Archivio Italiano di Urologia e Andrologia - Vol. 91 - n. 2 - 2019 by Edizioni Scripta Manent

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Archivio Italiano di Urologia e Andrologia / Archives of Italian Urology and Andrology - Vol. 91; n. 2 June 2019

Vol. 91; n. 2, June 2019

ORIGINAL PAPERS 69

Running suture hemostatic technique versus standard reconstruction of the surgical bed in Zero - Ischemia Time mini-flank Open Partial Nephrectomies. Retrospective, Match-Paired Case-Control Study Petar Kavaric, Aleksandar Magdelinic, Marko Vukovic

The variation of selective uNGAL levels after robot-assisted partial nephrectomy: Early results of a prospective single center study Ottavio Colamonico, Giuseppe Cardo, Edmondo Ceci, Marcello Scarcia, Michele Zazzara, Mario Dassira, Angelo Porreca, Giuseppe M. Ludovico

Prostatic calcifications are associated with a more severe symptom burden in men with type II chronic bacterial prostatitis Konstantinos Stamatiou, Vittorio Magri, Gianpaolo Perletti, Alberto Trinchieri, Richard Lacroix, Nektaria Rekleiti, Hippocrates Moschouris

Could pollen extract in association with vitamins be favorable in the reduction of chronic prostatic inflammation? A case-series analysis Michele Zazzara, Arjan Nazaraj, Ottavio Colamonico, Marcella Mastromauro, Giuseppe Cardo, Giuseppe Mario Ludovico

Comparison between “In-bore” MRI guided prostate biopsy and standard ultrasound guided biopsy in the patient with suspicious prostate cancer: Preliminary results Daniele D’Agostino, Federico Mineo Bianchi, Daniele Romagnoli, Paolo Corsi, Marco Giampaoli, Riccardo Schiavina, Eugenio Brunocilla, Walter Artibani, Angelo Porreca

Prostate volume effect on Gleason score upgrading in active surveillance appropriate patients Emre Çamur, Alper Coşkun, Övünç Kavukoğlu, Utku Can, Önder Kara, Arzu Develi Çamur, Kemal Sarıca, Kamil Fehmi Narter

Increased neutrophil/lymphocyte ratio in testicular cancer Aytaç Şahin, Tuncay Toprak, Musab Ali Kutluhan, Yasin Vural, Ahmet Ürkmez, Ayhan Verit

102

The impact of potassium citrate therapy in the natural course of Medullary Sponge Kidney with associated nephrolithiasis Elisa Cicerello, Matteo Ciaccia, Giandavide Cova, Mario Mangano

107

Mini-invasive robotic assisted pyelolithotomy: Comparison between the transperitoneal and retroperitoneal approach Daniele D’Agostino, Paolo Corsi, Marco Giampaoli, Federico Mineo Bianchi, Daniele Romagnoli, Simone Crivellaro, Giacomo Saraceni, Marco Garofalo, Riccardo Schiavina, Eugenio Brunocilla, Walter Artibani, Angelo Porreca continued on page III

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INSTRUCTIONS Official Journal of SIA, SIEUN, UrOP and GUN EDITORIAL BOARD EDITOR

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

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 – Fabio Campodonico, Urology Unit, Galliera Hospitals, Genoa, 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 – Luca Cindolo, Department of Urology, S. Pio da Pietrelcina Hospital, Vasto, Italy – 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 – Massimo Lazzeri, Department of Urology, Humanitas Research Hospital, Rozzano, Italy – Börje Ljungberg, Urology and Andrology Unit, Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden – Andrea Minervini, Urology and Surgical Andrology Unit, Careggi University Hospital, Florence, Italy – 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 – Richard Naspro, Urology Unit, Papa Giovanni XXIII Hospital, Bergamo, 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 – Salvatore Siracusano, Department of Urology, Trieste University Hospital, Trieste, 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

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, Città di Alessandria Clinic, Alessandria, Italy

UrOP EDITORIAL BOARD Mario Coscione, Department of Urology, Santa Rita New Clinic, Benevento, Italy – Gaspare Fiaccavento, Private Practitioner, San Donà di Piave (VE), Italy – Fabio Galasso, Department of Urology, Casa di Cura Malzoni Villa Platani, Avellino, Italy – Massimo Lazzeri, Department of Urology, Humanitas Research Hospital, Rozzano, Italy – Federico Narcisi, Urologia Casa di Cura Villa Anna, S. Benedetto del Tronto (AP), Italy – Christian Ranno, Catania, Oncological Institute of the Mediterranean (IOM), Viagrande (CT), Italy – Vito Pansadoro, Vincenzo Pansadoro Foundation, Rome, Italy – Manlio Schettini, Urology Unit, Casa di Cura Nuova Villa Claudia, Rome, Italy

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

GUN EDITORIAL BOARD

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

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

SIA ASSISTANT EDITORS

HONORARY EDITOR

SIA EDITOR

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

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

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ORIGINAL PAPERS 112

Ureteral access sheath use in retrograde intrarenal surgery Mustafa Karaaslan, Senol Tonyali, Mehmet Yilmaz, Sedat Yahsi, Sedat Tastemur, Erkan Olcucuoglu

115

A “real life” investigation on the prescriptive habits among Italian andrologists: The “CONSER” survey from Italian Society of Andrology (SIA) on Sildenafil oral film Alessandro Palmieri, Mauro Silvani, Bruno Giammusso, Giovanni Liguori, Nicola Mondaini, Fabrizio Palumbo, Stefano Pecoraro, Oreste Risi, Salvatore Sansalone, Fabrizio Ildefonso Scroppo, Alessandro Zucchi, Paolo Verze, Marco Capece, Tommaso Cai

119

Male-to-Female (MtoF) gender affirming surgery: Modified surgical approach for the glans reconfiguration in the neoclitoris (M-shape neoclitorolabioplasty) Andrea Cocci, Francesco Rosi, Davide Frediani, Michele Rizzo, Gianmartin Cito, Carlo Trombetta, Francesca Vedovo, Simone Grisanti Caroassai, Augusto Delle Rose, Valeria Matteucci, Piero Buccianti, Cristina Ceccarelli, Marco Carini, Andrea Minervini, Girolamo Morelli

125

Relationships between sperm DNA integrity and bulk semen parameters in Bulgarian patients with varicocele Viktor Alargkof, Larissa Kersten, Romil Stanislavov, Zdravko Kamenov, Panagiotis Nikolinakos

130

Klinefelter’s syndrome and taurodontism Emilia Giambersio, Vincenzo Barile, Antonio Marcello Giambersio

CASE REPORTS 133

Merkel cell carcinoma with kidney metastasis in a 81-year-old man. A rare case report Aikaterini Anastasiou, Napoleon Moulavasilis, Ioannis Leotsakos, Christos E. Nerantzis, Ioannis Anastasiou

135

Malignant solitary fibrous tumor of urinary bladder: A rare clinical entity Zisis Kratiras, Vasileios Spapis, Efthymios Koniaris, Diomidis Kozyrakis, Konstantinos Skriapas

137

A rare cause of clitoromegaly: Epidermoid cyst Selman Karaci, Deniz Kulaksiz, Cagri Akin Sekerci

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

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ll ruolo della SIEUN La SIEUN (Società Italiana di Diagnostica Integrata in Urologia, Andrologia, Nefrologia) riunisce diversi medici specialisti e non che si occupano di tutte quelle metodiche in cui gli ultrasuoni vengono utilizzati a scopo diagnostico ed interventistico in ambito uro-nefro-andrologico. La SIEUN organizza un Congresso Nazionale con cadenza biennale e diverse altre iniziative in genere con cadenza annuale (corsi monotematici, sessioni scientifiche in occasione dei congressi nazionali delle più importanti società scientifiche in ambito Uro-Nefro-Andrologico). Dal 2001 la SIEUN è affiliata all’ESUI (European Society of Urological Imaging); pertanto tutti i soci possono partecipare alla iniziative della Società Europea. L’Archivio Italiano di Urologia e Andrologia è l’organo ufficiale della SIEUN. Questa pagina permette una informazione puntuale sulla attività della nostra Società e consente al Consiglio Direttivo della SIEUN di comunicare non solo ai soci, ma ad una platea più ampia, ogni nuova iniziativa.

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DOI: 10.4081/aiua.2019.2.69

ORIGINAL PAPER

Summary

Objective: To estimate the efficacy of our technique of zero ischemia time partial nephrectomy (ZTPN) with hemostatic running suture and compare it to the standard technique, in terms of perioperative complications, operative time (OT) and estimated blood loss (EBL). Materials and methods: We retrospectively analysed 180 consecutive patients who underwent ZTPN using a supra 11th or supra 12th rib mini flank approach. First group numbered 90 patients treated with running suture hemostatic technique (RSHT), while the control group enrolled 90 patients in whom we performed standard reconstruction technique (SRT). According the propensity score, both groups were similar in terms of tumor size, age and PADUA score. Patients with solitary tumour limited to the kidney (T1-T2a) were included. Our technique included a running suture of surgical bed edges and closure of the renal cortex by the positioning of peri-renal fat within the cortical bed and fixation with interrupted sutures. Results: PADUA score and tumor size were comparable between groups (7.12 ± 1.33 vs 7.1 ± 2.11, p = 0.4 and 52.9 ± 14.8 vs 50.0 ± 13.2, p = 0.3). The mean operative time (OT) was significantly longer in first group (165.2 vs 95, p = 0.04), while median estimated blood loss (EBL) was significantly reduced (250 vs 460 ml, p = 0.02). Surgical resection margins were negative in 100% of cases and no patient developed a local or distant recurrence during follow up. There was significant difference in postoperative GFR value between groups (p < 0.05). Conclusions: Our technique could be safely performed in local, low volume facilities, thus reducing the need for expensive and more challenging minimal invasive surgical techniques..

KEY WORDS: Nephrectomy; Ischemia time; Hemostatic technique. Submitted 12 February 2019; Accepted 13 February 2019

INTRODUCTION

Partial nephrectomy (PN) for localized kidney tumor has oncological outcomes similar to that of radical surgery (1). According to current guidelines, patients with low grade renal cell carcinoma (RCC) should undergo nephron-sparing surgery rather than radical nephrectomy whenever possible (EAU guidelines). Utilizing minimally invasive surgical approaches to open nephrectomy, two mini-flank open techniques have been devel-

oped - the supra 11th rib mini flank approach and supra 12th rib approach (2, 3). These techniques provide optimum anatomical exposure and better aesthetic outcomes with a low risk of long-term complications (2). Typically, for a lower pole tumor, a supra 12th rib incision is more appropriate, while for mid and upper pole tumors a supra 11th incision ispreferred (3). Clamping of the hilar vessels during partial nephrectomy may cause ischemic damage to the kidney and subsequent chronic renal impairment, which implies the necessity for improving zero-ischemia time techniques, especially for long lasting procedures, where ischemia time can be more than 25-30 minutes (4, 5). This led to the development of techniques such as zero ischemia time partial nephrectomy (ZTPN) (6). There are however difficulties with this approach, which include increased intraoperative blood loss compared with on-clamp procedure, hence requiring new, technically less demanding haemostatic techniques with comparable blood loss. The aim of this study was to present our approach – open ZTPN using a running suture hemostatic technique for surgical bed – in order to reduce intraoperative blood loss and maintain stable renal function (RF), comparing to standard reconstruction technique.

PATIENTS

AND METHODS

From 543 patients who underwent tumour nephrectomy in our clinic between January 1997 and March 2017, we retrospectively analysed 186 consecutive patients who underwent PN using supra 11th or supra 12th rib mini flank approach (2, 3). First group numbered 96 patients with running suture hemostatic technique (RSHT), while the control group enrolled 90 patients in whom we performed standard reconstruction technique (SRT). The patients who underwent RSHT were matched to control group according to the following variables: tumor size, age and anatomic classification of renal tumors (PADUA) score. Finally, 90 patients from the first group were matched to 90 patients from the control group. The indication for surgery was solitary renal tumor limited to the kidney (cT1-cT2a). We used preoperative CT or MRI tumor staging according to the

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2004 World health organization (WHO) classification of renal epithelial tumors (7). Patients with the following criteria were excluded: those with blood disorders; evidence of locally advanced or systemic disease; regional adenopathy or previous kidney surgery. The presence of hereditary renal cancers was no contraindication for surgery. The variables we examined when reviewing our database were demographics (age, gender, body mass index), lesion characteristics (location, centrality and size), pathological stage and histological subtype, perioperative variables operative time (OT), estimated blood loss (EBL), postoperative glomerular filtration rate (pGFR), length of hospital stay and intraoperative and postoperative complications (POC) (3). POC were classified according to the modified Clavian system (8). â&#x20AC;˘ The primary end points evaluated included EBL, postoperative creatinine and pGFR, POC and hospital stay. â&#x20AC;˘ The secondary end points evaluated included OT, transfusion rate and surgical margin status. Tumour histology was evaluated using modified Heidelberg histopathological classifications of renal tumors (9). Surgical approach and hemostatic technique After positioning a patient in a standard flank position, we then perform a supra 11th or supra 12th skin and subcutaneous incision, using the mini-flank technique as described by Diblasio et al. (2). After the transection of abdominal wall muscle layers and division of the transverses abdominis fibers, we use a combination of blunt and sharp dissection (finger and Metzenbaum scissors) to divide the transversalis and lumbodorsal fascia, with displacement of the pleura using a sponge stick. We use a self-retaining retractor with an additional bladder blade or Morris retractor to retract the 10th or 11th rib superiorly. Typically, we do not perform resection of the 12th rib. After accessing the retroperitoneal space using bluntdissection and reflecting the kidney with surrounding fat tissue medially, we create the plane between the

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quadrates lumborum and psoas muscle. In the case of upper pole tumours, after medial and lateral mobilisation of the kidney we isolate the ureter from the lower pole and place it in a yellow vessel loop. When operating upper pole tumors, the adrenal gland would be inspected & palpated, and if there is no indication for adrenalectomy we proceed with mobilization of the upper pole of the kidney using LigaSure bipolar current (LigaSuretm, Covidien, Minneapolis, USA). After mobilization of surrounding fat, the kidney is carefully inspected to determine the depth and proximity of the tumour to the renal vessels and collecting system (2). For centrally located tumors and for endophitic ones, we use intraoperative ultrasonography in order to accurately identify tumour borders. Upon demarcation of tumor contours with monopolar current (Figure 1A), we use sharp dissection of tumour tissue together with resection of an approximately 0.5 cm thick rim of tissue from the tumour bed (Figure 1B-C ). We do not perform tumour margins frozen section routinely, even for deep renal tumour specimen. Prominent arterial branches within the tumor bed are ligated with 2/0 Vicryl ligature or clipped using surgical microclips, in order to selectively devascularize the tumour without interruption of normal renal perfusion (6). With incidental break (what do you mean) within the collecting system, the calyces are sutured with 4/0 PDS suture (Figure 1D). After the excision of tumour tissue, we utilize running 4/0 PDS suture of surgical bed edges, with additional hemostatic sutures in case of minor bleeding within the surgical bed (Figure 1E). At the end, we close the renal cortex by placing perirenal fat within the cortical bed and placing size 0 chromic liver interrupted sutures (Figire 1F). Standard reconstruction technique consists of tumor resection and reconstruction of the surgical bed with single, interrupted sutures, followed by application of hemostatic agents within resection cavity (Surgicel; Johnson and Johnson, New Brunswick, New Jersey). The renal capsule is reaproximated using 0 - Vicryl sutures pledged with Surgicel to prevent tearing of the renal cortical capsule and further bleeding (10). The surgical incision is closed using 3/0 absorbable sutures in a subcuticular fashion (2). During the early postoperative period (48h), blood pressure is tightly controlled (e.g. mean arterial pressure (MAP) between 60 - 100 mmHg) in order to avoid additional bleeding from renal parenchyma, but also to maintain safe tissue perfusion and oxygenation, preserving normal postoperative RF.

Figure 1. Surgical technique of ZTPN using running suture technique for surgical bed with fat tissue tamponade: demarcation of tumor with monopolar current (A); sharp dissection of tumor tissue with approximately 0.5 cm thick rim of renal tissue (B); tumor appearance after C); suturing of ruptured calyces and tumor bed (D); hemostatic running suture of wound edges (E); Fat tamponade (F).

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Open partial nephrectomy with specific hemostatic technique

Statistical analysis For statistical analysis we used SPPS v16.0, SPPS, Chicago, IL, USA. Methods of statistical description and significance included the Student T test and Mann Whitney U test. Descriptive analyses were also generated and some data are reported as median, interquartile range (IQR), or number (%). The difference of the obtained values was considered to be significant when p < 0.05, and highly significant when p < 0.01.

RESULTS

Following exclusion criteria and score matching, 180 patients were eligible for this study. According the propensity score, both groups were similar in terms of tumor size, age and PADUA score (52.9 ± 14.8 vs 50.0 ± 13.2 mm, p = 0.3; 57 ± 17.26 vs 55 ± 12.19 years, p = 0.5 and 7.12 ± 1.33 vs 7.1 ± 2.11, p = 0.4, respectively) (Table 1). Median follow up time was 52.75 months in first group and 59.25 within control group (p = 0.3). Additionally, hospital stay and surgical margin status did not differ between the groups. The mean PADUA score in first group was 7.12 ± 1.33 where 14.7% of patients had a score > 8 and 5 patients (5.25%) had a score > 10. The majority of masses (55.5%) were malignant with predominance of the clear cell subtype (67.7%) and exophitic growth (78.9%). The demographic data are given in Table 2. Intraoperatively, three patients (3.3%) from the first group and 7 from the control group (7.77%) required radical nephrectomy due to hilar or deeply penetrating endophytic tumours. Concomitant radical tumor nephrectomy of the other kidney was required in 9 and 7 patients (10% vs 7.77%), with no clinical confirmation of hereditary cancer occurence. No other complications were recorded during surgery. There were 11.2 % and 23.3% POC during follow-up, which were predominantly Clavien grade II (Table 1). Table 1. Comparison of perioperative outcomes between two groups. Mean (SD)/Median (IQR) Group I 90 patients Age (years) 57 (17.26) PADUA score 7.12 (1.33) Tumor size (mm) 52.9 (14.8) Operative time 165.2 (47.31) Estimated blood loss (ml) 250 (100-350) Hospital stay (days) 5 (2.5) Number (%) Surgical margin 0 (100) Transfusion rate 1 (1.1) Complications 11 (12.22) Clavien I 3 Clavien II 5 Clavien III 2 Clavien IV 1 N

Control group 90 patients 55 (12.19) 7.1 (2.11) 50 (13.2) 95 (32.1) * 460 (170-530)* 7 (1.5) 0 (100) 2 (2.2) 21 (23.3)* 7 8 4 2

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

Table 2. Demographic data within first group. Mean (SD)/Median (IQR) N 90 patients Male, n (%) 60 (66.6) Female, n (%) 30 (33.3) Median body mass index, kg/m2 30.75 (7.45) ASA class 3 (1-4) Indication for PN Number (%) Elective 80 (88.2) Solitary kidney 4 (4.4) Bilateral tumors 6 (6.6) Tumor location Number (%) Upper pole 45 (50) Mid pole 9 (10) Lower pole 31 (34.4) Renal hilus 5 (5.6) Tumor histology Number (%) Clear cell 61 (67.7) Papillary 15 (16.7) Oncocytoma 7 (7.8) Chromophobe 3 (3.4) Multilocular cystic 4 (4.4)

Table 3. Comparison of several parameters before and after surgical treatment between groups. First group Creatinine (mg/dl) GFR (ml/min) Control group Creatinine (mg/dl) GFR (ml/min)

Mean (SD)/Median (IQR) Before treatment 72 h after the treatment 1.16 (0.5) 1.10 (0.46) 91.66 (9.5) 95.86 (8.4)** Before treatment 72 h after the treatment 1.10 (0.3) 1.55 (0.76) 88.25 (8.7) 77 (6.8)

* Statistically significant difference comparing preoperativeand postoperative values within first group (p < 0.05). ** Statistically significant difference comparing postoperative values between first and control group (p < 0.05).

Postoperative transfusion rate was 1.1% and 2.2% with a maximum of 1 blood unit required; mean EBL was 250 and 460 ml, while average OT was 165.2 and 95 min. Intraoperative ultrasound was used in 26 patients (28.8%). Surgical resection margins were negative in 100% of all cases (Table 1) and no patient developed a local or distant recurrence during follow up. Table 3 shows pre and postoperative parameters between groups. There was no significant difference in preoperative creatinine value, GFR or haemoglobin (Hgb) between groups (p = 0.43; p = 0.51 and p = 0.6). Nevertheless, GFR was significantly increased in first group during the early postoperative period (98.86 ± 8.4 vs 77 ± 6.8, p = 0.01).

DISCUSSION

The primary goal of this study was to determine whether RSHT could substantially decrease the morbidity associated with SRT, regarding EBL, postoperative creatinine and pGFR. Our results showed that EBL and POC were sigArchivio Italiano di Urologia e Andrologia 2019; 91, 2

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nificantly reduced within first group, while postoperative GFR increased, compared to control group of patients. Nevertheless, OT was significantly prolonged using RSHT. The main goal in PN is to achieve negative tumor margins with a minimal decrease in renal function (RF) and minimal blood loss. Since warm ischemia may be detrimental to RF and cold ischemia may be difficult to achieve during minimally invasive PN, several techniques have been developed in order to avoid clamping of the renal artery (6). Anatomical zero-ischemia PN, introduced by Gill et al. (11) was based on clipping of tumor-specific arterial branches, in order to devascularize the tumor without interruption of normal renal perfusion. This technique led to low EBL (206 ml) with 100% negative surgical margins and a transfusion rate of 21% with POC grade > 3 of 3.5%. We used a similar concept during excision of tumour tissue and after final hemostasis of the surgical bed, mean EBL was 250 ml in first and 460 ml in control group, with a transfusion rate of 1.1% and 2.2% and a 100% negative surgical margin. Although we performed open PN in both groups, mean EBL was significantly lower in group treated with RSHT, which could be associated with meticulous surgical technique and suturing of surgical bed edges with additional fat tissue tamponade. The importance of the improving outcomes of RF through technical modification of resection techniques has already been emphasized (12), with an emphasis on minimization of resection margins and amount of tissue incorporated into renorrhaphy. Desai et al. (13) shares our attitudes on â&#x20AC;&#x2DC;tissue-sparingâ&#x20AC;&#x2122; technique using running suture for wound edges through their reporting of point-specific hemostasis of the parenchymal defect. However, it is worth noting limitations in comparing these techniques with simple interrupted renorrhaphy, as our study describes open technique of PN, while majority of other studies outline a laparoscopic or robotic assisted minimal invasive approach. One of the few papers comparing perioperative and functional outcomes for patients treated with open, off-clamp PN, is research made by Smith et al. (14), where authors retrospectively evaluated 192 patients and reported long operative times (226.5 min), significant EBL (500 ml) and a high transfusion rate (42%). Our study however, found a significantly better outcome in all above mentioned perioperative parameters, which reinforces the importance of the applied surgical technique. Moreover, lack of standardization in off-clamp surgical approach requires more comprehensive studies in order to establish proper technique with adequate hemostasis and preservation of surrounding parenchyma (15). This concept is strongly emphasized by Maurice MJ et al. (16), where volume loss of renal parenchyma was recognized to be the most important modifiable determinant of long term renal function. Tissue sparing technique with simple hemostatic principles could assist in achieving this goal. Kreigmar MC et al. (17) identified 40 cases of open partial nephrectomies, performed without clamping of the renal artery. The mean operative time was shorter compared to our study (106 vs 162.5 min), but EBL was significantly higher (521 vs 250 ml); nevertheless, their study included patients with PADUA scores > 8 and more complexity of tumour localization.

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This indicates that our surgical technique could be improved, since more favourable PADUA scores and tumour positions should lead to shorter operative time. However, complication rate and surgical margin status were comparable between studies. The most common tumour location in our study was upper pole and the majority of patients were elective, with a normal contralateral kidney. This is an important prerequisite for normal postoperative kidney function. Serum creatinine is the easiest and most commonly used tool to assess RF after PN; however, it is not reliable since its value is significantly affected by age, sex, and muscle mass, especially in the presence of a healthy contralateral kidney (18). Nevertheless, determination of GFR has been shown to reflect RF more accurately than serum creatinine. Our study showed significant improvement in RF in the early postoperative period after using RSHT, comparing GFR values between groups. This confirms effectiveness of our technique, even in patients with solitary or bilateral kidney tumours. The impact of different resection and renorrhaphy techniques on postoperative RF and perioperative blood loss has not been sufficiently investigated, and standardized reporting of these techniques for future PN series is warranted (19). Our technique consisted of nephron sparing PN with running suture of the surgical edges and fat tissue tamponade of the surgical bed and showed promising results. Operative time and EBL were at least comparable to other studies using open or minimal invasive ZTPN, with preservation of renal function, negative surgical margins and no signs of tumour recurrence during a median of three years follow up time, with additional low transfusion rate and relatively short hospital stay. Our research could be a starting point for future, so that more comprehensive studies comparing different surgical approaches could be developed. This research, however, has its limitations. First of all, our study concerned only patients treated with an open approach, a single technique and performed by one surgeon. Additionally, our study included only one patient with T2 stage RCC with a relatively low PADUA score. Only few patients had a solitary kidney tumour, so postoperative RF could not be accurately estimated without renal scintigraphy. Finally, the majority of tumours had polar localization (84.4%) and exophitic growth (78.9%), therefore, the risk of complications in our study population may have been inherently lower. During PN surgery, the most important considerations in preserving RF are efforts at minimizing blood loss and reducing operative time, while maximizing renal parenchyma volume. Our surgical technique showed satisfactory results regarding all perioperative outcomes, with no additional technical requirements. It could be safely performed in local, low volume facilities, thus reducing the need for expensive and more challenging minimal invasive surgical techniques. Statement of ethics Each subject signed the acceptance of the study protocol, in which the Ethical Principles for Medical Research Involving Human Subjects (The Helsinki Declaration) were clearly stated. They all signed the written consent form.

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The National Ethical Committee at the University of Montenegro approved this study.

classification of renal epithelial tumors in adults. Int J Urol. 2009; 16:432-43.

REFERENCES

10. Russo P, Mano R, Kimm S. Open Partial Nephrectomy. In: Kean TE and Graham SD, editors. Glennâ&#x20AC;&#x2122;s Urologic surgery. Lippincott Williams & Wilkins, Wolters Kluwer; 2016, p. 7-16.

1. Peycelon M, Hupertan V, Comperat E, et al. Long-Term Outcomes After Nephron Sparing Surgery for Renal Cell Carcinoma Larger than 4 cm. J Urol. 2009; 181:35-41.

11. Gill IS, Patil MB, Abreu AL, et al. Zero ischemia anatomical partial nephrectomy: a novel approach. J Urol. 2012; 187:807-15.

2. Diblasio CJ, Snyder ME, Russo P. Mini-flank supra 11-th rib incision for open partial or radical nephrectomy. BJU Int. 2006; 97:149-56.

12. Minervini A, Ficarra V, Rocco F, et al. Simple enucleation is equivalentto traditional partial nephrectomy for renal cell carcinoma: results of a nonrandomized, retrospective, comparative study. J Urol. 2011; 185:1604-10.

3. Wang H, Sun LA, Wang Y, et al. Mini-flank supra-12th rib incision for open partial nephrectomy for renal tumor with RENAL nephrometry score â&#x2030;Ľ10: an innovation of traditional open surgery. Medicine. 2015; 94:692.

13. Desai M, de Castro Abreu AL, Leslie S, et al. Robotic partial nephrectomy with superselective versus main artery clamping: a retrospective comparison. Eur Urol. 2014; 66:713-9.

4. Browne C, Lonergan PE, Bolton EM, et al. A single centre experience of zero-ischaemia laparoscopic partial nephrectomy in Ireland. Ir J Med Sci. 2017; 186:1023-1026. 5. Rod X, Peyronnet B, Seisen T, et al. Impact of ischaemia time on renal function after partial nephrectomy: a systematic review. BJU int. 2016; 118:692-705. 6. Simone G, Gill IS, Mottrie A, et al. Indications, techniques, outcomes and limitations for minimally ischemic and off-clamp partial nephrectomy: a systematic review of the literature. Eur Urol. 2015; 68:632-40. 7. Lopez-Beltran A, Scarpelli M, Montironi R, et al. 2004 WHO classification of the renal tumors of the adults. Eur Urol. 2006; 49:798-805. 8. 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. 9. Lopez-Beltran A, Carrasco JC, Cheng L, et al. 2009 update on the

14. Smith GL, Kenney PA, Lee Y, et al. Non-clamped partial nephrectomy: techniques and surgical outcomes. BJU Int. 2011; 107:1054-8. 15. Kopp RP, Mehrazin R, Palazzi K, et al. Factors affecting renal function after open partial nephrectomy - a comparison of clampless and clamped warm ischemic technique. Urology. 2012; 80:865-70. 16. Maurice MJ, Ramirez D, Maloc E, et al. Predictors of excisional volume loss in partial nephrectomy: is there still room for improvement? Eur Urol. 2016; 70:413-5. 17. Kriegmar M.C, Pfalzgraf D, Hacker A, et al. ZIRK -Technique: Zero ischemia resection in the kidney for high-risk renal masses: Perioperative outcome. Urol Int. 2015; 95:216-222. 18. Volpe A, Blute ML, Ficarra V, et al. Renal Ischemia and Function After Partial Nephrectomy: A Collaborative Review of the Literature. Eur Urol. 2015; 68:61-74. 19. Minervini A, Carini M, Uzzo RG, et al. Standardized reporting of resection technique during nephron sparing surgery: the surfaceintermediate-base margin score. Eur Urol. 2014; 66:803-5.

Correspondence Petar Kavaric, MD, PhD petar.kavaric@kccg.me Aleksandar Magdelinic, MD acomgd@yahoo.com Marko Vukovic, MD (Corresponding Author) marko.vukovic09@gmail.com Department of Urology, Clinical centre of Montenegro Ljubljanska bb, 81000 Podgorica, Montenegro Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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DOI: 10.4081/aiua.2019.2.74

ORIGINAL PAPER

The variation of selective uNGAL levels after robot-assisted partial nephrectomy: Early results of a prospective single center study Ottavio Colamonico 1, Giuseppe Cardo 1, Edmondo Ceci 2, Marcello Scarcia 1, Michele Zazzara 1, Mario Dassira 3, Angelo Porreca 4, Giuseppe M. Ludovico 1 1 Urology

Department, Ospedale Generale “F. Miulli”, Acquaviva delle Fonti, Bari, Italy; Clinical Biochemistry Department, Ospedale Generale “F. Miulli”, Acquaviva delle Fonti, Bari, Italy; 3 Nuclear Medicine Department, Ospedale Generale “F. Miulli”, Acquaviva delle Fonti, Bari, Italy; 4 Urology Department, Policlinico Abano Terme, Padova, Italy. 2 Specialistic

Summary

Objectives: Acute kidney injury (AKI) secondary to nephron-sparing surgery represents a significant problem in order to preserve renal function. Since serum creatinine alone underestimates the early detection of AKI several biomarker have been investigated. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is considered a good biomarker for AKI. Materials and methods: We report our experience in 28 patients affected by localized renal cell carcinoma and submitted to robot-assisted partial nephrectomy (RAPN). In each patient selective urinary NGAL levels were dosed before surgery, then 2 and 48 hours after the procedure, through a ureteral catheter inserted into the excretory axis of the operated kidney. Moreover, we evaluated split renal function of the preserved renal parenchyma by a 99mTC-DTPA renal scintigraphy, performed before surgery and three months later. Results: AKI was diagnosed, according to internationally criteria, in 3 patients (10.7%). The baseline selective urinary NGAL level was 20.02 ng/ml. This level significantly increased after surgery with a selective urinary NGAL level that reached 56.36 ng/ml (p < 0.0001). Moreover, a significant reduction in 99mTC-DTPA clearance of the operated kidneys after three months was detected (p < 0.0001). Conclusions: Selective urinary NGAL assay represent a sensitive biomarker of acute kidney injury after robotic nephron sparing surgery, capable of predicting the functional outcome of the operated kidney.

KEY WORDS: Neutrophil Gelatinase-Associated Lipocalin (NGAL); Acute kidney injury (AKI); Robot-assisted partial nephrectomy (RAPN). Submitted 18 January 2019; Accepted 25 January 2019

INTRODUCTION

Partial nephrectomy (PN) is the treatment of choice for cT1 (< 7 cm) renal tumors because has demonstrated to offer oncological control equal to that of radical nephrectomy (RN) with superior functional outcomes (1-3). The major goal of the nephron-sparing surgery is maximizing renal function preservation. The three main drivers of post-PN functional recovery, in order of importance, are pre-PN function, remnant vascularized nephron mass, and ischemia time (4) Nowadays robot-

assisted partial nephrectomy (RAPN) is generally preferred by several worldwide centers (5-6) which can performed either with or without hilar clamping. However unclamping hilar control techniques seem to be safe and feasible approaches, with potentially superior functional outcomes, and non-inferior oncological outcomes, when compared with main artery clamping (7). The direct surgical injury and nephron loss that occurs during PN are associated with the risk of occurrence of acute kidney injury (AKI) and chronic kidney disease (CKD). Current criteria for AKI diagnosis and classification depend on serum creatinine (sCr) changes and urine output. (8) Unfortunately, the evaluation of kidney injury by sCr alone underestimates the early diagnosis of AKI, a serious complication after renal surgery, associated with prolonged hospitalization, high morbidity and mortality. The early phase of AKI is accompanied with few symptoms or may be completely asymptomatic (9). Several biomarkers have been investigated in order to identify and anticipate the diagnosis of AKI. Among the others Neutrophil Gelatinase-Associated Lipocalin (NGAL) was extensively evaluated as biomarker of AKI and predictor of CKD (10, 11). NGAL is a ubiquitous 25-KDa protein which expression increases greatly in the presence of a renal damage after ischemia reperfusion injury and nephrotoxicity (12). Nowadays NGAL is considered a biomarker for AKI that has been extensively evaluated in adult and pediatric cardiopulmonary bypass patients (13), kidney transplant patients (14), and patients in intensive care units (15). Production of NGAL is upregulated following renal injury, and consequently detectable in serum and urine hours prior to sCr increases (16). The aim of this study was to evaluate urinary NGAL (uNGAL) both as a marker for early AKI in patients undergoing RAPN for a cT1 renal cell carcinoma and as a marker able to predict the loss of function of the operated kidney.

MATERIALS

AND METHODS

In this prospective study 28 patients undergoing partial robot-assisted nephrectomy for cT1 renal cell carcinoma No conflict of interest declared.

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The variation of selective uNGAL levels after robot-assisted partial nephrectomy: Early results of a prospective single center study

at “Francesco Miulli” Hospital from June 2017 to RAPN while the remaining eleven patients were submitDecember 2017 were enrolled. After approval from the ted to on-clamp RAPN. The choice of hilar clamping institutional review board, we obtained written consent during RAPN was performed according to the surgeon's from all patients. The preoperative clinical tumor staging experience and the characteristics of the tumor. In workup included computed tomography (CT) or magnetic patients who underwent on-clamp RAPN, the mean resonance imaging (MRI) of the abdomen and pelvis and warm ischemia time was 12.6 minutes (Table 2). chest radiography. We included patients with a solitary renal cortical tumour of ≤ 7 cm and imaging of a normal contralateral kidney before surgery. The patient’s age, Table 1. Pre- and peri-operative characteristics of patients gender, Charlson comorbidity index score, preoperative undergoing RAPN for cT1 RRC. sCr, preoperative eGFR: estimated Glomerular Filtration Rate (eGFR), intra and postoperative data and pathologSex Male: 15 (53.5%) ic features (tumor size, PADUA score, histologic type, Female: 13 (46.5%) and Fuhrman’s nuclear grade) were collected. We evaluAge 62.6 years (35-88) ated the post-operative onset of AKI according to KDIGO RCC histotype Clear cell Rcc: 24 (85.7%) criteria (8). In each patient was collected serum Chromophobe Rcc: 3 (10.7%) Neutrophil Gelatinase-Associated Lipocalin (sNGAL) and Papillary Rcc: 1 (3.6%) selective urinary Neutrophil Gelatinase-Associated Lipocalin Fuhrman grade I: 15 (53.5%) (uNGAL) before surgery, 2 and 48 hours after nephronII: 13 (46.5%) sparing surgery. In particular uNGAL was dosed on the pT1 a: 22 (78.5%) b: 6 (21.5%) urine collected selectively through a ureteral catheter inserted into the excretory axis of the operated kidney, Mean tumor diameter (cm) 3,1 (1.2-6.5) before surgery. NGAL was measured into the serum and PADUA score 6-7: 15 (53.6%) 8-9: 10 (35.7%) urine with a commercially available enzyme-linked ≥ 10: 3 (10.7%) immunosorbent assay kit (Human NGAL ELISA kit- KIT Surgical technique Off-clamp RAPN: 17 (60.7%) 036 RUO- Bioporto Diagnostics). The assay is a sandwich On-clamp RAPN: 11 (39.3%) ELISA performed in microwells coated with a monoMedium Warm Ischemia Time (min) 12,6 (7-22) clonal antibody to human NGAL. Bound NGAL is Post-operative AKI 3 (10.7%) detected with another monoclonal NGAL antibody Charlson Comorbidity Index 2.32 (0-6) labeled with biotin and the assay is developed with horseradish peroxidase (HRP)-conjugated streptavidin Preoperative eGFR (ml/min/1.73 m2) 87.03 (34-115) followed by the addition of a color-forming substrate. Preoperative sCr (mg/dl) 1.07 (0.63-1.73) The enzymatic reaction is stopped chemically, and the Preoperative uNGAL (ng/ml) 20.02 (36.8-4.9) color intensity is read at 450 nm. Furthermore preoperPreoperative operated kidney Cl 99mTC-DTPA (ml/min) atively, the split renal function of the operated kidneys 37.45 (58.7-14.2) was measured by a 99mTC-DTPA renal scan. After 3 RCC = renal cell carcinoma; RAPN: Robot‐Assisted Partial Nephrectomy; AKI = Acute Kidney Injury; eGFR = estimated glomerular filtration rate; sCr = serum months we detected the functional loss of the operated creatinine; uNGAL = urinary Neutrophil Gelatinase-Associated Lipocalin; Cl = clearance; kidneys through a second control 99mTC-DTPA renal 99mTC-DTPA= Technetium-99m-diethylenetriaminepentaacetic acid. scan. Sequential kidney scintigraphy is a method of choice for both static and dynamic Table 2. determination of kidney function separately. Statistical Analysis: We used one-way ANOVA Pre- and peri-operative characteristics of patients undergoing off-clamp vs on-clamp RAPN. in order to analyze post-operative dosage variations of uNGAL and sNGAL as well as comoff-clamp RAPN on-clamp RAPN p pare functional outcomes after on-clamp or No. 17 11 off-clamp robot-assisted partial nephrectomy Sex (RAPN). Statistical significance was considmale 8 9 ered at p < 0.05. Linear regression was applied female 7 4 to determine the correlation of selective uriAge (years) 65.8 (35-86) 57.6 (40-88) 0.097 nary NGAL assay 48 hours after surgery with Mean tumor diameter (cm) 2.89 ± 1.56 3.6 ± 1.51 0.832 the variation of 99mTC-DTPA clearance three PADUA score 7.23 ± 1.67 8.72 ± 1.67 0.070 months after surgery. The analysis was perCharlson Comorbidity Index 2.58 ± 1.66 1.90 ± 2.16 0.136 formed by using the statistical MedCalc softPreoperative sCr (mg/dl) 1.08 ± 0.31 0.88 ± 0.24 0.218 ware (Version 18.2.1, MedCalc, Inc., Belgium). 2

RESULTS

Twenty-eight patients were included, mean age was 62.6 (35-88) years. Table 1 resumes baseline characteristics and main intraoperative and perioperative data (Table 1). Seventeen patients underwent off-clamp

Preoperative eGFR (ml/min/1.73 m ) Preoperative uNGAL (ng/ml) Preoperative operated kidney CL 99MTC-DTPA (ml/min) AKI

72.58 ± 24.40 20.52 ± 15.91

86.45 ± 26.81 19.25 ± 6.73

0.880 0.079

35.79 ± 14.11 2 (11.7%)

40.00 ± 10.85 1 (9%)

0.181 0.831

RAPN: Robot-Assisted Partial Nephrectomy; AKI = Acute Kidney Injury; eGFR = estimated glomerular filtration rate; sCr = serum creatinine; uNGAL = urinary Neutrophil Gelatinase-Associated Lipocalin; Cl = clearance; Technetium-99m-diethylenetriaminepentaacetic acid.

