 5 acetyl- l- carnitine, fructose, CoQ10, vitamin C, zinc, folic acid and vitamin B12 for 6 months significantly improved the total sperm count and total and progressive motility in varicocele patients irrespective of grade; however, the pregnancy rate was not the end point in the study and cannot be assessed (28). In another study, 20 infertile patients with grade I varicocele were given multivitamins LC, vitamin C, coenzyme Q10, vitamin E, vitamin B9, vitamin B12, zinc, selenium and a significant improvement in sperm DNA quality and total sperm count was seen but other semen parameters were not affected (29). Patients with low-grade varicoceles might gain some benefit from the administration of LC in combination with other agents but future studies should explore the effect of conservative treatment on pregnancy rates especially in correlation with clinical grades.

In terms of comparison with standard of care of varicocelectomy, we identified two studies whom the conclusions should be examined carefully; none of the studies were randomized and one study had significant differences between the compared groups (14). Nevertheless, in the latter study, treating grade II varicocele conservatively with LC had similar results with treating grade III varicocele surgically and the authors concluded that conservative management could be an alternative to surgery in grade II varicoceles (14). In the study by Seo et al, treating subclinical varicocele with LC results in inferior pregnancy rates comparing to surgery but the performance was better than the observation (15). The observation comes is accordance with results from meta-analysis that subclinical varicocelectomy has some benefit in male infertility (30). Also, it seems that LC could be an alternative option in infertile patients with non-highgrade varicoceles, but the level of evidence is low. Last but not least, if LC is an alternative to surgery in lowgrade disease needs to be clarified in future, prospective, randomized studies.

Regarding the role of adjuvant LC in patients undergoing varicocelectomy one randomized study was identified which showed no clear benefit; however, there was a

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trend in favour of adjuvant treatment for motility and morphology (16). Similarly, other agents like ascorbic acid have been tested in the same manner with LC showing similar results (31). Although not fully relevant to humans, experimental data have shown that adjuvant treatment with LC may show significant benefit. In one study, Akdemir et al randomized 42 male rats into 7 groups comparing the effects of different varicocelectomy techniques with or without adjuvant LC on spermatogenesis and histopathological changes in testicular tissue (32). The authors observed that varicocelized rats treated with testicular non-artery sparing varicocelectomy and adjuvant LC administration had significantly increased mRNA expression levels of factors inducing the spermatogenesis comparing to other groups; additionally, in this group of patients the germ cells displayed almost total normalization in their cellular organisation (32). The discrepancy between the experimental studies and human cohorts might be associated with the nature of the condition as in experiments the varicocele is an acute phenomenon while in humans the varicocele represents a chronic disease with long-standing effects on the germ epithelium. Although this field is still unexplored, an effort to expand the efficacy of the surgery might be beneficial for some patients. A combined approach could help downgrade the indication in less invasive assisted-reproduction techniques, as this is the case with varicocelectomy in both clinical and subclinical forms (33). In that terms, adjuvant antioxidant treatment might be beneficial increasing the fatherhood chances and reducing the cost as well. If LC can act this role, it needs to be clarified with future research.

CONCLUSIONS LC has a significant physiological role in male reproductive system and its usage sounds promising when evaluating infertile patients with varicocele. As a therapeutic agent, it seems that LC might be used in selected patients, but it cannot replace interventions whereas the level of evidence to support the agent as adjuvant treatment or monotherapy in infertile patients with varicocele is low.

Future, randomized studies should investigate the optimal role of LC in the management of patients with varicocele.

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Correspondence Georgios Tsampoukas, MD scientific-Office@u-merge.com – tsampoukasg@gmail.com Noor Buchholz, MD noor.buchholz@gmail.com – U-merge scientific office Department of Urology, Princess Alexandra Hospital, Harlow (UK) U-merge scientific office 1, Menandrou Street, Athens 14561(Greece) Muhammad Faisal Khan, MD drfaisalkhan@gmail.com Department of Urology, North Devon Hospital, Barnstaple (UK) Antigoni Katsouri, MD a.katsr@gmail.com Department of Pharmacy, University of Patras, Patras (Greece) Waseem Akhter, MD waseemakhter@nhs.net Department of Urology, Princess Alexandra Hospital, Harlow (UK) Mohamad Moussa, MD mohamad.moussa@zhumc.org.lb Al Zahraa Hospital, University Medical Center, Lebanese University, Beirut (Lebanon) Konstantinos Deliveliotis, MD chdeliveli@gmail.com Athanasios Papatsoris, MD agpapatsoris@yahoo.gr 2nd Department of Urology, University Hospital of Athens, Athens (Greece)

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A giant adrenal hemorrhagic pseudocyst mimicking a parapelvic renal cyst: A case report and review of the literature Erhan Ates 1, Arif Kol 1, Gokce Su Gokce 2, Ahmet Emre Yildiz 1, Haluk Erol 1 1 Department 2 Department

of Urology, Aydin Adnan Menderes University School of Medicine, Aydin, Turkey; of Pathology, Aydin Adnan Menderes University School of Medicine, Aydin, Turkey.

Adrenal pseudocysts are rare, nonfunctional, asymptomatic cystic masses that originate from the adrenal gland and are usually located in the suprarenal area. They are usually incidentally discovered during imaging, but diagnosis can be challenging because they are similar to benign and malignant cystic lesions of the adrenal gland and adjacent organs. We describe a giant, adrenal hemorrhagic pseudocyst that was atypically located, extending from the middle to the lower poles of the kidney, admixed with a renal cortical cyst.

Summary

KEY WORDS: Adrenal gland; Adrenal hemorrhagic pseudocyst; Mimicking; Renal cyst.

Submitted 2 March 2020; Accepted 15 March 2020

INTRODUCTION Adrenal gland cysts are rare lesions that are frequently noted today because of the widespread use of imaging modalities. The incidence rate is 0.06-0.18% (1). The cysts are divided into four types: parasitic (7%), epithelial (9%), pseudocystic (39%), and endothelial (45%).

Adrenal pseudocysts are benign nonfunctional masses originating from the cortex or medulla of the adrenal gland. The luminal face is not paved with epithelium, and the walls contain dense fibrous connective tissue and (often) calcified and (sometimes) hyalinized areas (2). The cysts are mostly asymptomatic (being nonfunctional) and thus incidentally recognized (3). The masses are mostly small and located in the suprarenal region, but they may be confused with benign and malignant lesions of the adrenal gland and adjacent organs (4, 5).

We describe a huge (19 cm diameter) adrenal hemorrhagic pseudocyst that was atypically located, extending from the middle to the lower poles of the kidney, admixed with a renal cortical cyst.

CASE

PRESENTATION

A 21-year-old female with left flank pain 3 weeks in duration was referred to our clinic with a diagnosis of a giant parapelvic renal cyst. Her medical history revealed no additional disease, no anticoagulant medication, and no trauma. On physical examination, a palpable mass was detected on the left side. Routine laboratory tests including a complete blood count, biochemistry, and liver function tests were normal; the urine was sterile.

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Ultrasonographic imaging revealed a septate cystic mass in the left kidney. Contrast-enhanced abdominal computed tomography (CT) revealed a septate hypodense cystic lesion with a somewhat thickened, well-circumscribed, non-solid component 14Ă&#x2014;9Ă&#x2014;19 cm in dimension extending from the middle-lower plate of the left kidney to the pelvic region (Figure 1). The attenuation was 16 Hounsfield units (HU) without and 17 HU with contrast.

The lesion was considered a Bosniak type II renal cyst.

Decortication was planned and a lumbar incision was created. The Gerota fascia was opened and a giant cystic mass was observed in the medial, left inferior region of the renal hilum. When the thick fibrous cyst wall was resected from the anterior wall of the hilum, a thick viscous brown liquid with hemorrhagic characteristics was released. We biopsied a frozen section of the cyst wall.

The result was benign; we proceeded with decortication.

Pathological examination revealed a cystic structure featuring intense bleeding and histiocytes that were richly granulated. Cells/cell groups with clear cytoplasm were linearly arranged along the cyst wall (Figure 2A).

Multiple blocks containing cells with clear cytoplasm were negative for cytokeratin, cytokeratin 7, CD68, EMA, vimentin, and CD10 (Figure 2B).

However, melan-A staining was strong to diffuse, and inhibin and calretinin stained positively (Figure 3).

No sample contained epithelium. The findings were compatible with an adrenal hemorrhagic pseudocyst.