99mTC-DTPA=

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O. Colamonico, G. Cardo, E. Ceci, M. Scarcia, M. Zazzara, M. Dassira, A. Porreca, G.M. Ludovico

The sNGAL baseline level was 169.5 ng/ml and did not change postoperatively (p = 0.13). The selective uNGAL baseline level was 20.02 ng/ml and showed a not negligible increase at 2 and 48 hours after surgery (Figure 1). Variation after 48 hours after surgery was statistically significant (p < 0.0001). However no statistically significant differences emerged between patients subjected to onclamp vs off-clamp RAPN (66.17 ng/ml vs 50.02 ng/ml; p = 0.242). According to KDIGO criteria for AKI, we detected postoperative AKI in 3 of 28 patients, using sCr dosage 48 hours after surgery. Comparing the pre-operative creatinine with the 48-hours postoperative one, no statistically significant difference was found (p = 0.0669). Before comparing patients undergoing onclamp and off-clamp robot-assisted partial nephrectomy (Table 2), we evaluated the homogeneity of the two groups through ANOVA. They were homogeneous for eGFR pre-intervention (p = 0,88), preoperative sCr (p = 0.218), maximum tumor size (p = 0.83), PADUA score (p = 0.07), preoperative uNGAL (p = 0.07), Charlson Comorbidity Index (p = 0.13), age (p = 0.09) and preoperative selective 99mTC-DTPA clearance (p = 0.831). Evaluating postoperative functional outcome of the operFigure 1. Postoperative selective urinary excretion of NGAL (mean values).

Figure 2. Correlation between the variation in 99mTC-DTPA clereance 3 months after surgery with the selective dosage of uNGAL at 48 hours from surgery.

Archivio Italiano di Urologia e Andrologia 2019; 91, 2

ated kidneys at three months we highlighted a statistically significant reduction in 99mTC-DTPA clearance of the operated kidneys 3 months after surgery (p < 0.0001), with a mean functional loss of the operated kidneys by 8.2% (mean change in 99mTC-DTPA clearance of -3.081 ml/min). Stratifying the cohort according to the execution of clamping technique (on-clamp vs off-clamp RAPN), there was no statistically significant differences between the two groups (p = 0.414) as far as the variation of 99mTC-DTPA clearance of the operated kidneys. Finally, we evaluated the correlation between the variation in 99mTC-DTPA clearance 3 months after surgery with the selective dosage of uNGAL at 48 hours from surgery (Figure 2), finding a statistically significant association between the two variables (R2 = 0.2391, p = 0.0083). This correlation has not been highlighted by comparing the variation in 99mTC-DTPA clearance 3 months after surgery with sCr dosage 48 hours postoperatively (R2 = 0.12, p = 0.0669).

DISCUSSION

Urological patients represent a population at risk of AKI which can affect long-term renal function (17). The risk of occurrence of AKI in patients undergoing partial/radical nephrectomy and nephroureterectomy is about 43.1% (18). Currently, AKI is defined according to KDIGO criteria based on sCr changes and urine output, which arise after renal damage (8). AKI observed in renal surgery patients is largely related to direct renal damage. In particular, after a partial nephrectomy, AKI is caused by direct removal of renal parenchyma and damage of the remaining tissue from hyperfiltration or ischemia (19, 20). AKI does not act exclusively on the renal parenchyma but also systemically through the release of inflammatory cytokines (21). The post-operative onset of AKI leads to an increase in post-surgical complications, a lengthening of hospitalization time, an increase in the postoperative mortality rate and a significant increase in health care expenditure with an additional risk of CKD (9, 22, 23). Since traditional definitions of AKI seem to be not very sensitive until the healthy nephrons are reduced by 50%, a growing interest towards biomarkers able to evaluate even slight worsening of renal function represents an expanding research area (24, 25). Neutrophil gelatinase-associated lipocalin (NGAL) represents an acute renal injury marker that the latest Acute Dialysis Quality Initiative (ADQI) guidelines recommend use in patients with suspected AKI (26). Baseline reference values of sNGAL are 86.3 ng/ml in men and 88.9 ng/ml in women while uNGAL has a reference value of 5.7-17.7 ng/ml, but they may increase > 10-fold in serum and > 100-fold in urine following an acute injury. (27) However, human clinical studies have shown conflicting results on the potential clinical use of this biomarker for the assessment of acute kidney injury. Abassi has shown that the severity of acute renal injury after nephron sparing surgery is quantitatively correlated to the urinary dosing of NGAL (28). In contrast, Sprenkle highlighted that changes in urinary NGAL dosage of patients undergoing partial nephrectomy are comparable to those of patients undergoing thoracic surgery (29).

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The variation of selective uNGAL levels after robot-assisted partial nephrectomy: Early results of a prospective single center study

In addition, Kyo Chul Koo examining 176 patients who underwent partial open and laparoscopic nephrectomy, had not shown that uNGAL could represent a predictive marker of both postoperative AKI and CKD 6 months after surgery (30). To the best of our knowledge the current report represents the first prospective study that evaluates postoperative AKI and the functional outcome after 3 months from surgery, adopting selective uNGAL assay. First of all, we showed a statistically significant increase in the selective dosage of uNGAL after 48 hours from surgery. This result was not confirmed for the serum NGAL assay after 48 hours from surgery. Probably sNGAL dosage is significantly affected by postoperative blood loss (not considered in this study), as well as could be influenced by the patient's hydration status. For this reason, we decided to focus our interest on the uNGAL. Comparing selective uNGAL assay 48 hours after surgery between patients undergoing on-clamp and off-clamp RAPN, we did not find a statistically significant difference. In fact, it seems that hilar clamping does not influence the increase in selective uNGAL dosage and therefore the severity of the acute post-operative renal injury. On the other hand, the diagnosis of AKI using the KDIGO criteria allowed to diagnose postoperative AKI in only 3 patients, suggesting a lack of sensitivity of the diagnostic criteria worldwide used for AKI. Later we highlighted a worsening of renal function of the operated kidneys 3 months after surgery, through a sequential renal scintigraphy performed before and 3 months after surgery. This result should be explained not as a failure of nephron sparing surgery but as an effect of the high sensitivity of renal scintigraphy in detecting even small changes in renal function compared to the use of sCr. Indeed, the curvilinear relationship between serum creatinine and eGFR may lead to the lack of detection of early stages of AKI or CKD (31). The choice of the third postoperative month for the execution of the control scintigraphy, follows the KDIGO recommendations (8). Comparing patients undergoing on-clamp and off-clamp RAPN, there are no differences in losses of 99mTC-DTPA clearance 3 months after surgery. This result could be due either to the short post-operative follow-up period but also to the limited warm ischemia time of on-clamp procedures (the mean warm ischemia time was 12.6 minutes). As we know, warm ischemia time is an important, modifiable predictor of postoperative renal function. In particular, warm ischemia time should not exceed 25 minutes, to avoid a short and long-term reduction in renal function (32). The statistically significant association between the reduction in 99mTC-DTPA clearance 3 months after surgery with the selective dosage of uNGAL at 48 hours from surgery, highlighted a direct relationship between these two predictors. The limitations of this report should be acknowledged. First, the small number of patients as well as the short time of postoperative follow-up (3 months) limited the power of the analyses. Second, the normalized uNGAL (the ratio of urine NGAL to urine creatinine) was not used in this study; moreover, the postoperative urine collection for uNGAL was performed selectively through a ureteral catheter inserted into the excretory axis of the operated kidney, unlike previous studies where urine

was collected from the urethral catheter (28-30). Further studies are needed to understand the clinical use of the uNGAL although it seems clear the importance of implementing the definition of AKI with the introduction of new biomarkers. The importance of reno-protective surgery is not in question in this report but we tried to demonstrate the lack of sensitivity of traditional methods. Our findings support the concept that the development of reno-protective techniques can prevent the onset of small changes in postoperative renal function, not detected with the sCr dosage, but which may impact on the functional outcome of the operated kidney.

CONCLUSIONS

Selective uNGAL assay represent a sensitive biomarker in detecting postoperative AKI in patients submitted to RAPN for a cT1 renal cell carcinoma. Furtheremore, selective uNGAL assay may be consider a predictive biomarker of CKD after nephron-sparing surgery. In our opinion KDIGO criteria for AKI should be implemented with the clinical use of biomarkers such as uNGAL.

REFERENVES

1. Lee JH, You CH, Min GE, et al. Comparison of the surgical outcome and renal function between radical and nephron-sparing surgery for renal cell carcinomas. Korean J Urol. 2007; 671. 2. Van Poppel H, Da Pozzo L, Albrecht W. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol. 2011; 59:543-52. 3. Huang, WC, Elkin EB, Levey AS, et al. Partial nephrectomy versus radical nephrectomy in patients with small renal tumors is there a difference in mortality and cardiovascular outcomes? J Urol. 2009; 181:55-61. 4. Thompson RH, Lane BR, Lohse CM, et al. Renal function after partial nephrectomy: effect of warm ischemia relative to quantity and quality of preserved kidney. Urology. 2012; 79:356-60. 5. Vartolomei MD, Matei DV, Renne G, et al. Long-term oncologic and functional outcomes after robot-assisted partial nephrectomy in elderly patients. Minerva Urol Nefrol. 2019; 71:31-37 6. Castellucci R, Primiceri G, Castellan P, et al. Trifecta and Pentafecta Rates After Robotic Assisted Partial Nephrectomy: Comparative Study of Patients with Renal Masses < 4 and â&#x2030;Ľ 4 cm. J Laparoendosc Adv Surg Tech A. 2018; 28:799-803. 7. Cacciamani GE, Medina LG, Gill TS, et al. Impact of Renal Hilar Control on Outcomes of Robotic Partial Nephrectomy: Systematic Review and Cumulative Meta-analysis. Eur Urol Focus. 2018; pii: S2405-4569(18)30013-0. 8. KDIGO AKI Working Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2012; 2:1-138. 9. Schmid M, Ravi P, Abd-El-Barr AE, et al. Chronic kidney disease and perioperative outcomes in urological oncological surgery. Int J Urol. 2014; 21:1245-1252. 10. Rysz J, Gluba-BrzĂłzka A, Franczyk B, et al. Novel Biomarkers in the Diagnosis of Chronic Kidney Disease and the Prediction of Its Outcome. Int J Mol Sci. 2017; 18 pii: E1702. 11. Antonelli A, Allinovi M, Cocci A, et al. AGILE Group. The Predictive Role of Biomarkers for the Detection of Acute Kidney Injury Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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O. Colamonico, G. Cardo, E. Ceci, M. Scarcia, M. Zazzara, M. Dassira, A. Porreca, G.M. Ludovico

After Partial or Radical Nephrectomy: A Systematic Review of the Literature. Eur Urol Focus. 2018; pii: S2405-4569(18)30293-1. 12. Mishra J, Ma Q, Prada A, et al. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol. 2003; 14:2534-43. 13. Bennett M, Dent CL, Ma Q, et al. Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a prospective study. Clin J Am Soc Nephrol. 2008; 3:665-73. 14. Parikh CR, Jani A, Mishra J, et al. Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation. Am J Transplant. 2006; 6:1639-45. 15. Cruz DN, de Cal M, Garzotto F, et al. Plasma neutrophil gelatinase-associated lipocalin is an early biomarker for acute kidney injury in an adult ICU population. Intensive Care Med. 2010; 36:444-51. 16. Koyner JL, Vaidya VS, Bennett MR, et al. Urinary biomarkers in the clinical prognosis and early detection of acute kidney injury. Clin J Am Soc Nephrol. 2010; 5:2154-65. 17. Cho A, Lee JE, Kwon GY, et al. Post-operative acute kidney injury in patients with renal cell carcinoma is a potent risk factor for new-onset chronic kidney disease after radical nephrectomy. Nephrol Dial Transplant. 2011; 26:3496-501. 18. Caddeo G, Williams ST, McIntyre CW, Selby NM. Acute kidney injury in urology patients: incidence, causes and outcomes. Nephrourol Mon. 2013; 5:955-61.

23. Lameire NH, Bagga A, Cruz D, et al. Acute kidney injury: an increasing global concern. Lancet. 2013; 382:170-9. 24. Slocum JL, Heung M, Pennathur S. Marking renal injury: can we move beyond serum creatinine? Transl Res. 2012; 159:277-89. 25. Hostetter TH, Olson JL, Rennke HG, et al. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. J Am Soc Nephrol. 2001; 12:1315-1325. 26. Haase M, Bellomo R, Devarajan P, et al. Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis. 2009; 54:1012-1024. 27. Schmid M, Dalela D, Tahbaz R, et al. Novel biomarkers of acute kidney injury: Evaluation and evidence in urologic surgery. World J Nephrol. 2015; 4:160-168. 28. Abassi Z, Shalabi A, Sohotnik R, et al. Urinary NGAL and KIM1: biomarkers for assessment of acute ischemic kidney injury following nephron sparing surgery. J Urol. 2013; 189:1559-1566. 29. Sprenkle PC, Wren J, Maschino AC, et al. Urine neutrophil gelatinase associated lipocalin as a marker of acute kidney injury after kidney surgery. J Urol. 2013; 190:159-64.

19. Brenner BM, Lawler EV, Mackenzie HS. The hyperfiltration theory: a paradigm shift in nephrology. Kidney Int. 1996; 49:17741777.

30. Kyo CK, Jung HH, Hye SL, et al. Accuracy of Urinary Neutrophil Gelatinase-Associated Lipocalin in Quantifying Acute Kidney Injury after Partial Nephrectomy in Patients with Normal Contralateral Kidney. PLoS One. 2015; 10:e0133675.

20. Lane BR, Babineau DC, Poggio ED, et al. Factors predicting renal functional outcome after partial nephrectomy J Urol. 2008; 180:2363-8.

31. Steubl D, Block M, Herbst V, et al. Plasma uromodulin correlates with kidney function and identifies early stages in chronic kidney disease patients. Medicine. 2016, 95, e3011.

21. Hoke TS, Douglas IS, Klein CL, et al. Acute renal failure after bilateral nephrectomy is associated with cytokine-mediated pulmonary injury. J Am Soc Nephrol. 2007; 18:155-164.

32. Volpe A, Blute ML, Ficarra V, et al. Renal Ischemia and Function After Partial Nephrectomy: A Collaborative Review of the Literature Eur Urol. 2015; 68:61-74.

Correspondence Ottavio Colamonico, MD ottaviocolamonico@gmail.com Giuseppe Cardo Marcello Scarcia Michele Zazzara Giuseppe M. Ludovico Urology Department, Ospedale Generale “F. Miulli” Via Enrico Toti n. 2 Acquaviva delle Fonti (BA) (Italy) Edmondo Ceci Specialistic Clinical Biochemistry Department, Ospedale Generale “F. Miulli”, Acquaviva delle Fonti, Bari (Italy) Mario Dassira Nuclear Medicine Department, Ospedale Generale “F. Miulli”, Acquaviva delle Fonti, Bari, (Italy) Angelo Porreca Urology Department, Policlinico Abano Terme, Padova (Italy)

22. Chertow GM, Soroko SH, Paganini EP, et al. Mortality after acute renal failure: models for prognostic stratification and risk adjustment. Kidney Int. 2006; 70:1120-1126.

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DOI: 10.4081/aiua.2019.2.79

ORIGINAL PAPER

Prostatic calcifications are associated with a more severe symptom burden in men with type II chronic bacterial prostatitis Konstantinos Stamatiou 1, Vittorio Magri 2, Gianpaolo Perletti 3, Alberto Trinchieri 4, Richard Lacroix 1, Nektaria Rekleiti 1, Hippocrates Moschouris 1 1 Tzaneio

Hospital, Piraeus, Greece; Nord Milano, Italy; 3 Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, Italy; 4 CDC Ambrosiana Cesano B, Milano, Italy. 2 ASST

Summary

Introduction/Aim: Although prostatic calculi/calcifications are encountered frequently in the urological practice, little is known about the incidence of such lesions, their mechanism of formation, their relationship to other prostate conditions and their clinical significance. The purpose of this study is to describe the characteristics and to investigate the clinical significance of prostatic calcifications (PCs) in patients with chronic bacterial prostatitis (CBP). Materials and methods: This study was conducted between 01/02/2013 and 20/02/2018. The patient population for this study included subjects with or without PCs and a confirmed diagnosis of NIH category II Chronic Bacterial Prostatitis (CBP). Demographics and clinical history of each assessed patient were reviewed. Eligible patients underwent prostatic ultrasound with post-void residual measurement, and the Meares-Stamey “4-glass” test. Symptom severity was measured using the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and the International Prostatic Symptoms Score (IPSS). Antimicrobials were administered to confirmed cases of CBP according to the results of susceptibility tests. After four weeks off-therapy, the NIH-CPSI and IPSS tests were repeated. Variables were compared between patients with and without prostatic calcifications. Results: Ninety-five CBP patients were included in the study. According to the presence of PCs detected by ultrasound examination, patients were divided into two groups: 41 had PCs (group 1) and 54 didn’t (group 2). No significant between-group baseline differences were found regarding age, marital status, prostate volume, the proportion of common CBP pathogens. Concerning highrisk sexual behavior, a significantly higher number of men with PCs practiced anal penetration. Moreover, a significantly higher number of men with PCs had a history of chronic prostatitis relapsing episodes. Microbiological eradication and the complete resolution of clinical symptoms occurred in similar proportions between the two groups. However, intergroup analysis resulted in significantly higher scores of the NIH-CPSI test in group 1, both at the pre-therapy and at the post-therapy time points. Conversely, no IPSS score differences between groups 1 and 2 were found at both pre- and post-therapy time points. Conclusions: Prostatic calcifications do not seem to influence the microbiological outcome of antibacterial treatment. However, the CBP symptoms appear to be more severe in carriers of prostatic calcifications, either before or after antibacterial therapy.

KEY WORDS: Prostate; Prostatitis; Chronic bacterial prostatitis; Calcifications; Calculi; Stones. Submitted 20 February 2019; Accepted 11 March 2019

INTRODUCTION

The terms prostatic calcifications (PCs), prostatic stones and prostatic calculi are used to describe hyperechoic calcium deposits within the prostate gland. They are a relatively common ultrasound finding whose pathophysiology is partially understood. However, the clinical relevance of these lesions and their association with prostatic diseases remains unclear. Traditionally, calcifications are considered to be a random finding of no clinical significance, probably associated with previous infection of the prostate. In fact, are usually found incidentally and are often not associated with a history of prostatitis. While histopathologic investigation showed that most calculi are associated with inflammatory changes, many of the relevant studies haven’t correlated the presence of prostate calcifications with chronic bacterial prostatitis (CBP) (1). Nowadays the relation between PCs and CBP remains uncertain and it is still unknown if PCs are clinically insignificant or whether they have the potential to affect the treatment outcome. However, it is deemed important for specialists to become familiar with this entity. In this prospective, observational study, we wished to characterize the clinical features of PCs in men with chronic bacterial prostatitis (NIH Category II CBP) and to assess the outcome of therapy in order to better understand their impact on CBP. Comparison between CBP patients with or without signs of prostatic calcifications was also attempted.

PATIENTS

AND METHODS

This study was conducted between 01/02/2013 and 20/02/2018, after approval by the local Ethics Committee. Participants enrolled for this study were first-referral urological male outpatients presenting with CBP symptoms. Group 1 consisted of patients with PCs and confirmed diagnosis of CBP, whereas group 2 included CBP patients without ultrasound evidence of PCs. Demographic data and clinical history of each assessed patient were reviewed. Inclusion criteria The Inclusion criterion for this study was a diagnosis of

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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K. Stamatiou, V. Magri, G. Perletti, A. Trinchieri, R. Lacroix, N. Rekleiti, H. Moschouris

category II CBP according to National Institutes of Health (NIH) (2) definition and a microbiological assessment of causative pathogens. Exclusion criteria Patients suffering from conditions that influence bacterial virulence or host response (eg. immunodeficiency, abnormalities of the urogenital system) and patients who received antibiotics or immunosuppressive treatment within 4 weeks of the recorded visits were excluded from the study. Patients diagnosed upon investigation with prostatic diseases other than CBP (category I acute bacterial prostatitis, category III chronic prostatitis/chronic pelvic pain syndrome, overt symptomatic benign prostatic hyperplasia, neoplasia) as well as patients exhibiting confounding factors (e.g., indwelling catheters, cystostomy, ureterostomy, ureteral stents, previous prostatic surgery or radiotherapy, incomplete compliance to antibacterial therapy assessed by interviewing patients at the end of treatment) were also excluded. Patient assessment Participants underwent a brief interview in which a complete clinical history was collected. Symptom severity was measured using the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and the International Prostatic Symptoms Score (IPSS) (3). Urological visits also included digitorectal examination and urine and/or prostatic secretion sample collection, abdominal ultrasound and post-void residual measurement. Calcification evaluation A transrectal ultrasound scan was additionally performed to those who were found with PCs in order to provide both axial and sagittal images, thus improving the evaluation of the number, location, and length of calcifications. TRUS was performed using an 8.0-MHz rectal probe (GE Healthcare, LOGIQ 3). The prostate volume (PV) was measured by TRUS using the formula for an elliptic volume. Besides larger, more echogenic foci that caused acoustic shadowing, also linear calcifications mainly located between transitional and peripheral zone of the gland- were assessed and recorded. Calculi were measured instantly at the time when they were detected on TRUS. A single urologist performed all TRUS procedures and measured calculi. Microbiological evaluation Eligible patients underwent the Meares-Stamey “4-glass” test, based on cultures of first-void (VB1), pre-prostatic massage/midstream (VB2) and post-prostatic massage urine (VB3) specimens, and expressed prostatic secretions (EPS) obtained during prostatic massage (4). Appropriate antimicrobial agents -accordingly to susceptibility tests- were administered to confirmed cases of CBP for a period of 4 weeks. Microbiological tests were considered positive when: 1) bacteria grew in the culture of EPS and VB3 specimens and did not in VB1 and VB2; 2) bacterial colonies in VB3 were higher in number compared to VB1 and VB2 specimens. Given that no standard cutoff levels of the num-

Archivio Italiano di Urologia e Andrologia 2019; 91, 2

ber of bacteria in both urine and prostate secretion samples are defined by consensus for the diagnosis of chronic bacterial prostatitis, we defined no lower acceptable level for either one. Cultures, identification and semiquantitative assay for Mycoplasma hominis and Ureaplasma urealyticum were performed using the Mycoplasma IST 2 kit (bioMerieux). Chlamydia trachomatis was detected by direct immunofluorescence, using monoclonal antibodies against lipopolysaccharide membranes (Kallestad). Urine samples were cultured undiluted in blood and MacConkey agar plates (Kallestad Lab., TX, USA) and subjected to centrifugation for microscopic examination of the sediment. Evaluation of culture results was performed by two specialist microbiologists, who were blinded to patient records. Identification of traditional pathogens was performed by conventional methods and the Vitek-2 Compact system (bioMerieux, France), and susceptibility testing was performed by disc diffusion and/or the Vitek-2 system. Interpretation of susceptibility results was based on Clinical and Laboratory Standards Institute (CLSI) guidelines. Therapy outcome evaluation After four weeks of therapy, the NIH-CPSI and IPSS tests were repeated. Follow-up included also interview, physical examination, transrectal ultrasound and the “4-glass” test. The microbiological response to antibacterial therapy was defined in a manner similar to that of Naber et al.: i) eradication: baseline pathogen was eradicated; ii) persistence: baseline pathogen was not eradicated; iii) superinfection: baseline pathogen was eradicated with the appearance of a new pathogen (5). Statistical analysis Medians and interquartile ranges (IQR) were used to measure the central tendency and data dispersion of questionnaire ordinal scores. For continuous variables, means and standard deviations were calculated. The Wilcoxon signed rank test was applied to analyze pre- vs. post-therapy paired differences in NIH-CPSI and IPSS scores, whereas the Wilcoxon rank sum test was used to calculate the significance of differences between different treatment arms at a given time-point. For continuous variables, paired or unpaired t-tests were used to analyze differences between means. All tests were twotailed if not otherwise indicated, and an alpha error inferior to 5% was set as significance level for each comparison. Comparison between proportions of eradicated patients was made using the Z-test with the Yates’ continuity correction. All inferential calculations were performed using the R open-source software environment.

RESULTS

Ninety-five out of 172 eligible patients were assessable at the end of the trial. All patients reported chronic pelvic discomfort and genital pain, with or without lower urinary tract symptoms and sexual dysfunction. The remaining patients, who were not compliant to therapy or who were lost during follow-up were excluded from the study.

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Prostatic calcifications are associated with a more severe symptom burden in men with type II chronic bacterial prostatitis

According to the presence/absence of PCs in ultrasound examination, patients were divided into two groups: 41 individuals had PCs (group 1) and 54 showed no signs of PCs (group 2). The most common symptom in both groups was scrotal/testicular pain (reported by 12 and 17 patients of Group 1 and Group 2 respectively, P > 0.05, Ztest). The most common pathogen in both groups was E. Coli (found in 9 and 11 patients of Group 1 and Group 2 respectively P > 0.05, Z-test). Data regarding patient demographics, history, clinical symptom presentation and microbiological profiles are listed in Tables 1-3. No significant differences were found between groups regarding age, marital status, prostate volume and most sexual behaviors. However, a significantly higher number of men with PCs practiced anal penetration (Table 1). Incidentally, the vast majority of these subjects Table 1. Patient demographic and baseline data. Clinical sample Number of patients

Study group 41

Controls 54

p -

46.8 37

45.1 21

p > 0.05 p > 0.0001

19 7 4 2 9

26 9 8 1 10

p > 0.05 p > 0.05 p > 0.05 p > 0.05

21 19 2 6 40.1

24 16 3 11 39.4

p > 0.05 p = 0.047a p > 0.05 p > 0.05 p > 0.05

Mean age (years) Chronic prostatitis history (n.) Marital status Married (n.) Unmarried (n.) Divorced (n.) Widower (n.) Unknown (n.) Sexual Behaviour Vaginal penetration (n.) Anal penetration (n.) Absence of sexual activity (n.) Unknown (n.) Mean prostate volume a

Table 3. Pathogens found in monomicrobial and polymicrobial isolates. Isolate

Perineal pain

4 5

7 6

Dysuria Feeling of unusual heaviness in the scrotum Frequent urination

1 2

Haematospermia Difficult urination

Penile pain

3 1

Suprapubic pain Feeling of burning across urethra Local discomfort

13 0 2 1 1 1 8 21 2

19 5 0 0 0 1 16 21 2

Intergroup significance p > 0.05 na na na na na p > 0.05 p > 0.05 na

na = not assessable.

showed enterococcal infections (data not shown). A significantly higher number of men with PCs had a history of chronic prostatitis relapsing episodes (Table 1). A variety of pathogens were isolated from CBP patients (Table 3). In general, patients showing PCs showed a more Table 4. Microbiological and clinical outcomes at the end of therapy. Outcome

Group 1

Group 2

Pathogen eradicated (%)

26/41 (63%)

41/54 (75%)

p > 0.05

Pathogen not eradicated

10/41

9/54

p > 0.05

5/41

4/54

Superinfection Clinical resolution No clinical resolution

Table 2. Main and coexisting signs and symptoms in both groups. Group 1 Group 2 Main symptom 12 17 Scrotal/testicular pain

Group 2

Escherichia coli Proteus mirabilis Klebsiella pneumoniae Morganella morganii Haemophilus spp. Acinetobacter baumannii Enterococcus spp. Staphylococcus coagulase-negative Streptococcus spp.

Uncertain clinical resolution

One-tailed test.

Group 1

Frequently assessed coexisting symptoms Perineal and suprapubic pain, haematuria, frequent urination, nocturia, painful ejaculation, dysuria, penile pain, erectile dysfunction Scrotal pain, dysuria, sexual dysfunction, frequent urination Scrotal pain, perineal pain, sexual dysfunction Sexual dysfunction, perineal pain Testicular pain, mild erectile dysfunction, burning, suprapubic pain, scrotal pain Frequent urination, scrotal pain, erectile dysfunction Dysuria, scrotal pain, dysuria, feeling of burning, frequent urination Dysuria Frequent urination, scrotal pain, sexual dysfunction

23/41 (56.9%) 37/54 (68.5%)

p > 0.05 p > 0.05

18/41

11/54

p = 0.012

6/54

diverse variety of Gram-negative pathogens. However, the intergroup proportions of the most frequently isolated species (E. coli, Enterococcus spp., Staphylococcus spp.) were not significantly different. In general, patients showing PC showed a more diverse variety of Gram-negative pathogens. Microbiological eradication occurred in similar proportions between the two groups (Table 4). Similarly, the resolution of clinical symptoms occurred in equivalent numbers of patients belonging to groups 1 and 2. However, more patients showing no resolution of clinical symptoms belonged to group 1 (n = 18), compared to group 2 (n = 11; p = 0.012; Z-test). This difference is likely due to the presence of patients showing uncertain resolution of clinical symptoms in group 2 (n = 6) (Table 4). The latter are absent in group 1. The NIH-CPSI and the IPSS test were used to assess the degree of severity of CBP symptoms in the present study. Paired analysis Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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Table 5. Scores of NIH-CPSI and IPSS symptom questionnaires. Symptom test questionnaire

Group 1 score Pre-therapy median NHI-CPSI value (IQR) 22 (9) Post-therapy NHI-CPSI value (IQR) 10 (16) p < 0.0001a Pre-therapy median IPSS value (IQR) 4 (9) Post-therapy median IPSS value (IQR) 1 (7) p < 0.0001a a Wilcoxon

b Wilcoxon

Group 2 score 19 (6) 3 (3) p < 0.0001a 4 (9) 2 (5) p < 0.0001a

p p = 0.036b p = 0.024b p = 0.91b p = 0.84b

signed rank test (paired); rank sum test (unpaired intergroup).

showed in both groups highly significant improvements of symptoms, assessed with both tests (Table 5). Intergroup analysis resulted in significantly higher scores of the NIHCPSI test in group 1, both at the pre-therapy and at the post-therapy time points. Concerning the IPSS test, no differences between groups 1 and 2 were found at both pre- and post-therapy time points (Table 5).

DISCUSSION

While PCs are a common ultrasound finding, their exact prevalence is not known. It has been reported to vary widely, from 7% to 70% with greater incidences occurring in symptomatic conditions (6, 7). Differences are mainly due to varieties in the methodology of the studies, as PCs frequency increase with age and in certain conditions, such as prostate hyperplasia and chronic prostatitis. In addition, several studies have strict criteria for prostatic stone definition; thus a large number of cases of prostatic calculi is often overlooked. As mentioned in the methods section, there are two types of echo patterns of calcifications: type I, discrete, multiple small echoes, usually located in the transition and peripheral zones of the prostate or diffusely distributed throughout the gland, and type II, defining large masses of multiple, coarser echoes (8). Some authors consider true stones only those with diameter greater than 3 millimeters (6, 7). In our study the prevalence of PCs among patients with CBP symptoms was about 43%. This finding is similar to that of Shoskes et al., who reported a 46.8% incidence in a population of relatively younger patients with pelvic pain syndrome (9). However, contrary to our study, these authors excluded cases with stones smaller than 3 mm. On the contrary, Harada et al. defined no limitations on PCs size and found an incidence of 68.8% in a population of patients with benign prostatic hypertrophy with a higher average age (8). According to autopsy studies, the frequency of PCs in the general population is high and has an increasing age distribution rising up to 99% in men over 99 years of age (10). Notably, the histological analysis of autopsy material observed histological characteristics of prostatitis in up to 50% of prostates with calcifications -independently to their size- additionally questioning on the relation between CBP and PCs (10). In fact, the pathophysiology, the clinical relevance

Archivio Italiano di Urologia e Andrologia 2019; 91, 2

and the association of prostatic calculi with prostatic diseases remain unclear. The exact process of PCs formation is not known. However, it likely involves many factors and according to the origin of the calcification material, PCs may be distinguished in exogenous and endogenous. The basis for the creation of exogenous PCs is urine reflux to the prostatic ducts as a result of urine flow obstruction. In such case, urine components cause local ionic changes and pH elevation, which causes the precipitation of salts and the formation of stones. These calculi are usually larger, situated mainly in the prostatic ducts and their composition is similar to stones found anywhere in the urinary tract (11). The basis for the generation of endogenous PCs is the calcification of amyloid particles (a mixture of protein compound rich in lecithin accumulates and degenerated epithelial cells) within the prostatic ducts. This acts as a foreign body, triggering the deposition of calcium and phosphorus salts by epithelial cells (12). A morphological study showed that most PCs (83%) had bacterial imprints suggesting bacterial colonization and biofilm formation, while another study found DNA and proteins from Escherichia coli in PC bodies (13, 14). It is well established that other bacteria such as Gram-positive Enterococcus faecalis and Staphylococcus spp., are also biofilm formers. However, in this study Escherichia coli, Enterococcus faecalis and Staphylococcus spp., were found in equivalent proportions in groups 1 and 2 (Table 3). Of note, Cai et al., performed ultrastructural analysis of prostate biopsy cores obtained from radical prostatectomy specimens and they found prostate calcifications in 60%, positive cultures in 30% and a structured microbial biofilm in 10% of the sample (15). As long as biopsy performed for epidemiological purposes provides an instant image of a certain situation, the findings of Cai et al., along with our observations suggests that involvement of pathogenic bacteria follows the formation of calcifications. As PCs cause mechanical and chemical corrosive effects on the surrounding tissue, the consequent development of fibrosis and edema results in local narrowing of the prostatic ducts, causing stasis of prostatic fluid and new stone formation in a chronic infection process. In such a condition, larger PCs cause greater obstruction, and in this respect Park et al. reported that prostatic inflammatory changes were closely associated with type II calcifications (16). Given that in most cases PCs are detected incidentally during a random ultrasound check, it is believed that the stones themselves do not usually cause symptoms. However, some researchers demonstrated that the presence of calcifications is more frequently observed in patients with chronic bacterial prostatitis and is related to urinary symptoms (17). Other researchers found significant correlations between the percentage of PCs and the severity of the NIH-CPSI urological symptom subdomain (18). A recent study showed that the presence of PCs may be associated with the severity and worsening of storage symptoms (19), while another recent study showed that PCs plays an important role in sexual dysfunction in middle-aged men with chronic pelvic pain syndrome or chronic prostatitis (20). In the present

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Prostatic calcifications are associated with a more severe symptom burden in men with type II chronic bacterial prostatitis

study, significantly higher total scores of the NIH-CPSI test were assessed in group 1, not only before antibacterial treatment, but also after having achieved pathogen eradication (Table 5). This suggests that PC are associated with more severe symptoms of chronic prostatitis, at least in the case of chronically occurring infections. Such increased severity of symptoms is in agreement with the fact that a significantly higher number of patients belonging to group 1 did not show resolution of clinical symptoms at the end of therapy, compared with men without documented calcifications. In contrast to NIHCPSI results, no difference was found between either pre- or post-therapy scores of the IPSS test (Table 5). In this respect, one should consider that the IPSS test has been tailored for patients with benign prostatic hyperplasia and deals mainly with obstructive voiding symptoms, whereas the NIH-CPSI test also includes pain symptoms, pain scales, irritative symptoms, and a specific quality of life domain. Thus, this latter test is optimal for assessing prostatitis patients, whereas the former is not, though it is often used to complement the NIHCPSI test. Our results also suggest that the presence of PCs is associated with a previous history of CBP. In fact, PC may serve as a pathogen niche, acting as a source of recurring infection, also caused by biofilm-embedded pathogens, since after treatment the obstructive stones still remain and the inflammatory process continues. Recurrent infection, causing increasing deposition of calcifications, may also occur in patients showing sexual behaviors at high-risk for prostatic infections, like anal sexual intercourse (Table 1).

sues. A combined biophysical and histological study. Pathol. Microbiol. 1968; 31:97-107. 11. Meares EM. Infection stones of the prostate gland. Urology. 1974;4:560-566. 12. Magura CE, Spector M. Scanning electron microscopy of human prostatic corpora amylacea and corpora calculi. Scan Electron Microsc. 1979; 3:713-20. 13. Dessombz A, MĂŠria P, Bazin D, Daudon M. Prostatic stones: evidence of a specific chemistry related to infection and presence of bacterial imprints. PLoS One 2012; 7:e51691. 14. Sfanos KS, Wilson BA, De Marzo AM, Isaacs WB. Acute inflammatory proteins constitute the organic matrix of prostatic corpora amylacea and calculi in men with prostate cancer. Proc Natl Acad Sci USA. 2009; 106:3443-8. 15. Cai T, Tessarolo F, Caola I, et al. Prostate calcifications: A case series supporting the microbial biofilm theory. Investig Clin Urol. 2018; 59:187-193. 16. Park SW, Nam JK, Lee SD, Chung MK. Are prostatic calculi independent predictive factors of lower urinary tract symptoms? Asian J Androl. 2010; 12:221-6. 17. Boltri M, Magri V, Montanari E, et al. Computer-assisted quantitative assessment of prostatic calcifications in patients with chronic prostatitis. Urol Int. 2018; 100:450-455. 18. Engelhardt PF, Seklehner S, Brustmann H, et al. Association between asymptomatic inflammatory prostatitis NIH category IV and prostatic calcification in patients with obstructive benign prostatic hyperplasia. Minerva Urol Nefrol. 2016; 68:242-9. 19. Hyun JS. Clinical Significance of Prostatic Calculi: A Review. World J Mens Health. 2018; 3615-21. 20. Cao JJ, Huang W, Wu HS, et al. Prostatic Calculi: Do They Matter? Sex Med Rev. 2018; 6:482-491.

REFERENCES

1. Park B, Choo SH. The burden of prostatic calculi is more important than the presence. Asian J Androl. 2017; 19:482-485. 2. Krieger JN, Nyberg L Jr, Nickel JC. NIH consensus definition and classification of prostatitis. JAMA. 1999; 282:236-7. 3. Asvestis C, Varvadesis T, Maravelakis PE. Greek Version of the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), its linguistic adaptation and the pilot test of its validity. Hellenic Urol. 2014; 26:1. 4. Stamey TA. Prostatitis. J R Soc Med. 1981; 74:22-40. 5. Naber KG. European Lomefloxacin Prostatitis Study Group. Lomefloxacin versus ciprofloxacin in the treatment of chronic bacterial prostatitis. Int J Antimicrob Agents. 2002; 20:18-27. 6. Geramoutsos I, Gyftopoulos K, Perimenis P, et al. Clinical correlation of prostatic lithiasis with chronic pelvic pain syndromes in young adults. Eur Urol. 2004; 45:333-7. 7. Kim WB, Doo SW, Yang WJ, Song YS. Influence of prostatic calculi on lower urinary tract symptoms in middle-aged men. Urology. 2011; 78:447-9. 8. Harada K, Igari D, Tanahashi Y. Gray scale transrectal ultransonography of the prostate. J Clin Ultrasound. 1979; 7:45-9. 9. Shoskes DA, Lee CT, Murphy D, et al. Incidence and significance of prostatic stones in men with chronic prostatitis/chronic pelvic pain syndrome. Urology. 2007; 70:235-8. 10. Hassler O. Calcifications in the prostate gland and adjacent tis-

Correspondence Konstantinos Stamatiou, MD (Corresponding Author) stamatiouk@gmail.com Richard Lacroix, MD rlacroix@ureach.com Nektaria Rekleiti, MD nekrek@gmail.com Hippocrates Moschouris, MD hipmosch@gmail.com Tzaneio Hospital, Piraeus (Greece) Vittorio Magri, MD vittorio.magri@yahoo.it ASST Nord Milano (Italy) Gianpaolo Perletti, MD gianpaolo.Perletti@uninsubria.it Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, (taly) Alberto Trinchieri, MD alberto.trinchieri@gmail.com CDC Ambrosiana Cesano B, Milano (Italy)

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ORIGINAL PAPER

DOI: 10.4081/aiua.2019.2.84

Could pollen extract in association with vitamins be favorable in the reduction of chronic prostatic inflammation? A case-series analysis Michele Zazzara 1, Arjan Nazaraj 1, Ottavio Colamonico 1, Marcella Mastromauro 2, Giuseppe Cardo 1, Giuseppe Mario Ludovico 1 1 Urology

Department, Ospedale Generale Regionale “F. Miulli", Acquaviva delle Fonti (BA), Italy; Anatomy Department, Ospedale Generale Regionale “F. Miulli", Acquaviva delle Fonti (BA), Italy.

2 Pathological

Summary

The aim of the present case-series analysis was to assess the safety and efficacy of pollen extract in association with vitamins in order to reduce the chronic prostatic inflammation in patients with class IV chronic prostatitis (CP). Nineteen non-consecutive patients performed a prostate biopsy for a suspect of prostate cancer. The biopsy histopathological examination showed a class IV CP, in presence of mild/moderate/high degree of inflammation, in association with an extensive (multiple biopsy sites, i.e., ≥ 3) high-grade prostatic intraepithelial neoplasia PIN (HGPIN) and/or atypical small acinar proliferation (ASAP). According to EAU Prostate Cancer Guidelines prostate biopsy was repeated after 6 months, because of the presence of extensive HGPIN or ASAP. Oral administration of pollen extract in association with vitamins (two capsules every 24 h) was prescribed until the repeat biopsy. Repeat biopsy histopathological examination showed, in 13 patients (68.4%), a lower degree of inflammation (absent/mild/moderate).

Figure 1. Microscopic pathological features in hematoxylin and eosin stain: absent (a), mild (b), moderate (c), high (d) degree of inflammation.

KEY WORDS: Prostate; Phytotherapeutics; Benign prostatic hyperplasia. Submitted 2 January 2019; Accepted 8 February 2019

INTRODUCTION

Chronic prostatic inflammation (CPI) leads to symptomatic or asymptomatic benign prostatic hyperplasia (BPH) (1, 2). Under the circumstances that CPI leads to BPH and, therefore, to lower urinary tract symptoms (LUTS) due to BPH, CPI could be a target for medical treatment, in patients with asymptomatic or symptomatic BPH, acting on prostatic enlargement and LUTS. Phytotherapeutics are a value options due to their generally minimal side-effects. The aim of the present caseseries analysis was to assess the safety and efficacy of pollen extract in association with vitamins (DEPROX 500®) in order to reduce the chronic prostatic inflammation in patients with class IV chronic prostatitis (CP).

CASE

PRESENTATION

Nineteen non-consecutive patients performed a prostate biopsy for a suspect of prostate cancer (PCa). The biopsy

histopathological examination showed a class IV CP, in presence of mild/moderate/high degree of inflammation (Figure 1), in association with an extensive (multiple biopsy sites, i.e., ≥ 3) high-grade prostatic intraepithelial neoplasia PIN (HGPIN) and/or atypical small acinar proliferation (ASAP). About degree of inflammation, the biopsy histopathological examination showed in 6 patients (31.6%) a mild degree of inflammation, in 9 patients (47.3%) a moderate degree of inflammation and in 4 patients (21.1%) an high degree of inflammation. According to the classification of the National Institutes of Health (NIH), class IV chronic prostatitis (CP) are the asymptomatic inflammatory prostatitis (histological prostatitis) with no chronic pelvic pain syndrome (CPPS) (3). The mean patient age was 61.1 ± 7.33 years and the median IPSS score was 8 (6.5-13.5). The median prostate-specific antigen value, at biopsy, was 5.7 ng/ml (4.9-6.8 ng/ml). According to EAU Prostate Cancer Guidelines (4), a prostate biopsy was repeated, after 6 months, because of the presence of extensive HGPIN or ASAP. No conflict of interest declared.

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Could pollen extract in association with vitamins be favorable in the reduction of chronic prostatic inflammation? A case-series analysis

Figure 2. a) Moderate degree of inflammation before the treatment; (b) mild degree of inflammation after the treatment.

growth, prostatic enlargement, and bladder outlet obstruction (7). A prostatic inflammation classification, based on a histologic grading related to the extension of inflammatory cells, has been described (8). Specifically, histologic grading can be classified as: Grade 0 - absent, no inflammation; Grade 1 - mild, scattered inflammatory cell infiltrate without nodules; Grade 2 - moderate, no confluent lymphoid nodules; and Grade 3 - high, large inflammatory areas with confluence.

Table 1. Degree of inflammation.

Under the circumstances that CPI leads to BPH and, therefore, to LUTS due to BPH, CPI could be a target for medical treatment, in patients with asymptomatic or symptomatic BPH, acting on prostatic enlargement and LUTS. In fact, it is described the favorable effects of nonsteroidal anti-inflammatory drugs (NSAIDs) (9), but their side effects related with long-term use mostly limit their prescription in patients with BPH-related LUTS. Phytotherapeutics are a value options due to their generally minimal side-effects. In the present case-series analysis was observed that the use of pollen extract in association with vitamins (DEPROX 500®) is safe and aids to reduce the severity of chronic prostatic inflammation in patients with class IV chronic prostatitis (CP). This effect is possibly due to the association between the pollen extract and vitamins B6 and B12 that improve the antioxidant activity and anti-inflammatory effect of pollen extract. The present case-series analysis had few limitations that should be taken into account: the small number of enrolled patients, a short follow-up period, a selected patient population, the lack of control group and that this was not a blinded study.

Degree of inflammation (before DEPROX 500®) - Pts Mild - 6 Pts Moderate - 9 Pts High - 4 Pts

Degree of inflammation (after DEPROX 500®) - Pts Mild - 4 Pts Moderate - 7 Pts High - 2 Pts

Under the circumstances of the histological prostatitis diagnosed, a medical oral administration of DEPROX 500® (two capsules every 24 h) was prescripted until the repeat biopsy. The repeat biopsy histopathological examination showed in 6 patients (31.6%) prostate cancer, in 3 patients (15.8%) extensive HGPIN or ASAP and in 10 patients (52.6%) benign prostatic hyperplasia (BPH). Moreover, the repeat biopsy histopathological examination showed, in 13 patients (68.4%), a lower degree of inflammation (absent/mild/moderate). Specifically, 4 patients (30.8%) showed absent instead of mild degree of inflammation, 7 patients (53.8%) showed mild instead of moderate degree of inflammation (Figure 2) and 2 patients (15.4%) showed moderate instead of high degree of inflammation (Table 1). The median prostate-specific antigen value, at repeat biopsy, was 5.2 ng/ml (4.3-5.8 ng/ml). DEPROX 500® was generally well tolerated over the full period.

DISCUSSION

Chronic prostatic inflammation (CPI) leads to symptomatic or asymptomatic BPH (1, 2). CPI has been observed in a large proportion of patients treated surgically for lower urinary tract symptoms (LUTS) due to BPH and in the histological examination of prostatic biopsies performed for suspect of PCa (5). Moreover, CPI has been associated with higher prostate volume and a more severe International Prostate Symptom Score (IPSS) (5, 6). Histologically, CPI is characterized by the presence of large confluent inflammatory nodules in prostatic tissue (5, 6). These nodules release multiple inflammatory mediators that have been shown to stimulate prostatic cell growth. Nodules also damage the architecture of the gland, resulting in a chain reaction that further sustains the inflammatory response and promotes prostatic cell

CONCLUSIONS

The pollen extract in association with vitamins, such as DEPROX 500®, could have a favorable effect in the reduction of chronic prostatic inflammation. We expect further studies to evaluate its effect in chronic prostatic inflammation in the near future; in fact, more clinical data are needed to support the use of pollen extract in association with vitamins in a context of an evidence-based medicine. Currently, the use of this drug should be considered empirical.

REFERENCES

1. Ficarra V, Rossanese M, Zazzara M, et al. The role of inflammation in lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) and its potential impact on medical therapy. Curr Urol Rep. 2014; 15:463. 2. Gandaglia G, Briganti A, Gontero P, et al. The role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (BPH). BJU Int. 2013; 112:432-41. 3. Workshop Committee of the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK). Chronic Prostatitis Workshop, Bethesda, MD, 7-8 December, 1995. 4. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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M. Zazzara, A. Nazaraj, O. Colamonico, M. Mastromauro, G. Cardo, G.M. Ludovico

Mottet N, Bellmunt J, Bolla M, Briers E, Cumberbatch MG, De Santis M, Fossati N, Gross T, Henry AM, Joniau S, Lam TB, Mason MD, Matveev VB, Moldovan PC, van den Bergh RCN, Van den Broeck T, van der Poel HG, van der Kwast TH, Rouvière O, Schoots IG, Wiegel T, Cornford P. Eur Urol. 2017; 71:618-629. 5. Robert G, Descazeaud A, Nicolaïew N, et al. Inflammation in benign prostatic hyperplasia: A 282 patients’ immunohistochemical analysis. Prostate. 2009; 69:1774-80. 6. Nickel JC, Roehrborn CG, O'Leary MP, et al. The relationship between prostate inflammation and lower urinary tract symptoms: examination of baseline data from the REDUCE trial. Eur Urol. 2008; 54:1379-84.

Correspondence Michele Zazzara, MD michele.zazzara@gmail.com Arjan Nazaraj, MD ari.nazaraj@hotmail.it Ottavio Colamonico, MD ottaviocolamonico@gmail.com Giuseppe Cardo, MD giuseppecardo@hotmail.com Giuseppe Mario Ludovico, MD giuseppeludovico@hotmail.com Urology Department, Ospedale Generale Regionale “F. Miulli" Strada Prov. 127 Acquaviva - Santeramo Km. 4.100, 70021 Acquaviva delle Fonti (BA) (Italy) Marcella Mastromauro, MD marcella.mastromauro@libero.it Pathological Anatomy Department, Ospedale Generale Regionale “F. Miulli" Acquaviva delle Fonti (BA), Italy

Archivio Italiano di Urologia e Andrologia 2019; 91, 2

7. Kramer G, Mitteregger D, Marberger M. Is benign prostatic hyperplasia (BPH) an immune inflammatory disease? Eur Urol. 2007; 51:1202-16. 8. Irani J, Levillain P, Goujon JM, et al. Inflammation in benign prostatic hyperplasia: correlation with prostate specific antigen value. J Urol. 1997; 157:1301-3. 9. Kahokehr A, Vather R, Nixon A, Hill AG. Non-steroidal antiinflammatory drugs for lower urinary tract symptoms in benign prostatic hyperplasia: Systematic review and meta-analysis of randomized controlled trials. BJU Int. 2013; 111:304-11.

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DOI: 10.4081/aiua.2019.2.87

ORIGINAL PAPER

Comparison between “In-bore” MRI guided prostate biopsy and standard ultrasound guided biopsy in the patient with suspicious prostate cancer: Preliminary results Daniele D’Agostino 1, Federico Mineo Bianchi 2, Daniele Romagnoli 1, Paolo Corsi 1, Marco Giampaoli 1, Riccardo Schiavina 2, Eugenio Brunocilla 2, Walter Artibani 1, Angelo Porreca 1 1 Department 2 Department

of Robotic Urological Surgery, Abano Terme Hospital, Abano Terme, Italy; of Urology, University of Bologna, Bologna, Italy.

Summary

Objectives: To evaluate the detection rate of prostate cancer (PCa) in patients who underwent to “in bore” Magnetic Resonance Imaging -guided prostate (MRI-GB) biopsy compared to the standard transrectal ultrasound guided prostate biopsy (TRUS-GB). Materials and methods: Between January 2017 and March 2015 a cohort of 39 consecutive patients was prospectively enrolled. All the patients underwent an "in-bore" guided MRI prostatic biopsy and subsequently ultrasound-guided standard prostate biopsy. Results: Median age of patients was 65.5 years (SD ± 6.6), median total PSA serum level was 6.6 ng/ml (SD ± 4.1), median prostate total volume was 51.1 cc (SD ± 26.7). Thirty of 39 (76.9%) were biopsy-naïve patients while 7/39 (17.9%) had at least one previous negative random TRUS-GB; 2/39 (5.1%) patients were already diagnosed as PCa and were on active surveillance. In 18/39 (53.8%) men Pca was diagnosed; as regards the MRI-GB results related to the PI-RADS score, biopsies of PIRADS 3 lesions were positive in 5/18 cases (27.8%), while the number of positive cases of PI-RADS 4 and 5 lesions was 7/11 (63.6%) and 6/10 (60%)respectively. At the histological examination, 4/39 (10.3%) had a PCa ISUP grade group 1, 11/39 (28.2%) had a ISUP 2, 6/39(15.4%) had a ISUP grade group 3 and 2/39 (5.1%) had a ISUP 4-5. Conclusions: MRI-GB represents a promising technique that may offer some of advantages compared to standard systematic TRUSGB. Our preliminary experience in MRI-GB resulted safe and feasible and represents a viable procedure for the diagnosis and characterization of PCa.

KEY WORDS: Prostate cancer; MRI guided biopsy; Ultrasound guided biopsy. Submitted 27 March 2019; Accepted 29 April 2019

INTRODUCTION

Prostate Cancer (PCa) represents the most common neoplasm diagnosed in men and the second cause of death after lung cancer (1). Digital rectal examination, serum PSA assay and ultrasound-guided biopsy (TRUS-GB) are common methods for prostate cancer diagnosis (2) although not devoid of some limitations and questionable validity. In fact, during prostate ultrasound, the yield of cancer detection remains very low, ranging between 20 and 30% for patients with a serum PSA value between 2 and 4 ng/ml (3, 4); moreover, in a non-negligible per-

centage of cases (25-30%), PCa may arise from the anterior part of the gland (anterior horn of peripheral gland, central/transitional zones and fibromuscular stroma). For these reasons, “random” TRUS-GB has a false negative rate of up to 40-50% (5, 6) and clinically significant tumors can often be undetected, especially in larger glands. A higher number of cores can improve the rate of tumors identified but, at the same time, increases the risk of diagnosis of indolent diseases: an aggressive management of these overdiagnosed cases will inevitably lead to an overtreatment, thereby negatively affecting the patients' quality of life. Magnetic Resonance Imaging (MRI) is a tool of growing importance in PCa diagnosis; furthermore, with the introduction of multiparametric MRI (mpMRI) the accuracy for characterization of prostate lesion is significantly improved. mpMRI, performed before the biopsy, can improve the detection of occult tumors in the areas of prostate generally undersampled during random TRUS-GB. A growing body of evidences suggest that an accurate tumor identification and sampling can improve risk classification and should reduce false-negative rates and the necessity of repeat biopsies both in biopsy-naïve patients and in patients with prior negative-biopsy (710). However, the increasingly widespread use of the mpMRI for the detection of clinically significant PCa has involved the need for targeted biopsy reducing the sampling in non-suspicious areas. The techniques for targeted biopsy include visual estimation TRUS-GB, software co-registered MRI ultrasound fusion and in-bore MRIguided biopsy (MRI-GB); the latter provides the great advantage of direct visualization of the targeted lesion with the same system. Thus, the aim this study was to evaluate the detection rate of prostate cancer in patients underwent to “in bore” MRI-guided prostate biopsy compared to the standard ultrasound guided prostate biopsy; for secondary endpoint we evaluated the morbility and the complications of both procedures.

MATERIALS

AND METHODS

Study methodology and population Between January 2017 and March 2015 a cohort of 39

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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D. D’Agostino, F. Mineo Bianchi, D. Romagnoli, P. Corsi, M. Giampaoli, R. Schiavina, E. Brunocilla, W. Artibani, A. Porreca

consecutive patients was prospectively enrolled. The study was conducted with the approval of the institutional review board and all the procedures and reporting were in accordance with the Helsinki protocol. Patients were informed and a subsequent written consent was acquired. All patients had a suspicion for PCa – raised Prostate Specific Antigen (PSA) serum level and/or abnormal digital rectal examination (DRE) – and showed at the mp-MRI previously conducted in our institution at least one suspicious area where the presence of a clinically significant PCa was defined equivocal/likely/highly likely, corresponding to a PI-RADS (Prostate Imaging Reporting and Data System) score ≥ 3 according to the European Society of Urogenital Radiology (ESUR) guidelines (17). Patients with any usual contraindications for MRI (eg. metallic implants and/or cardiac pacemakers) were excluded from the study. All patients underwent a "in-bore" guided MRI prostatic biopsy and subsequently ultrasound-guided standard prostate biopsy; the urologist who performed the ultrasound-guided prostatic biopsy was always the same and was not aware of the result of mpMRI. MRI examination and analysis All the MRI examinations were performed with a 32 channels 1.5 T whole body scanner (Achieva XR; Philips Medical Systems, Best, Netherlands) with a 32-channels phasedarray surface coil without endorectal coil. After local threeplane acquisition, required for the correct positioning of the sequences, the morphological and functional studies were carried out. Morphological study of the prostate gland were obtained with Turbo Spin Echo (TSE) T2weighted sequences (TE 100 msec, TR 4074 msec, Slice Thickness 3 mm, Slice Spacing 0.3 mm, Field of View – FOV 180 x 180 mm and matrix size 276 x 205) in the sagittal, axial and coronal planes, including seminal vesicles and the entire prostate gland. For the functional study, DWI, DCE-MRI and MRS acquisition were performed. The DWI acquisition was carried out in the axial plane, using a single-shot echo-planar imaging (SSEPI) sequence, with three b-values (0, 600 and 1500 s/mm2), slice thickness of 3 mm, FOV 180 x 180 mm and matrix size 80 x 71. The DCE-MRI was obtained using three-dimensional (3D) T1W High Resolution Isotropic Volume Examination (THRIVE) sequence during the intravenous injection of a contrast bolus of 0,1 mmol per kilogram of body weight of Meglumine gadobenate (Multihance, Bracco Diagnostics, Milan, Italy), at flow rate of 3,5 ml/sec followed by 15 ml of saline solution. Conduct of the “in-bore” MRI-guided biopsy The biopsies were performed on a different day from the diagnostic mpMRI study (within 2-4 weeks) by a single urologist. All patients received oral antibiotic prophylactic therapy 2 days before the maneuver; biopsies were performed transrectally with the patient prone on a 1.5 T MR scanner (Achieva XR; Philips Medical Systems, Best, Netherlands) using a 18-G automatic core-needle, a titanium double-shot biopsy gun, a Gadolinium-filled needle-guide, a non-magnetic portable biopsy device (DynaTRIM, Invivo, Gainesville, FL) and a dedicated software package for device tracking and target localization (DynaCAD, Invivo, Gainesville, FL). Before biopsy, DRE

Archivio Italiano di Urologia e Andrologia 2019; 91, 2

was performed in order to evaluate any potential anatomic or pathologic condition that could hinder transrectal biopsy and to approximate the position of the gland. The needle sleeve is also a marker for software localization; after the sleeve was assembled on the arm of the biopsy device, fixed on the tabletop of the magnet, and inserted into the rectum, the patient was positioned into the scanner. T2w images in the axial and sagittal direction were obtained for visualization of the prostate and identification of the suspicious lesion; simultaneously, the Gadolinium-filled needle guide was properly identified and marked for subsequent track calibration: oblique axial T2w images were aligned with the needle guide in order to allow software registration showing three-dimensional adjustments required to align the track of the biopsy needle through the needle guide and the target lesion. After manual calibration adjustments on the arm of the biopsy device attached to the needle guide, sagittal T2w images in parallel with the long axis were obtained in order to confirm the correct position and the proper direction of the needle guide to the target; reconfirmation of the needle track were repeated until proper alignment was obtained. Once the patient was taken from the scanner, biopsy was performed with a median of 2 (range 1-2) cores taken from each target lesion. If targeting was not certain, due to lesion size or subjective judgement of the operator, subsequent axial and sagittal T2w images with the needle in place were obtained to detect needle position and be able to make adjustments for the next core. Total table time was appreciatively 45 to 70 minutes per patient. After the procedure, patients were observed for 1 hour and were re-evaluated by outpatient visit after 7-10 days in order to record any potential complication. Specimens were processed by routine hystopathological fixation with formalin solution and evaluated by a single dedicated uropathologist with 20 years of experience. Conduct of ultrasound guided prostate biopsy The standard biopsy was performed by transrectal approach; the examination was tipically 12 cores collected in a sextant template of biopsies from the medial and lateral area of the apical, mid and the base of prostate, on the left and right lobe. During the TRUS guided biopsy the mpMRI data target was not available. Total table time was appreciatively 15 to 30 minutes per patient. After the procedure, patients were observed for 1 hour and were re-evaluated by outpatient visit after 7-10 days in order to record any potential complication. antibiotic prophylaxis was continued by patients for seven days after the procedure. Specimens were processed by routine hystopathological fixation with formalin solution and evaluated by a single dedicated uro-pathologist with 20 years of experience. Statistical analysis Simple descriptive statistical techniques were used to analyze data, in particular median with interquartile range (IQR) and mean ± standard deviation (SD) were used to report continuous variables, whereas frequencies with percentages were used to describe categorical ones. Oneway ANOVA and Kruskal-Wallis k-samples were used to

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Comparison between “In-bore” MRI guided prostate biopsy and standard ultrasound guided biopsy in the patient with suspicious prostate cancer...

compare means and medians between three groups. Pearson’s Chi-Square test and Mc-Nemar test were used to compare the association between clinical and pathologic variables. Two-tailed P values less than 0.05 were considered statistically significant. Statistical analyses were conducted using SPSS® version 21.0 for Macintosh® (IBM Corp, Armonk, NY).

RESULTS

Patient characteristics: Median age of patients was 65.5 years (SD ± 6.6), median total PSA serum level was 6.6 ng/ml (SD ± 4.1), median prostate total volume was 51.1 cc (SD ± 26.7). Thirty of 39 (76.9%) were biopsynaïve patients while 7/39 (17.9%) had at least one previous negative random TRUS-GB; 2/39 (5.1%) patients were already diagnosed pCa on active surveillance. Clinical, radiological and pathological characteristics of the entire population of the study are listed in Table 1. Detection rate All patient enrolled in the study have been subjected both the MRI-GB and the TRUS-GB. The majority of suspected lesions identified with mpMRI were located in the posterior zone of the prostate (69% of cases). The mean number of bioptic cores taken from patient was 1 in MRI-GB series (range 1-2) and 12 in TRUS-GB (range 12-14).As reported in table 5, about overall detection rate (DR) of patients who underwent “in-bore” MRIGB and TRUS-GB, in 23/39 (59%) men PCa was diagnosed; as regards the MRIGB results related to the PI-RADS score, biopsies of PI-RADS 3 lesions were positive in 5/18 cases (27.8%), while the number of positive cases of PI-RADS 4 and 5 lesions was 7/11 (63.6%) and 6/10 (60%) respectively. Analyzing the results of MRI-GB, globally 17/39 (43.5%) patients presented a clinically significant PCa (ISUP group ≥ 2), while the DR for clinically significant PCa in TRUS-GB was 15/39 patients (38.4%). In the series of “biopsy naïve” patient we observed 14/30 (46.7%) cases of PCa detected by MRI-GB and 13/30 (43.3%) cases in the series of TRUS-GB. In patients with previous negative biopsies we observed PCa in 2/7 (28.6%) cases both in MRI-GB and TRUS-GB. In the “active surveillance” group we detected 2/2 (100%) men with PCa in MRI-GB series and 1/2 (50%) in TRUS-GB

Table 1. Clinical and radiologic features of patients who underwent “in-bore” biopsy. Overall (n = 39) Age, years 65.5 ± 6.6 Mean ± SD PSA, ng/ml 6.6 ± 4.1 Mean ± SD PSA density, ng/ml/cc 0.14 ± 0.09 Mean ± SD Prostate volume, cc 51.1 ± 26.7 Mean ± SD Diameter mpMRI area, mm 11.9 ± 5.1 Mean ± SD Area location mpMRI+, n (%) Posterior Anterior PI-RADS-v2, n (%) 3/5 4/5 5/5

Biopsy näive (n = 30) 65.3 ± 6.8

Previous Active negative biopsy surveillance (n = 7) (n = 2) 66.6 ± 7.1 63.5 ± 2.1

p value 0.8

11.7 ± 4.9

10.9 ± 7.4

6.2 ± 1

0.007

0.14 ± 0.09

0.15 ± 0.05

0.13 ± 0.04

0.95

46.7 ± 22.2

70.4 ± 38.1

52 ± 8.5

0.1

11.7 ± 4.9

13.1 ± 6.5

10 ± 5.7

0.7

27 (69.2) 12 (30.8)

21 (70) 9 (30)

4 (57.1) 3 (42.9)

2 (100) 0 (0)

0.5

18 (46.2) 11 (28.2) 10 (25.6)

14 (46.7) 8 (26.7) 8 (26.7)

2 (28.6) 3 (42.9) 2 (28.6)

2 (100) 0 (0) 0 (0)

0.5

Table 2. Overall and stratified according to clinical status “in-bore” results. Overall Detection rate PCa, n (%)

18/ 39 (53.8)

Biopsy Previous Active p näive negative biopsy surveillance value 14/ 30 (46.7) 2/7 (28.6) 2/ 2 (100) 0.2

Detection rate csPCa, n (%)

17/ 39 (43.5)

14/ 30 (46.6)

2 /7 (28.6)

1/ 2 (50)

0.1

csPCa/overall PCa rate, % ISUP grade group, n (%) Negative 1 2 3 4-5

17/18 (94.4)

14/14 (100)

2 /7 (28.6)

1/ 2 (50)

0.2

21 (53.8) 1 (2.5) 10 (25.6) 4 (10.3) 3 (7.6)

16 (53.3) 0 (0) 10 (33.3) 2 (6.6) 2 (6.6)

5 (71.4) 0 (0) 0 (0) 1 (14.2) 1 (14.2)

0 (0) 1 (50) 0 (0) 1 (50) 0 (0)

0.1

Table 3. “In-bore” biopsy results stratified according to PIRADS Score. Overall

PIRADS score 3 Number of Pts, (%) 39 18 (46.2) Detection rate PCa, n (%) 18/39 (53.8) 5/18 (27.8) Detection rate csPCa, n (%) 17/39 (43.5) 3/18 (16.7) Detection rate csPCa/PCa, % 17/18 (94.4) 3/5 (60) ISUP grade group, n (%) Negative 21 (53.8) 13 (72.2) 1 1 (2.5) 1 (5.5) 2 10 (25.6) 3 (16.6) 3 4 (10.3) 1 (5.5) 4-5 3 (7.6) 0 (0)

PIRADS score PIRADS score p 4 5 value 11 (28.2) 10 (25.6) 7/11 (63.6) 6/10 (60) 0.3 5/11 (45.5) 5/10 (50) 0.1 5/7 (71.4) 5/6 (83.3) 0.7 4 (36.4) 0 (0) 5 (45.4) 1 (9.1) 1 (9.1)

4 (40) 0 (0) 2 (20) 2 (20) 2 (20)

0.1

Table 4. Number of bioptic cores taken from patients who underwent in-bore and random biopsies. Number of cores Total In bore biopsy Random biopsy

Overall (n = 39) 13 (13-14) 1 (1-2) 12 (12-12)

Biopsy näive (n = 30) 13 (13-14) 1 (1-2) 12 (12-12)

Previous negative biopsy (n = 7) 13 (13-15) 1 (1-1) 12 (12-14)

Active surveillance (n = 2) 13 (13-13) 1 (1-1) 12 (12-12)

p value 0.5 0.5 0.5

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Table 5. Overall “detection rates” and “pathologic results” of patients who underwent “in-bore” biopsies and random biopsies. Number of cores Detection rate PCa, n (%) Detection rate csPCa, n (%) csPCa/PCa detection rate, % ISUP grade group, n (%) Negative 1 2 3 4-5

Overall (n = 39) 23/39 (59) 20/39 (51.3) 20/23 (87)

In-bore biopsy 18/39 (53.8) 17/39 (43.5) 17/18 (94.4)

Random biopsy 18/39 (53.8) 15/39 (38.4) 15/18 (83.3)

p value 0.9 0.7 0.8

16 (41) 4 (10.3) 11 (28.2) 6 (15.4) 2 (5.1)

21 (53.8) 1 (2.5) 10 (25.6) 4 (10.3) 3 (7.6)

21 (53.8) 5 (12.8) 7 (17.9) 5 (12.8) 1 (2.6)

0.6

Table 6. Overall “detection rates” and “pathologic results” of biopsy näive patients who underwent “in-bore” biopsies and Random biopsies. Detection rate PCa, n (%) Detection rate csPCa, n (%) csPCa/PCa detection rate, % ISUP grade group, n (%) Negative 1 2 3 4-5

Overall (n = 30) 16/30 (75.4%) 15/30 (50%) 15/16 (93.8%)

In-bore biopsy 14/30 (46.7) 14/30 (46.6) 14/14 (100)

Random biopsy 1 /30 (43.3) 13/30 (43.3) 13/13 (100)

p value 0.8 0.8 0.5

14 (46.7) 1 (3.3) 9 (30) 5 (16.7) 1 (3.3)

16 (53.3) 0 (0) 10 (33.3) 2 (6.6) 2 (6.6)

17 (56.7) 0 (0) 8 (26.7) 4 (13.3) 1 (3.3)

0.7

Table 7. Overall “detection rates” and “pathologic results” of patients with previous negative biopsies who underwent “in-bore” biopsies and random biopsies. Detection rate PCa, n (%) Detection rate csPCa, n (%) csPCa/PCa detection rate, % ISUP grade group, n (%) Negative 1 2 3 4-5

Overall (n = 7) 4/7 (57.4) 2/7 (42.9) 2/4 (50)

In-bore biopsy 2/7 (28.6) 2/7 (28.6) 2/7 (28.6)

Random biopsy 2/7 (28.6) 1/7 (14.2) -

p value 0.3 0.1 -

1 (14.3) 4 (57.1) 0 (0) 1 (14.3) 1 (14.3)

5 (71.4) 0 (0) 0 (0) 1 (14.2) 1 (14.2)

5 (71.2) 2 (28.6) 0 (0) 0 (0) 0 (0)

0.2

Table 8. Overall “detection rates” and “pathologic results” of patients in Active Surveillance who underwent “in-bore” biopsies and random biopsies. Detection rate PCa, n (%) Detection rate csPCa, n (%) csPCa/PCa detection rate, % ISUP grade group, n (%) Negative 1 2 3 4-5

Overall (n = 2) 2/2 (100 2/2 (100) 2/2 (100)

In bore biopsy 2/ 2 (100) 1/ 2 (50) 1/ 2 (50)

Random biopsy 1/2 (50) 1/2 (50) 1 /1 (100)

p value 0.5 1 0.5

0 (0) 0 (0) 1 (50) 1 (50)) 0 (0)

0 (0) 1 (50) 0 (0) 1 (50) 0 (0)

1 (50) 0 (0) 1 (50) 0 (0) 0 (0)

0.3

Archivio Italiano di Urologia e Andrologia 2019; 91, 2

series. The details of results are reported in table 2-8. As far as the secondary endpoint is concerned, we have not observed any complications related to procedures.

DISCUSSION

TRUS-GB represents the “gold-standard” technique of histological diagnosis of prostate cancer. Aim of this study was to investigate the real diagnostic accuracy of a novel prostate biopsy technique MRI guided compared to the standard TRUS-guided biopsy (11). During the recent years, there was an increasing use of mpMRI in stadiation of prostate cancer e in order to improve quality of surgery during radical prostatectomy (12). Other important application of mpMRI is the guide to prostate biopsy in order to improve PCa diagnosis with the aim to refine PCa risk classification (13) and, simultaneously, to overcome the limitations of contemporary standard TRUS-GB: low-risk patients could be spared from biopsies reducing overdetection of low-risk cancer while a lower number of cores could be required in men with suspicious MRI findings reducing also potential complications related to the procedure and all the consequence on quality of life (14-16). Targeted MRI-GB has become an alternative approach to TRUS-GB and several MRI-GB methods have been proposed for the diagnosis of PCa. In the “cognitive” technique, TRUS-GB is planned on the basis of MR images; in spite of reduced costs, this method has a long learning curve and the sampling of suspicious lesions may not be guaranteed. The MRI-US “fusion” biopsy is simply described as a way to align a pre-registered MRI to an intraprocedural US in order to identify and target suspected lesions within the gland through a dedicated hardware platform targeting areas found during mpMRI and not clearly visible during US scan; the advantages are the high reproducibility and the real time feedback though counterbalanced by the high up-front cost of the device. The “in bore” technique consists in the execution of the biopsies directly inside the MRI scanner with dedicate non-magnetic biopsy devices. Despite a longer operative time and higher costs, this method has realtime feedback in needle placement, fewer sampled cores and a low likeli-

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Comparison between “In-bore” MRI guided prostate biopsy and standard ultrasound guided biopsy in the patient with suspicious prostate cancer...

hood of missed target. Therefore, the use of “in bore” MRI-GB has the potential to reduce the sampling error associated with unselective standard biopsy scheme by providing better disease localization; moreover, accurate risk stratification through improved cancer sampling may impact therapeutic decision making (13, 17). In our experience the overall detection rate of MRI-GB and TRUS-GB are similar; in particular, in the series of MRIGB, we observed a slightly higher PCa diagnosis of clinically significant disease (43.5% vs 33.3%), although this result was not statistically significant. A recent systematic review showed that MRI-GB improved significant PCa detection compared to standard TRUS-GB (relative sensitivity 1.26, 95% CI 1.08-1.46) (18). In their preliminary experience with in-bore technique, Panebianco et al. (19) showed a DR for the diagnosis of PCa of 80% and 90% of PCa cases had intermediate grade aggressiveness. Whereas there was currently not enough evidence to recommend mpMRI before a first set of prostate biopsies (2), the use of targeted biopsy often achieved significantly higher cancer DR in the repeat biopsy setting. In patients with prior negative biopsy, MRI-GB showed a median DR of 42%, significantly higher than those reported in repeating systematic biopsy (20). Our preliminary experience in MRI-GB confirmed the feasibility and the reproducibility of an “in-bore” strategy on a 1.5 T MR scanner using a 32-channel coil. Enghelard et al. (21) reported a DR of 38% in 37 consecutive men with elevated PSA levels and negative prostate biopsies underwent a MRI-GB in a 1.5-T scanner in the supine position; in similar but larger cohorts, Roethke et al. (22) and Hoeks et al. (10) found a DR of 52% (52/100) and 41% (14/37), respectively. In our cohort, analyzing the series of patients with previous negative biopsies, the overall DR of MRI-GB was higher than TRUS-GB (57.1% vs 28.6%), particularly in the clinically significant disease (28.5% vs 14.2%). Our preliminary results highlighted the excellent correlation between the PI-RADS score at mpMRI and the ISUP grade groups in MRI-GB cores: this data allows us to infer, on one hand, a high capability of the mpMRI to predict the biological aggressiveness of neoplastic lesions and, on the other hand, the good performance of the MRI-GB procedure. Moreover, the mpMRI procedure with this setting and patients in the prone position has been well tolerated and feasible to perform. Given an initial learning curve, we believe that the time needed for the procedure can be further reduced optimizing the setting and the positioning of the needle guide. Finally, Jung et al. (23) found that the rate of positive MRI-GB resulted as a function of target size and level of suspicious. It could be argued that obvious that larger target with higher level of suspicious were most likely to yield a positive biopsy; however, the authors concluded that this finding could be helpful when deciding whether to perform a MRI-GB. Engelhard et al. (21) concluded that suspicious lesions with a diameter > 10 mm could be successfully punctured using this device. In spite of reliable feasibility and the preliminary promising results with an acceptable DR, some limitations of the present study have to be kept in mind. First, the number of patients was small and, as a part of study design, the patients analyzed were only men with posi-

tive findings at mpMRI: this selected patient population from a single institution series may have a positive influence on the number of tumors detected; however, the study was thought as an initial experience to compare the MRI-GB technique and standard TRUS-GB in order to evaluate its feasibility. Consequently, the preliminary results are far from being meaningful and have to be interpreted carefully. Second, the study lacks follow up data and no prostate specimen histology can confirm the results of a negative MRI-GB; further series with radical prostatectomy specimen as reference standards are required in order to corroborate the benefit of a MRI-GB procedure. Finally, it is important to highlight that initially MRI-GB can represent a time-consuming and expensive procedure but, as reported by other authors (24), initial costs could be written off by reducing treatment related costs and improving risk tumor evaluation and quality of life preventing unnecessary radical treatment of insignificant tumors.

CONCLUSIONS

MRI-GB represents a promising technique that may offer some of these advantages compared to standard systematic TRUS-GB. Our preliminary experience in MRI-GB resulted safe and feasible and represents a viable procedure for the diagnosis and characterization of PCa especially in a subgroup of patient with clinically significant disease. Further investigations are needed in order to identify who should undergone prostate biopsy and the technique that should be used with the aim of detecting significant PCa and reducing the burden of biopsies.