DISCUSSION The classification of adrenal cysts was modified by Foster in 1966; four types were recognized: parasitic (7%), epithelial (9%), pseudocystic (39%), and endothelial (45%) (2). Pseudocysts are fibrous walled cysts lacking an epithelium and may develop because of vascular malformation, bleeding of the adrenal gland, or cystic degeneration of a primary adrenal or vascular neoplasm (6). Although pseudocysts are the second most common type of adrenal cysts encountered in the clinic, they constitute the largest group (60%) of cysts encountered intraoperatively (7). They are usually asymptomatic and thus incidentally diagnosed (3). Pseudocysts are more likely to be symptomatic than other adrenal cysts (8).

Although the cysts are usually small, large cysts can cause infection, rupture, hemorrhage, and compression No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2020; 92, 3

Adrenal pseudocyst mimicking a renal cyst

Figure 1.

Cystic mass on the left side in the computed tomography sections.

Figure 2.

2A. Large cells with different sizes of vacuolar cytoplasm and some hyperchromatic cells are observed together; 2B. Cells with vacuolar clear cytoplasm were not stained with CD68.

Figure 3.

Histiocyte-like cells with vacuolar cytoplasm and melan A positive in these cells.

of surrounding organs (3). The increased use of imaging modalities has increased the detection rate of adrenal

cystic lesions (1). Computed tomography, which is 100% sensitive in terms of identifying small tumors, is the gold standard diagnostic method for adrenal masses (9).

The radiological characteristics of adrenal pseudocysts are typical. In CT, most present as uni- or multi-locular cystic lesions with a thin but well-confined wall filled with a liquid similar to water. However, unlike simple cysts, they may exhibit intracavitary blood and septa extending into the cystic cavity, and a solid component that may be focally calcified, inviting confusion with adrenal tumors. In most cases, the lower wall of the cyst is concave or straight, following the contour of the top kidney pole. The renal parenchyma is separated from the cyst wall by anywhere from a few centimeters to 20-30 mm. Thus, adrenal lesions can be differentiated from renal cysts (which are more common) and cystic tumors of the kidney (10). However, it is not always possible to definitively diagnose adrenal pseudocysts, particularly large lesions, via imaging. The differential diagnosis includes malignant adrenal tumors; cystic pathologies of the spleen, liver, and kidney; cystic neoplasms of the pancreatic tail; retroperitoneal mucinous cystic neoplasms; and mesenteric and urachal cysts (5, 11) There are several reasons why an adrenal pseudocyst may be radiologically diagnosed as a renal cyst. An adrenal cyst may develop from an adrenal tumor. In addition, a cyst developing in an adrenal gland that is heterotopically located in the kidney may be wrongly radiologically diagnosed (5). In addition, an adrenal cyst may originate from congenital, adrenal residual tissue or intrarenal, accessory adrenal tissue (12).

Surgical excision is recommended for all adrenal lesions larger than 5 cm in diameter and functional adrenal pseudocysts that may be malignant (13). Some studies have found that adrenal cysts < 4 cm in diameter may also be malignant (9). CT follow-up of lesional size is recommended after a few months (14). Open surgery is preferred because masses larger than 6 cm in diameter may be malignant and open surgery facilitates mass control (15). However, some authors report that a laparoscopic approach is safe in any benign and malignant adrenal mass (16, 17).

There are even studies reporting that the transumbilical approach for laparoendoscopic single-site adrenalectomy for adrenal tumors is a viable and safe alternative to standard laparoscopic adrenalectomy (18). Upon macroscopic examination of surgically resected cysts, endothelial cysts are thin-walled, multiloculated, and contain yellow serous fluid; as in our case, pseudocysts are usually thick-walled, unilocular, and filled with blood or a yellow-brown amorphous liquid (19).

Archivio Italiano di Urologia e Andrologia 2020; 92, 3

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E. Ates, A. Kol, G. Su Gokce, A. Emre Yildiz, H. Erol

CONCLUSIONS Adrenal pseudocysts, which are usually asymptomatic and incidentally diagnosed, may become symptomatic because of infection, rupture, haemorrhage, or (when large) compression of surrounding organs. Imaging may be misleading in terms of diagnosis. Benign and malignant masses of adjacent organs, particularly the adrenal gland and kidney, should be kept in mind during differential diagnosis. A definitive diagnosis requires pathological examination after surgical excision.

REFERENCES 1. Sebastino S, Zhao X, Deng F, et al. Cystic lesions of the adrenal gland: our experience over the last 20 years. Hum Pathol. 2013; 44:1797-1803.