REFERENCES

1. Siegel R, Naishadham D, Jemal A. Cancer statistics 2012. CA Cancer J Clin. 2012; 62:10-21. 2. Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer, part 1: screening, diagnosis, and local treatment with curative intent - update 2013. Eur Urol. 2014; 65:124-137. 3. Delongchamps NB, De la Roza G, Chandan V, et al. Diagnostic accuracy of extended biopsies for the staging of microfocal prostate cancers in autopsy specimen. Prostate Cancer Prostatic Dis. 2009; 12:137-142. 4. Roehl KA, Antenor JA, Catalona WJ. Serial biopsy results in prostate cancer screening study. J Urol. 2002; 167:2435-9. 5. Jones JS. Saturation biopsy for detecting and characterizing prostate cancer. BJU Int. 2007; 99:1340-1344. 6. Lane BR, Zippe CD, Abouassaly R, et al. Saturation technique does not decrease cancer detection during follow up after initial prostate biopsy. J Urol. 2008; 179:1746-1750. 7. Watanabe Y, Terai A, Araki T, et al. Detection and localization of prostate cancer with the targeted biopsy strategy based on ADC map: a prospective large-scale cohort study. J Magn Reson Imaging. 2012; 35:1414-1421. 8. Numao N, Yoshida S, Komai Y, et al. Usefulness of pre-biopsy multiparametric magnetic resonance imaging and clinical variables to reduce initial prostate biopsy in men with suspected clinically localized prostate cancer. J Urol. 2013; 190:502-508. 10. Siddiqui MM, Rais-Bahrami S, Truong H, et al: Magnetic resoArchivio Italiano di Urologia e Andrologia 2019; 91, 2

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nance imaging/ultrasound fusion biopsy significantly upgrades prostate cancer versus systematic 12-core transrectal ultrasound biopsy. Eur Urol. 2013; 64:713-719. 11. Schiavina R, Vagnoni V, D'Agostino D, et al. "In-bore" MRIguided prostate biopsy using an endorectal nonmagnetic device: a prospective study of 70 consecutive patients. Clin Genitourin Cancer. 2017; 15:417-427. 12. Schiavina R, Bianchi L, Borghesi M, et al. MRI displays the prostatic cancer anatomy and improves the bundles management before robot-assisted radical prostatectomy. J Endourol. 2018; 32:315321. 13. Vagnoni V, Bianchi L, Borghesi M, et al. Adverse features and competing risk mortality in patients with high-risk prostate cancer. Clin Genitourin Cancer. 2017; 15:e239-e248. 14. Porreca A, Noale M, Artibani W, et al. Pros-IT CNR study group. Disease-specific and general health-related quality of life in newly diagnosed prostate cancer patients: the Pros-IT CNR study. Health Qual Life Outcomes. 2018; 16:122. 15. Gacci M, Noale M, Artibani W, et al. Pros-IT CNR study group. Quality of life after prostate cancer diagnosis: data from the Pros-IT CNR. Eur Urol Focus. 2017; 3:321-324. 16. Noale M, Maggi S, Artibani W, et al. Pros-IT CNR study group. Pros-IT CNR: an Italian prostate cancer monitoring project. Aging Clin Exp Res. 2017; 29:165-172. 17. Grasso AA, Cozzi G, De Lorenzis E, et al. Multicenter analysis of pathological outcomes of patients eligible for active surveillance according to PRIAS criteria. Minerva Urol Nefrol. 2016; 68:237-41.

Correspondence Daniele D’Agostino, MD (Corresponding Author) dott.dagostino@gmail.com Daniele Romagnoli, MD dromagnoli@casacura.it Paolo Corsi, MD pcorsi@casacura.it Marco Giampaoli, MD mgiampaoli@casacura.it Walter Artibani, MD prof.artibani@gmail.com Angelo Porreca, MD angeloporreca@gmail.com Department of Robotic Urological Surgery, Abano Terme Hospital Piazza Cristoforo Colombo 1, 35031 Abano Terme (PD) (Italy) Federico Mineo Bianchi, MD federico.mineobianchi@gmail.com Riccardo Schiavina, MD rschiavina@yahoo.it Eugenio Brunocilla, MD eugenio.brunocilla@unibo.it Department of Urology, University of Bologna, Bologna (Italy)

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18. Schoots IG, Roobol MJ, Nieboer D. et al. Magnetic resonance targeted biopsy may enhance the diagnostic accuracy of significant prostate cancer detection compared to standard transrectal ultrasound guided biopsy: a systematic review and meta- analysis. Eur Urol. 2015; 68:438-450. 19. Panebianco V, Barchetti F, Manenti G, et al. MR imaging-guided prostate biopsy: technical features and preliminary results. Radiol Med. 2015; 120:571-578. 20. Overduin CG, Futterer JJ, Barentsz JO. MRI-guided biopsy for prostate cancer detection: a systematic review of current clinical results. Curr Urol Rep. 2013; 14:209-213. 21. Engelhard K, Hollenbach HP, Kiefer B, et al. Prostate biopsy in the supine position in a standard 1.5-T scanner under real time MRimaging control using a MR- compatible endorectal biopsy device. Eur Radiol. 2006; 16:1237-1243. 22. Roethke M, Anastasiadis AG, Lichy M, et al. MRI-guided prostate biopsy detects clinically significant cancer: analysis of a cohort of 100 patients after previous negative TRUS biopsy. World J Urol. 2012; 30:213-218. 23. Jung AJ, Westphalen AC, Kurhanewicz J, et al. Clinical Utility of Endorectal MRI-Guided Prostate Biopsy: Preliminary Experience. J Magn Res Imag. 2014; 40:314-323. 24. de Rooij M, Crienen S, Witjes JA, et al. Cost-effectiveness of Magnetic Resonance (MR) Imaging and MR-guided targeted biopsy versus systematic transrectal ultrasound–guided biopsy in diagnosing prostate cancer: a modelling study from a health care perspective. Eur Urol. 2014; 66:430-436.

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DOI: 10.4081/aiua.2019.2.93

ORIGINAL PAPER

Prostate volume effect on Gleason score upgrading in active surveillance appropriate patients Emre Çamur 1, Alper Coşkun 2, Övünç Kavukoğlu 3, Utku Can 4, Önder Kara 5, Arzu Develi Çamur 6, Kemal Sarıca 7, Kamil Fehmi Narter 8 1 Amasya

University Sabuncuoglu Serefeddin Training And Research Hospital Urology Department, Amasya, Turkey; Training And Research Hospital Urology Clinic, Sanlıurfa, Turkey; 3 Gumushane State Hospital Urology Clinic, Gumushane, Turkey; 4 Erzurum Training And Research Hospital Urology Clinic, Erzurum, Turkey; 5 Kocaeli University Medical Faculty Hospital Urology Clinic, Kocaeli, Turkey; 6 Suluova State Hospital, Internal Medicine Clinic, Amasya, Turkey; 7 Kafkas University Training And Research Hospital Urology Clinic, Kars, Turkey; 8 Acıbadem Mehmet Ali Aydınlar University Hospital Urology Clinic, Istanbul, Turkey. 2 Sanlıurfa

Summary

Introduction: Gleason Score (GS) upgrading rates in the literature are reported to be around 33-45%. The relationship between prostate volume and GS upgrading should be defined, aiming to reduce upgrading rates in patients with low risk groups who are eligible for active surveillance (AS) or minimally invasive treatment, by varying biopsy cores, or lengths of cores according to prostate volumes. In this regard, the aim of our study was to establish the relationship between prostate volume and GS upgrading. Materials and methods: We retrospectively analyzed the medical records of 78 patients, who were appropriate for AS between 2011-2016 at our hospital. Inclusion criteria were patient age under 65 years, PSA level under 10 ng/ml, GS (3 + 3) or (3 + 4), and 3 or less positive cores, clinical stages ≤ T2. GS increase in radical prostatectomy specimen was considered as 'upgrading' and in addition, score reported by biopsy as 3 + 4 but in surgical specimen as 4 + 3 were also considered as 'upgrading'. The effect of prostate volume on Gleason grade upgrading was examined by calculating upgrading rates separately for patients with prostate volume 30 ml or less, those with 30 to 60 ml, and those over 60 ml. Results: As a result of the analysis of the data, upgrading was seen in 35 (44.8%) of 78 patients included in the study. In the cohort mean prostate volume was 49.8 (± 26.3) ml. Twenty-two patients (28.2%) had prostate volume 30 ml or less, 34 (43.6%) 30 to 60 ml, and 22 (28.2%) 60 ml or more. The patients were divided into two groups as those with and without GS upgrading. Between the groups prostate volume and prostate volume range (0-30/31-60/> 60) were not significantly different (p value > 0.05). Conclusions: Gleason grade upgrading causes patients to be classified in a lower risk group than they actually are, and may lead to inappropriate treatment. This condition has a direct effect on the decision of active surveillance. Therefore, it is important to define the factors that can predict GS upgrading in active surveillance appropriate patients. In this study, we found that prostate volume has no significant effect on upgrading in active surveillance appropriate patients.

KEY WORDS: Prostate cancer; Gleason score; Upgrading; Active surveillance. Submitted 5 January 2019; Accepted 11 March 2019

INTRODUCTION

Prostate cancer is the second most common cancer worldwide and the fifth most common cause of cancerrelated deaths. Because of this reason, there are lots of studies on prostate cancer (1-2). Active surveillance (AS) has been defined in the appropriate group of patients for low-risk prostate cancer. Gleason Score (GS) is the most important criteria for patient selection for AS and used in the nomograms. In most studies and nomograms (3+3) GS in the biopsy is used as an inclusion criterium. Recently, researchers have included some eligible patients with a biopsy GS 3 + 4 to their studies (3-6). In patients, considered AS option, all pathological data, including GS are dependent on prostate needle biopsy. So that, the accuracy of the GS in needle biopsies is very important for this patient groups. However, there may be a significant difference between GSs in needle biopsies and radical prostatectomy specimens. If the score in prostatectomy specimen is higher than needle biopsy, that is defined as ‘upgrading’, if it is lower, 'downgrading' is mentioned. Upgrading rates in the literature are reported to be around 33-45% (7). Because of upgrading, patients who are not actually suitable for AS can be recommended with inappropriate treatment options. The reason for this high pathological disruption seems to be that less than 1% of the prostate tissue can be sampled with needle biopsy. Assessment in such a small tissue volume can cause tumor tissue to be undetectable or even missed (8-9). This is supported by studies showing that rates of upgrading in needle biopsies of enlarged prostate are lower (10-14). In most of previous studies, an inverse correlation was found between prostate volume and upgrading rates (15-17). Kulkarni et al. have not found significant relationship between prostate volume and upgrading rates, in a retrospective study published in 2006 in which they reviewed 369 patients (18). If the relationship between prostate volume and GS upgrading can be assessed, it may be aimed to reduce upgrading rates in patients with low risk groups who are

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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eligible for active follow-up or minimally invasive treatment, by varying biopsy cores, or lengths of cores according to their prostate volumes. In this regard, the aim of our study is to establish the relationship between prostate volume and GS upgrading.

MATERIALS

AND METHODS

RESULTS

As a result of the analysis of the data, upgrading was seen in 35 (44.8%) of 78 patients included in the study. The mean age of patients included in the study was 60.6 (± 4.4) years, and the mean PSA was 6.0 (± 2.2) ng/ml. According to needle biopsy reports, 65 patients (83.3%) had a GS of (3 + 3) and 13 patients (16.7%) had (3 + 4). In cohort mean prostate volume was 49.8 (± 26.3) ml. Twenty-two patients (28.2%) have prostate volume 30 ml or less, 34 (43.6%) 30 to 60 ml, and 22 (28.2%) 60 ml or more. The demographic and clinico-pathological

We retrospectively analyzed the medical records of 78 patients, who are appropriate for AS between 2011-2016 at our Hospital (Dr. Lütfi Kırdar Kartal Training and Research Hospital, Istanbul, Turkey). Age, prostate-specific antigen (PSA), prostate volume, total Table 1. number of cores in the preoperative biopsy, cancer posiDemographics and clinico-pathological outcomes tive core number in the biopsy, GS in the biopsy report, of the patients undergoing radical prostatectomy. clinical stage, GS in prostatectomy specimen, presence of Range Median Mean+/-SD prostatic intraepithelial neoplasia (PIN), extracapsular extenAge 46.0+/-65.0 61.5 60.6+/-4.4 sion (ECE), vascular invasion, surgical margin status, perPSA 2.3-10.0 5.7 6.0+/2.2 ineural invasion (PNI), seminal vesicle involvement (SVI) Prostate volume 14-135 43.0 49.8+/-26.3 were evaluated. Study protocol was approved by Ethics Prostate volume 0-30 22 28.2% Committee of Dr.Lütfi Kırdar Training and Research Hospital. Inclusion criteria were patient age under 65 years, PSA 31-60 34 43.6% level under 10 ng/ml, GS (3+3) or (3+4), and 3 or less >60 22 28.2% positive cores, clinical stages ≤ T2. Prostate volumes Gleason Score Biopsy 3+3 65 83.3% were measured transrectally during biopsy, all biopsies 3+4 13 16.7% were 12 cores and pathologic examination was perStage T2c 26 33.3% formed by two experienced uro-pathologists in our hosT2 52 16.7% pital. GS, total cores, and cancer positive core numbers N° positive cores I 31 39.7% were noted in the biopsy specimens that detected adeII 17 21.8% nocarcinoma. The length or percentage of the cancer III 30 38.5% positive tissue couldn’t found in most reports. GS, PIN, Gleason Score Specimen 3+3 38 48.7% surgical marginal status, PNI, SVI, ECE, presence of vascu3+4 25 32.1% lar invasion were registered. Biopsy and prostatectomy specimens were evaluated according to 2005 International 4+3 9 11.5% Society of Uro-pathologists (ISUP) modified Gleason system. 4+4 5 6.4% GS increase in radical prostatectomy specimen was 4+5 1 1.3% assessed as 'upgrading' and in addition also cases in which Upgrade (-) 43 44.8% the score reported by biopsy was 3 + 4 and the score found (+) 35 55.1% in the specimen was 4 + 3 were evaluated as 'upgrading'. The effect of prostate volume on Gleason grade upgrading was examined. Patients initially Table 2. Comparison of the upgraded and non-upgraded groups. were divided into GS upgrading or not. These groups were compared in terms of age, PSA Upgrade (-) Upgrade (+) p value, prostate volume, number of total biopsy Mean Median Mean Median cores, number of positive cores, clinical stages, Age 59+/-4.8 61 61.4+/-3.8 62 0.183 m surgical margin status, and SVI, presence of PSA 5.8+/-2.2 5.4 6.2+/-2.2 5.9 0.529 m ECE, PIN, PNI, and vascular invasion. Prostate volume 53.1+/-28 46 45.8+/-23.9 39 0.303 m Upgrading rates were calculated separately for Prostate volume 0-30 12 27.9% 10 28.6% 0.604 x2 patients with prostate volume 30 ml or less, 31-60 17 39.5% 17 48.6% those with 30 to 60 ml, and those over 60 ml. > 60 14 32.6% 8 22.9% In the descriptive statistics of the data, mean, standard deviation, median lowest, highest, freGS biopsy 3+3 35 81.4% 30 85.7% 0.611 x2 quency and ratio values were used. The distribu3+4 8 18.6% 5 14.3% tion of the variables was measured with the N° positive cores I 18 41.9% 13 37.1% 0.747 x2 Kolmogorov Simirnov test. Mann-Whitney U II 8 18.6% 9 25.7% test was used for quantitative independent data III 17 39.5% 13 37.1% analysis. Chi-square test was used for the analyGS specimen 3+4 5 11.6% 20 57.1% 0.000 x2 sis of qualitative independent data and SPSS 4+3 0 0 9 25.7% 22.0 (Statistical Package for the Social Sciences) 4+4 0 0 5 14.3% program was used in the analysis. P value below 4+5 0 0 1 2.9% 0.05 were considered statistically significant m: Mann-Whitney U test; x²: Chi-Square test. (p < 0.05).

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Prostate volume and Gleason score upgrading

outcomes of the patients included in the study are summarized in the Table 1. The patients were divided into two groups as those with and without GS upgrading. In the analysis, no significant difference was observed between these groups in terms of age, PSA values, biopsy GS, number of positive biopsy cores, clinical stage (p > 0.05). GS (3 + 3) was significantly higher in non-upgrading group (p > 0.05) (Table 2). Between the groups with different prostate volume (030/31-60/> 60) no significant difference was found (p value > 0.05) (Table 2).

DISCUSSION

Treatment options in prostate cancer differ according to defined risk groups. Low risk patients have better prognosis than middle and high risk group and lower biochemical recurrence rates after radical prostatectomy. In these patients, active follow-up, brachytherapy and focal therapies are used in order to avoid the complications and side effects of radical prostatectomy or radiotherapy (17, 19-20). PSA level, clinical stage and GS are used to determine these risk classification (21-22). GS is the most important prognostic factor of prostate cancer risk for classification and choice of treatment options (16, 22-23). Accurate determination of patient's risk group and GS at the time of diagnosis is important in order to choose the appropriate treatment options. However, there are significant pathological differences between needle biopsies and radical prostatectomy specimens such as GS upgrading in 33-45%. This high rate led investigators to examine the factors that might be effective to predict upgrading. PSA level, number of cores taken, number of positive cores are some of these factors. Also there are several studies on the effect of prostate volume on GS upgrading. (10, 15, 24-27). In 2008 Turley et al. investigated 586 patients retrospectively. In this study, GS elevation rate was found to be increased as prostate volume decreased (28). In a study that Moon et al. reviewed 107 patients retrospectively demonstrating that 12 or less number of cores in the biopsy and prostate volume of 36.5 ml or less were a predictive factor of GS upgrading (15, 29). Davies et al. published a retrospective study on prostate volume effect on GS upgrading in 2011. In this large study, medical records of 1.251 low-risk patients were retrospectively investigated and it was found that risk of GS upgrading was more than fifty percent in subjects with prostate volume 36 cm3 compared to those with 58 cm3 (16). Similarly, Chung et al., in a retrospective study of 247 patients published in 2013, reported that patients with prostate volumes of 25 cm3 or lower had a GS upgrading risk of 2.7 times more than patients with a prostate gland volume of 40 cm3 or more (15). However, in a retrospective study of 369 patients, Kulkarni et al. reported no significant relationship between prostate volume and GS upgrading (18). Gleason grade elevation is most important in active sur-

veillance. However, a study that examined the effect of prostate volume on GS upgrading in active surveillance appropriate patients has not been previously mentioned in the literature. In this study, 78 patients with active monitoring were included. Inclusion criteria were patient age under 65 years, PSA level under 10 ng/ml, GS 3+3 or 3+4 and 3 or less positive cores, clinical stage ≤ T2. Prostate volume effect on GS upgrading in active surveillance appropriate patients was examined, and patients with prostate volume of 30 ml or less, between 30 ml and 60 ml and greater than 60 ml were compared. According to our results prostate volume found to have no significant effect on GS upgrading in patients who are eligible for active surveillance. Retrospective nature and small number size of this study, and the calculation of prostate dimensions by different clinicians were the limitations of our study.

CONCLUSIONS

Treatment alternatives in prostate cancer may differ according to risk groups. So that it is important to classify patients in the correct risk group. Gleason grade upgrading causes patients to be classified in a lower risk group than they actually are, and may lead to inappropriate treatment. This situation has a direct effect on the decision of active surveillance. Therefore, it is important to define the factors that can predict GS upgrading in active surveillance appropriate patients. In this study, we found that prostate volume has no significant effect on upgrading in active surveillance appropriate patients.

COMPLIANCE

WITH ETHICAL STANDARDS

Funding: This study was not funded. Conflict of Interest: All authors declare that they have no conflict of interest. Ethical approval: 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.

REFERENCES

1. International Agency for Research on Cancer (IARC) Cancer Fact Sheets - Prostate Cancer - Source Globoscan 2018 http://globocan iarc fr/Pages/fact_sheets_cancer aspx (20 March 2014, date last accessed). 2014. 2. Humphrey P, Schuz J. Cancers of the male reproductive organs. World Cancer Report Lyon: World Health Organization. 2014; pp 453-64. 3. Thomsen FB, Brasso K, Klotz LH, et al. Active surveillance for clinically localized prostate cancer––A systematic review. J Surg Oncol. 2014; 109:830-5. 4. Loeb S, Bruinsma SM, Nicholson J, et al. Active surveillance for Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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E. Çamur, A. Coşkun, Ö. Kavukoğlu, Utku Can, Ö. Kara, A. Develi Çamur, K. Sarıca, K. Fehmi Narter

prostate cancer: a systematic review of clinicopathologic variables and biomarkers for risk stratification. Eur Urol. 2015; 67:619-26.

EAU-ESTRO-SIOG guidelines on prostate cancer. EAU Guidelines Office. Arnhem, The Netherlands, 2016, pp 14-27.

5. Ploussard G, Isbarn H, Briganti A, et al. (editors) Can we expand active surveillance criteria to include biopsy Gleason 3+ 4 prostate cancer? A multi-institutional study of 2,323 patients. Urol Oncol. 2015; 33:71.e1-9.

22. D’Amico AV, Moul J, Carroll PR, et al. Cancer specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific antigen era. J Clin Oncol. 2003; 21:2163-72.

6. Schiavina R, Borghesi M, Brunocilla E, et al. The biopsy Gleason score 3 + 4 in a single core does not necessarily reflect an unfavourable pathological disease after radical prostatectomy in comparison with biopsy Gleason score 3 + 3: looking for larger selection criteria for active surveillance candidates. Prostate Cancer Prostatic Dis. 2015; 18:270-5.

23. Zincke H, Bergstralh EJ, Blute ML, et al. Radical prostatectomy for clinically localized prostate cancer: long-term results of 1,143 patients from a single institution. J Clin Oncol. 1994; 12:2254-63.

7. Bostwick DG, Cheng L. Urologic surgical pathology. 3 ed: Elsevier/Saunders; 2014. p. 408-531. 8. Partin A. Prostat tümörlerinin patolojisi In: Yaman Ö (ed.) Campbell Walsh Üroloji 10 ed: Saunders/Günes Tıp Kitabevleri 2014: pp 2726-34. 9. Epstein JI. Diagnosis and reporting of limited adenocarcinoma of the prostate on needle biopsy. Mod Path. 2004; 17:307-15. 10. Freedland SJ, Kane CJ, Amling CL, et al. Upgrading and downgrading of prostate needle biopsy specimens: risk factors and clinical implications. Urology. 2007; 69:495-9 11. Pinthus JH, Witkos M, Fleshner N, et al. Prostate cancers scored as Gleason 6 on prostate biopsy are frequently Gleason 7 tumors at radical prostatectomy: implication on outcome. J Urol. 2006; 176:979-84. 12. King CR, McNeal JE, Gill H, Presti JC. Extended prostate biopsy scheme improves reliability of Gleason grading: implications for radiotherapy patients. Int J Radiat Oncol Biol Phys. 2004; 59:38691.

24. Kulkarni GS, Lockwood G, Evans A, et al. Clinical predictors of gleason score upgrading. Cancer. 2007; 109:2432-8. 25. Hong SK, Han BK, Lee ST, et al. Prediction of Gleason score upgrading in low-risk prostate cancers diagnosed via multi (≥ 12)core prostate biopsy. World J Urol. 2009; 27:271-6. 26. Miyake H, Kurahashi T, Takenaka A, et al. Improved accuracy for predicting the Gleason score of prostate cancer by increasing the number of transrectal biopsy cores. Urol Int. 2007; 79:302-6. 27. Moussa AS, Li J, Soriano M, et al. Prostate biopsy clinical and pathological variables that predict significant grading changes in patients with intermediate and high grade prostate cancer. BJU Int. 2009; 103:438. 28. Turley RS, Hamilton RJ, Terris MK, et al. Small transrectal ultrasound volume predicts clinically significant Gleason score upgrading after radical prostatectomy: results from the SEARCH database. J Urol. 2008; 179:523-8. 29. Moon SJ, Park SY, Lee TY. Predictive factors of Gleason score upgrading in localized and locally advanced prostate cancer diagnosed by prostate biopsy. Korean J Urol. 2010; 51:677-82.

13. Emiliozzi P, Maymone S, Paterno A, et al. Increased accuracy of biopsy Gleason score obtained by extended needle biopsy. J Urol. 2004; 172:2224-6. 14. San Francisco IF, DeWolf WC, Rosen S, et al. Extended prostate needle biopsy improves concordance of Gleason grading between prostate needle biopsy and radical prostatectomy. J Urol. 2003; 169:136-40. 15. Chung MS, Lee SH, Lee DH, Chung BH. Is small prostate volume a predictor of Gleason score upgrading after radical prostatectomy? Yonsei Med J. 2013; 54:902-6. 16. Davies JD, Aghazadeh MA, Phillips S, et al. Prostate size as a predictor of Gleason score upgrading in patients with low risk prostate cancer. J Urol. 2011; 186:2221-7. 17. Kim KH, Lim SK, Shin TY, et al. Upgrading of Gleason score and prostate volume: a clinicopathological analysis. BJU Int. 2013; 111:1310-6. 18. Kulkarni GS, Al-Azab R, Lockwood G, et al. Evidence for a biopsy derived grade artifact among larger prostate glands. J Urol. 2006; 175:505-9. 19. Partin AW, Yoo J, Carter HB, et al. The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol. 1993; 150:1104. 20. D'Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998; 280:969-74. 21. Mottet N, Bellmunt J, Briers E, et al. Diagnostic evaluation.

Archivio Italiano di Urologia e Andrologia 2019; 91, 2

Correspondence Emre Çamur, MD (Corresponding Author) emre.camur@outlook.com Amasya University Sabuncuoglu Serefeddin Training And Research Hospital Urology Department, Amasya (Turkey) Alper Coşkun, MD dr.alper05@gmail.com Sanlıurfa Training and Research Hospital Urology Clinic, Sanlıurfa (Turkey) Övünç Kavukoğlu, MD ovunckavukoglu@hotmail.com Gumushane State Hospital Urology Clinic, Gumushane (Turkey) Utku Can, MD utkucan99@yahoo.com Erzurum Training and Research Hospital Urology Clinic, Erzurum (Turkey) Önder Kara, MD onerkara@yahoo.com Kocaeli University Medical Faculty Hospital Urology Clinic, Kocaeli (Turkey) Arzu Develi Çamur, MD develiarzu@hotmail.com Suluova State Hospital, Internal Medicine Clinic, Amasya (Turkey) Kemal Sarıca, MD saricakemal@gmail.com Kafkas University Training and Research Hospital Urology Clinic, Kars (Turkey) Kamil Fehmi Narter, MD fehminarter66@gmail.com Acıbadem University Hospital Urology Clinic, Istanbul (Turkey)

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ORIGINAL PAPER

DOI: 10.4081/aiua.2019.2.97

Increased neutrophil/lymphocyte ratio in testicular cancer AytaĂ§ SĚ§ahin, Tuncay Toprak, Musab Ali Kutluhan, Yasin Vural, Ahmet Ă&#x153;rkmez, Ayhan Verit SBU Fatih Sultan Mehmet Training and Research Hospital, Istanbul.

Summary

Objective: Testicular cancers, which are less common than other cancers, are important in terms of being seen in young people. Physical examination, imaging, laboratory and tumor markers are used for diagnosis. There are some studies of some blood parameters that can be involved in inflammation and tumorogenesis. We retrospectively compared hematological values measured in our patients who were diagnosed with testicular tumor in comparison with patients with similar age group who underwent varicocelectomy repair. Materials and methods: This cross-sectional retrospective study included 120 patients who underwent radical inguinal orchiectomy for testicular tumor between January 2010 and December 2018, and 171 patients who underwent varicocelectomy as a control group. Patients with an active infection and hematological disorders were excluded from the study. We evaulated hematological parameters including neutrophil (NEU), lymphocyte (LYM), platelet (PLT) count, and mean platelet volume. The study was conducted on 291 patients. divided in two groups: tumor (n = 120) and varicocele (n = 171). Results: There was no statistically significant difference between the groups in terms of PLT / lymphocyte ratio and mean platelet volume (MPV) levels (p > 0.05). The neutrophil /lymphocyte ratio (NLR) of the tumor group was significantly higher than the varicocele group (p = 0.001; p < 0.05). There was a statistically significant difference between the tumor stages in terms of PLT / Lymphocyte ratios (p = 0.006; p < 0.05). Conclusions: There was only a statistically significant increase in NLR values in the testicular tumor group compared to the varicocele group. Larger, randomized controlled studies are needed at this field.

KEY WORDS: Testis; Cancer; Mean platelet volume (MPV); Neutrophil/lymphocyte ratio (NLR). Submitted 13 January 2019; Accepted 2 April 2019

INTRODUCTION

Testicular cancers, which are less common than other cancers, are important because they are often seen in young people. It is the most common solid organ cancer in men between the ages of 15-35 while it contitutes 11.5% of all male cancers. In developed countries there is an increase incidence for testicular cancer (1). Both testes can be easily examined and results of early diagnosis of testicle tumours are very favorable enhancing the importance of early diagnosis and treatment of testicular tumors. Physical examination, imaging, laboratory and tumor markers are used for diagnosis. With early

diagnosis more effective treatment schedules can be applied contributing to better survival. At this point, simple, inexpensive and easily applicable markers can be useful in the clinical approach. There are some studies that some blood parameters can be associated to inflammation and tumorogenesis. Studies have shown that inflammatory response is closely related to tumorigenesis and tumor invasion (2). Interactions occur between the tumor and inflammation according to complex and various mechanisms. At each stage of carcinogenesis; inflammation has an important role (3). Changes in systemic inflammatory response can be assessed by hematological parameters. For example, changes in C-reactive protein (CRP) and neutrophil to lymphocyte ratio (NLR) show signs of systemic inflammatory response in various malignancies (4). There are also reports that elevated NLR is associated with poor prognosis in some urothelial cancers (5). The vast majority of studies have reported that the increase in NLR is associated with poor prognosis in many malignant tumors. For this reason, NLR can be used not only as a marker of systemic inflammatory response, but also in various tumor types and inflammatory conditions (6). In order to predict cancer prognosis and inflammatory conditions, there is a growing interest in simple blood methods such as NLR. NLR, lymphocytemonocyte ratio (LMR), platelet-lymphocyte ratio (PLR) and mean platelet volume (MPV) can be used as factors to determine the prognosis of patients in various clinical situations (7). Platelets are seedless cells derived from megakaryocytes in the bone marrow. Platelets, an element of the immune system, also play a role in cancer formation, progression and metastatization. It is known that activated platelets have critical roles in tumor proliferation, neoangiogenesis and release of mitogenic mediators in the microenvironment of cells that exhibit tumoral behavior, although their production, maturation and clearance from circulation are still not fully elucidated (8). Yun ZY et al. Reported that decreased MPV may be a marker of poor prognosis in renal cell cancer (9). Because it is known that MPV is an index of bioactive platelets activated for any reason and incorporated into the inflammation process, rather than platelet count (10). These markers, which are easily applicable in practice, were retrospectively analyzed in our patients who were diagnosed with testicular tumor and compared with the values of patients with similar age group of patients who underwent varicocelectomy repair.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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A. Şahin, T. Toprak, M. Ali Kutluhan, Yasin Vural, A. Ürkmez, A. Verit

MATERIALS

AND METHODS

This cross-sectional retrospective study included 120 patients who underwent radical inguinal orchiectomy for testicular tumor between January 2010 and December 2018, and 171 patients who underwent varicocelectomy as a control group. Patients with acute infections, chronic inflammatory disease, malignancies or hematological disorders, those using anticoagulant treatment, and subjects with a history of hormonal treatment in the last 12 months or blood product administration in the last month were excluded. Hematological parameters were evaluated with peripheral blood samples taken preoperatively. These hematological parameters include neutrophil (NEU), lymphocyte (LYM), platelet count, and mean platelet volume (MPV). The staging of patients with testicular tumors was performed by examining the computed tomography and by measurement of beta human chorionic gonadotropin, alpha fetoprotein and lactate dehydrogenase (LDH) as tumor markers.

Table 1. Evaluation of groups in terms of PLT/Lymphocyte, Neutrophil/Lymphocyte ratio and MPV.

PLT/lymphocyte

Tumor Mean ± SD (median)

Varicocele Mean ± SD (median)

128.91 ± 95.19 (110.4)

125.45 ± 63.3 (110.8)

0.9071

4.22 ± 3.54 (3.5)

3.49 ± 2.79 (2.7)

0.001*, 1

8.05 ± 1.46

8.28 ± 1.56

0.2142

Neutrophil/lymphocyte MPV 1 Mann

Whitney U Test;

2 Student

t test;

< 0.05.

Figure 1. Stone expulsion duration in the groups.

Statistical analysis To evaluate the findings obtained in this study, IBM SPSS Statistics 22 for statistical analysis (SPSS IBM, Turkey) program was used. Conformity of the parameters to the normal distribution was evaluated by the Shapiro Wilks test. Descriptive statistical values were computed (mean, standard deviation, frequency) and the comparison of quantitative data were done by Kruskal Wallis test and the Mann Whitney U test was used for the determination of the group causing the difference. Mann-Whitney U test was used for the two-group comparisons of the parameters that did not show normal distribution, and Student's t test was used for the parameters with normal distribution. The cut-off point was chosen based on the ROC curve analysis. A p < 0.05 was considered significant.

RESULTS

The study was conducted on 291 patients with ages ranging from 1 to 85 years. The mean age was 34.25 ± 16.56 years. The cases were divided into two groups:

tumor (n = 120) and varicocele (n = 171). There was no statistically significant difference between the groups in terms of PLT/lymphocyte ratio and MPV levels (p > 0.05). The neutrophil/lymphocyte ratio of the tumor group was significantly higher than the varicocele group (p = 0.001; p < 0.05) (Table 1, Figure 1). There was a statistically significant difference between the tumor stages in terms of PLT/Lymphocyte ratios (p = 0.006; p < 0.05). Paired comparisons demonstrated that PLT/lymphocyte ratio of pT3 group was significantly higher than pT1 and pT2 (p1 = 0.002; p2 = 0.003; p < 0.05). There was no significant difference between pT1 and pT2 stages (p > 0.05). There was no statistically significant difference in neutrophil/lymphocyte ratio and MPV levels between tumor stages (p > 0.05) (Table 2). The ROC curve for neutrophil/lymphocyte ratio (NLR) was plotted in the diagnosis of testicular tumor. The area

Table 2. Evaluation of groups in terms of PLT/Lymphocyte, Neutrophil/Lymphocyte ratio and MPV.

PLT/Lymphocyte

pT1 (n = 60) Mean ± SD (median)

pT2 (n = 43) Mean ± SD (median)

pT3 (n = 5) Mean ± SD (median)

115.57 ± 58.01 (108.1)

140 ± 135.35 (110.4)

231.27 ± 74.21 (212.5)

0006*

Neutrophil/lymphocyte

3.83 ± 2.58 (3.4)

4.62 ± 4.94 (3.5)

5.78 ± 1.87 (6.3)

0.108

MPV

8.26 ± 1.62 (7.9)

7.92 ± 1.19 (7.8)

7.24 ± 0.82 (7.2)

0.107

Kruskal Wallis Test; * p < 0.05. NOTE: Since the number of patients with pT3 was 5, Kruskal Wallis test was used despite the normal distribution of MPV.

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Increased neutrophil/lymphocyte ratio in testicular cancer

Figure 2. ROC curve for NLR in the diagnosis of testicular tumor.

Cut off point determination for NLR in the diagnosis of testicular tumors.

under the curve is 0.612 and the standard deviation is 0.03. The area under the ROC curve was significantly higher than 0.5 (p = 0.001; p < 0.05). The cut-off point for NLR in the diagnosis of testicular tumor is > 3.16. The sensitivity of this value was 63.87% and the specificity was 63.16% (Figure 2).

DISCUSSION

Inflammation plays an important role in tumor development and progression. The relationship between inflammation and cancer has long been known. In 1863, Virchow put forward the hypothesis that cancer occurs in the areas of chronic inflammation, and that some irritants increase cell proliferation along with inflammation leading to tissue injury (11). Although the effect of this proliferation is clear, cells alone do not cause cancer. Continuous cell proliferation, inflammatory cells, growth factors, activated stroma and DNA-damage enhancing agents increase or promote neoplastic risk. Neutrophils mediate inflammation through various biochemical mechanisms such as release of arachidonic acid metabolites and platelet aggravating factors (12). Neutrophilia could represent a consequence of ectopic production of myeloid growth factors as part of a paraneoplastic syndrome (13) or, more likely, a nonspecific response to cancer-related inflammation secondary to tissue destruction and cytokine releases. Lymphopenia is associated with cortisol induced stress response (12). High NLR occurring as a result of the added effect of increased NEU response to LYM suppression can support the development of cancer by inhibiting the antitumor immune response (14). Experimental data have

shown that active neutrophils can stimulate tumor growth directly and indirectly (15). NLR and platelet/lymphocyte ratio (PLR) have also been shown to be reliable markers of systemic inflammation by many studies (16). According to the type of malignancy, inflammatory and immune responses to systemic tumor cells and secreted peptides can vary. Today, systemic inflammatory response indicators such as cytokine, CRP, albumin, serum amyloid A and leukocytes have gained importance in the patients with malignancy and it has been thought that they can be independent prognostic factors (17). The immune system has a positive and negative effect on cancer development and progression. It can eliminate tumor cells or increase the metastatic ability and invasion capacities of active malignant cells, leading to tumor progression. The excess of circulating NEUs is thought to play an important role in tumor progression and angiogenesis. Therefore, increased number of NEUs should be associated with poor prognosis (18). MPV represents the mean platelet size in the blood. It can be altered in various diseases such as cancer, thrombosis, sepsis, respiratory distress syndrome, and acute appendicitis (19). PLTs are frequently observed in the cancer microenvironment and are thought to stimulate proliferation and transformation of cancer cells by platelet derived growth factor (PDGF) release (20). In the study of Russell et al., It was reported that increased PDGF alpha receptor expression was associated with bone metastasis in castration-resistant PCa (21). Even in the current literature, anti-platelet therapy has been reported to have a role in PCa adjuvant therapy (22). MPV measurement is a useful method in determining the presence of these activated PLTs (9). A high MPV means that your platelets are larger than average. This is sometimes a sign that you're producing too many platelets. Platelets are produced in the bone marrow and released into the bloodstream. Larger platelets are usually young and more recently released from the bone marrow. Smaller platelets are more likely to have been in circulation for a few days. When someone has a low platelet count and a high MPV level, it suggests that the bone marrow is rapidly producing platelets. This may be because older platelets are being destroyed, so the bone marrow is trying to compensate. Increased MPV is associated with platelet activation, which can happen when platelets encounter tumor byproducts. Still, a high MPV doesn't mean you have cancer. The diagnostic role of mean platelet volume (MPV) is reported in various malignant tumors such as ovary (23), pancreas (24), and colon (25) cancers, the diagnostic and prognostic role of MPV cannot be precisely demonstrated for testicular tumors. In a study conducted by Gokcen K et al., 36 patients with testicular tumors were investigated. WBC, NEU, PLR, and NLR values were significantly higher in testicular tumors however MPV was significantly lower than the control group p < 0.05). Also differences between hematological parameters of patients with testicular cancer according to the stages were examined, and differences were observed between mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean platlet volume (MPV) (p < 0.05). MCV was significantly higher in Stage 1 compared Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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A. Şahin, T. Toprak, M. Ali Kutluhan, Yasin Vural, A. Ürkmez, A. Verit

to Stage 2 or 3 tumour (p = 0.035 and p = 0.025, respectively). MCH was significantly higher in Stage 1 compared to Stage 3 (p = 0.022). MPV was significantly lower in Stage 1 compared to Stage 3 (p = 0.016) (26). In our study, the neutrophil/lymphocyte ratio of the tumor group was significantly higher than the varicocele group (p = 0.001; p < 0.05), but there was no statistically significant difference between the groups in terms of PLT/lymphocyte ratio and MPV levels (p > 0.05). On the other hand we found that there was no statistically significant difference between the tumor stages in terms of Neutrophil/lymphocyte ratio and MPV levels (p > 0.05). In contrast, there was a statistically significant difference in terms of PLT/lymphocyte ratios (p: 0.006; p < 0.05). As a result of paired comparisons PLT/lymphocyte ratio of pT3 group was significantly higher than pT1 and pT2 (p1: 0.002; p2: 0.003; p < 0.05). There was no significant difference between pT1 and pT2 stages (p > 0.05). Limited numbers of reports are available on immune resistance in patients with testicular cancer. Considerable evidence supports the view that the biological behavior of tumors and in particular, their capacity to metastasize are in part determined by immunological factors requiring participation of T lymphocytes, B lymphocytes, macrophages and natural killer cells. Immunological reactivity has been analyzed in a wide spectrum of solid tumors and a vast literature indicates a correlation between depressed cell-mediated immunity and the stage of the disease. On the contrary, there is little evidence about the role of immunological factors in the development and spread of testicular tumors.