2. Foster DG. Adrenal cysts: review of the literature and report of a case. Arch Surg. 1966; 92:131-143.

3. Papaziogas B, Katsikas B, Psaralexis K, et al. Adrenal pseudocyst presenting as acute abdomen during pregnancy. Acta Chir Belg.

2006; 106:722-725.

4. Yue CT, Liao A, Huang P, et al. A large adrenal pseudocyst mimicking malignant intraabdominal tumor: a case report. Zhonghua Yi Xue Za Zhi (Taipei). 1997; 60:321-325.

5. Fan F, Pietrow P, Wilson LA, et al. Adrenal pseudocyst: a unique case with adrenal renal fusion, mimicking a cystic renal mass. Ann Diagn Pathol. 2004; 8:87-90.

9. Yip L, Tublin ME, Falcone JA, et al. The adrenal mass: correlation of histopathology with imaging. Ann Surg Oncol. 2010; 17:846-852.

10. Lockhart ME, Smith JK, Kenney PJ. Imaging of adrenal masses.

Eur J Radiol. 2002; 41:95-112.

11. Marwah S, Marwah N, Garg S, et al. Adrenal pseudocyst mimicking cystic neoplasm of pancreatic tail. Clin J Gastroenterol. 2011; 4:262-265.

12. Mitchell N, Angrist A. Adrenal rests in the kidney. Arch Pathol.

1943; 35:46-52 13. Wedmid A, Palese M. Diagnosis and treatment of adrenal cyst.

Curr Urol Rep. 2010; 11:44-50.

14. Passoni S, Regusci L, Peloni G, et al. A giant adrenal pseudocyst mimicking an adrenal cancer: Case report and review of the literature. Urol Int. 2013; 91:245-258.

15. Stimac G, Katusic J, Sucic M, et al. A giant hemorrhagic adrenal pseudocyst: case report. Med Princ Pract. 2008; 17:419-421.

16. Ramacciato G, Mercantini P, La Torre M, et al. Is laparoscopic adrenalectomy safe and effective for adrenal masses larger than 7 cm? Surg Endosc. 2008; 22:516-521.

17. Abate D, Giusti G, Caria N, et al. Surgical approach to adrenal ganglioneuroma: Case report and literature review. Arch Ital Urol Androl. 2018; 90:145-146.

6. Mohan H, Aggarwal R, Tahlan A, et al. Giant adrenal pseudocyst mimicking a malignant lesion. Can J Surg. 2003; 46:474.

18. Carvalho JA, Nunes PT, Antunes H, et al. Transumbilical laparoendoscopic single-site adrenalectomy: A feasible and safe alternative to standard laparoscopy. Arch Ital Urol Androl. 2019; 91:1-4.

7. Groben PA, Roberson IB. Immunohistochemical evidence for the vascular origin of primary adrenal pseuodocyts. Arch Pathol Lab Med. 1986; 110:121.

19. Carvounis E, Marinis A, Arkadopoulos N, et al. Vascular adrenal cysts: a brief review of the literature. Arch Pathol Lab Med. 2006; 130:1722-1724.

Correspondence Erhan Ates, MD, Assistant Professor of Urology (Corresponding Author) drerhanates@yahoo.com Arif Kol, MD, Assistant Professor of Urology drarifkol@gmail.com Ahmet Emre Yildiz, MD, Urology aemreyildiz@gmail.com Haluk Erol, MD, Professor of Urology halukerol@yahoo.com Department of Urology, Aydin Adnan Menderes University School of Medicine, 09010, Aydin (Turkey) Gokce Su Gokce, MD gkc.gkc@windowslive.com Department of Pathology, Aydin Adnan Menderes University School of Medicine, Aydin (Turkey)

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8. Erickson LA, Lloyd RV, Hartman R, et al. Cystic adrenal neoplasms. Cancer. 2004; 101:1537-1544.

Archivio Italiano di Urologia e Andrologia 2020; 92, 3

DOI: 10.4081/aiua.2020.3.271

CASE REPORT

Cylinder rerouting for lateral extrusion after inflatable penile prosthesis implantation - Surgical technique revision Paulo Jorge Pinto Pe Leve, João Pedro Cardoso Felício, Pedro Simões de Oliveira, José Manuel Palma dos Reis, Francisco Alves Estrócio Martins Urology Department, Centro Hospitalar Universitário Lisboa Norte, Lisboa, Portugal.