CONCLUSIONS In this study, there was only statistically significant increase in NLR values in the testicular tumor group compared to the varicocele group. There was no statistically significant result for MPV and PLR. In the evaluation of patients with testicular tumors according to their stages, the PLT/lymphocyte ratio of the pT3 group was found to be significantly higher than the pT1 and pT2 stages. Although there are many studies on hematological parameters related to other cancers, there is limited data for testicular tumors in the literature. The limitations of our study were that it was a retrospective one with limited study group and had not a prognostic predictive design. Larger, randomized controlled studies are needed at this field.

REFERENCES

1. Borghesi M, Brunocilla E, Schiavina R, et al. Role of testis sparing surgery in the conservative management of small testicular masses: oncological and functional perspectives. Actas Urol Esp. 2015; 39:57-62. 2. Gregory AD, Houghton AM. Tumor associated neutrophils: New targets for cancer therapy. Cancer Res. 2011; 71:24116. 3. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010; 140:88399.

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4. Duan H, Zhang X, Wang FX, et al. Prognostic role of neutrophil lymphocyte ratio in operable esophageal squamous cell carcinoma. World J Gastroenterol. 2015; 21:55917. 5. Viers BR, Boorjian SA, Frank I, et al. Pretreatment neutrophil to lymphocyte ratio is associated with advanced pathologic tumor stage and increased cancer specific mortality among patients with urothelial carcinoma of the bladder undergoing radical cystectomy. Eur Urol. 2014; 66:115764. 6. Templeton AJ, McNamara MG, Šeruga B, et al. Prognostic role of neutrophil to lymphocyte ratio in solid tumors: A systematic review and metaanalysis. J Natl Cancer Inst. 2014; 106:dju124. 7. Lee JS, Kim NY, Na SH, et al. Reference values of neutrophil-lymphocyte ratio, lymphocyte-monocyte ratio, platelet-lymphocyte ratio, and mean platelet volume in healthy adults in South Korea. Medicine (Baltimore) 2018; 97:e11138. 8. Goubran HA, Stakiw J, Radosevic M, et al. Platelet-cancerinteractions. Semin ThrombHemost. 2014; 40:296-305. 9. Yun ZY, Zhang X, Liu ZP, et al. Association of decreased mean platelet volume with renal cell carcinoma. Int J Clin Oncol. 2017; 22;1076-1080. 10. Gasparyan AY, Ayvazyan L, Mikhailidis DP, et al.Meanplateletvolume: a link between thrombosis and inflammation. Curr Pharm Des. 2011; 17:47-58. 11. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001; 357:539-545. 12. Tamhane UU, Aneja S, Montgomery D, et al. Association between admission neutrophil to lymphocyte ratio and outcomes in patients with acute coronary syndrome. Am J Cardiol. 2008; 102:653-7. 13. Vassilatou E, Fisfis M, Morphopoulos G, et al. Papillary thyroid carcinoma producing granulocyte-macrophage colony-stimulating factor is associated with neutrophilia and eosinophilia. Hormones (Athens). 2006; 5:303-9. 14. Schaider H, Oka M, Bogenrieder T, et al. Differential response of primary and metastatic melanomas to neutrophils attracted by IL 8. Int J Cancer. 2003; 103:33543 15. Fridlender ZG, Sun J, Kim S et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1”versus “N2” TAN. Cancer Cell. 2009; 16:183-94. 16. Guthrie GJ, Charles KA, Roxburgh CS, et al. The systemic inflammation-based neutrophil lymphocyte ratio: experience in patients with cancer. Crit Rev Oncol Hematol. 2013; 88:218-30. 17. Moore MM, Chua W, Charles KA, Clarke SJ. Inflammation and cancer: Causes and consequences. Clin Pharmacol Ther. 2010; 87:5048. 18. Kusumanto YH, Dam WA, Hospers GA, et al. Platelets and granulocytes, in particular the neutrophils, form important compartments for circulating vascular endothelial growth factor. Angiogenesis. 2003; 6:2837. 19. Albayrak Y, Albayrak A, Albayrak F, et al. Mean platelet volume: a new predictor in confirming acute appendicitis diagnosis. Clin Appl Thromb Hemost. 2011; 17:362-6. 20. Ustach CV, Taube ME, Hurst NJ, et al. A potential oncogenic activity of platelet-derived growth factor d in prostate cancer progression. Cancer Res. 2004; 64:1722-9. 21. Russell MR, Liu Q, Fatatis A. Targetingthe {alpha} receptor for

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platelet-derived growth factor as a primary or combination therapy in a preclinical model of prostate cancer skeletal metastasis. Clin Cancer Res. 2010; 16:5002-10.

mean platelet volume in differential diagnosis of non functional pancreatic neuroendocrine tumors from pancreatic adenocarcinomas. Eur J Intern Med. 2011; 22:e95-8.

22. Mezouar S, Frere C, Darbousset R, et al. Role of platelets in cancerandcancer-associated thrombosis: Experimental and clinical evidences. Thromb Res. 2016; 139: 65-76.

25. Kilincalp S, Çoban S, Akinci H, et al. Neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and mean platelet volume as potential biomarkers for early detection and monitoring of colorectal adenocarcinoma. Eur J Cancer Prev 2015; 24:328-3.

23. Kemal Y, Demirag G, Ekiz K, et al. Mean platelet volume could be a useful biomarker for monitoring epithelial ovarian cancer. J Obstet Gynaecol. 2014; 34:515-8. 24. Karaman K, Bostanci EB, Aksoy E, et al. The predictive value of

26. Gokcen K, Dundar G, Gulbahar H, et al. Can routine peripheral blood counts like neutrophil to lymphocyte ratio be beneficial in prediagnosis of testicular cancer and its stages? J Res Med Sci. 2018; 23:64.

Correspondence Aytaç Şahin MD (Corresponding Author) draytacsahin@gmail.com Tuncay Toprak, MD drtuncay55@hotmail.com Musab Ali Kutluhan, MD dr.musab151@hotmail.com Yasin Vural, MD yasin_vural@windowslive.com Ahmet Urkmez, MD ahmeturkmez@hotmail.com Ayhan Verit, Prof. veritayhan@yahoo.com Urology Clinic SBU Fatih Sultan Mehmet Training and Research Hospital Atasehir, "stanbul 34752 Turkey Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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DOI: 10.4081/aiua.2019.2.102

ORIGINAL PAPER

The impact of potassium citrate therapy in the natural course of Medullary Sponge Kidney with associated nephrolithiasis Elisa Cicerello, Matteo Ciaccia, Giandavide Cova, Mario Mangano Urology Unit, Department of Surgery, Ospedale Ca’ Foncello, Treviso, Italy.

Summary

Objectives: The present study was carried out to evaluate the effectiveness of medical therapy with potassium citrate in preventing calculosis complicating Medullary Sponge Kidney (MSK) without renal acidification defects. Materials and methods: In a open, uncontrolled, retrospective analysis, 49 MSK patients with nephrolithiasis without renal tubular acidosis, underwent a complete metabolic evaluation and received potassium citrate therapy 4-6 g/day. The course of stone disease before and after citrate therapy was determined in each patient from a combination of clinical history, past records, radiographs and kidney ultrasound. The rate of new stone formation/pt/yr, of endourological and extracorporeal procedures, of urinary tract infection (UTI) and number of hospitalization before and after medical treatment were calculated. Results: Metabolic anomalies (hypercalciuria, hypocitraturia, hyperuricuria and hyperoxaluria) were present in 83% of the patients. Follow-up before and after alkali citrate therapy was comparable (4.7+/-1.4 and 4.9+/-1.7 years respectively). Medical treatment significantly reduced rates of stone formation from 2.0+/-1.0 to 0.2+/-0.5 pt/yr, ureteroscopy (URS) from 0.9+/0.8 to 0.4+/-0.5 pt/yr, extratracoporeal lithotripsy (ESWL) from 1.1+/-0.8 to 0.4+/-0.6 pt/yr, urinary tract infections (UTIs) from 0.8+/-1.2 to 0.3+/-0.5 pt/yr and hospitalization from 1.1+/-0.6 to 0.2+/-0.3 pt/yr, p < 0.001. This effect was observed also in MSK patients without metabolic anomalies. In 35 patients the asymptomatic disappearance of calcium stones was also observed. Conclusions: Our study documents the effectiveness of potassium citrate therapy in preventing neprolithiasis in MSK patients also in the absence of distal tubular acidosis. It suggests that in MSK patients alkali citrate may promote calcium stone dissolution by oral administration.

according to radiographic criteria that include the characteristic “paint brush” appearance of the dilated tubules draining into flattened calyces (2) which may favour salts crystallization and precipitation with consequently stone formation. Nephrolithiasis in MSK causes pain and urinary infection and requires radiological and ultrasound exams and urological treatments for stone removal. Medical treatment to prevent nephrolithiasis has been known from 30 years and numerous studies suggest the effectiveness of potassium citrate in preventing stone formation in different form of nephrolithiasis with economic advantages (3, 4). Previous works have demonstrated in MSK a variety of metabolic abnormalities which, together the papillary collecting duct dilatation, could play a role in stone formation, including hypercalciuria, hypocitraturia, hyperuricuria and urinary acidification defects (5-7). Also the concurrence of hyperparathyroidism and MSK has been reported which suggest that renal hypercalciuria from disordered nephron function may lead to parathyroid hyperplasia and adenoma (8). In the past medical treatment with potassium citrate was performed only in the presence of acidification defects and hypocitraturia was shown to normalize with concorrent reduction in stone formation (9). The present study was carried out to evaluate the effectiveness of medical therapy with potassium citrate in preventing calculosis complicating MSK in the absence of acidification defects.

KEY WORDS: Medullary Sponge Kidney (MSK); Nephrolithiasis; Potassium citrate therapy.

PATIENTS

Submitted 6 March 2018; Accepted 6 December 2018

INTRODUCTION

Medullary Sponge Kidney (MSK) is a congenital abnormality of the renal medulla characterized by the presence of multiple small cysts. These changes were described by the Italian radiologist Leonarduzzi and a decade later Cacchi e Ricci confirmed these finding histopatologically (1). The condition is diagnosed on excretory urograms

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AND METHODS

From January 1994 to June 2013 in the Urologic clinic of the Treviso General Hospital we evaluated 842 patients with recurrent calcium stones. Sixty-one (7.2%) had the characteristic features of MSK on intravenous pyelograms (2), i.e. radial distribution of calcification around enlarged papillae, flattened calyces and dilated collecting tubules with or without cystic deformities. In 58 patients the defect was bilateral and in all cases tubular ectasia involved three or more papillae. For this study, all radiographs were reviewed by one of us and at least one radiologist unaware of the previous diagnosis and diagnostic conclusion was confirmed in 100% of the cases. No conflict of interest declared.

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Starting from 2000, our standard medical treatment for all MSK stone formers was potassium citrate (4 to 6 gm. per day orally in 2-3 doses). For the aim of this study, we have retrospectively evaluated patients with at least 2 years of continuos potassium citrate therapy and in whom distal renal tubular acidosis (RTA) had been excluded. Complete RTA is diagnosed when at least 2 of the following conditions are observed: morning urinary pH higher than 5.5 (in sterile urine), systemic acidemia, urinary citrate excretion lower 100 mg /24 h. When only one of the three above is observed, an oral ammonium chloride test (NH4CL load 0.05g/kg/body weight over 3 days) was performed and a fasting urine pH after test higher than 5.6 coincident with systemic acidemia was considered diagnostic of RTA. As a whole 49 patients (31 males and 18 females, mean age 37.7+/-16.3 and 30.7+/15.2 yrs. respectively) with adequate follow-up and compliance to medical treatment form the bases of this report; all patients had defect and the fully developed form of the anatomic features. Patients had been evaluated before the beginning of potassium citrate therapy with a clinical and metabolic protocol, radiological and ultrasound examinations. Three 24-hour urine samples were collected on an outpatient basis, while eating the usual diet. Urine was analyzed for levels of oxalate, uric acid, calcium, citrate, creatinine, sodium and potassium. After at least 10 hours fasting, venous blood samples were drawn for calcium, phosphate, uric acid, creatinine, and morning spot urine was collected. Idiopathic hypercalciuria was defined as 24 hr urine calcium excretion greater than 300 mg, normocalcemia and exclusion of other hypercalciuric conditions. Hyperuricuria was definited as a 24 hr uric acid excretion above 800 mg, hypocitraturia as less than 350 mg and hyperoxaluria as more than 40 mg.

Mean follow-up before and after treatment was 4.7+/-1.4 and 4.9+/-1.7 yrs. respectivelly. The course of stone disease before and after medical treatment was determined in each patient from clinical history, past records, radiographs (KUB xRay, pielography) and kidney ultrasounds: namely, the number of passed stones, of not expulsed stones, of urological procedures (intracorporeal or extracorporeal treatments), of urinary tract infections (UTIs) was registered. UTI episodes were defined as episode of chills, fever and flank pain that led to medical care. These patients were monitored during potassium citrate theraphy every 6 months with blood creatinine, sodium and potassium and urine analysis. The compliance to medical treatment was evaluated by urinary pH since potassium citrate alkalinizes the urine. Ultrasound was carried out every 6 months and KUB X-ray with tomography once year to ascertain the exact number of stones. CT scan was only performed in few cases and was excluded for the aim of this study. A new stone was defined as the radiographic apperance, removal, or passage of a stone not present on a prior radiograph. Passed or removed stone were analyzed whenever possible. The rate of new stone formation/year, of endourological and extracorporeal procedures, of UTI and number of hospitalization before and after medical treatment were calculated as means +/- SD of values from each patient. The statistical analysis was carried out by the Student ttest for paired data.

RESULTS

Hypercalciuria was present in 21 (43%) patients, hypocitraturia in 23 (47%), hyperuricuria in 14 (28%) and hyperoxaluria in 8 (16%). Thirteen patients were hyper-

Table 1. Effect of potassium citrate therapy on complications in MSK patients with index episodes. Pre-treatment (all patients) Stones/pt/yr URS/pt/yr ESWL/pt/yr UTI/pt/yr Hospitalization/pt/yr

2.0 ± 1.0 0.9 ± 0.8 1.1 ± 0.8 0.8 ± 1.2 1.1 ± 0.6

p value Post-treatment (all patients) (Student t-paired test) 0.2 ± 0.5 0.4 ± 0.5 0.4 ± 0.6 0.3 ± 0.5 0.2 ± 0.3

< 0.001 < 0.001 < 0.001 < 0.001 < 0.001

Pre-treatment (patients without metabolic anomalies) 1.6 ± 1.0 0.9 ± 0.6 1.1 ± 0.9 0.8 ± 07 1.1 ± 0.9

Post-treatment (patients without metabolic anomalies) 0.03 ± 0.07 0.2 ± 0.4 0.2 ± 0.3 0.2 ± 0.3 0.2 ± 0.3

p value (Student t-paired test) < 0.005 < 0.05 < 0.05 < 0.01 < 0.01

Table 2. Effect of potassium citrate therapy on complications in MSK patients without index episodes. Pre-treatment (all patients) Stones/pt/yr URS/pt/yr ESWL/pt/yr UTI/pt/yr Hospitalization/pt/yr

1.9 ± 1.0 0.9 ± 0.7 1.1 ± 0.7 0.8 ± 1.1 1.0 ± 0.6

p value Post-treatment (all patients) (Student t-paired test) 0.2 ± 0.5 0.4 ± 0.5 0.4 ± 0.6 0.3 ± 0.5 0.2 ± 0.3

< 0.001 < 0.001 < 0.001 < 0.001 < 0.001

Pre-treatment (patients without metabolic anomalies) 1.5 ± 0.9 0.9 ± 0.6 1.0 ± 0.8 0.8 ± 07

Post-treatment (patients without metabolic anomalies) 0.03 ± 0.07 0.2 ± 0.4 0.2 ± 0.3 0.2 ± 0.3

1.0 ± 0.9

0.2 ± 0.4

p value (Student t-paired test) < 0.005 < 0.05 < 0.05 < 0.01 < 0.01

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calciuric and hypocitraturic, 4 hyperuricuric and hypercalciuric and 5 hyperuricuric, hypercalciuric and hypocitraturic). In 9 patients (17%) no metabolic anomaly was found. No patient with MSK was hypercalcemic and none had hyperparathyroidism. The chemical analysis of stone removed or passed was calcium oxalate (CaOx) and /or calcium phosphate (CaP) and mixed (CaOx plus uric acid) in 5 patients. Starting from the first control after beginning potassium citrate therapy urinary pH significantly increased (from 5.63+/-0.61 to 6.74+/-0.55 respectively, p < 0.0001) without significant changes in plasma creatinine, calcium, phosphate, uric acid, sodium and potassium. Furthermore medical treatment significantly reduced rates of stone formation from 2.0+/-1.0 to 0.2+/-0.5 pt/yr, ureteroscopy (URS) from 0.9+/0.8 to 0.4+/-0.5 pt/yr, extratracoporeal lithotripsy (ESWL) from 1.1+/-0.8 to 0.4+/-0.6 pt/yr, urinary tract infections (UTIs) from 0.8+/-1.2 to 0.3+/-0.5 pt/yr and hospitalization from 1.1+/-0.6 to 0.2+/-0.3 pt/yr, p < 0.001. This effect was observed also in MSK patients without metabolic abnormalities (Table 1). To rule out that these results were due to a â&#x20AC;?regression to the meanâ&#x20AC;? bias, we excluded from the analysis the index episodes bringing patients to our attention. A

A Figure 2. Man 39 yrs old admitted to our clinic for right flank pain. A, B, X-Ray plus urogram showed bilateral nephrolithiasis, more evident on the right kidney. The patient was given potassium citrate (4 g per day orally in 2 doses). C, X-Ray 3 yrs later revealed the asymptomatic disappearance of most of the stones. No urological treatment had been performed.

Table 2 shows the amended results and confirms the favourable activity of alkali citrate treatment. Furthermore, in 35 patients we have observed the disappearance of stones present on previous x-Ray (Figures 1, 2).

DISCUSSION

Figure 1. Woman 57 yrs old affected by recurrent calcium nephrolithiasis. A, B, X-Ray plus urogram performed before the start of treatment with potassium citrate (6 g per day orally in 3 doses). C, X-Ray after 6 yrs continuous therapy. Most of the left kidney stones disappeared asymptomatically, while for the right ureteral stone ureteroscopy was required. C

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The frequency of radiographic features of MSK may vary from 2.3 to 21% of patients with calcium stones (5, 8). The incidence of MSK in our patients whith recurrent calcium nephrolithiasis was 7.2%; for the aim of this study only those patients with the fully developed form of the anatomic defect, easily recognized on routine intravenous pyelograms, were considered. Patients with MSK usually come to the attention of physicians because of kidney stones. The frequent occurrence of kidney stones is both dependent on the metabolic and anatomic abnormalities. Anatomical abnormalities, which determine stasis of urine and infection, may account for renal stones in 17% of our cases lacking metabolic abnormalities. The fact that not all MSK patients have metabolic abnormalities has been already reported (5, 10). Therefore, when urinary infection is present, it could be the result rather than the cause of the stones (11). Our data show a dramatic reduction in the stone rate

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The impact of potassium citrate therapy in the natural course of Medullary Sponge Kidney with associated nephrolithiasis

during citrate therapy in MSK patients without RTA and irrespective of the presence of metabolic stone risk factor. As consequence, also a parallel reduction in urological treatment, UTI and hospitalization was observed. Such an effect is neither prejudiced by a â&#x20AC;&#x153;regression to the meanâ&#x20AC;? bias (Table 2) nor by an ascertainment bias of episodes due to the retrospective nature of the study period before the establishment of potassium citrate therapy. Although we cannot rule out some imprecision in counting the number of episodes, particulary the number of stones, we are confident that our conclusion about the clinical actvity of citrate treatment is correct, since the given estimates before the treatment could only be lower than in real ones. It is well known that renal tubular acidosis is a common cause of calcium neprolithiasis and nephrocalcinosis. This defect is associated with high urinary pH and low urinary citrate causing the formation of calcium stones. It has also been reported that potassium citrate can correct the acidosis and ameliorate the hypocitraturia preventing calcium nephrolithiasis (9). Citrate is known to reduce the urinary saturation of calcium oxalate by complexing calcium and reducing its ionic concentration; it also inihibits nucleation and crystal growth of calcium, oxalate and phosphate. Citrate treatment increases urinary citrate excretion, urinary pH and decreases stone formation also in normocitraturic patients (3). Furthermore, it has also been reported that potassium citrate therapy seems to be effective in preventing renal stones in patients with MSK and nephrolithiasis (12). Thus, citrate therapy modifies the urinary milieu leading to condition less prone to stone formation. However, we also unexpectedly observed by x-Ray examination the disappearance of preesisting stones in 35 patients (Figures 1, 2). In some patients during the citrate therapy follow-up, we observed at first a fragmentation of the stones (similar to the effect of shock wave lithotripsy), thereafter the disappearance of small fragments, and at last of all fragments. The initial disaggregation of stones suggests that citrate may exert some dissolving effect on the concretions occurring in MSK. While the effect of citrate therapy on dissolution of uric acid is known from a long time, the effect of citrate therapy on dissolution of calcium stones is astonishing. However, in a previosus study Pak too observed a similar finding, i.e., the dissolution of calcium stones after citrate therapy in 8 patients (13). It is generally assumed that calcium stones cannot be dissolved by systemic therapy. Only the local irrigation with different solution, some containing also potassium citrate, is considered to be capable to dissolve calcium stones (14). In this case, the high citrate concentration, the high levels of calcium complexing molecules such as EDTA and high fluxes used most likely explain the efficacy of local irrigation. It is difficult to speculate on the mechanism explaining the dissolving effect of potassium citrate after oral administration. Of course, one has to admit that citrate may enter into the stone, destroyng the binding between calcium and oxalate or phosphate and fragmenting the stone in chippings that later are asymptomatically eliminated with the urine. However, the urinary levels of citrate after oral assumption are much

lower than those constituing the irrigation solution and certainly do not have the same strong calcium chelating power. This migh be congruent with the slower dissolution of the stones in our MSK patients. Furthemore, also the fact that stones in MSK, because of the anatomical abnormalities of precaliceal collecting tubules, are immobilized longer than in non-MSK stones, might play a role. In fact, a longer immobilization should allow a more intense and prolonged effect of even relatively low concentrations of citrate, so that these might be effective. Since the occurrence of mixed calcium and urate stones in MSK is not unsual (in our case population was observed in 9% of patients), the alternative hypothesis that citrate therapy dissolve the urate component of stones and in such way disaggregated stone may also be advanced. We have previously reported that citrate therapy improves the clearance of residual stone fragments after ESWL and hypothesized that the action may due to the inhibition of growth and aggregation of calcium salts. According to present results we could advance that citrate therapy promotes the dissolution of calcium stones, like for uric and cistinuric stones. If urinary infection is present, adeguate antibiotic therapy could prevent the growth of infection stones, also reported in our previous study (15). MSK rarely causes renal failure, but if not treated it could worse the quality of life. However, further studies are necessary to investigate this last issue.

REFERENCES

1. Gambaro G, Feltrin GP, Lupo A, et al. Medullary Sponge Kidney (Leonarduzzi-Cacchi- Ricci disease): a Padua medical school discovery in the 1930s. Kidney Int 2006; 69:663-670. 2. Cameron S. Medullary sponge kidney. In: Oxford Textbook of Clincal Nephrology, 3rd edn, edited by Davidson AM, Cameron JS, Grunfeld J-P, Ponticelli C, Ritz E, Winearls CG, van Ypersele C. Oxford, Oxford University Press, 2004; pp 2495-2501. 3. Pak CYC. Citrate and renal calculi: An update. Min Electrolyte Metab. 1994; 20:371-377. 4. M SC Morgan, Pearle MS. Medical management of renal stones. BMJ. 2016; 352:i52. 5. O' Neill M, Breslau NA, Pak CYC. Metabolic evaluation of nephrolithiasis in patients with medullary sponge kidney. JAMA 1981; 12:1233-1236. 6. Yagisawa T, Kobayashi C, Hayashi T, et al. Contributory metabolic factors in the development of nephrolitiasis in patients with medullary sponge kidney. Am J Kidney Dis. 2001; 37:1140-1143. 7. Osther PJ, Mathiasen H, Hansen AB, Nissen HM. Urinary acidification and urinary excretion of calcium and citrate in women with medullary sponge kidney. Urol Int. 1994; 52:126-130. 8. Maschio G, Tessitore N, D'Angelo A, et al. Medullary Sponge Kidney and hyperparathyroidism-a puzzling association. Am J Nephrol. 1982; 2:77-84. 9. Preminger GM, Sakhaee K, Skurla C, Pak CYC. Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal tubular acidosis. J Urol. 1985; 134: 20-23. Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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10. Yendt ER, Cohanim M. Renal calculi. Proc 8th Int Cong. Nephrol 1975, Karger Basel, p 1175.

correction and prevention of calcium stone formation by potassium citrate therapy. Trans Ass Amer Phys. 1983; 96:294-305.

11. Parks J, Coe F, Strauss A. Calcium nephrolithiasis and medullary sponge kidney. N Engl J Med. 1982; 306:1088-191.

14. Nakatsuka S, Kinoshita H, Ueda H, et al. Combined treatment of Medullary Sponge Kidney by EDTA potassium citrate and extracorporeal shock wave lithotripsy. Eur Urol. 1988; 14:339-342.

12. Fabris A, Lupo A, Bernich P,, et al. Long-term treatment with potassium citrate and renal stones in Medullary Sponge Kidney. CJASN. 2010; 5:1663-1668. 13. Pak CYC, Skhaee K, Fuller CJ. Physiological and physiochemical

Correspondence Elisa Cicerello, MD (Corresponding Author) elisa.cicerello@tin.it Matteo Ciaccia, MD matteo.ciaccia@aulss2.veneto.it Giandavide Cova, MD giandavide.cova@aulss2.veneto.it Mario Mangano, MD mario.mangano@aulss2.veneto.it Urology Unit, Department of Surgery, Ospedale Caâ&#x20AC;&#x2122; Foncello, Treviso, Italy

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15. Cicerello E, Merlo F, Gambaro G, et al. Effect of alkaline citrate therapy on clearance of residual renal stone fragments after extracorporeal shock wave lithotripsy in sterile calcium and infection nephrolitiasis patients. J Urol. 1994; 151:5-9.

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DOI: 10.4081/aiua.2019.2.107

ORIGINAL PAPER

Mini-invasive robotic assisted pyelolithotomy: Comparison between the transperitoneal and retroperitoneal approach Daniele D’Agostino 1, Paolo Corsi 1, Marco Giampaoli 1, Federico Mineo Bianchi 2, Daniele Romagnoli 1, Simone Crivellaro 3, Giacomo Saraceni 2, Marco Garofalo 2, Riccardo Schiavina 2, Eugenio Brunocilla 2, Walter Artibani 1, Angelo Porreca 1 1 Department

of Robotic Urological Surgery, Abano Terme Hospital, Abano Terme, Italy; of Urology, University of Bologna, Bologna, Italy; 3 Division of Urology, Department of Surgery, University of Illinois at Chicago, Chicago, IL, USA. 2 Department

Summary

Objective: To compare the retroperitoneal with the transperitoneal approach in a series of patients underwent to robotic-assisted pyelolithotomy (RP). Materials and methods: From January 2015 to December 2018 we evaluated 20 patients subjected to robotic pyelolithotomy; 11 patients were treated with retroperitoneal approach (RRP) and 9 with transperitoneal approach (TRP). For each patient intra and perioperative data were recorded: operative time (OT), blood loss (BL), length of hospital stay (LOS), stone clearance, post-operative complications and time to remove the drain. The presence of stone fragments < 4 mm was considered as stone free rate. Results: The principal stone burden was greater in the TRP group than in the RRP group (48 ± 10 mm vs 32 ± 14 mm, p = 0.12). Preoperative hydronephrosis was present in 7 (64%) patients in RRP group and a mild hydronephrosis in 3 of TRP group (p = 0.04). The average operative time was higher in the RRP group than in the TRP group (203 ± 45 min vs 137 ± 31 min, p = 0.002). The average blood loss was 305 ± 175 ml in the RRP group versus 94 ± 104 ml in the TRP group (p = 0.005). The stone free rate was similar between the two groups, 36% (4 patients) in the RRP group and 44% (4 patients) in the TRP (p = 0.966). Conclusions: RP appears to be a safe and effective minimally invasive treatment for some patients with renal staghorn calculi or urinary tract malformations. The TRP may give lower operative time and better results in terms of blood loss and length of hospital stay.

KEY WORDS: Transperitoneal pyelolithotomy; Retroperitoneal pyelolithotomy. Submitted 28 February 2019; Accepted 21 March 2019

INTRODUCTION

Stone disease is a highly prevalent condition that unites all countries around the world; the incidence of urolithiasis depends on geographical, racial, and socioeconomic factors. There are a lot of variety of therapeutic option for renal stones: extracorporeal shock wave lithotripsy (ESWL), ureteroscopy (URS) and percutaneous nephrolithotomy (PNL) (1). Surgical management will depend on many factors including availability of different technologies. “Staghorn” stones are large branching stones that fill part of all of the renal pelvis and renal calyces and they can be complete or partial depending on the level of occupancy of the collect-

ing system (2). Although, the term ‘staghorn’ provides description of stone configuration, it lacks specific volume criteria and information about stone composition (3). PCNL remains the gold-standard for the management of larger and “staghorn” renal stones. Robot assisted laparoscopic surgery (RALS) may be useful in the management of upper tract (UT) urolithiasis and it has been frequently considered as an alternative procedure in the management of large or complex renal stones to PNL or open surgery. The mayor advantages are: the possibility to remove the stones integrally, the ability to minimize the bleeding, less pain and lower morbidity. The use of robotic surgery has allowed more success rates than reconstructive urinary tract surgery (4). In addition to remove the stones, the advantages of robotic pyelolithotomy are the possibility to perform reconstructive surgery in presence of anatomical anomalies (e.g. pelvic or horseshoe kidney and malrotated kidneys, failed PNL and stones associated with congenital renal anomalies such as ureteropelvic junction obstruction (UPJO) (3). As for the robotic surgery of renal neoplasms (5) RP can be performed transperitoneally or retroperitoneally and there is no evidence of which approach is better than the other. Aim of the study is to compare the perioperative outcomes and stone free status between the transperitoneal and retroperitoneal approach of robotic pyelolithotomy .

MATERIAL

AND METHODS

From January 2015 to December 2018 we retrospectively evaluated 20 patients subjected to robotic pyelolithotomy from 3 high volume centers. The indication for robotic surgical treatment of urolithiasis was discussed with all patients when the informed consent was signed, indicating that the percutaneous nephrolithotomy was the gold standard treatment; however the main indications for the robotic surgical treatment were highlighted as extrarenal pelvis, anatomical abnormalities (e.g. pelvic kidney or horseshoe kidney), simultaneous management of coexisting pathologies such pelvic-ureteral junction obstruction or failed endourological procedure. All the patients enrolled presented an extrarenal pelvis to the preoperative CT scan and pyelolitotomy was proposed as

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a treatment for stones even in the absence of reconstructive surgery. The population is divided into 2 groups: 11 patients were treated with retroperitoneal approach (RRP) and 9 with transperitoneal approach (TRP). Patients with coagulation disorder, cardiorespiratory diseases, musculoskeletal deformities and morbid obesity were excluded from the study. For each patient the preoperative evaluation included renal function tests, urine routine and microscopic examination. The patients with urinary infection received a course of antimicrobial therapy and they underwent the procedure after the urine culture was sterile. A CT-scan (Computed Tomography) was performed for each patient to obtain information about the stone location, hydronephrosis, the status of contralateral kidney and the presence of anatomical abnormalities such as UPJO or malrotated kidney. All patients were operated under general anesthesia; in the presence of concomitant UPJO, pyeloplasty was performed according to the Anderson-Hynes technique. At the end of each procedure a ureteral stent (double J) and an abdominal (intraperitoneal or retroperitoneal) drain were inserted. The double J stent was removed after 2-3 weeks and the abdominal drain was removed when no traces of creatinine were found in it. For each patient intra and perioperative data were recorded: operative time (OT), blood loss (BL), length of hospital stay (LOS), stone clearance, post-operative complications and time to remove the drain. The presence of stone fragments < 4 mm was considered as stone free rate. Surgical technique Transperitoneal approach: The patient was placed in lateral decubitus position at 45° angle. A 12-mm camera port was placed lateral and superior to the umbilicus and three 8-mm robotic working ports were placed under direct vision in the ipsilateral upper quadrant, lower quadrant, and lateral abdomen. A 12-mm assistant port is usually placed close to the midline, midway between the camera port and the robotic ports (Figure 1). Sometimes a fourth robotic arm was used to aid retraction of the kidney and exposure of the renal pelvis and hilum. Figure 1. Position of trocars on transperitoneal approach.

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The line of Toldt was incised, the renocolic ligament was incised, and the colon was dissected and reflected medially to provide clear exposure of the ureteropelvic junction. The ureter was identified, recognizing its peristalsis and dissected. The renal pelvis was exposed by releasing adjacent structures with sharp and blunt dissection. A vertical incision was made in the pelvis, until the stone is exposed. A robotic ProGrasp forcep was then used to carefully dislodge and remove the stone/s; if the stone was too large it was placed in a specimen retrieval bag and removed at the end of the procedure. Direct calyceal vision inspection was performed initially with the 30° optic, and the flexible cystoscope was placed through the 10-mm port, if required, to remove possible remaining stones. A ureteral double-J stent was placed, and thepyelotomy was closed in running fashion with absorbable suture. The perirenal fat was then approximated over the renal pelvis. A drain was placed through one of the trocar sites, the fascia and were closed in standard fashion. Retroperitonal approach: The patient was positioned on full flank position, the umbilicus on the break point of the of the table, the legs were positioned and a pillow was put in between (the internal leg was flexed at 45°, while the external leg was totally extended) (Figure 2). The table was broken until maximum skin extension was reached in order to have as much working space as possible. The technique of applying trocars has been described (6): an oblique 1.5 cm incision was made at the tip of the 12th rib following the direction of the exterFigure 2. Position of patient on retroperitoneal approach.

Figure 3. Position of trocars on retroperitoneal approach.

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nal oblique muscle. The muscle fibers were gently dissected without cutting to the internal oblique muscle fibers, the dissection was then extended through the fascia. A minimal incision (2-3 mm) was done on the internal oblique fascia and the space was first blindly created with the finger through trasversalis fascia then with the introduction and subsequent inflation of a glove connected to the end of a nasal-gastric probe. A 12 mm trocar for the camera was positioned under finger guidance on the iliac crest along the mid-axillary line. An 8 mm robotic trocar was then positioned along the psoas muscle below the 12th rib-vertebra angle. A 12 mm laparoscopic trocar was positioned along the psoas muscle behind the iliac crest. Then 12 mm Hasson trocar was finally positioned and the working space was created by CO2 inflation. The second 8 mm robotic trocar was positioned, after the laparoscopic dissection of the anterior peritoneal reflection, on the anterior axillary line on the same axis as the umbilicus (Figure 3). Using the robotic scissors and grasper the paranephric fat was first dissected then removed by a ring-clip to increase the workspace. After the identification of ureter, the kidney with its fat was isolated first posteriorly along psoas muscle, and, when necessary, anteriorly. The Gerota fascia was incised exposing the perinephric fat. The hilum was then identified, renal pelvis was incised longitudinally and the stones should be easily dislodge and remove using the robotic ProGrasp. If needed, a flexible cystoscope was introduced through the assistant port to inspect the remaining of the renal pelvis and the calices. A stone basket was used to remove small residual stones from within the kidney. As in other robotic procedures the renal pelvis was then closed using a barbed bidirectional 3.0 suture. The choice of the suture depends by the thickness of the incision of renal pelvis. In the presence of UPJO, pyeloplasty was performed both in the transperitoneal approach and in the retroperitoneal approach. Statistical analysis All data were statistically analyzed using SPSS v 21 for Macintosh. Continuous variables were expressed as means ± standard deviation (SD) whereas categorical variables were expressed as frequencies with percentages. The indipendent-samples T-test and Chi-Square test were used to compare means and frequencies between the two groups, respectively.

RESULTS

The preoperative characteristics of the 2 groups (Table 1) were comparable about age, sex, body mass index (BMI) and number and localization of the stones. The principal stone burden was greater in the TRP group (transperitoneal approach) than in the RRP group (retroperitoneal approach) (48 ± 10 mm vs 32 ± 14 mm, p = 0.12). Preoperative hydronephrosis was present in 7 (64%) patients in RRP group; in three patients in TRP group was present a grade I hydronephrosis (p = 0.04); a ureteral stent was placed preoperatively in 1 (9%) patients in RRP group and in 5 (56%) of patients in TRP group (p = 0.024). Table 2 presents a comparison between the intra and peri-

operative outcomes between the two groups. The average operative time was higher in the RRP group than in the TRP group (203 ± 45 min vs 137 ± 31 min, p = 0.002). The average blood loss was 305 ± 175 ml in the RRP group versus 94 ± 104 ml in the TRP group (p = 0.005). The stone free rate was similar between the two groups, 36% (4 patients) in the RRP group and 44% (4 patients) Table 1. Patients characteristics. Retroperitoneal approach

Transperitoneal approach

p value

56 ± 10

51 ± 11

0.352

3 (27) 8 (73)

4 (44) 5 (56)

0.33

26 ± 4.5

26 ± 3

0.788

5 (46) 2 (18) 4 (36) 0 (0) 0 (0)

6 (67) 2 (22) 0 (0) 0 (0) 1 (1)

0.26

7 (64) 4 (36) 0 (0)

3 (33) 6 (67) 0 (0)

0.25

32 ± 14

48 ± 10

0.12

5 (45) 6 (55)

5 (56) 4 (44)

0.65

7 (64) 4 (36)

3 (30) 7 (70)

0.003

1 (9) 10 (91)

5 (56) 4 (44)

0.024

Transperitoneal approach (n 9)

p value

203 ± 45

137 ± 31

0.002

305 ± 175

94 ± 104

0.005

4 (36) 7 (64) 61 ± 19

4 (44) 5 (56) 58 ± 12

0.966

1 (9) 10 (91)

3 (33) 6 (67)

0.18

4.27 ± 2.7

1 ± 2.7

0.013

5.3 ± 2.7

2 ± 2.7

0.013

10.6 ± 13.5

7.2 ± 5.6

0.48

Age Mean ± SD Gender (%) Male Female BMI Mean ± SD Stone Number (%) 1 2 3 4 5 Principal Stone Location (%) Pelvis Staghorn Lower Pole Principal Stone Burden (mm) Mean ± SD Side (%) Left Right Hidronephrosis (%) Yes No Previous Stent (%) Yes No

Table 2. Comparison between TRP and RRP. Retroperitoneal approach (n 11) Operation time (min) Mean ± SD Blood loss (ml) Mean ± SD Stone free rate (%) Yes No Residual stone burden (mm) Concomitant pieloplasty sec. Anderson-Hynes (%) Yes No Drain (days) Mean ± SD Lenght of hospital stay (days) Mean ± SD Follow-up (months) Mean ± SD

0.08

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in the TRP (p = 0.966). The stone burden of any residual kidney stones was reported in Table 2; these are fragments < 1 cm migrated to the lower pole of the kidney which did not require further treatment. Concomitant pyeloplasty sec. Anderson-Hynes was performed with retroperitoneal approach in 1 (9%) patient and with transperitoneal approach in 3 (33%) patients, p = 0.18. The drain was on average removed after 4.27 ± 2.7 days in the RRP group and after 1 ± 2.7 days in the TRP group (p = 0.013). The length of hospital stay was lower in the TRP group compared to the RRP group (2 ± 2.7 days in the TRP group vs 5.3 ± 2.7 days in the RRP group, p = 0.013).

DISCUSSION

The role of robotic assisted surgery continues to develop within the field of urological surgery. In literature, the growing evidence demonstrating that the breadth and complexity of surgical procedures performed using the da Vinci platform is continually expanding (7, 8, 4). The robotic surgery, whilst maintaining the benefits of standard laparoscopy, provides the surgeon with additional advantages of greater dexterity, a wider range of movement, tremor filtration, three-dimensional vision, and primary surgeon camera control; moreover, we observed significant continuous improvement in terms of bleeding, complications, hospital stay and global quality of life of patients (9-11). In the treatment of urolithiasis laparoscopic and robotic surgery represent valid options in specific cases; in particular the coexistence of UPJO and kidney stones is one of the main indications for the laparoscopic treatment (12). Robotic surgery has some advantages over laparoscopic surgery, such as three-dimensional (3D) view, wristed instruments and stable camera. Although anatomical and stone characteristics play a crucial role in case selection, RP appears to be the technique most widely used, conceivably as parenchymal bleeding and potential nephron loss are avoided. The majority of the existing literature on robotic-assisted renal surgery (in particular partial and radical nephrectomy) describe transperitoneal approach and only few papers are published on retroperitoneal technique. The papers on the transperitoneal approach emphasize the advantages of robotic surgical system including: 3D visualization, increased degrees of freedom of movement, and enhanced-reconstructive capabilities. Based on our experience with laparoscopic retroperitoneal approach for renal cancer (5), we recognized that the retroperitoneal approach combines the advantages of robotic technology (3D visualization, increased degrees of freedom of movements) with the advantages of retroperitoneal approach which includes advantages of direct access to the renal hilum and reduced lesion risk to abdominal organs, earlier return of bowel function and shorter length of hospital stay. A recent meta-analysis has shown that there is no difference in terms of complications, blood loss, time of ischemia, conversion and positive surgical margins in the treatment of renal masses between the retroperitoneal and transperitoneal approach, but a reduction of the operation time with the retroperitoneal approach has been highlighted (13). The use of rigid laparoscopic

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instruments in the small space of retroperitoneum cavity has made the retroperitoneal approach less used than the transperitoneal approach (14). In the literature, the cases describing the robotic pyelolithotomy were performed with a transperitoneal approach; Atug et al. (15), described transperitoneal robotic pyelolithotomy in 55 patients with concomitant UPJO: the mean operative time was 275.8 minutes, the mean blood loss was 48.6 ml, the mean length of hospital stay was 1.1 days and the stone free rate was 100%. In our series, the mean operative time, blood loss, length of hospital stays and stone free rate with transperitoneal approach were respectively 137 ± 31 min, 94 ± 104, 2 ± 2.7 days and 44%. For our knowledge this is the first study which compares pyelolithotomy with a retroperitoneal and transperitoneal approach for the management of renal stones: the mean operative time, blood loss and length of hospital stay was lower with the transperitoneal approach, but the stone free rate was similar. Swearingen et al. (16) in their series evaluated 27 patients treated with robotic pyelolithotomy and nephrolitotomy with transperitoneal or retroperitoneal access: the mean operative time was 182 min, the mean estimated blood loss was 38 ml and the mean length of stay was 1.7 days. In our series the perioperative outcomes are greater than in the retroperitoneal approach, but the retroperitoneal approach can guarantee some advantages: decreased risk of damage of intraperitoneal structures, direct access to the renal hilum, quicker return of bowel function and earlier mobilization of the patient (17). However, this is a study that contains some limitations such as reduced number of cases evaluated retrospectively, and the absence of long-term follow-up data. Further prospective studies are necessaries in order to better analyse the differences between the retroperitoneal approach in relation to the transperitoneal.

CONCLUSIONS

Robotic pyelolithotomy with retroperitoneal or transperitoneal approach appears to be a safe and effective minimally invasive treatment for some patients with renal stones, in particular the case of staghorn calculi or urinary tract malformations such as UPJO. The transperitoneal approach may give lower operative time and better results in terms of blood loss and length of hospital stay.

REFERENCES

1. Türk C, Petfík A, Sarica K, et al. EAU Guidelines on Diagnosis and Conservative Management of Urolithiasis Eur Urol. 2016; 69:468-474. 2. Healy KA, Ogan K. Pathophysiology and management of infectious staghorn calculi. Urol Clin North Am. 2007; 34:363-374. 3. Preminger GM, Assimos DG, Lingeman JE, et al. Chapter 1: AUA guideline on management of staghorn calculi: diagnosis and treatment recommendations. J Urol. 2005; 173:1991-2000. 4. Schiavina R, Zaramella S, Chessa F, et al. Laparoscopic and robotic ureteral stenosis repair: a multi-institutional experience with a long-term follow-up. J Robot Surg. 2016; 10:323-330. 5. Porreca A, D'agostino D, Dente D, et al. Retroperitoneal

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Mini-invasive robotic assisted pyelolithotomy: Comparison between the transperitoneal and retroperitoneal approach

approach for robot-assisted partial nephrectomy: technique and early outcomes. Int Braz J Urol. 2018; 44:63-68. 6. Bove P, Iacovelli V, Sandri M, et al.. Entry techniques in laparoscopic radical and partial nephrectomy: a multicenter international survey of contemporary practices. Minerva Urol Nefrol. 2018; 70:414-421. 7. Porreca A, Chessa F, Romagnoli D, et al.Robot assisted radical cystectomy with totally intracorporeal urinary diversion: initial, single-surgeonâ&#x20AC;&#x2122;s experience after a modified modular training. Minerva Urol Nefrol. 2018; 70:193-201. 8. Porreca A., Salvagio A. Dandrea M, et al. Robotic-Assisted Radical Prostatectomy with the Use of Barbed Sutures. Surg Technol Int. 2017; 30:39-43. 9. Noale M, Maggi S, Artibani W, et al. Pros-IT CNR: an Italian prostate cancer monitoring project. Aging Clin Exp Res. 2017; 29:165-172. 10. Porreca A, Noale M, Artibani W, et al. Disease-specific and general health-related quality of life in newly diagnosed prostate cancer patients: the Pros-IT CNR study. Health Qual Life Outcomes. 2018; 16:122.

11. Gacci M, Noale M, Artibani W, et al. Quality of Life After Prostate Cancer Diagnosis: Data from the Pros-IT CNR. Eur Urol Focus. 2017; 3:321-324. 12. Ramakumar S, Lancini V, Chan DY, et al. Laparoscopic pyeloplasty with concomitant pyelolithotomy. J Urol 2002; 167:1378-80. 13. 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. 14. Ng CS, Gill IS, Ramani AP, et al. Transperitoneal versus retroperitoneal laparoscopic partial nephrectomy: patient selection and perioperative outcomes. J Urol. 2005; 174:846-9. 15. Atug F, Castle EP, Burgess SV, et al. Concomitant management of renal calculi and pelvi-ureteric junction obstruction with robotic laparoscopic surgery. BJU Int. 2005; 96:1365-1368. 16. Swearingen R, Sood A, Madi R, et al. Zero-fragment Nephrolithotomy: A Multi-center Evaluation of Robotic Pyelolithotomy and Nephrolithotomy for Treating Renal Stones. Eur Urol. 2017; 72:1014-1021. 17. Hu JC, Treat E, Filson CP, et al. Technique and outcomes of robot-assisted retroperitoneoscopic partial nephrectomy: a multicenter study. Eur Urol. 2014; 66:542-9.

Correspondence Daniele Dâ&#x20AC;&#x2122;Agostino, MD (Corresponding Author) dott.dagostino@gmail.com Paolo Corsi, MD pcorsi@casacura.it Marco Giampaoli, MD mgiampaoli@casacura.it Daniele Romagnoli, MD dromagnoli@casacura.it Walter Artibani, MD prof.artibani@gmail.com Angelo Porreca, MD angeloporreca@gmail.com Department of Robotic Urological Surgery, Abano Terme Hospital Piazza Cristoforo Colombo 1, 35031 Abano Terme (PD) (Italy) Federico Mineo Bianchi, MD federico.mineobianchi@gmail.com Giacomo Saraceni, MD giacomo.saraceni@gmail.com Marco Garofalo, MD marco.garofalo@unibo.it Riccardo Schiavina, MD rschiavina@yahoo.it Eugenio Brunocilla, MD eugenio.brunocilla@unibo.it Department of Urology, University of Bologna, Bologna (Italy) Simone Crivellaro, MD crivellaro76@hotmail.com Division of Urology, Department of Surgery, University of Illinois at Chicago, Chicago, IL, (USA)

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DOI: 10.4081/aiua.2019.2.112

ORIGINAL PAPER

Ureteral access sheath use in retrograde intrarenal surgery Mustafa Karaaslan, Senol Tonyali, Mehmet Yilmaz, Sedat Yahsi, Sedat Tastemur, Erkan Olcucuoglu University of Health Sciences, Turkiye Yuksek Ihtisas Training and Research Hospital, Clinic of Urology, Ankara.

Summary

Objective: To determine if there is a difference between postoperative urinary infection rates after retrograde intra-renal surgery (RIRS) when ureteral access sheath (UAS) was used or not used. Materials and methods: We retrospectively analyzed the medical records of all patients who underwent RIRS at our institution between January 2016 and October 2018. Results: 129 patients were included in the study. The mean age of the patients was 48.8 ± 12.1 years; 94 patients were male and 35 were female. The mean stone size (largest diameter), stone attenuation and stone volume were 15.3 ± 5.8 mm, 1038 ± 368 HU and 1098 ± 1031 mm3, respectively. Out of 129 patients, 81 were treated by using UAS (Group 1) and 48 were treated without use of UAS (Group 2). There was no statistically significant difference between the two groups in terms of post-operative infection (p = 0.608). However, the operative time of patients with post-operative infection was statistically higher than the other patients; 88.35 ± 22.5 min versus 59.37 ± 22.1 min (p = 0.017). In multivariate regression analysis, operation time (p = 0.02, r = 1.07) was found to be the sole predictor of post-operative infection. Conclusions: Using UAS during RIRS might reduce the intrarenal pressure and also has several advantages. However not prolonging the operation time too much could be of higher importance than UAS use in terms of preventing post-operative infection after RIRS.

KEY WORDS: Nephrolithiasis; Sepsis; Ureteral access sheath; Intrarenal pressure. Submitted 27 February 2019; Accepted 21 March 2019

INTRODUCTION

Nephrolithiasis was historically treated with open surgery, however currently, minimally invasive modalities such as extracorporeal shoch wave lithotripsy (SWL), percutaneous nephrolithotripsy (PNL) and retrograde endoscopic interventions [ureteroscopy (URS), retrograde intrarenal surgery (RIRS)] and laparoscopic surgeries are frequently being the treatment of choice. RIRS is used more frequently by technological advancements of flexible ureterorenoscopes, which was first used by Marshall (1) in 1964 (2). PNL is recommended as the first-line treatment for kidney stones larger than 2 cm in the European Urology Association (EAU) guidelines. SWL or endoscopic procedures are recommended for renal stones smaller than 2 cm. Flexible URS (fURS) could be presented as a second treatment option for stones larger than 2 cm with PNL being the first treatment option, and for lower pole stones larger than 1.5 cm where SWL activity was limited (3). When we look at the

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history of the use of ureteral access sheath (UAS) in fURS, for the first time Takayasu and Aso (4) used a Teflon tube throughout the ureter in 1974. The use of UAS in fURS has many advantages and disadvantages. UAS allows repeated access to the upper urinary tract, provides better visibility, allows removing small stone fragments without damaging the ureter, and reduces pyelolymphatic and pyelovenous reflux by lowering renal pelvic pressure (5). In addition, it was reported that it was not uncommon to have severe ureter wall damage during UAS placement into the ureter (6). In a multi-centre prospective study, it has been shown that using UAS in fURS might result in a decrease in the incidence of post-operative fever, urinary tract infection, and in particular sepsis (7). In this study, we aimed to determine if there is a difference between postoperative urinary infection rates after fURS which UAS was used or was not used.

MATERIALS

AND METHODS

After obtaining the approval of institutional review board, we retrospectively analysed the medical records of all patients who underwent RIRS at our institution between January 2016 and October 2018. The study was conducted in accordance with the latest version of the Declaration of Helsinki. Informed consent form is not required due to the retrospective nature of the study. Patients with anatomical abnormalities such as horseshoe kidney, pelvic kidneys, kidneys with multiple collecting system, and patients who underwent surgery under antibiotic supression were excluded from the study. All patients were evaluated with kidney-ureter-bladder (KUB) radiography, non-contrast abdominal computed tomography (CT), complete blood count, serum creatinine, bleeding and clotting times, complete urinalysis and urine culture. Patients who have bacteria growth in urine culture were treated with adequate antibiotic therapy and control urine culture confirmed no bacterial growth. The longest diameter of renal stone was determined as stone size. The examined parameters included patient’s demographic information, stone characteristics (size, volume, localization and Hounsfield unit), duration of operation, use of ureteral access sheath (UAS), stone-free rate, postoperative sepsis and urinary tract infection. Stone volume was calculated using the formula: stone volume = length x width x height x π x 0.167. The stone localization was defined as lower pole and non-lower pole. The diagnosis of sepsis was made by determining the focus of the infection and by No conflict of interest declared.

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the presence of two or more SIRS findings. The diagnosis of SIRS was based on the criteria of the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) Consensus Conference Committee as having 2 or more of the following criteria: 1. body temperature less than 36°C or greater than 38°C; 2. heart rate greater than 90 beats/min; 3. respiration rate > 20/min or PaCO2 < 32 mmHg; 4. white blood cell counts greater than 12.000/mm3 or less than 4.000/mm3 (8).

Table 1. Comparison of patient’s characteristics in UAS group and non-UAS group. Variables Mean stone size (mm) Mean stone volume (mm3) Mean stone attenuation (HU) Mean operation time (min) Stone localization Post-operative Infection Sepsis Urinary tract infection

Surgical procedure All procedures were performed under general anesthesia by giving 1 gr cefazolin prophylaxy before the procedure and using flexible ureteroscopes 7.5 and 7.8 French (FlexX2TM Flex Scope, Karl Storz, Germany and Semi-flex ScopeTM, MaxiFlex, USA). Patients were placed in the lithotomy position. Mobile C-armed fluoroscopy was used in all procedures. A 0.035 or 0.038 inch guidewire was inserted into the pelvis with a rigid ureterorenoscope. Then, 12/14F 45 cm (Rocamed) UAS was placed into the ureter till the ureteropelvic junction (UPJ) under the guidence of fluoroscopy. Alternatively, depending on the surgeon's preference, the operation was performed by reaching the kidney with flexible ureterorenoscope over the guidewire without inserting the UAS. Continuous irrigation was performed through fURS with 3000 mL 0.3% isotonic solution at 50 cm above the patient. A 270 micron holmium YAG laser was used for stone fragmentation. The stone fragments were left for spontaneous passage and no basket was used for stone removal. Statistical analysis Statistical analysis was performed using IBM SPSS Statistical Package v.22.0 for Windows (IBM SPSS Corp., Armonk, NY, USA). Quantitative values are shown as mean ± standard deviation for parametric data and as median ± range for nonparametric data. Qualitative values are shown in numbers and percentages. The normality test was performed using the Shapiro-Wilk test. The chi-square test was used to compare post-operative infection in patients with or without UAS, and Mann-Whitney U test was used to compare the duration of operation. Multivariate regression analysis was used to evaluate the most important determinant of post-operative infection. The level of statistical significance was accepted as p < 0.05.

RESULTS

A total of 210 patients were reviewed. 129 patients who met the study criteria were included in the study. The mean age of the patients was 48.8 ± 12.1 years; 94 patients were male and 35 were female. The mean stone size (largest diameter), stone attenuation and stone volume were 15.3 ± 5.8 mm, 1038 ± 368 HU and 1098 ± 1031 mm3, respectively. Out of 129 patients, 81 were treated using UAS patients (Group 1) and 48 were treated without UAS (Group 2). The mean operative time was 60.2 ± 22.8

UAS group 14.9 ± 5.7 1022 ± 1026 1067 ± 383 61.75 ± 22.3 Lower pole: 50 (62%) Non-lower pole: 31 (38%) 3 (2.7%) 2 1

Non-UAS group 15.8 ± 6 1226 ± 1038 988 ± 340 57.79 ± 23.5 Lower pole: 16 (33%) Non-lower pole: 32 (66.7%) 1 (2.1%) 1

p value 0.341 0.261 0.149 0.327 0.002 0.608

min. Stone free rate (SFR) was 52.7% (68/129). Patient, stone and operation characteristics are given in Table 1. The mean stone size, stone volume, stone HU and operation time were similar in Group 1 and Group 2 (p = 0.34, p = 0.26, p: 0.14 and p: 0.33, respectively). Lower pole stone localisation rate was significantly higher in Group 1 (62% versus 33%, p = 0.002). There was no statistically significant difference between the two groups in terms of post-operative infection (p = 0,608). However, the operative time of patients with post-operative infection was statistically higher than the other patients; 88.35 ± 22.5 min versus 59.37 ± 22.1 min (p = 0.017). In multivariate regression analysis operation time (p = 0.02, r = 1.07) was found to be the sole predictor of post-operative infection whereas age, sex, stone volume, HU, stone location and UAS use were not, (p = 0.65, p = 0.20, p = 0.22, p = 0.95, p = 0.35 and p = 0.78, respectively).

DISCUSSION

In 1964, a stone in the ureter was observed by a 26F cystoscope and the first fURS use was reported. By the end of the 1980s, the development of fURS has gained momentum. In the 1980s and 1990s initial fURS series were published (2). The new generation fURS allows the management of proximal ureteral and intrarenal pathologies, including complete removal of the ureter and kidney stones, with high success rates. Pyelovenous and pyelolymphatic reflux secondary to irrigation is one of the most important limitations of fURS (5). Flexible URS is the first treatment option in many cases of treatment of kidney stones. It is recommended as the first treatment option in lower calyceal stones, especially between 1.5-2 cm (3). UASs were initially developed to facilitate difficult ureteroscopic access (9). Studies have shown the advantages and disadvantages of using UAS. The use of UAS has been shown to provide better view, multiple entries, removal of fragmented stones and, in particular, to reduce intrapelvic pressure (10). The results of studies on the effect of UAS use on SFR after RIRS differ. In a study conducted by Berquet et al. (11) on 280 patients, there was no difference in the SFR between the patients who were treated using UAS or not. Also in the present study SFR was similar in the two groups. There are UASs of different diameters and lengths. In the study by Wright et al. conducted with 10/12F and 12/14F UASs in cadaveric pig kidney, the mean intrapelvic pressure was < 40 cm H2O. When hand-assisted manual pump Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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was used, it was shown that intrapelvic pressure increased up to 129 cm H2O in cases treated with 10/12F UAS, and that this remained at low levels when 12/14F UAS was used (12). In another study, intrarenal pressure during fURS was measured using a pressure transducer inserted from percutaneous nephrostomy in patients who had percutaneous nephrostomy due to obstructive ureteric stones. The mean pressure in the collecting system was 13.6 mmHg (18.4 cm H2O) before the procedure, while the mean intrarenal pressure in the renal pelvis during fURS rose to 94.4 mmHg (128.3 cm H2O) in patients without UAS and to 40.6 mmHg (55 cm H2O) in patients with UAS (5). In a study conducted using human cadaveric kidney with continuous irrigation with a pressure of 200 cm H2O, renal pelvic pressure increased to 59 cm H2O in patients without UAS, and intrapelvic pressure was reported to be below 30 cm H2O in patients with UAS depending on the diameter and length of the UAS (13). In the present study, we used 12F/14F UAS in all cases and we did not use manual irrigation pump. We were not able to measure intrarenal pressure in renal pelvis, but, in the light of the aforementioned studies, our clinical practice might be associated with lower intrarenal pressures. In a prospective study conducted with 2239 patients, it was shown that there was a decrease in the incidence of post-operative fever, urinary tract infection, and especially sepsis in patients who were treated by using UAS compared to patients who were treated without UAS (7). In a systematic review and meta-analysis, the efficacy and safety of UAS was evaluated in a total of 3099 patients, and SFR, intra-operative complications, duration of operation and length of hospital stay were found similar between UAS group and non-UAS group. Postoperative complications (bleeding, fever, urinary tract infection, bladder cramps, pulmonary embolism, and sepsis) were higher in patients treated by using UAS (14). In our study, no significant difference was found between patients who were treated with UAS or not in terms of post-operative infection. In-vitro studies have shown that pyelovenous reflux exists in case of a pelvic pressure > 35 mmHg (15). The use of manual water pumps raises pressures even higher (12). This may increase the risk of postoperative infection by increasing pyelovenous reflux in parallel with the increase in intrapelvic pressure. In our study, high intrapelvic pressures should have been avoided because we did not use a manual pump so explaining the absence of a significant difference in postoperative infection between the group treated with UAS and the group treated without UAS. In a study by Zhong et al., post-operative SIRS was detected in 21 (8.1%) patients amomg 260 cases of fURS using UAS. The duration of operation was not statistically significant, but it was found to be higher in the SIRS group (16). In our present study, the operation time of the patients who developed post-operative infection was significantly higher than that of the other patients.

CONCLUSIONS

Using UAS during RIRS reduces the intrarenal pressure and has also several advantages. However not prolonging the operation time too much might be of greater impor-

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tance than the use of UAS in terms of preventing postoperative infection after RIRS.

REFERENCES

1. Marshall VF. Fiber optics in urology. J Urol. 1964; 91:110-114. 2. Van Cleynenbreugel B, Kilic O, Akand M. Retrograde intrarenal surgery for renal stones - Part 1. Turk J Urol. 2017; 43:112-121. 3. Türk C, Petfík A, Sarica K, et al. EAU guidelines on interventional treatment for urolithiasis. Eur Urol. 2016; 69:475-482. 4. Takayasu H, Aso Y. Recent development for pyeloureteroscopy: guide tube method for its introduction into the ureter. J Urol. 1974; 112:176-178. 5. Auge BK, Pietrow PK, Lallas CD, et al. Ureteral access sheath provides protection against elevated renal pressures during routine flexible ureteroscopic stone manipulation. J Endourol. 2004; 18:33-36. 6. Traxer O, Thomas A. Prospective evaluation and classification of ureteral wall injuries resulting from insertion of a ureteral access sheath during retrograde intrarenal surgery. J Urol. 2013; 189:580-584. 7. Traxer O, Wendt-Nordahl G, Sodha H, et al. Differences in renal stone treatment and outcomes for patients treated either with or without the support of a ureteral access sheath: The Clinical Research Office of the Endourological Society Ureteroscopy Global Study. World J Urol. 2015; 33:2137-2144. 8. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992; 101:1644-1655. 9. Kourambas J, Byrne RR, Preminger GM. Dose a ureteral access sheath facilitate ureteroscopy? J Urol. 2001; 165:789-793. 10. Breda A, Territo A, López-Martínez JM. Benefits and risks of ureteral access sheaths for retrograde renal access. Cur Opin Urol. 2016; 26:70-75. 11. Berquet G, Prunel P, Verhoest G, et al. The use of a ureteral access sheath does not improve stone-free rate after ureteroscopy for upper urinary tract stones. World J Urol. 2014; 32:229-232. 12. Wright A, Williams K, Somani B, Rukin N. Intrarenal pressure and irrigation flow with commonly used ureteric access sheaths and instruments. Central European J Urol. 2015; 68:434. 13. Rehman J, Monga M, Landman J, et al. Characterization of intrapelvic pressure during ureteropyeloscopy with ureteral access sheaths. Urology 2003; 61:713-718. 14. Huang J, Zhao Z, AlSmadi JK, et al. Use of the ureteral access sheath during ureteroscopy: A systematic review and meta-analysis. PloS one 2018; 13:e0193600. 15. Wang J, Zhou DQ, He M, et al. Effects of renal pelvic high-pressure perfusion on nephrons in a porcine pyonephrosis model. Exp Ther Med. 2013; 5:1389-1392. 16. Zhong W, Leto G, Wang L, Zeng G. Systemic inflammatory response syndrome after flexible ureteroscopic lithotripsy: a study of risk factors. J Endourol. 2015; 29: 25-8. Correspondence Mustafa Karaaslan - mustafakaraaslan23@gmail.com Senol Tonyali, MD (Corresponding Author) senoltonyali@hotmail.com Mehmet Yilmaz - yilmazmehmet88@hotmail.com Sedat Yahsi - sedatyahsi@yahoo.com Sedat Tastemur - sedattastemur@yahoo.com Erkan Olcucuoglu, MD - erkanolcucuoglu@gmail.com

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ORIGINAL PAPER

DOI: 10.4081/aiua.2019.2.115

A “real life” investigation on the prescriptive habits among Italian andrologists: The “CONSER” survey from Italian Society of Andrology (SIA) on Sildenafil oral film Alessandro Palmieri 1, Mauro Silvani 2, Bruno Giammusso 3, Giovanni Liguori 4, Nicola Mondaini 5, Fabrizio Palumbo 6, Stefano Pecoraro 7, Oreste Risi 8, Salvatore Sansalone 9, Fabrizio Ildefonso Scroppo 10, Alessandro Zucchi 11, Paolo Verze 1, Marco Capece 1, Tommaso Cai 12 1 Department

of Urology, University of Naples, Naples, Italy; 2 Urology Unit, Hospital "degli Infermi", Biella, Italy; Clinic, Catania, Italy; 4 Department of Urology, University of Trieste, Trieste, Italy; 5 Urology Unit, Nuovo San Giovanni di Dio Hospital, Florence, Italy; 6 Urology Unit, San Giacomo Hospital, Monopoli, Bari, Italy; 7 Malzoni Center, Avellino, Italy; 8 Neuro-Urology Unit, Treviglio, Bergamo, Italy; 9 Department of Urology, University of Tor Vergata, Rome, Italy; 10 Urology Unit, Ospedale di Circolo di Varese, Varese, Italy; 11 Department of Urology, University of Perugia, Perugia, Italy. 12 Department of Urology, Santa Chiara Hospital, Trento, Italy. 3 Morgagni

Summary

Even if oral type 5 phosphodiesterase inhibitors (PDE5i) seem an effective treatment for erectile dysfunction (ED), the drop-out is high among patients. For this reason, pharmaceutical companies are encouraged to develop new administration routes, such as the orally disintegrating film. The aim of this study was to analyse the prescription habit of Italian andrologists affiliated to Italian Society of Andrology (SIA) in the era of new oro-dispersible formulation of sildenafil. A 12-items dedicated questionnaire has been distributed to 77 urologists andrologists. As a result of the questionnaire, sildenafil is still the preferred drug of Italian andrologists as it is considered the safest and the most effective. It combines the speed of action and the discretion of the intake that are very important issues for the adherence to the treatment according to the Italian sample. Physicians have also reported the positive feedback of the patients taking sildenafil film as they consider the oro-dispersible formulation either comparable or superior to the old tablet. In conclusion this new formulation has given a new life to an old molecule like sildenafil, and Italian andrologists considered this new pharmaceutical formulation as a good tool to improve the patient’s adherence to the treatment and quality of life.

KEY WORDS: Erectile dysfunction; Sildenafil; Oro-dispersible; Quality of life; Survey; Andrology. Submitted 6 May 2019; Accepted 10 May 2019

INTRODUCTION

Over the last 20 years the use of phosphodiesterase type 5 inhibitors (PDE5i) has revolutionized classification and treatment of erectile dysfunction (ED) becoming a firstline therapy as recommended by the guidelines of all major scientific societies (1-3). After the marketing of Viagra in 1998, the various international drug companies have approved the use of different molecules characterized by identical mechanisms of action but with different pharmacokinetic properties: in chronological order Tadalafil, Vardenafil and Avanafil. Although international medical literature is consistent in

defining PDE5i efficacy in over 80% of cases of ED, the fact remains that only a minority of men with ED currently seek help by consulting an Andrologist and 6070% of those who decide to undertake specific medical care stop treatment for a variety of reasons (4-6). So-called "adherence" to therapy is therefore a primary determinant in the success of treatment but unfortunately there are many factors that often cause a drop-out from the treatment: specialists who prescribe PDE5is and give inadequate information to the patient often as result of a superficial andrological visit, expectations of a patients who take ineffective drugs, side effects and high costs. Despite the enormous amount of data available in the literature, identification of the specific reasons for patients suspending ED pharmacological treatment is extremely difficult, above all because "evidence-based" studies are lacking. So far, no randomized clinical trial (RCT) has been published which compares the efficacy and tolerability of Sildenafil, Vardenafil, Tadalafil and Avanafil. The reasons for this gap are largely attributable to the different characteristics of pharmacokinetics, bioavailability and methods of administration of these drugs which affect absorption time, duration and onset of action, methods of use, etc., making comparisons impossible. In addition, published subjective assessment studies, based predominantly on patient opinion, have serious design defects such as comparisons between different drug assays and/or short treatment duration (7-11). Despite these difficulties some authors have attempted, for the very first time, a meta-analysis "Trade off" aimed at identifying what could be the optimal PdE5i in the treatment of ED relative to efficacy and incidence of side effects (5). This analysis was performed on 82 studies (47.626 patients) for efficacy evaluations and 72 studies (20.325 patients) on different molecules’ adverse events. Analysis of available data allowed for the identification of Sildenafil 50 mg as the most effective drug but was burdened by a higher incidence of adverse events compared to competitors. Authors conclude that Sildenafil, first put on the mar-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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ket more than 20 years ago, at a dosage of 50 mg can be considered an initial choice in the treatment of ED of patients for whom high drug efficacy is a priority. Although Sildenafil is the oldest molecule available on the market, it is the first one engineered in oro-dispersible tablets and oro-dispersible film to improve the pharmacokinetics characteristics with the latter being the latest (12). Starting from these considerations it is crucial to understand the efficacy of the drugs in relation to the various formulations and how these ones impact on the specialists’ clinical practice. The aim of this work is to add new elements to define how the introduction of a new sildenafil oro-soluble film has changed ED management in a selected group of Italian andrologists from Italian Society of Andrology (SIA).

Table 1. Which of these aspects can represent a limit to your full satisfaction in the therapeutic approach to the patient with erectile deficit? Answer Cost/refund Dosage Side effects Poor efficacy Total

Number 49 5 7 16 77

% 63.6 6.5 9.1 20.8 100

Table 2. Which of these aspects related to therapy represent a limit to the patient?

Answer Number % Survey Cost/refund 53 68.8 In the period between May 2017 and December 2017, the Italian Society of Andrology (SIA) conducted a survey on Dosage 1 1.3 PDE5i involving numerous Italian Andrologists. The projSide effects 12 15.6 ect is named “CONSER” (“conservare l’erezione”). Poor efficacy 11 14.3 A 12-items ad-hoc created and dedicated questionnaire Total 77 100 has been sent via registered mail to 77 andrologists affiliated to SIA and homogenously distributed on the wide Italian regions. Some remarkable statistical data have been Figure 1. extrapolated from the overall analysis of the What are the pharmacological characteristics of a PDE5-i that, according to your clinical practice, are decisive for therapeutic success? answers, which envisages the prescription reality of PDE5i, with attention given, not only from the point of view of the andrological specialist, but also regarding the needs of the patient which, if disregarded, are the priSpeed of action mary cause of poor therapeutic compliance. The first interesting data resulting from analyLong duration of action sis of the survey, is that according to the andrologists only 9% of the patients have been completely satisfied with the pharmacoPossibility of intake without liquids logical therapy they had been prescribed. The problems encountered were mainly Possibility of intake with food cost/reimbursement and low efficacy, thus these factors are the major issues involved in either the specialist prescription and in patient’s adherence to the therapy (Tables 1, 2). According to the survey, the most important features a PDE5i should ensure are the speed of Figure 2. action and the duration of the effect for either What do patients ask from a PDE 5-i? the specialist and the patient (Figures 1, 2). Regarding to the pharmacokinetics, it is commonly believed that the starting dosage depends on the type of PDE5i used. Almost two thirds of the patients preferred Sildenafil as Speed of action first therapeutic choice (64.3%), followed by Tadalafil, Vardenafil e Avanafil (20.3%, 8.5% Long duration of action and 6.8% respectively). Sildenafil is still the preferred drug of Italian andrologists as it is Possibility of intake without liquids considered the safest and the most effective. Finally, with regard to the new oro-soluble film formulation of Sildenafil, physicians believe Possibility of intake with food that the new administration route combines the advantages of the speed of action and the discretion of the intake. Furthermore, it has been reported that patients easily accept this

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Sildenafil oral film

Table 3. How is the oral formulation received by patients? Answer Optimally Very well Without difference compared to the other formulations With mistrust Total

Number 21 36

% 35.6 61

2 0 59

3.4 0 100

form of treatment because of its efficacy, that is either comparable or superior to other oral formulations (Table 3). The new formulation of oro-dispersible Sildenafil film was prescribed by most of the andrologists involved in the survey with extreme confidence both in naïve patients and in the presence of co-morbidities.

DISCUSSION

In the recent years alternative drug-delivery systems have been developed to improve patient compliance and adherence to the therapy. With regards to the drug absorption, the route of administration is the main factor, and the variables influencing it are represented by the pharmaceutical formulation (coefficient of distribution /dissolubility) and the characteristics of the absorbing surface (extension, permeability, vascularization). Having stated that, the best results can be obtained with a greater contact surface between the drug and the mucous membranes which are highly vascularized, a good distribution coefficient of the drug (liposolubility/hydrosolubility ratio) and good permeability of the contact surface (e.g. oral mucous membrane). Previous studies have evaluated the efficacy of Sildenafil and tested its absorption in the oral mucosa. A first study by El-Rashidy et al. (13) proposed a sublingual (delitescent) formulation for Sildenafil. The formulation involved the use of the drug (Sildenafil), an osmotic agent (mannitol), a hydrophilic carrier (microcrystalline cellulose), and a water-soluble polymer (cellulose derivative). These additional components to the drug had the task of facilitating the transmucosal passage of Sildenafil by favouring its absorption (carrier). Unfortunately there are no data available on the results. A second study proposed by De Siati in 2003 (14) conducted in Italy proposed an evaluation of the effects of oral intake of Sildenafil (the “old” tablets formulation) for 3 months by comparing the data after a further 3 months of therapy in which the patient pulverized the tablet and placed the powder produced under the tongue. The results obtained showed that the time for the drug to be effective was halved: 62.8 min. (whole tablets) vs. 29.3 min. (sublingual). In the same study all patients stated that they preferred the sublingual route for the most rapidity of action of the drug. Wang in 2008 (15) pointed out that Sildenafil is a lipophilic molecule and therefore can easily be absorbed at the sublingual level however noted that poor solubility in saliva is a limiting factor for absorption at the level of the oral mucosa and this parameter therefore needs to be improved (16). After about 10 years, research and technology have suc-

ceeded in developing new formulations, as in the case of Sildenafil in delitescent leaflets (SILER) which can be absorbed at the level of the oral mucosa. The new formulation in orodispersible film now has all the characteristics to facilitate sublingual absorption as it is composed of Sildenafil, a lipophilic molecule easily absorbed by the oral mucosa, maltodestrine which acts as a "filmogenic" and a solubilizing agent. The maltodestrine also works as a carrier that facilitates its absorption through the oral mucosa (17, 18); stimulating salivation agents such as citric acid, which favor its rapid disintegration, modifying the salivary pH towards acidity and in this way improving the absorption of the drug (19, 20). In a recent paper the “old” oral tablets have been compared to the new sildenafil film whose median action time was 20 minutes. The greater rapidity of absorption, attributed to its pre-gastric absorption, ratified its superiority to the traditional tablet (21). Despite its twenty years-long history, our survey declares Sildenafil the first choice of Italian andrologists. Our analysis cannot estimate whether these results are related to the marketing of the new formulations or to the patients’ feedback, however both hypothesis are not mutually exclusive. Therefore it is likely that both have contributed to the actual Italian state of affairs. The analysis also demonstrate that the new formulation of Sildenafil is well known to Italian andrologists and that they think the patients would prefer the characteristics of the new formulation to the old one. The new administration route, developed by IBSA (Lugano, Switzerland) and approved in Europe at doses of 25, 50, 75, and 100 mg, is considered a safe and effective alternative to the conventional tablets. Finally it gives the possibility of chosing a 75 mg dosage that previous formulations did not consider. CONCLUSIONS

In conclusion, in the world of PDE5 inhibitors orodispersible film of Sildenafil represents a real technological innovation with a product that is easy to ingest, with great rapidity of action and fewer side effects. In particular, we demonstrated that the advantage of the new formulation of Sildenafil in oro-dispersible film is represented, not only by the fact that it can be taken discreetly and without water, but above all by the possibility that the drug can be absorbed, at least in part, directly at the level of the oral mucosa, entering immediately into circulation with no first liver passage.