Lateral cylinder extrusion is a potential complication of penile prosthesis implantation. Several methods have been proposed for repairing this complication. We present a case where a cylinder re-routing technique, first described by Dr. John Mulcahy, was used and a revision of the literature.

Summary

KEY WORDS: Penile prosthesis; Lateral extrusion; Surgery.

Submitted 2 March 2020; Accepted 15 March 2020

Introduction Implantation of an inflatable penile prosthesis (IPP) is the definitive solution for the treatment of organic erectile dysfunction (ED) in patients who have failed or are unfit for medical treatment and are motivated to pursue continued erectile function and sexual activity (1).

Although IPP patient satisfaction rates are high, 7.5% of these devices are subject to reoperation, often as a result of mechanical failure. Other common indications for reoperation include patient dissatisfaction, chronic IPP pain, and impending distal or lateral cylinder extrusion.

IPP extrusion comprises approximately 5-33% of reoperations (2). The risk of IPP extrusion appears to be associated with increased time from initial prosthesis placement, prior history of IPP placement, and the presence of corporal fibrosis or deformity.

Several methods have been proposed for repairing IPP extrusion such as closure of the distal corpus cavernosum with replacement of the penile prosthesis in its original position or the use of a patch in order to reinforce the corpus cavernosum (3). If there is no skin erosion this complication can be solved by a cylinder rerouting technique, a technique first described by Dr. John Mulcahy in 1999 (4). His method has been adopted as an elegant and effective approach that avoids the use of foreign material. We present a case where this surgical approach was used and a revision of the literature.

CLINICAL

CASE

A 67-year-old male patient, with a past history of hypertension, type 2 diabetes mellitus, hypothyroidism and ED refractory to medical treatment underwent IPP implantation (AMS 700 CX®) 2 years ago. In the last year he started to complain of inability to deflate the prosthesis and penile axis deviation. He was submitted to a prosthesis surgical revision and a cylinder lateral extru-

sion was identified. He underwent a cylinder re-routing with replacement of both pump and cylinders by the modified Mulcahy technique (4). The surgery was carried out under general anesthesia and lasted 75 minutes.

A 14 Fr Foley catheter was inserted into the bladder and was removed 24 hours after the procedure. There were no intraoperative complications. The prosthesis was maintained inflated for 24 hours post operation. The patient was discharged on the first postoperative day. He resumed sexual intercourse 3 months after the surgery.

At the moment he is satisfied with the functional outcome. No postoperative complications were documented.

Surgical technique description After flexible urethroscopy was performed to ensure that there was no cylinder erosion through the urethra, a subcoronal penile degloving was made and the affected cylinder was exposed (Figure 1A). A lateral longitudinal corporotomy was made over the cylinder. The cylinder was then exposed through the corporotomy (Figure 1B).

Then, a penoscrotal incision was made and prosthesis cylinders and pump were removed. The back wall of the fibrotic sheath (pseudocapsule) containing the cylinder was incised transversely, and a new plane of dissection was developed through homolateral corpus cavernosum behind the sheath, distally to the glans (Figure 1C).

A new space in the distal end of the corpus cavernosum was created and dilated to fit the appropriate cylinder caliber. In this manner, the pseudocapsule back wall that formerly comprised the medial wall of the capsule became the lateral aspect of the new capsule. The new cylinder was introduced into the new space in the corpus cavernosum by the penoscrotal approach using a Keith needle and Furlow inserter (Figure 1D). The incision of the fibrotic sheath and corporotomy were then closed with absorbable suture. The cylinder is now protected by 2 though layers comprising the back wall of the fibrotic sheath and the wall of the corpus cavernosum albuginea.

DISCUSSION This technique was first described by Mulcahy et al. (4) He reported a series of 14 patients with a follow-up of about 2 years with optimal functional outcomes.

Carson and Noh compared corporoplasty using Mulcahy

No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2020; 92, 3

271

P.J. Pinto Pe Leve, J.P. Cardoso Felício, P.S. de Oliveira, J.M. P. dos Reis, F. Alves Estrócio Martins

Figure 1.

A. Affected cylinder exposition. B. Cylinder retraction through the corporotomy. C. Dissection of the posterior plane beneath the pseudocapsule. D. Introduction of the new cylinder in the new cavity by penoscrotal incision.

technique with Gore-tex windsock repair based on their experience with 28 patients who presented with impending extrusion. Mulcahy Rerouting technique was performed in 18 men, with the remaining 10 undergoing repair with Gore-tex windsock.

The authors reported that the operative time was shorter for corporoplasty (mean 53 minutes, range 36-81) compared to the windsock repair (mean 90 minutes, range 64-142). There were no infections or recurrences among men underwent distal corporoplasty. One patient who had a windsock repair developed postoperative infection and two had recurrence of extrusion (6 and 18 months, respectively). Functional results were similar in both groups. The authors concluded that distal corporoplasty is an overall superior method because of fewer major complications and reduced surgical time (5).

Shindel et al. developed a transglanular repair method but reported only 6 cases and identified some limitations such as small working space and brisk bleeding of the glans (6).

We opted for the Mulcahy procedure because of its technical simplicity, less operating time, and avoidance of synthetic material which increases the infection risk and surgical cost (1).

Recently, Carrino et al. evaluated 18 consecutive patients with this corporoplasty technique. The operative time was 85 (± 13.1) minutes. No intraoperative complications were reported. One patient (5.55%) had postoperative infection (7).

This technique is a simple and safe procedure in the

Correspondence Paulo Jorge Pinto Pe Leve, MD (Corresponding Author) paulo.peleve@gmail.com Rua Jaime Cortesão, nº 21, 7050-250 Montemor-o-Novo (Portugal) João Pedro Cardoso Felício, MD Praceta Fernando Valle, nº6 8ºB, 1750-489 Lisboa (Portugal) Pedro Simões de Oliveira,MD pedrosimoesdeoliveira@gmail.com Rua Maria Lamas, 2, 9º direito, 1500-438 Lisboa (Portugal) José Manuel Palma dos Reis, MD jpalmareis@gmail.com Francisco Alves Estrócio Martins, MD faemartins@gmail.com Avenida Professor Egas Moniz, 1649-028 Lisboa (Portugal)

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Archivio Italiano di Urologia e Andrologia 2020; 92, 3

treatment of lateral cylinder extrusion when the prosthetic material is not exposed to the outside surface. It also avoids the costs of the use of additional artificial material.

REFERENCES 1. Levine LA, Becher E, Bella A, et al. Penile prosthesis surgery: current recommendations from the International Consultation on Sexual Medicine. J Sex Med. 2019; 13:489-518.

2. Fuentes JL, Yi YA, Davenport MT, et al. Long-term sequelae of inflatable penile prosthesis: clinical characteristics of patients who develop distal cylinder tip extrusion. Transl Androl Urol. 2020; 9:38-42.

3. Stember DS, Kohler TS, Morey AF. Management of perforation Injuries during and following penile prosthesis surgery. J Sex Med. 2015; 12(Suppl 7):456-461.

4. Mulcahy J. Distal corporoplasty for lateral extrusion of penile prosthesis cylinders. J Urol. 1999; 161:193-195.

5. Carson CC, Noh CH. Distal penile prosthesis extrusion: treatment with distal corporoplasty or Gortex windsock reinforcement.

Int J Impot Res. 2002; 14:81-4.

6. Shindel AW, Brant WO, Mwamukona K, et al. Transglanular repair of impending penile prosthetic cylinder extrusion. J Sex Med. 2010; 7:2884-90.

7. Carrino M, Chiancone F, Battaglia G, et al. Distal corporoplasty for distal cylinders extrusion after penile prosthesis implantation”.

Actas Urol Esp. 2016; 84:38-39.

DOI: 10.4081/aiua.2020.3.273

CASE REPORT

Renal myxoma: An unforeseen diagnosis Rui Miguel Bernardino 1, Luis Severo 1, Luis Mascarenhas Lemos 2, Luis Campos Pinheiro 1 1 Urology

Department, Central Lisbon Hospital Center, Lisbon, Portugal; Department, Central Lisbon Hospital Center, Lisbon Portugal.

2 Pathology

Myxomas are rare tumours that can be found in many anatomical locations.

There are only 17 cases of renal involvement documented.

Our case is an 85 year-old man followed in our consultation with recurrent hematuria after a transurethral resection of a bladder tumour. Evaluation with CT showed a solid lesion with 23 x 18 mm partially obliterating the left inferior calyx.