REFERENCES

1. Hatzimouratidis K. Can we cure erectile dysfunction? Eur Urol. 2010; 58:249-50. 2. Eardley I, Donatucci C, Corbin J, et al. Pharmacotherapy for erectile dysfunction. J Sex Med. 2010; 7:524-40. 3. Porst H, Burnett A, Brock G, et al. SOP conservative (medical and mechanical) treatment of erectile dysfunction. J Sex Med. 2013; 10:130-71. 4. Corona G, Mondaini N, Ungar A, et al. Phosphodiesterase type 5 (PDE5) inhibitors in erectile dysfunction: the proper drug for the proper patient. J Sex Med. 2011; 8:3418-32. Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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5. Chen L, Staubli SE, Schneider MP, et al. Phosphodiesterase 5 inhibitors for the treatment of erectile dysfunction: a trade-off network meta-analysis. Eur Urol. 2015; 68:674-80. 6. Fagelman E, Fagelman A, Shabsigh R. Efficacy, safety, and use of sildenafil in urologic practice. Urology 2001; 57:1141-4. 7. Govier F, Potempa AJ, Kaufman J, et al. A multicenter, randomized, double-blind, crossover study of patient preference for tadalafil 20 mg or sildenafil citrate 50 mg during initiation of treatment for erectile dysfunction. Clin Ther. 2003; 25:2709-23. 8. von Keitz A, Rajfer J, Segal S, et al. A multicenter, randomized, double-blind, crossover study to evaluate patient preference between tadalafil and sildenafil Eur Urol. 2004; 45:499-507. 9. Strรถberg P, Murphy A, Costigan T. Switching patients with erectile dysfunction from sildenafil citrate to tadalafil: results of a European multicenter, open-label study of patient preference. Clin Ther. 2003; 25:2724-37. 10. Althof SE. Quality of life and erectile dysfunction. Urology. 2002; 59:803-10. 11. Maurice DH, Wilson LS, Rampersad SN, et al. Cyclic nucleotide phosphodiesterases (PDEs): coincidence detectors acting to spatially and temporally integrate cyclic nucleotide and non-cyclic nucleotide signals., Biochem Soc Trans. 2014; 42:250-6. 12. De Toni L, De Rocco Ponce M, Franceschinis E, et al. Sublingual administration of sildenafil oro-dispersible film: new profiles of drug tolerability and pharmacokinetics for PDE5 inhibitors. Front Pharmacol. 2018; 6; 9:59. 13. El-Rashidy R. Controlled Release of Sildenafil Delivered by Sublingual or Buccal Administration. WO 00/5477. 2002.

14. De Siati M, Saugo M, Franzolin N. The start of pharmacological activity after sublingual administration of sildenafil citrate in 30 patients affected by erectile dysfunction. Arch Ital Urol Androl. 2003; 75:18-20. 15. Wang Y, Chow MSS, Zuo Z. Mechanistic analysis of pH-dependent solubility and trans-membrane permeability of amphoteric compounds: Application to sildenafil International Journal of Pharmaceutics. 2008; 352:217-224 16. Rathbone MJ, Ponchel G, Ghazali FA. Systemic oral mucosal drug delivery and delivery systems. In: Rathbone, M.J. (Ed.), Oral Mucosal Drug Delivery. Marcel Dekker, Inc., New York, 2004. 17. Smyth HDC, Hickey AJ. Carriers in drug powder delivery. American Journal of Drug Delivery. 2005; 3:117-132. 18. Parikh A, Agarwal S, Raut K. A Review on applications of Maltodextrin in pharmaceutical industry. IJPBS 2014; 4:67-74. 19. Shweta Kalyan, Mayank Bansal. Recent Trends in the Development of Oral dissolving Film. International Journal of Pharm Tech Research. 2012; 4:725-733. 20. Kathpalia H, Gupte A. An Introduction to fast dissolving oral thin film drug delivery systems: a review. Current Drug delivery. 2013; 10:667-684. 21. Cocci A, Capece M, Cito G, et al. Effectiveness and safety of orodispersible sildenafil in a new film formulation for the treatment of erectile dysfunction: comparison between sildenafil 100-mg filmcoated tablet and 75-mg oro-dispersible film. J Sex Med. 2017; 14:1606-1611.

Correspondence Alessandro Palmieri, MD Paolo Verze, MD Marco Capece, MD Department of Urology, University of Naples, Naples (Italy) Mauro Silvani, MD Urology Unit, Hospital "degli Infermi", Biella (Italy) Bruno Giammusso, MD Morgagni Clinic, Catania (Italy) Giovanni Liguori, MD Department of Urology, University of Trieste, Trieste (Italy) Nicola Mondaini, MD Urology Unit, Nuovo San Giovanni di Dio Hospital, Florence (Italy) Fabrizio Palumbo, MD Urology Unit, San Giacomo Hospital, Monopoli, Bari (Italy) Stefano Pecoraro, MD Malzoni Center, Avellino (Italy) Oreste Risi, MD Neuro-Urology Unit, Treviglio, Bergamo (Italy) Salvatore Sansalone, MD Department of Urology, University of Tor Vergata, Rome (Italy) Fabrizio Ildefonso Scroppo, MD Urology Unit, Ospedale di Circolo di Varese, Varese (Italy) Alessandro Zucchi, MD Department of Urology, University of Perugia, Perugia (Italy) Tommaso Cai, MD ktommy@libero.it Department of Urology, Santa Chiara Hospital - Largo Medaglie d'Oro 9, Trento (Italy)

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DOI: 10.4081/aiua.2019.2.119

ORIGINAL PAPER

Male-to-Female (MtoF) gender affirming surgery: Modified surgical approach for the glans reconfiguration in the neoclitoris (M-shape neoclitorolabioplasty) Andrea Cocci 1, Francesco Rosi 2, Davide Frediani 2, Michele Rizzo 3, Gianmartin Cito 1, Carlo Trombetta 3, Francesca Vedovo 3, Simone Grisanti Caroassai 1, Augusto Delle Rose 1, Valeria Matteucci 4, Piero Buccianti 4, Cristina Ceccarelli 4, Marco Carini 1, Andrea Minervini 1, Girolamo Morelli 2 1 Careggi

Hospital, Department of Urology, University of Florence, Florence, Italy; of Urology, University of Pisa, Pisa, Italy; 3 Department of Urology, University of Trieste, Trieste, Italy; 4 Department of General Surgery, University of Pisa, Pisa, Italy. 2 Department

Summary

Purpose: The aim of this article is to describe our modified surgical technique for the reconfiguration of the glans in the clitoris and the labia minora, known as the “M-shape neoclitorolabioplasty”. Methods: The glans with all its neurovascular bundle is isolated from the corpora cavernosa, incised in Y-shape mode and spread in order to obtain an M-shape glandular flap. The “belly” of the M-shape glans will constitute the triangular neoclitoris meanwhile the lateral flaps will constitute the labia minora. The inferior apex of the neoclitoris is fixed to the superior apex of the previously spatulated urethra. The two glans flaps are incised transversally to increase their length and sutured to the sides of the spatulated urethra forming the labia minora. Our technique permits to create an aesthetically pleasing neovagina preserving all the glandular erogenous sensitivity. Results: 94 patients have been treated with our modified technique of male-to-female (MtoF) gender affirming surgery. At median follow-up of 27.57 months, 81 (86.1%) patients reported vaginal intercourse and 78 (82.9%) patients referred presence of erogenous sensitivity during dilatations, intercourse or masturbations. All the glandular tissue is preserved and reconfigured forming the neoclitoris and the labia minora. The M-shape reconfiguration permit to create an aesthetically pleasant neoclitoris. Conclusions: This technique could be applied safely and easily to patients undergoing gender affirming surgery, allowing the creation of a neovagina with the best possible erogenous sensitivity without losing aesthetical results.

KEY WORDS: Male to female; Gender affirming surgery; Transgender/transsexual. Submitted 15 January 2019; Accepted 26 January 2019

INTRODUCTION

Gender Dysphoria (GD) and Gender Identity Disorder have been defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (1) and in the International Classification of Diseases, Tenth Edition (2). According to the Standards of Care of the World Professional Association of Transgender Health (WPATH) (3), the management of patients presenting with Male-to-Female (MtoF) GD is

complex and multifactorial. The surgical treatment of GD is the gender affirming surgery. In MtoF patients, gender affirming surgery involves the creation of a neovagina (vaginoplasty) and the reconstruction of a sensate neoclitoris (neoclitoroplasty) from the penile glans. During the years we have perfected the neoclitorolabioplasty with the specific goal of preserving as much erogenous tissue as possible in order to achieve best possible functional and aesthetic outcomes. The aim of this paper is to illustrate our gender affirming surgery technique focusing on the M-shape neoclitorolabioplasty and its outcomes.

MATERIALS

AND METHODS

Indications for procedure Transsexual women are sent to MtoF gender affirming surgery according to the seventh version of the WPATH (3) standard of care. Furthermore, according to Italian laws, all patients have to obtain a formal court authorization for this specific procedure. Preoperative preparation All the patients interrupt Progynova® (estradiol valerate) 30 days before gender affirming surgery (for thromboembolic risk) and start it again 15 days after gender affirming surgery. A low-residue diet and bowel preparation are recommended to avoid postoperative contamination of the surgical wound. Metronidazole and amoxicillin clavulanate are given routinely as prophylactic antibiotics. Patients are placed in lithotomy position and intermittent pneumatic compression is used to prevent deep venous thrombosis. The procedure is performed under General anesthesia. A urethral catheter is placed to locate the urethra during the entire procedure. The surgical area is sterilized with Betadine® (povidone-iodine) solution. The standard equipe included two surgical teams each composed by two surgeons who perform this surgery. Team A operates between the legs of the patient and team B is positioned at the level of the abdomen.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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Intraoperative considerations The surgery is divided in three main steps: A) Management of the perineal space, performed by team A: 1. Castration (orchiectomy) 2. Creation of the neovaginal cavity; 3. Excision of the crura; 4. Reduction of the bulb of penis, preparation of urethral stump and spatulating of it; B) Management of the penis, performed by team B: 5. Degloving of the penis, dissection of the gland and its neurovascular bundle; 6. Dissection of the pendulous urethra and excision of the corpora cavernosa; 7. Creation of the neoclitoris and the labia minora (neoclitorolabioplasty); C) Management of the reconstruction of the external genitalia, performed by the two teams: 8. Creation of the labia majora and preparation of the cutaneous grafts; 9. Creation of the vulval vestibule, the clitoral hood and the urethral neo-meatus; 10. Creation of the cul-de-sac; 11. Introflection of the cul-de-sac and suture of the labia majora. Step A) and B) are performed at the same time by the two teams working independently. Step C) is performed when the other two steps are completed. A) Management of the perineal space, performed by team A 1. Castration (orchiectomy) Initially, a racket shape marking is drawn for the incision in the perineal foreskin by a dermographic pen. The incision is performed along the medial raphe from the scrotum up to the perineum. The perineal skin flap, thus obtained, is inverted downwards, maintaining subcutaneous fat and preserving its vascularization. The testes and the spermatic cords are ligated and dissected at the level of the external inguinal rings, which are closed with a 2/0 Monocryl® continuous suture to prevent postoperative hernia formation. The peri-testicular fat is conserved for the secondary purpose of filling and shaping of the labia majora. 2. Creation of the neovaginal cavity Undoubtedly this is the most complicated and risky step of the whole gender affirming surgery. Injuring of the rectum or the membranous urethra are possible complications. Fibers of bulbocavernous muscles are divaricated on the midline line and the bulbar urethra is completely freed. The bulbocavernous muscles are totally removed. The perineum is dissected creating a neo-cavity between the urethra and anus. Superficial and deep transverse perineal muscles are divaricated laterally. The inferior fascia of urogenital diaphragm is exposed and cut laterally. After that a bluntly dissection is performed in order to create the neovaginal cavity. The dissection proceeds from the medial part of ischial tuberosity until the ischiorectal fossa through the endopelvic fascia. At the end of these procedure membranous urethra and the apex of prostate are reached. Then neovaginal cavity is enlarged detaching tissue between the urethra,

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the prostate, the urinary bladder anteriorly and the rectum posteriorly, up to the peritoneal reflection of the rectovesical pouch. The obtained depth is measured with a centimetered vaginal stent, which must be at least 12 cm. 3. Excision of the crura Meanwhile the penile urethra is bluntly dissected from the corpora cavernosa by team B, team A excises both the crura from their respective ischiopubic ramus. Remnants of spongiosus tissue are sutured with semicontinuous in Monocryl® 3/0. 4. Reduction of the bulb of penis, preparation of the urethral stump and spatulating of it The bulb of penis is completely excised in order to increase the space of the vulvar introit. At this point the distal urethra is excised and the residual stump is ventrally spatulated and cut to create a lance-like shape of the urethral plate. The apex is fixed to the anterior portion of pubis with a single Monocryl® 3/0 stitch. The spatulated urethral plate are sutured with semicontinuous in Monocryl® 3/0 at both sides to the ischial branches. With this urethral reconfiguration the anterior part of the neovagina until the neoclitoris is provided by urethral mucosa. B) Management of the penis, performed by team B 5. Degloving of the penis, dissection of the glans and its neurovascular bundle Team B starts with the degloving of the penis. A circumferential subcoronal incision is made and a cylindrical penile skin flap is created, including the foreskin in uncircumcised patients. The penile skin is bluntly dissected from the albuginea. The degloved penis is passed through the posterior scrotal window to facilitate the disassembly. The penile skin flap will constitute part of the wall of the neovagina. After clamping the penis at its base, the dorsal part of the glans along with its neurovascular bundle is bluntly dissected from the corpora cavernosa. 6. Dissection of the pendulous urethra and excision of the corpora cavernosa The corpora cavernosa are bluntly dissected from the pendulous urethra (then cut and spatulated by team A), and excised at the levels of the pubis attachment. 7. Creation of the neoclitoris and the labia minora (neoclitorolabioplasty) A Y-shape marking is drawn for the incision on the dorsal glans by a dermographic pen. The Y-shape incision is performed using the electro-cautery and following the markings. In this way an M-shape glans is obtained when it is spread. The “belly” of the M-shape glans will constitute the triangular neoclitoris meanwhile the lateral flaps will constitute the labia minora (Figures 1, 2). During this step the neurovascular bundle is folded up on itself and the reflected side is fixed with three 3/0 Monocryl® simple stitches to the soprapubic region thus forming the mons Veneris. The inferior apex of the neoclitoris is fixed with a 3/0 Monocryl® simple stitch to the superior apex of the spatulated urethra. The two glans flaps are incised transversally so that their length is increased and sutured

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Figure 3. Creation of the clitoral hood and the labia majora.

Figures 1, 2. The M-shape glans.

with 3/0 Monocryl® to the sides of the spatulated urethra thus forming the labia minora. C) Management of the reconstruction of the external genitalia, performed by the two teams 8. Creation of the labia majora and preparation of the cutaneous grafts The peri-testicular fat (previously conserved by team A) is sutured with 2/0 Monocryl® to the inferior apex of perineum. The purpose of this action is to give volume and thickness to the labia majora. The latero-inferior portions of the penile skin flap are fixed with 2/0 Prolene® simple stitches to the lower sides of the racket shape incision (initially made by team A). In this manner the inferior apex of the labia majora is formed. The redundant skin is drawn by dermographic pen and excised by electro-cautery. It will be used as cutaneous graft. On the surgical bench the two cutaneous grafts are thinned out of the subcutaneous fat and sutured together with 2/0 Monocryl®. 9. Creation of the vulval vestibule, the clitoral hood and the urethral neo-meatus At this point team B has finished its job and team A completes the surgery. The cylindrical penile skin flap is

reversed like a glove finger. Then the cutaneous base of it is stretched downwards. In this manner the skin covers sequentially the folded neurovascular bundle (forming the mons veneris), the neoclitoris, the labia minora and the spatulated urethra. The cutaneous base is fixed laterally and internally to the entrance of the neovaginal cavity with 2/0 Monocryl® simple stitches. Afterwards a longitudinal incision is made with scalpel on the covering skin paying attention not to cut the underlying structures. This action is made in order to evert the neclitoris, the labia minora and the spatulated urethra. The edges of the incision are spread. The anterior apex of the incision is sutured with 2/0 Monocryl® to the top of neoclitoris forming the clitoral hood (Figure 3). The lateral sides are sutured to the labia minora. The posterior apex is sutured to the overturned urethral mucosa forming the urethral neo-meatus. Once these actions are completed, the vulval vestibule is obtained. In this manner the mucosa of the spatuleted urethra is used for the creation of the vulval vestibule so that the sensitive surface is increased. 10. Creation of the cul-de-sac The vaginal stent is placed in the neovaginal cavity. The part that comes out of the cavity is used as a model to create the cul-de-sac. The penile skin flap is put on the vaginal stent and sutured with continuous in Monocryl® 3/0 to the perineal skin flap and the cutaneous grafts in order to obtain the cul-de-sac (Figure 4). 11. Introflection of the cul-de-sac and suture of the labia majora The vaginal stent is removed and the cul-de-sac is turned inside out and pulled into the neovaginal cavity to become the wall of the neovagina. The labia majora are closed with 2/0 Monocryl® running intradermal suture in order to obtain the best aesthetical outcome (Figure 5). 12. Dressing Once the surgery is completed, five gauzes impregnated with Betadine® and Gentalyn® are sewed sequentially and inserted in the neovaginal cavity. A tie-over dressing is Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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Figure 4. Creation of the cul-de-sac.

Figure 5. Suture of labia majora.

then performed around the neo-meatal orifice. It is fixed with a Nylon skin suture. A customized elastic compressive dressing is applied to prevent bleeding. Postoperative management and follow-up During all the postoperative in-stay antibiotic prophylaxis with amoxicillin clavulanate 1 g per 3 days and Clexane速 (enoxaparin sodium) is given. Patients are encouraged to mobilize 24 hours after the surgery. They sit with the help of a donut cushion avoiding pressures on the neovagina. The vaginal intruder, the tie-over dressing, the compressive dressing and the urinary catheter are removed 4 days after the surgery and patients are trained to correctly perform daily vaginal dilatation two times per day for 30 minutes each. They are advised to clean the vagina daily with 1/3 Betadine速 and 2/3 Saline solution through a 60 cc cone-catheter syringe before and after the dilations. At the end of dilation, a dressing with gauzes and Gentalyn速 is applied above the site of surgery. Patients are usually discharged

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within 1 week. Progynova速 is restarted 15 days after the intervention. The vaginal dilations prosecute for 2 weeks with the same protocol. Then dilations are mandatory 3 times per day increasing gradually the diameter of the dilators according to individual tolerance. Dilations are continued at least for 2 months after the operation until the patients have regular sexual intercourse. Follow-up visits are scheduled at 15, 30 and 60 days after the intervention, then every 3 months. At each visit, physical examination to assess congruous vaginal length and width, neoclitoris and labia minora sensation, cosmetic appearance of the reconstructed vagina and occurrence of any complication are performed. At 60 days visit postoperative urodynamic studies are also performed. At each visit patients are asked regarding frequency and quality of sexual intercourse, ability to achieve orgasm and regrets about the procedure. A reference e-mail address is left to each patient where they can send any photo, question or doubt regarding the surgery and its follow-up (Figures 6, 7). Figure 6. 6 months long-term follow-up.

Figure 7. Over 1-year long-term follow-up

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RESULTS

From February 2011 to April 2018, 94 transsexual women underwent MtoF gender affirming surgery. Mean age was 29,5 years (IQR: 24.75-34 months). Mean follow-up was 27.57 months (IQR: 25.77-29.45). All patients were taking feminizing hormonal therapy with cyproterone acetate and estradiol for at least 3 years before surgery. Complications are reported in Table 1. During the 7 postoperative days 4 (4.25%) patients required hematic transfusion. Partial necrosis of the labia minora occurred in 5 (5.3%) patients but any of them required surgical revision. Vaginal stenosis occurred in 6 (6.38%) patients who did not follow the daily vaginal dilatations program because complained uncomfortable filing during the procedure. Urethral meatus stricture occurred in 1 (1.1%) patient. One (1.1%) patient developed a rectovaginal fistula and protective colostomy was necessary. One (1.1%) required 10 days of antibiotic therapy for a postoperative infectious complication. Two patients underwent surgical revision for hematoma and edema of the lower limbs. At median follow-up of 27 months, 81 (86.1%) patients reported vaginal intercourse and 78 (82.9%) patients referred presence of erogenous sensitivity during dilatations, intercourse or masturbations.

DISCUSSION

The provision of erogenous and tactile sensitivities of the neoclitoris in gender affirming surgery was first described by Brown (4) and Wesser (5), and this technique is used by most surgeons (6-12). However, most surgeons give the neoclitoris an oval or a triangular shape by excising a part of the glans and “wasting” erogenous tissue (13). In literature Dr. Preecha and his team (14) have developed a surgical technique where a good part of the glans is preserved by giving it an M-shape and its lateral flaps are used to form the labia minora. For the incision, they draw an M-shape marking on the dorsal glans by dermographic pen. Nevertheless, they excise the tissue included below the M-shape marking. Our approach differs from Preecha’s because we draw a Yshape marking on the dorsal glans. Then we incise following the markings. At the end we obtain an M-shape Table 1. Postoperative complications in the period 2011-2018 (n° tot patients = 94). Complication Bleeding Asymmetries Vaginal stenosis Urethral stenosis Recto-Vagina fistula Hypoesthesia of lower limb Hematoma of lower limb Edema of lower limb Urethral dolor Infection

N° (%) 4 (4.25) 3 (3.19) 6 (6.38) 1 (1.06) 1 (1.06) 4 (4.25) 1 (1.06) 1 (1.06) 1 (1.06) 1 (1.06)

glans spreading it after the incision. The central part of the M-shape glans forms the triangular neoclitoris meanwhile the lateral flaps are incised transversally for elongating themselves and form the labia minora. In this manner we obtain aesthetically pleasing genitalia esterna. With this technique cosmetic outcome and erogenous sensitivity are improved. Wagner et al. reported in a prospective trial the outcomes of sexual functions of 50 patients that underwent MtoF sex reassignment surgery. In this study 30% patients did not reported presence of clitoral orgasm (15). Lawrence et al. analyzed retrospectively 232 patients, he reported that 15% of patients rarely refers presence of orgasm during masturbations while 18% never experienced an orgasm (16). In both studies approximately 30% of patients reported insufficient orgasmic function. Our technique of neoclitoridolabioplasty could be considered a value option to reduce the risk of insufficient erogenous sensitivity. Some authors should advocate that hypersensitivity represent a commonly reported issue that routinely leads to a secondary surgical procedure to cover the clitoris with a hood flaps in order to protect it from an over stimulation (12). Remarkably discomfort due to an excessive sensitivity of the neoclitoris could be easily correct while lack of sensitivity is a not corrigible condition. Finally, good erogenous sensitivity may permit more pleasant and comfortable dilatations that are essential to preserve the depth of the neovagina and patients particularly enjoyed the idea to preserve as much erogenous tissue as possible.

ETHICAL

CONSIDERATIONS

The present study was designed in accordance with the ethical principles of the Declaration of Helsinki. Considering the retrospective design, the study did not require approval by the local ethics committee and informed consent was not required because all procedures were performed according to the Standards of Care for the Health of Transsexual, Transgender, and GenderNonconforming People, Version 7.

CONCLUSIONS

Many procedures to reconfigure the glans in a neo-clitoris have been proposed and are currently used but any has been proven to be superior in terms of aesthetically and functional outcomes. Remarkably in some series up to 30% of patients refer inability to achieve orgasm due to an insufficient neoclitoris sensitivity. M-shape neoclitorolabioplasty represent a feasible alternative to the technique commonly used that permits the preservation of all the glans erogenous sensitivity.

REFERENCES

1. Association AP. Diagnostic and Statistical Manual of Mental Disorders (DSM-5®): American Psychiatric Publishing; 2013. 2. Organization WH. International Classification of Diseases, Tenth Edition. 3. Coleman E, Bockting W, Botzer M, et al. Standards of Care Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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for the Health of Transsexual, Transgender, and GenderNonconforming People, Version 7. International Journal of Transgenderism. 2012; 13:165-232. 4. Brown J. Creation of a functional clitoris and aesthetically pleasing introitus in sex conversion. Transactions of the sixth international congress of plastic and reconstructive surgery Paris: Masson; 1976; p. 5.

11. Hage JJ, Karim RB. Sensate pedicled neoclitoroplasty for male transsexuals: Amsterdam experience in the first 60 patients. Annal Plas Surg. 1996; 36:621-4.

5. Wesser DR. A single stage operative technique for castration, vaginal construction and perineoplasty in transsexuals. Arch Sex Behav. 1978; 7:309-23.

12. Sigurjonsson H, Mollermark C, Rinder J, et al. Long-Term Sensitivity and Patient-Reported Functionality of the Neoclitoris After Gender Reassignment Surgery. J Sex Med. 2017; 14:269-73.

6. Selvaggi G, Monstrey S, Ceulemans P, et al. Genital sensitivity after sex reassignment surgery in transsexual patients. Ann Plas Surg. 2007; 58:427-33.

13. Trombetta C, Liguori G, Benvenuto S, et al. [Neo-urethroclitoroplasty according to Petrovic]. Urologia 2011; 78:267-73.

7. Fang RH, Chen CF, Ma S. A new method for clitoroplasty in male-to-female sex reassignment surgery. Plast Reconstr Surg. 1992; 89:679-82.

14. Wangjiraniran B, Selvaggi G, Chokrungvaranont P, et al. Maleto-female vaginoplasty: Preecha's surgical technique. J Plast Surg Hand Surg. 2015; 49:153-9.

8. Eldh J. Construction of a neovagina with preservation of the glans penis as a clitoris in male transsexuals. Plast Reconstr Surg. 1993; 91:895-900.

15. Wagner S, Greco F, Hoda MR, et al. Male-to-female transsexualism: technique, results and 3-year follow-up in 50 patients. Urol Int. 2010; 84:330-3.

9. Rubin SO. Sex-reassignment surgery male-to-female. Review, own results and report of a new technique using the glans penis as a pseudoclitoris. Scand J Urol Nephrol Suppl 1993; 154:1-28.

16. Lawrence AA. Patient-reported complications and functional outcomes of male-to-female sex reassignment surgery. Arch Sex Behav. 2006; 35:717-27.

Correspondence Andrea Cocci, MD, Ph.D. (Corresponding Author) cocci.andrea@gmail.com Augusto Delle Rose, MD augustodellerose@libero.it Marco Carini, MD, PhD carini@unifi.it Andrea Minervini, MD, PhD Careggi Hospital, Department of Urology, University of Florence Largo Brambilla, 3 - 50139, Florence (Italy) Francesco Rosi, MD francescorosi@gmail.com Davide Frediani, MD davide.frediani@gmail.com Girolamo Morelli, MD girolamomorelli@gmail.com Department of Urology, University of Pisa, Pisa (Italy) Michele Rizzo, MD mik.rizzo@gmail.com Carlo Trombetta, MF, PhD Francesca Vedovo, MD Department of Urology, University of Trieste, Trieste (Italy) Gianmartin Cito, MD gianmartin.cito@gmail.com Simone Caroassai Grisanti, MD simonecaroassai@libero.it Valeria Matteucci, MD Piero Buccianti, MD Cristina Ceccarelli, MD Department of General Surgery, University of Pisa, Pisa (Italy)

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10. Rehman J, Melman A. Formation of neoclitoris from glans penis by reduction glansplasty with preservation of neurovascular bundle in male-to-female gender surgery: functional and cosmetic outcome. J Urol. 1999; 161:200-6.

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DOI: 10.4081/aiua.2019.2.125

ORIGINAL PAPER

Relationships between sperm DNA integrity and bulk semen parameters in Bulgarian patients with varicocele Viktor Alargkof 1, Larissa Kersten 2, Romil Stanislavov 3, Zdravko Kamenov 4, Panagiotis Nikolinakos 1 1 Medical

University - Sofia, Sofia, BG; of Essex, UK; 3 Genika, Genetic and Medico-Diagnostic Laboratory, Sofia, BG; 4 Clinic of Endocrinology, Alexandrovska University Hospital, Sofia, BG. 2 University

Summary

Objective: This exploratory retrospective study aimed to compare the level of Sperm DNA Fragmentation (SDF) and investigate its association with bulk semen parameters, for the first time in Bulgarian patients with varicocele, using a distinct methodology. Material and methods: Standard semen analysis was performed according to the 2010 criteria of the European Society of Human Reproduction and Embryology - Nordic Association for Andrology (ESHRE-NAFA-2010) and DNA fragmentation was assessed using the HalospermÂŽ kit. The total sample included 28 males: the control group consisted of men with normal genital examination and unknown fertility (n = 10), group one consisted of men with varicocele, normozoospermia and DNA fragmentation > 15% (n = 9) and group two consisted of men with varicocele, abnormal sperm parameters and DNA fragmentation > 15% (n = 9). Results: DNA fragmentation was found to be higher in patients with abnormal sperm parameters (43.78 Âą 30.78) compared to the normozoospermic group (21.22 Âą 3.93) (p = 0.008). In normozoospermic patients, no statistically significant correlations were observed between SDF and bulk semen parameters. In patients with abnormal sperm parameters, DNA fragmentation exhibited significant very strong negative association with motility (a+b), vitality and typical morphology (p < 0.001). Conclusions: DNA integrity assays could be used for a better evaluation and management of male infertility, particularly in normozoospermic varicocele patients.

KEY WORDS: Male Infertility; Sperm DNA fragmentation; Sperm DNA damage; Varicocele; Semen Analysis. Submitted 26 November 2018; Accepted 15 December 2018

INTRODUCTION

Varicocele, an abnormal dilation and tortuosity of the internal spermatic veins within the plexus pampiniformis, is the most frequently identified lesion in males undergoing infertility evaluation (1). It is a common condition in men with normal spermatogenesis but also in men with abnormal semen parameters. It is found in approximately 15% of the general population and is reported in 35% of men with primary infertility and 75 to 81% of men with secondary infertility (2). Varicocele is a complex entity as its effects on sperm quality are both difficult to define and predict. Not all men with varicocele are infertile (3) and patients with

clinically evident varicocele may present with normal values on primary semen assays. On the other hand, patients may present with altered spermatogenesis, poor bulk seminal parameters and oligoasthenoteratozoospermia (OAT syndrome) (4). The mechanisms by which varicoceles lead to spermatogenic failure are not completely elucidated. However, most authors investigating how varicoceles impair the reproductive function consider the primary event to be an increase in intratesticular temperature secondary to interruption in the counter-current heat exchange provided in the plexus pampiniformis with opposing flow vectors in a central arterial system and surrounding veins. The proposed mechanisms by which male fertility is impaired by this effect mainly include DNA fragmentation, apoptosis and oxidative stress. Other associated factors include testicular hypoxia secondary to venous stasis, reflux of renal/adrenal toxic metabolites and hypertension in the internal spermatic veins (5). Numerous researchers have recently examined the association between varicocele and Sperm DNA Fragmentation (SDF). Although a cause-and-effect relationship is not established, multiple reviews and meta-analyses conclude that there is indeed evident association between varicocele and increased DNA fragmentation (6). Although sperm DNA damage represents a reproducible sperm function marker, the American Society for Reproductive Medicine and the American Urological Association (AUA) do not recommend routine clinical use of sperm DNA testing (7). The utility of SDF testing is currently appreciated by the AUA and the European Association of Urology (EAU) for the evaluation of Assisted Reproductive Technology (ART) success (8, 9). Studies have shown that sperm DNA damage is associated with negative influence on embryo development and lower pregnancy rates (lower natural pregnancy rates and lower pregnancy rates after intrauterine insemination and in vitro fertilization) (10, 11). A significant finding is the increased risk for spontaneous abortions with increasing sperm DNA fragmentation. Comprehensive meta-analyses have shown that higher levels of DNA fragmentation are linked with an approximately double risk ratio (RR) of miscarriages (12). The current study included Bulgarian men clinically

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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diagnosed with varicocele and SDF level higher than 15%, which is defined as the normal threshold for in vivo fertilization using the Halosperm® kit (13). The objective was to compare the levels of DNA fragmentation between varicocele patients with normozoospermia and abnormal sperm parameters and to investigate the correlation of SDF and bulk semen parameters as well as describe the relationships between them, for the first time in the Bulgarian population. At the same time a secondary aim was to collect data using a distinct methodology which is not utilized as frequently in literature. Namely, the normozoospermic patients in the current study are defined according to the ESHRENAFA-2010 criteria which are stricter in defining normal parameters and make the additional distinction of borderline parameters in comparison to the WHO manual. Finally, there is great variability in literature in the methods used to determine SDF, which renders making correlations and drawing conclusions difficult (14). SDF in the present study was analyzed using the Halsoperm® kit, aiming to add to the pool of data acquired via Sperm Chromatin Dispersion.

MATERIALS

AND METHODS

Study group The study included 28 men assessed by the andrology laboratory department at Genika, Genetic and MedicoDiagnostic Laboratory in Sofia, Bulgaria. A retrospective study was designed involving one control group of men with unknown fertility, normal genital examination and normal bulk semen parameters (n = 10) and two groups of patients with clinically diagnosed varicocele and infertility. The varicocele was diagnosed by palpation and Doppler ultrasound examination. Among the patients with varicocele, the first group (n = 9), presented with normozoospermia and levels of DNA fragmentation higher than 15%. The second group (n = 9) presented with abnormal sperm parameters and levels of DNA fragmentation higher than 15%. In all men, medical history was obtained, including occupation, smoking habits, alcohol intake and the use of prescription medication. Exclusion criteria for all groups were: current or previous systemic diseases that would lead to testicular alterations such as cancer and endocrinopathies (and their treatments) and a history of excessive alcohol and drug consumption. According to the laboratory’s protocol, informed consent is acquired from all patients at the time of registration for the anonymous inclusion of their sperm analysis results in potential medical studies and research. Sperm collection and semen analysis Semen samples were collected by masturbation after three to seven days of ejaculatory abstinence and were analyzed within one hour of collection. Additionally, patients were instructed to abstain from alcohol consumption for three to seven days and maintain a good general status for three months before the examination as well as present afebrile on the day of the analysis, without having consumed any antibiotics (they were instructed to report any received medications). In all patients, the

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semen sample was (up to 25 minutes post ejaculation) retained in a 37 °C thermostat for circa 15 minutes. After complete semen liquefaction, pH and volume were measured and a standard seminal analysis was performed according to the criteria of the European Society of Human Reproduction and Embryology - Nordic Association for Andrology 2010 (ESHRE-NAFA-2010). Analysis was performed on the computer microscopic fluorescent platform Sperm Class Analyzer (SCA - v.5.0) and the parameters measured included total sperm count, motility, vitality and morphology. Sperm morphology was assessed using Kruger’s strict criteria. Sperm vitality was assessed using Eosin Y to stain spermatozoa and Negrosin to stain the background. In comparison to WHO-5, 2010, the criteria of ESHRE-NAFA-2010 interpret results in three categories: normal, borderline and pathologic. The borderline results represent a buffer zone of clinical importance. Patients in this zone are regarded as having the potential to shift to either normal or pathological spectra depending on the persistence of offending factors. Determination of DNA integrity Sperm nuclear DNA integrity was evaluated by use of the Halosperm® kit (Halotech® DNA SL, Madrid, Spain). This test is a modified and improved version of the sperm chromatin dispersion (SCD) test (15). The clinical threshold for percentage of spermatozoa with DNA fragmentation has been established as (1) < 15% for in vivo fertilization, (2) < 30% for in vitro fertilization. The kit included: 10 Super Coated Slides, 10 Eppendorf agarose tubes, one tube with denaturizing solution (1 mL), and two bottles of Lysis solution (60 mL ×2). The first step included inserting the semen sample in agarose microgel. The lysis solution was first left in room temperature. The semen sample was diluted with an extender or PBS until a concentration of 5-10 ×106/ml. The Eppendorf tube with the agarose was placed in a float for five minutes at 90 to 100 °C until the agarose melted. The tube was then moved along with the float into a water bath with a temperature of 37 °C and was left there for five minutes. 60 mL of the semen sample were transferred to the Eppendorf tube and were gently mixed. The Super-Coated Slide to be used was placed on a cold surface area (glass plate) at 4 °C. Once the slide had been cooled, cell suspension was transferred from the Eppendorf tube to the slide, towards the side that was treated and marked by a dark point. A coverslip was placed on top very carefully, to avoid creating bubbles. A drop of 14, 20 or 50 μL for the slides is used for the respective magnifications of 18×18mm, 22×22 mm or 24×60 mm. The slides were maintained in horizontal orientation throughout the whole procedure. The cooled glass plate with the slide was then placed in the fridge and the sample was left to jellify for five minutes. Processing the sample followed. The denaturizing agent was prepared by adding 80 μL from the acid denaturizing solution to 10 μL distilled water and was placed in an incubator tray. The cover slip was slid off the slide and the slide was immediately immersed in the denaturizing solution in horizontal orientation, leaving it to incubate for seven minutes at room temperature (22°C). After putting on gloves, the slide was picked up with the help of pincers. While remaining in horizontal position it was placed

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in another incubation tray containing 10 μL of lysis solution. It was left to incubate for 25 minutes. The slide was picked up and placed in a Petri dish filled with distilled water in order to wash off the lysis solution. It was left to incubate for five minutes. The slide was picked up and was placed horizontally in a Petri dish with 70% ethanol for two minutes, 90% ethanol for two minutes and 100% ethanol for two minutes. The slide was left to dry and once completely dried the prepared slide was stained for observation under light microscopy. Wright’s staining solution was mixed with Phosphate-buffered saline (PBS) in 1:1 ratio and one layer of the staining solution was placed horizontally in order to cover the wet slide. The slide was left to stain for five to 10 minutes. The slide was carefully rinsed with running water and was left to dry. Subsequently direct microscopic visual analysis was performed. The nucleoid that corresponds to deproteinized nuclei of spermatozoa is made up of two parts: a core located centrally and a peripheral halo of chromatin/DNA dispersion. The spermatozoa tails are also visible. A minimum of 500 spermatozoa are studied per sample and scored according to the following criteria. Sperm classification The categorization of the different halo sizes is performed using the minor diameter of the core from the own nucleoid as a reference to which the halo width is compared. The SCD patterns established are the following (15): Sperm cells without DNA fragmentation a) Sperm cells with large halo: those whose halo width is similar or higher than the minor diameter of the core. b) Sperm cells with medium-size halo: the halo size is between: maximum one third of the minor diameter of the core and minimum the length of the minor diameter of the core. Sperm cells with DNA fragmentation c) Sperm cells with small halo: the halo width is similar or smaller than one third of the minor diameter of the core. The core may have irregular form or barely distinguishable (< 150 μm2). d) Sperm cells without halo e) Sperm cells without halo-degraded: there is no halo and the core presents granule-like fragmentation and is weakly stained.