The patient underwent a left nephroureterectomy. Microscopic examination showed a mass within renal parenchyma adjacent to the renal pelvis composed of plump mildly atypical spindle cells distributed in a copious myxoid matrix.

Immunohistochemical staining for Vimentine, Pankeratin (AE1/AE3-), CD34, CD31 and smooth muscle actin were negative. With these histopathological and immunohistochemical findings, the case was diagnosed as renal myxoma.

Summary

KEY WORDS: Kidney; Cancer; Myxoma.

Submitted 2 March 2020; Accepted 15 March 2020

INTRODUCTION Myxomas are rare benign tumours that can be found in many anatomical locations, such as skin, bones and heart. There are only 17 cases of renal involvement documented. We report a case of a renal myxoma in an old man with history of urothelial tumour, presenting the preoperative imaging evaluation as well as the pathological findings. The present article reports the second case of renal myxoma published in English Literature, that was associated with extensive haemorrhage and the first case of a renal myxoma in a patient with past history of urothelial tumour, which made the differential diagnosis even more difficult.

CASE

PRESENTATION

We present an 85-year-old man, followed in our Institution since January 2017 for bladder tumour.

He underwent transurethral resection of a left lateral wall bladder polyp whose anatomy revealed low grade noninvasive papillary urothelial (or transitional cell) carcinoma(pTa). After surgery the patient maintained haematuria.

Follow-up cystoscopy (3 months after the surgery) did not show lesions suggestive of relapse. The patient had an emergency in June 2017 due to massive haematuria with clots and with repercussion in the hemogram, hemoglobin of 6.5 g/dL, receiving two units of erythrocyte concentrate.

Evaluation with Computed Tomography (CT) showed a solid lesion with 23 x 18 mm partially obliterating the left inferior calyx (Figures 1, 2). At this time, surgery was recommended for this patient not only due to malignant fea-

tures on CT but also for his past history of urothelial tumour. He underwent a left laparoscopic nephroureterectomy. After one year of follow-up, the patient was well and completely symptom-free and the annually routine CT didnâ&#x20AC;&#x2122;t show relapse. He died one year and a half after the surgery from myocardial infraction.

Imaging findings Ultrasound: Renal ultrasound revealed a solid nodular lesion in the middle third of the left kidney with about 23 x 18 mm. Right Kidney had no alterations.

CT: CT scan confirmed a solid lesion partially obliterating the lower left calyx, suspected of urothelial neoplasia (Figures 1, 2). MRI was not done in our case, as the patient had a past history of urothelial tumour, and CT was high suspicious for urothelial neoplasia.

Renogram: He performed renogram showing normal renal function (Left Kidney - 57% and Right Kidney 43%).

Pathological findings Lesion within renal parenchyma adjacent to the renal pelvis, circumscribed, somewhat lobulated, composed of plump mildly atypical spindle cells distributed in a copious myxoid matrix (Figure 3). A subset of these cells had irregular atypical nuclei, although the atypia was more prominent adjacent to the ulcerated surface of the lesion and may therefore be reactive in nature. There is no significant pleomorphism, mitotic activity or necrosis (Figure 4). The lesion cells were positive for vimentin, negative for pankeratin, multifocally positive for smooth muscle actin, while were negative for S-100 protein, CD34, CD31 and pancytokeratin. With the above findings, the lesion was labelled as an atypical myxoid spindle cell neoplasm, consistent with renal myxoma. The lesion has expansive growth conditioning extension and erosion of the adjacent pyelocalyceal structures and no extracapsular extension was documented.

DISCUSSION There is no reports of specific clinical presentation for renal myxoma and, due to its rarity, renal myxoma is often mislead with other malignant lesions (1). When there were clinical manifestations, flank pain was the most common presenting symptom reported in the 17 cases (2). It is known so far that there is no invasion, metastasis or tumour recurrence (3). In our renal myxoma case, the patient had concomitant past history of

No conflict of interest declared.

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R. Miguel Bernardino, L.Severo, L. Mascarenhas Lemos, L.Campos Pinheiro

Figure 1.

CT scan (excretory phase) - confirmed a solid lesion partially obliterating the lower left calyx of about 23 x 18 mm, suspected of urothelial neoplasia.

Figure 2.

Same lesion as shown in figure 1 but in nephrographic phase.

Figure 3.

(100x) – H&E stain Benign mesenchymal lesion, intraparenchymatous, composed of spindle cells, with a slightly eosinophilic cytoplasm and light and focal cytological atypia, arranged around vessels or scattered on a background of myxoid and haemorrhagic stroma.

Figure 4.

(400x) – H&E stain No mitosis or necrosis is documented.

role of percutaneous biopsy? In general, a biopsy should be performed only to avoid unnecessary or incorrect treatment. Appropriate laboratory and diagnostic imaging tests should be exhausted first. Only when these steps prove to be inconclusive should a patient be subjected to the risks, discomfort, and expense of a biopsy (4). In our case, as the patient had a history of urothelial bladder tumour, and the CT was high suspicious for urothelial neoplasia, a percutaneous biopsy was not indicated.

As the radiological characteristics are very close to those of malignancy, they must be treated as malignant tumors, with the patient being surgically treated. For most cases reported, nephrectomy was the treatment of choice due to suspicion to malignancy. Although imaging is required to differential diagnosis, pathological evaluation is needed to differentiate a myxoma from malignancy. Advanced imaging models such as CT guided biopsy can help us to get closer to the diagnosis, but for definitive diagnosis, we need immunohistochemistry evaluation (5). Tumour enucleation of the myxoma would be enough not only for diagnosis but also for treatment, and overall prognosis of this disease is good (1).

CONCLUSIONS • Renal myxomas are extremely rare mesenchymal tumours of the kidney.

• The radiological characteristics are very close to thoseof malignancy, therefore they must be treated as malignant tumors.

• Pathological evaluation is needed to differentiate a myxoma from malignancy.

• If the diagnosis of the lesion before surgery is renal myxoma for sure, the best treatment option would be, tumour enucleation.

REFERENCES 1. Shah A, Sun W, Cao D. Myxoma of the kidney associated with hemorrhage. Indian J Surg. 2013:75(Suppl. 1):S480-3.

urothelial bladder tumour, which made the differential diagnosis with a urothelial neoplasia even more difficult.

The origin of renal myxoma from the renal capsule is less common than parenchymal renal myxoma (1).

Fibroblast is the originary cell of myxoma.

Macroscopically, this tumour shows a gelatinous gross appearance due to production of glycosaminoglycan and it is well-defined (3). Microscopically, the spindle-shaped cell can be seen in the myxoid stroma, and no mitotic activity is seen. In all reported cases, the tumour cells stained positive for vimentin and in most cases negative for S-100 protein, pancytokeratin and CD34.

Renal myxoma is a large heterogeneous mass in imaging exams, predominantly hyperechoic in ultrasonography (US) and hypodense in CT. Myxomas characteristics in imaging is a relatively regular, multilobulated and welldefined mass, only displacing the adjacent structures without invading them. Therefore, pre-operative imaging cannot confidently distinguish myxoma from other renal masses and therefore histopathological confirmation is the only reliable way of doing so. In this context, what is the

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2. Suthar KS, Vanikar AV, Patel RD, et al. Renal myxoma-A rare variety of benign genitourinary tumour. J Clin Diagn Res. 2015; 9:ED11.

3. Hakverdi S, Görür S, Yaldiz M, et al. Renal myxoma: case report and review of the literature. Turk J Urol. 2010; 36:318-21.

4. Young M, Leslie SW. Renal Biopsy. (Updated 2019 Jun 17). In: StatPearls (Internet). Treasure Island (FL): StatPearls Publishing; 2019 Jan-.Available from: https://www.ncbi.nlm.nih.gov/books/ NBK470275/ 5. Salehipour M, Geramizadeh B, Dastgheib N, Makarem A, Asadollah Poor A, Taheri N. Renal myxoma, a case report and review of the literature. Urol Case Rep. 2018; 23:21-22.

Correspondence Rui Miguel Bernardino, MD (Corresponding Author) ruimmbernardino@gmail.com Luis Severo, MD - luis.severo@sapo.pt Luis Mascarenhas Lemos, MD - luisalbuquerquermascarenhas@gmail.com Luis Campos Pinheiro, MD - luiscampospinheiro@gmail.com Centro Hospital de Lisboa Central, EPE - Serviço de Urologia, Alameda de Santo António dos Capuchos, 1169-050 Lisboa (Portugal)

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Note: In any method of payment you choose, kindly specify: 1. journal name; 2. paper ID number; 3. first author.

IMPORTANT REGISTERED

TO KNOW

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.

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

DI

UROLOGIA

E

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 - (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.