’’Others’’ Nucleoids that do not correspond to spermatozoa. One of the morphological characteristics that distinguish them is the absence of tail. These cells are not included in the estimation of frequency of sperm with fragmented DNA. Statistical analysis Data analysis was performed using the R software environment for statistical computing and graphics. For each variable the mean, the standard deviation and interquartile range (IR) are presented to indicate the relevant distribution. The Shapiro-Wilk test was applied to test whether variables are normally distributed. For normally distributed data a Student’s test was conducted to test whether means differ across groups. In the case of not normally distributed variables a MannWhitney-Wilcoxon test was applied to test whether the distribution across two groups differs. For both tests, the Null-Hypothesis (difference in means/populations) was rejected if the p-value was smaller than 0.05. Correlation coefficients were calculated according to the Pearson method. Statistically significant correlation coefficients were interpreted as: weak from 0.20 to 0.39 (or -0.20 to -0.39); moderate from 0.40 to 0.59 (or -0.40 to -0.59); strong from 0.60 to 0.79 (or -0.60 to -0.79); very strong from 0.80 to 1.0 (or -0.80 to -1.0). If the p-value was smaller than 0.05 then the correlation coefficient was interpreted as being statistically significant.

RESULTS

All 18 patients entering the study presented varicocele in the left testis, which was detected by physical examination and confirmed by Doppler ultrasound. The median age (years) was 31 ± 6.182 (26.25-34.5) for controls, 32 ± 6.648 (30-37) for patients with normal semen parameters (G1) and 36 ± 6.464 (35-42) for patients with abnormal semen parameters (G2). No statistically significant difference was found between the groups with respect to age apart from between the controls age and the G2 age, p = 0.01905. Standard semen analysis parameters The main sperm parameters of controls and varicocele patients are presented in Table 1. G1 (n = 9) had normal

Table 1. Comparison of standard sperm parameters between control subjects, varicocele patients with normal sperm parameters (G1) and varicocele patients with abnormal sperm parameters (G2). Numbers represent mean ± standard deviation and range is shown in parentheses.

pH Volume (mL) Number (x 106/mL) Motility (% a+b) Vitality (%) Morphology: Typical (%)

Control (n = 10)

Normal Sperm Parameters (G1) n = 9

Abnormal Sperm Parameters (G2) n = 9

7.54 ± 0.07 (7.5-7.575) 3.87 ± 2.465 (2.525-4.4) 448.4 ± 317.518 (251.2-651.7) 57.8 ± 3.225 (56-60.5) 78.2 ± 3.676 (78-81) 17.7 ± 1.947 (16-18)

7.611 ± 0.078 (7.6-7.7) 3.944 ± 1.474 (2.7-5.1) 293.9 ± 109.582 (214.6-362.3) 57 ± 3.640 (55-58) 76.67 ± 3.464 (73-79) 16.56 ± 1.667 (16-17)

7.733 ± 0.132 (7.6-7.8) 3.889 ± 2.070 (2.6-5.5) 117.3 ± 115.782 (41.1-169.3) 24.89 ± 13.897 (26-32) 48.89 ± 19.127 (46-62) 4.111 ± 2.028 (4-5)

A: p value B: p value between controls between controls and G1 and G2 0.052 0.002 0.595 0.744 0.488 0.008 0.594 <0.001 0.337 < 0.001 0.256 < 0.001

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Figure 1. DNA fragmentation by group.

0.001), vitality (r = -0.93; p < 0.001) and typical morphology (r = -0.89; p < 0.001). The latter three indicate a very strong association.

DISCUSSION

60 20

Percentage

This exploratory study aimed to answer the following question: do varicocele patients with abnormal sperm parameters have higher levels of SDF than varicocele patients with normozoospermia? According to the literature research performed by the authors, it was impossible to identify other studies using the same design: directly comparing the DNA fragmentation levels, by use of the Halosperm® kit, between varicocele patients with normozoospermia and varicocele patients with abnormal sperm parameters, while performing semen analysis according to the ESHRENAFA-2010 criteria. The results of our study indicate that Abnormal Sperm Control Normal Sperm there is clearly a higher degree of Parameters Parameters SDF in patients with varicocele. Group Furthermore, in our study varicocele patients with abnormal sperm sperm parameters. G2 (n = 9) showed an abnormality in parameters were found to have higher levels of SDF than one or more of the bulk semen parameters. Particularly, varicocele patients with normozoospermia. five patients had oligoasthenoteratozoospermia and four This finding is consistent with what other authors have had asthenoteratospermia. Furthermore, six patients also demonstrated regarding infertile men (16). The fact presented with more than 20% decapitated forms. that the levels of fragmentation in the group of patients with abnormal sperm parameters are higher, could Sperm DNA fragmentation measured reflect the more advanced effects of varicocele on sperby the Halosperm® kit matogenesis. In the control group the mean SDF percentage was calMoreover, in men with abnormal sperm parameters, we culated as 11.4 ± 1.35 (10.25-12). This was lower in established statistically significant, very strong correlacomparison to G1 (p < 0.001) and G2 (p < 0.001). SDF tions between DNA fragmentation and three semen was found to be higher in patients with abnormal sperm parameters: progressive motility, vitality and typical parameters 43.78 ± 30.78 (26-38) compared to the normorphology. These results are comparable to what other mozoospermic group 21.22 ± 3.93 (18-23) (p = 0.008). authors have observed (17). SDF by group is presented in Figure 1. Weaknesses of this study are the limited number of participating patients as well as the absence of data regardRelationships between DNA fragmentation ing the grade of varicocele which do not allow the drawand bulk semen parameters ing of any major conclusions. This being an exploratory In patients with varicocele and normal sperm paramestudy, the authors urge other researchers both in ters, DNA fragmentation was negatively correlated with Bulgaria and abroad to collect more data using the sperm pH (r = -0.54, p = 0.135) and motility (a+b) (r = methodology described, to obtain a more thorough -0.31, p = 0.410), and positively correlated with sperm understanding of the correlations between SDF and bulk volume (r = 0.10, p = 0.799), number (r = 0.14, p = semen parameters in patients with varicocele. 0.713), vitality (r = 0.05, p = 0.894) and typical morCriticisms regarding the utility of SDF tests to evaluate phology (r = 0.38, p = 0.314). In all cases the strength of male infertility include: that the minimum number of association ranges from very weak to moderate only, of spermatozoa without fragmentation required for in vivo which none is significant (i.e., p > 0.05). conception is unknown, that a simple sperm vitality On the other hand, in the group of patients with abnormal assessment could suffice given its correlation to SDF sperm parameters, DNA fragmentation was positively cor(18), and that more studies investigating the cost effecrelated with pH (r = 0.08, p = 0.840) and volume (r = tiveness of SDF testing are required to determine its role 0.15, p = 0.706); and negatively correlated with number alongside the standard sperm analysis. While the (r = -0.47, p = 0.204), motility (a+b) (r = -0.94; p < Halosperm® kit is only available in a few laboratories in

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our country, it can be argued that it is cost-and-time effective, since the results are produced on the same day and the average price of 100 EUR for the combined standard semen and SDF analysis is affordable. In conclusion, it has already been proven by numerous studies that sperm DNA damage is associated with decreased pregnancy rates in both in vivo and in vitro fertilization. There is an association of SDF with miscarriage and some studies have demonstrated the potential of reversing it by varicocelectomy (19). In patients with abnormal sperm parameters, SDF levels could be expected to be higher. In normozoospermic patients, SDF testing could potentially alter management as increased levels of SDF could present a therapeutic target. DNA fragmentation testing can be another arrow in the quiver of the clinician for the better understanding of male infertility and the management of selected patients with varicocele.

8. Jarrow J, Sigman M, Kolettis P, et al. Optimal Evaluation of the Infertile Male. AUA Best Practice Statement reviewed and validity confirmed. 2011.

REFERENCES

14. Evgeni E, Lymberopoulos G, Touloupidis S, et al. Sperm nuclear DNA fragmentation and its association with semen quality in Greek men. Andrologia. 2015; 47:1166.

2. Gorelick J, Goldstein M. Loss of fertility in men with varicocele. Fertil Steril. 1993; 59:613.

15. Fernandez J, Muriel L, Goyanes V, et al. HalospermÂŽ is an easy, available, and cost-effective alternative for determining sperm DNA fragmentation. Fertil Steril. 2005; 84:860.

1. Jarow J. Effects of varicocele on male fertility. Hum Reprod Update. 2001; 7:59.

3. Kursh E. What is the Incidence of Varicocele in a Fertile Population?. J Urol. 1988; 139:665. 4. World Health Organization. The influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. Fertil Steril. 1992; 57:1289. 5. Masson P, Brannigan R. The Varicocele. Urol Clin North Am. 2014; 41:129. 6. Zini A, Dohle G. Are varicoceles associated with increased deoxuribonucleic acid fragmentation?. Fertil Steril. 2011; 96:1283 7. Practice Committee of American Society for Reproductive Medicine. The clinical utility of sperm DNA integrity testing. Fertil Steril. 2008; 90:178.

9. Jungwirth A, Giwercman A, Tournaye H, et al. European Association of Urology guidelines on Male Infertility: the 2012 update. Eur Urol. 2012; 62:324. 10. Giwercman A, Lindstedt L, Larsson M, et al. Sperm chromatin structure assay as an independent predictor of fertility in vivo: a case-control study. Int J Androl. 2010; 33:221. 11. Collins J, Barnhart K, Schlegel P. Do sperm DNA integrity tests predict pregnancy with in vitro fertilization?. Fertil Steril. 2008; 89:823. 12. Robinson L, Gallos I, Conner S, et al. The effect of sperm DNA fragmentation on miscarriage rates: a systematic review and metaanalysis. Hum Reprod, 2012; 27:2908. 13. Evenson D, Wixon R. Meta-analysis of sperm DNA fragmentation using the sperm chromatin structure assay. Reprod Biomed Online. 2006; 12:466.

16. Moskovtsev S, Willis J, White J, et al. Sperm DNA Damage: Correlation to Severity of Semen Abnormalities. Urology. 2009; 74:789. 17. Omran H, Bakhiet M, Dashti M. DNA integrity is a critical molecular indicator for the assessment of male infertility. Mol Med Rep. 2013; 7:1631. 18. Mitchell LA, De Iuliis GN, Aitken RJ. The TUNEL assay consistently underestimates DNA damage in human spermatozoa and is influenced by DNA compaction and cell vitality: development of an improved methodology. Int J Androl. 2011; 34:2. 19. Roque M, Esteves S. Effect of varicocele repair on sperm DNA fragmentation: a review. Int Urol Nephrol. 2018; 50:583.

Correspondence Viktor Alargkof, MD valargoff@yahoo.gr 24 Rue du Bugnon, Lausanne, 1005, CH Larissa Kersten, MD larissa.kersten@gmail.com 4 Theodor-Heuss STR, 45731 Waltrop, DE Romil Stanislavov, MD rstanik@abv.bg 84 Ami Bue STR. 1000, Sofia, BG, Zdravko Kamenov, MD zkamenov@hotmail.com 1 Sveti Georgi Sofiyski STR, 1431, Sofia, BG Panagiotis Nikolinakos, MD pnikolinakos@yahoo.gr 139 Pentelis AVE, 15127, Athens, GR

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DOI: 10.4081/aiua.2019.2.130

ORIGINAL PAPER

Klinefelter’s syndrome and taurodontism Emilia Giambersio 1, Vincenzo Barile 2, Antonio Marcello Giambersio 1 1 “Ambulatorio 2 UOC

Klinefelter” ASP Potenza, Italy; of Radiology “Poliambulatorio Madre Teresa” ASP Potenza, Italy.

Summary

Objective: Taurodontism is a dental anomaly characterized by an enlarged pulp chamber and apycal displacement of the pulpar floor. The prevalence of taurodontism in normal population is controversial. It has been reported that taurodontism is frequently observed in Klinefelter’s patients. The purpose of this study was to assess the prevalence of taurodontism in a group of Italian Klinefelter’s patients and in a randomly selected male population of Italy and to compare the results with published data. Materials and methods: Digital panoramic radiographs of 16 Klinefelter’s patients and of 100 normal males were retrospectively studied in order to investigate the prevalence of taurodontism in these groups of patients. Results: Taurodont teeth were observed in 2 of the 16 Klinefelter’s patients (12.5%) and in 2 of 100 normal males (2.0%). Conclusions: Our results confirm the higher prevalence of taurodontism in Klinefelter’s patients compared to the normal population (12.5% vs. 2.0%). Due to the wide discrepancy of incidence of taurodontism reported in literature (0.04%-48.0% in normal population; 12.5%-88.0% in Klinefelter’s patients), we conclude that it is not possible to state which is the prevalence of taurodontism in a normal population nor among Klinefelter’s patients.

KEY WORDS: Klinefelter’s syndrome; Taurodontism; 47,XXY; Dental anomaly; Digital panoramic radiographs. Submitted 30 January 2019; Accepted 11 March 2019

INTRODUCTION

Taurodontism is defined as a change in the shape of molar teeth characterized in an enlarged pulp chamber, apical displacement of pulpar floor and no constriction at the level of cementoenamel junction (1). The origin of the word comes from the Greek tauros, which means bull and odontos which refers to tooth (“bull-like” teeth). The prevalence of taurodontism in normal population has been reported to range between 0.04% (2) and 48.0% (3). An increased incidence of taurodontism has been observed in Klinefelter’s patients with a prevalence of 19.4% (4) to 88.0% (5). The purpose of this study was to assess the incidence of taurodontism in a group of Italian Klinefelter’s patients and in a randomly selected male population of Italy and to compare the results with published data of different normal population groups and of Klinefelter’s patients.

130

PATIENTS

AND METHODS

We retrospectively studied the digital panoramic radiographs of 16 Klinefelter’s patients who attended the “Ambulatorio Klinefelter” in Italy in order to investigate the prevalence of taurodontism in this group of patients. Orthopantomograms of 100 randomly selected patients of the same male Italian population were examined as a control group. Dental radiographs were analyzed for the presence of taurodontic molars using the categorization hypo-, meso-, and hyper- taurodont based on the degree of apical displacement of the pulp chamber floor. A tooth was considered as taurodont when there was an enlarged pulp chamber that was apically displaced and a lack of constriction at the cementoenamel junction (5).

RESULTS

Of the 16 Klinefelter’s patients, 2 were found to exhibit taurodontic teeth (1 hypo and 1 meso-taurodont) (12.5%) (Figure 1). In the group of 100 normal patients we found 2 patients with taurodontic teeth (2 meso-taurodont) (2.0%).

DISCUSSION

Clinically, a taurodont tooth appears as normal: its distinguishing features cannot be recognized clinically, therefore the diagnosis is made from radiographs. Several criteria have been proposed to define a taurodont tooth, each of them having pros and cons (1, 5-8). Moreover, most Authors do not provide an objective analysis of cases presented, preferring a subjective diagnosis (1). It has been stated that the incidence of taurodontism is very low in normal population (8-10), others claim that taurodontism is not a rare trait in the modern man (5). Some Authors report that taurodontism is the most common dental anomaly observed (11), others even consider taurodontism a simple variation of normal teeth (12). The prevalence of taurodontism has been reported to show a wide range of discrepancy in different populations. It was 0.04% in an Italian population (2), 1.4% in children of Saudi Arabia (13), 2.25% in a German population (14), 2.5% in a Finnish population (15), 5.6% in young adult Israeli patients (6), 15.06% in a French population of 551 patients (where it was the most common dental anomaly observed) (11), 22.9% in an Iranian population (7), 46.4% in a young Chinese No conflict of interest declared.

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Klinetaurodontism

Figure 1. Radiograph of a taurodontic molar in a Klinefelter's patient with enlarged pulp chamber, apical displacement of the pulpar floor and lack of constriction at the level of the cementoenamel junction.

tion; 12.5%-88.0% in Klinefelter’s patients) does not allow to determine which is the prevalence of taurodontism in a normal population nor the prevalence among Klinefelter’s patients.

REFERENCES

1. Jafarzadeh H, Azarpazhooh A, Mayhall JT. Taurodontism: a review of the condition and endodontic treatment challenges. Int Endod J. 2008; 41:375-88. 2. Laganà G, Venza N, Borzabadi-Farahani A, et al. Dental anomalies: prevalence and associations between them in a large sample of non-orthodontic subjects, a cross-sectional study. BMC Oral Health. 2017; 17:62-8. 3. Toure B, Kane AW, Sarr M, et al. Prevalence of taurodontism at the level of the molar in the black Senegalese population 15 to 19 years of age. Odontostomatol Trop. 2000; 23:36-9. 4. Komatz Y, Tomoyoshi T, Yoshida O, et al. Taurodontism and Klinefelter’s syndrome. J Med Genet. 1978; 15:452-4. 5. Jaspers MT, Witkop Jr CJ. Taurodontism, an isolated trait associated with syndromes and X-chromosomal aneuploidy. Am J Hum Genet. 1980; 32:396-413.

population (16) and 48% in a black Senegalese population (3). The prevalence of taurodontism that we have found in our group of 100 normal patients was 2.0%. It has been claimed that the wide discrepancy observed could be due to racial variations (17), but the inconsistency of prevalence observed in studies exploring the same populations (0.4% of 4143 patients (9, 18) and 2.8% of 1000 patients (19) in two north Indian populations and 0.26% of 6912 patients (12) and 11.2% of 1200 patients (20) in two Turkish populations) seems to indicate that the differences reported can be rather due to different criteria used to define taurodontism rather than ethnic variations. An increased prevalence of taurodontism has been reported in Klinefelter’s patients. The prevalence observed was 19.4% of 31 Klinefelter’s patients (4), 24% of 25 patients (21), 30% of 30 Finnish 47,XXY males (15), 40% of 35 Klinefelter’s patients (22), 75% of 24 patients (23), 88% of 9 Klinefelter’s patients (5). The prevalence of taurodontism that we have found in our group of 16 Klinefelter’s patients (12.5%) appears to be lower than what observed in other Klinefelter’s populations. Taurodontism seems to be associated with several other syndromes such as Down’s syndrome (24), 48,XXYY syndrome (25), Prader-Labhart-Willi syndrome (26), WolfHirschhorn syndrome (27-28), Pierre Robin syndrome (29); it is also more frequent in familial groups (5, 8), in families with WNT10A defects (30) and it is a typical trait frequently found in Neanderthal teeth (17).

CONCLUSIONS

Our results confirm the higher prevalence of taurodontism in Klinefelter’s patients compared with the prevalence observed in a normal population (12.5% vs. 2.0%). The wide discrepancy of incidence of taurodontism reported in literature (0.04%-48.0% in normal popula-

6. Shifman A, Chanannel I. Prevalence of taurodontism found in radiographic dental examination of 1,200 young adul Israeli patients. Community Dent Oral Epidemiol. 1978; 6:200-3. 7. Jamshidi D, Tofangchiha M, Pozve NJ, et al. Prevalence of taurodont molars in a selected Iranian adult population. Iran Endod J. 2017; 12:282-7. 8. Panigrahi A, Panigrahi RG, Srilatha KT, et al. Non syndromic familial bilateral decidious taurodontism - a first case report. J Clin Diagn Res. 2014; 8:ZD01-2. 9. Patil S, Doni B, Kaswan S, Rahman F. Prevalence of taurodontism in the north Indian population. J Clin Exp Dent. 2013; 5:e179-82. 10. Jayashankara CM, Shivanna AK, Sridhara KS, Kumar PS. Taurodontism: a dental rarity. J Oral Maxillofac Pathol. 2013; 17:478. 11. Baron C, Houchmand-Cuny M, Enkel B, Lopez-Cazaux S. Prevalence of dental anomalies in French orthodontic patients: a retrospective study. Arch Pediatr. 2018: 25:426-30. 12. Colak H, Tan E, Byraktar Y, et al. Taurodontism in a central anatolian population. Dent Res J. 2013; 10:260-3. 13. Yassin SM. Prevalence and distribution of selected dental anomalies among saudi children in Abha, Saudi Arabia. J Clin Exp Dent. 2016; 8:e485-90. 14. Burklein S, Breuer D, Schafer E. Prevalence of taurodont and pyramidal molars in a German population. J Endod. 2011; 37:158-62. 15. Varrela J, Alvesalo L. Taurodontism in 47,XXY males: an effect of the extra X chromosome on root development. J Dent Res. 1988; 67:501-2. 16. MacDonald-Jankowski DS. Taurodontism in a young adult Chinese population. Dentomaxillofac Radiol. 1993; 22: 140-4. 17. Benazzi S, Nguyen HN, Kullmer O, Hublin J. Exploring the biomechanics of taurodontism. J Anat. 2015; 226:180-8. 18. Patil S, Doni B, Kaswan S, Rahman F. Prevalence of dental anomalies in Indian population. J Clin Exp Dent. 2013; 5:e183-6. 19. Bharti R, Chandra A, Tikku AP, Arya D. Prevalence of taurodont molars in a north Indian population. Indian J Dent. 2015; 6:27-31. Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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20. Bilge NH, Yesiltepe K, Torenek Agirman K, et al. Investigation of prevalence of dental anomalies by using digital panoramic radiographs. Folia Morphol. 2018; 77:323-8. 21. Hillebrand U, Mohr C, Plewa G. Taurodontism in patients with sex chromosome anomalies. Dtsch Z Mund Kiefer Gesichtschir. 1990; 14:187-9. 22. Rossiwall B. Taurodontism in Klinefelterâ&#x20AC;&#x2122;s syndrome. In: Bandmann HJ, Breit R, editors. Klinefelterâ&#x20AC;&#x2122;s syndrome. Berlin: Springer-Verlag, 1984, p. 80-4. 23. Schulman GS, Redford-Badwal D, Poole A, et al. Taurodontism and learning disabilities in patients with Klinefelter syndrome. Pediatr Dent. 2005; 27:389-94. 24. Alpoz AR, Eronat C. Taurodontism in children associated with trisomy 21 syndrome. J Clin Pediatr Dent. 1997; 22:37-9. 25. Krishnamoorthy S, Gopikrishna V. Endodontic management of a

Correspondence Emilia Giambersio, MD emilia.giambersio@gmail.com Antonio Giambersio, MF giambersio@libero.it ASP Poliambulatorio Madre Teresa - Ambulatorio Klinefelter Viale del Gallitello, 85100 Potenza (Italy) Vincenzo Barile, MD vincenzo.barile@aspbasilicata.it ASP Poliambulatorio Madre Teresa - UOC of Radiology Viale del Gallitello, 85100 Potenza (Italy)

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hypertaurodontic tooth associated with 48,XXYY syndrome: a review and case report. J Conserv Dent. 2015; 18:265-8. 26. Bassarelli V, Baccetti T, Bassarelli T, Franchi L. The dentomaxillofacial characteristics of the Prader-Labhart-Willi syndrome. A clinical case report. Min Stomatol 1991; 40:811-9. 27. Babich SB, Banducci C, Teplitsky P. Dental characteristics of the Wolf-Hirschhorn syndrome: a case report. Spec Care Dentist. 2004; 24:229-31. 28. Johnston NJ, Franklin DL. Dental findings of a child with WolfHirschhorn syndrome. Int J Paediatr Dent. 2006; 16:139-42. 29. Mateo-Castillo JF, Pagin O, Marchi Carvalho IM, et al. Novel dental phenotype in non-syndromic Pierre Robin sequence: a retrospective study. Arch Oral Biol. 2019; 97:170-5. 30. Yang J, Wang S, Choi M, et al. Taurodontism, variations in tooth number, and misshapened crowns in Wnt10a null mice and human kindreds. Molecular Genetics & Genomic Medicine. 2015; 3:40-58.

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DOI: 10.4081/aiua.2019.2.133

CASE REPORT

Merkel cell carcinoma with kidney metastasis in a 81-year-old man. A rare case report Aikaterini Anastasiou 1, Napoleon Moulavasilis 1, Ioannis Leotsakos 1, Christos E. Nerantzis 2, Ioannis Anastasiou 1 1 1st

University Urology Clinic, Laiko Hospital, Athens Greece; Medical Service of Athens, Athens, Greece.

2 Forensic

Summary

Merkel cell carcinoma (MCC) is a primary neuroendocrine carcinoma of the skin. The prognosis of the disease is considered poor. Secondary metastasis is common, however a secondary metastasis to kidney from Merkel cell is a very rare phenomenon. We report a case of a man with a MCC metastasis to the right kidney. The suggested management is surgery and afterwards a platinum-based chemotherapy.

KEY WORDS: Merkel cell carcinoma; Metastasis; Kidney. Submitted 13 March 2019; Accepted 21 March 2019

INTRODUCTION

Merkel cell carcinoma (MCC) is a rare non melanoma cutaneous malignancy with a high recurrence and mortality rates (1, 2). It commonly metastasizes to lymph nodes, liver, lung and bone. It occurs mainly in elderly, and people with immunosuppression due to organ transplantation and HIV infection (1, 2). Secondary kidney tumors in patients without evidence of disseminated non-renal malignancy are rarely observed (3). We present a rare case of a 81-year-old man with a MCC metastasis to the right kidney.

CASE

DISCUSSION

Merkel cell carcinoma is a primary neuroendocrine carcinoma of the skin (1). It is a highly aggressive tumor with common metastasis to lymph nodes, liver, lung and bone (1). The clinical presentation is a rapidly expanding, 1-2 cm sized, asymptomatic, red/pink nodule seen on sun-exposed skin (1). Thus it usually affects the head, neck and limbs (1). The mean latency from the primary tumor diagnosis to a systemic metastasis is 2.1 years. Merkel cell carcinoma can be metastasized to every organ, with liver and lungs being the most commonly affected solid organs. Distant dissemination occurs in up to 40-50% of patients that develop visceral metastasis (4). Our patient first was presented with a submaxillary gland tumor. The evolution of the MCC in our patient was also rapid and after 3 months he was diagnosed with a cervical gland tumor and lastly after 4 months with a tumor in parotid. One year later an MRI showed a metastasis to the right kidney (Figure 1).

PRESENTATION

A 81-year-old man was presented to our Urology Department (1st University Urology Clinic, Laiko hospital, Athens, Greece) after an MRI scan revealed a solid lesion to his right kidney. A biopsy was performed and the histology revealed Merkel Cell Carcinoma (MCC) (Figure 1). The patient, has been diagnosed from MCC in the left submaxillary gland, which in the previous year metastasized in the cervical and parotid glands. These tumors where managed with surgery, chemotherapy and radiotherapy. MCC is known for its aggressiveness and in our case the kidney was the rare secondary metastasis of the tumor. The oncology board decided that the patient had to be submitted to a platinum based chemotherapy. Today, 3 years after the last cycle of the chemotherapy our patient is without recurrence.

Figure 1. Histology of Merkel cell carcinoma.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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A. Anastasiou, N. Moulavasilis, I. Leotsakos, C.E. Nerantzis, I. Anastasiou

Male sex, advanced age, white skin population, vitamin D deficiency, exposure to ultraviolet B and sun are reported to worsen the prognosis. MCC prognosis is also affected by immunosuppression from organ transplant and HIV infection (2). Diagnosis is based on histological and immunohistochemical analysis.. Histological features include a triad of vesicular nuclei with tiny nucleoli, numerous mitoses and apoptosis, with accompanying lymphovascular invasion (1). The choice of treatment depends on the characteristics of the disease, the stage at the presentation, the regional lymph node involvement, comorbidities and the performance status of the patient. Surgery is the primary option for patients with locoregional primary MCC. A combination therapy with adequate surgical removal and selective adjuvant radiotherapy, can reduce the local recurrence rate in a higher percentage (2). However, it is still common for patients with clinically positive lymph nodes to present a high percentage of recurrence in the form of distant disease. Finally, MCC is considered to be a chemotherapy- sensitive tumor especially for the treatment of metastatic MCC (stage IV), and it is mostly indicated to palliate symptoms (2). Accordingly our patient for the first 10 months, the tumors of the glands where managed with surgery, chemotherapy (Etoposide 100 x 6, and Filgastin) and then radiotherapy. When the MRI showed a suspected solid lesion to the right kidney we performed a biopsy and two

Correspondence Aikaterini Anastasiou, MD aikatianast@gmail.com Napoleon Moulavasilis, MD Napomoul@hotmail.com Ioannis Leotsakos, MD j_leot@yahoo.gr Iohannis Anastasiou, MD ekati2@otenet.gr 1st University Urology Clinic, Laiko Hospital Ag.Thoma 17, Athens 11527 (Greece) Christos E. Nerantzis, MD theano9@otenet.gr Forensic Medical Service of Athens, Athens (Greece)

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tumors were found. After the surgery the patient was submitted to a chemotherapy (Platinum x 8) and 3 years after the operation is without an evidence of a recurrence

CONCLUSIONS MCC is an aggressive neoplasm, which usually affects the head and the neck. The disease has an average age of presentation of 72 years. Metastasis are observed in almost half of the patients. The most common are the lungs, liver and bones. A kidney metastasis is very rare in MCC patients, however it is possible to occur.

REFERENCES 1. Medhi S, Purandare NC, Dua SG, Gujral S. Bilateral renal metastases in a case of Merkel cell carcinoma. J Cancer Res Ther. 2010; 6:353-5. 2. Schadendorf D, LebbĂŠ C, Zur Hausen A, et al. Merkel cell carcinoma: epidemiology, prognosis, therapy and unmet medical needs. Eur J Cancer. 2017; 71:53-69. 3. Pollheimer VS, Bodo K, Pollheimer MJ, et al. Merkel cell carcinoma metastasizing to the kidney mimicking primary neuroendocrine renal cancer. APMIS. 2007; 115:774-7. 4. Kouzmina M, Koljonen V, Leikola J, et al. Frequency and locations of systemic metastases in Merkel cell carcinoma by imaging. Acta Radiol Open. 2017; 6:1-7.

Kratiras_Stesura Seveso 02/07/19 08:58 Pagina 135

DOI: 10.4081/aiua.2019.2.135

CASE REPORT

Malignant solitary fibrous tumor of urinary bladder: A rare clinical entity Zisis Kratiras 1, 2, 3, Vasileios Spapis 1, Efthymios Koniaris 2, Diomidis Kozyrakis 3, Konstantinos Skriapas 4 1 Department

of Urology, Hippokratio General Hospital of Athens, Athens, Greece; of Pathology, Hippokratio General Hospital of Athens, Athens, Greece; 3 Department of Urology, General Hospital of Volos, Volos, Greece; 4 Department of Urology, General Hospital of Larisa, Larisa, Greece. 2 Department

Summary

Solitary Fibrous Tumors (SFTs) are mesenchymal tumors occurring in several sites. Urinary bladder SFTs are quite rare. Eighteen cases are described in the literature and only two of them had malignant features. SFTs comprise a histologic spectrum of mesenchymal neoplasms that show fibroblastic differentiation. The signs and symptoms are non specific. Immunohistochemistry plays a pivotal role in the diagnosis, differentiating SFTs from other spindle cell mesenchymal tumors. Malignant criteria are considered the large size, increased mitotic activity, focal necrosis or hemorrhage, nuclear atypia, hypercellularity and infiltrative margins. Clinical and biological behavior of bladder SFTs is usually not aggressive but cannot be safely predicted based on the pathologic features. Complete surgical resection is the cornerstone of treatment. We present the third bladder SFT case with malignant features and a mini literature review.

KEY WORDS: Solitary fibrous tumor; Hemangiopericytoma; Bladder tumors; Mesenchymal tumors.

lymph nodes or distant metastasis. Patient was driven to theatre and an urgent transurethral resection was performed, revealing a solid looking bladder tumor occupying the bladder dome and part of the left lateral wall. The pathology revealed that the tumor was composed of ovoid- to spindle-shaped cells with alternating hypercellular and hypocellular areas. They had a staghorn vascular pattern with a mixed variable with evidence of necrosis and hemorrhage. Nuclear atypia was present with increased mitotic activity, focally up to 23/10 HPF, and a proliferation rate Ki67 positive 30-35% (Figure 1). Immunohistochemistry revealed that the tumor was positive for Vimentin, bcl-2, CD99 and CD34 and negative for Actin, Desmin, CD117 and CKAE1/AE3. Patient underwent a magnetic resonance imaging (MRI) for local staging followed by an uneventful radical cystectomy and ileal conduit as diversion. The tumor was completely removed with clear surgical margins. He had a successful recovery

Submitted 17 February 2019; Accepted 11 March 2019

INTRODUCTION:

In 1931 Klemperer and Rabin were the first to describe the solitary fibrous tumor (SFT) as a mesothelial tumor arising from the pleura. Since then numerous extrapleural sites of SFT had been described (1). SFTs originating from the urinary bladder are uncommon; only 18 cases have been described in the English literature. We report a case of a SNT of the bladder with malignant features in a 31-year old male patient.

CASE

Figure 1. Pathology revealed ovoid- to spindle-shaped cells with a staghorn vascular pattern.

REPORT

A 31- year old male patient self-presented to the Accident and Emergency department of our hospital reporting frank heamaturia, accompanied with dysuria, dull abdominal pain and blood clots. He denied any systemic symptoms and his clinical examination was unremarkable. From his past medical history, he was an ex-smoker but otherwise fit and healthy. His blood chemistry was in the normal range. A computed tomography (CT) that was performed revealed a 42 x 53 mm solid mass at the left lateral wall and the bladder dome without any evidence of No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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Z. Kratiras, V. Spapis, E. Koniaris, D. Kozyrakis, K. Skriapas

without any immediate post operative complication. He was discharged home at day 9 post op and he was reviewed in clinic after 3 months. His final pathology verified the initial diagnosis of SNT of the bladder with malignant features.

DISCUSSION

Solitary fibrous tumors comprise a histologic spectrum of rarely metastasizing mesenchymal neoplasms that show fibroblastic differentiation and can occur in any anatomical position. Extrapleural SFTs are usually diagnosed between the 5th and the 6th decade of life, having an equal distribution between races and sexes. They are normally slowly growing and symptoms arise due to local invasion of the tumor. The usual presenting symptoms are abdominal pain along with palpable abdominal mass. Heamaturia and dysuria might also be the first symptoms of a bladder SFT as in our case. Symptomatic hypoglycemia might occur as paraneoplasmatic syndrome in a small subset of tumors (2). There is no diagnostic or treatment algorithm. Imaging plays the most contemporary role in the diagnosis. Certain, but not specific, imaging features have been described. CT usually reveals an enhancing heterogenous, well defined mass demonstrating the vascular nature of the tumor. Areas of hemorrhage or necrosis might be present. MRI usually reveals heterogenous and variable signals depending on the vascularity and the fibrous stroma of the neoplasm. Macroscopically the tumor is usually a well circumscribed, tan colored mass that may be encapsulated by a thin and vascular pseudocapsule. It usually arises from the bladder submucosa although cases arising from bladder serosa have been described. Microscopically it consists of hypocelullar and hypercellular areas consisting of ovoid and spindle-shaped cells (2, 3). Staghorn configuration of blood vessels is common. Immunohistochemistry plays a pivotal role in differentiating SFTs from other spindle cell mesenchymal tumors. SFTs are immunoreactive to Vimentin, CD34, CD99 and bcl-2 and they are negative for actin, desmin (in smooth muscle tumors), keratin and CD117 (in GISTs) (2, 3). Malignant criteria are considered the large size, increased mitotic activity (more than 4 mitosis in 10 high power fields), focal necrosis or hemorrhage, nuclear atypia, hypercellularity and infiltrative margins. Clinical and biological behavior of bladder SFTs is usually not aggressive but cannot be safely predicted based on the pathologic features. Even benign tumors can act aggressively by invading structures at the proximity of the tumor or reoccurring, while malignant ones might have a less aggressive behavior without recurrence or metastasis (2, 3). Complete surgical resection is the cornerstone of treatment. Adjuvant radiotherapy is a useful asset for the local control of the disease, while adjuvant chemotherapy appears to have limited efficacy. Chemoradiotherapy has been used for non-resectable tumors with variable success. High quality evidence is not available due to the rarity of the disease and the data are from only small case series. In our case the tumor was completely excised with radical cystectomy. Unfortunately the patient

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returned to his homeland 5 months after the operation and longer follow is not available.

CONCLUSIONS

Bladder SFTs are extremely rare mesenchymal neoplasms, usually arising from the bladder submucosa. Although they usually have benign features, their clinical behavior cannot be safely predicted. Signs and symptoms are non specific, while radiology findings are indictive of an enhancing bladder lesion. Immunohistochemistry is pivotal for the diagnosis of SFTs. Although the literature is sparse and the level of evidence is low, radical surgical excision is the mainstay of treatment.

REFERENCES

1. Cheng SH, Wang SS, Lee CH, et al. Malignant solitary fibrous tumor of the urinary bladder. J Chin Med Assoc. 2012; 75:479-82. 2. Varaldo M, Ferrarazzo C, Tunesi G, et al. Solitary fibrous tumor. Solitary fibrous tumor. Rare Tumors. 2010; 2:e64. 3. Spairani C, Squillaci S, Pitino A, et al. A case of concomitant occurrence of solitary fibrous tumor and urothelial high-grade invasive carcinoma of the urinary bladder. Int J Surg Path. 2014; 22:252-9.

Correspondence Zisis Kratiras, MD (Corresponding Author) zkratiras@gmail.com Diomidis Kozyrakis, MD dkozirakis@yahoo.gr Department of Urology, General Hospital of Volos Dimokratias 126, 37300 Volos (Greece) Vasileios Spapis, MD vspapis@hotmail.com Department of Urology, Hippokratio General Hospital of Athens, Athens (Greece) Efthymios Koniaris, MD ethimiok@hotmail.com Department of Pathology, Hippokratio General Hospital of Athens, Athens (Greece) Konstantinos Skriapas, MD kostas.skriapas@hotmail.com Department of Urology, General Hospital of Larisa, Larisa (Greece)

Karaci_Stesura Seveso 02/07/19 08:59 Pagina 137

DOI: 10.4081/aiua.2019.2.137

CASE REPORT

A rare cause of clitoromegaly: Epidermoid cyst Selman Karaci 1, Deniz Kulaksiz 2, Cagri Akin Sekerci 3 1 Trabzon

Kanuni Research and Training Hospital, Plastic & Reconstructive Surgery, Trabzon, Turkey; Kanuni Research and Training Hospital, Gynecology & Obstetrics, Trabzon, Turkey; 3 Trabzon Kanuni Research and Training Hospital, Pediatric Urology, Trabzon, Turkey. 2 Trabzon

Summary

Clitoromegaly due to non-hormonal causes is rare. In this case, we aimed to present an epidermal cyst that caused clitoromegaly after traditional female circumcision. A 22-year-old African female was referred to our clinic with enlarged clitoris. There is a mobile, soft, nonfluctuant mass with a size of 6 cm originating from the clitoral region at physical examination. Under spinal anesthesia the clitoral mass was excised totally and labioplasty was performed. Histopathologic examination was reported as epidermal cyst. Epidermal cyst should be considered after hormonal reasons are excluded in patients with clitoromegaly who have a history of trauma.

KEY WORDS: Clitoromegaly; Epidermoid cyst; Female circumcision. Submitted 1 Februart 2019; Accepted 1 April 2019

INTRODUCTION

Clitoromegaly often occurs with an increase in endogenous androgen release or by exogenous androgens in women. Non-hormonal causes of clitoral hypertrophy is rare and usually present with benign neoplasms. Fibroma, leiomyoma, angiokeratoma, pseudolymphoma, hemangioma, hemangiopericytoma, granular cell tumor and neurofibroma were reported as bening neoplasm causing clitoromegaly; carcinoma, endodermal sinus tumor, sarcoma, rhabdomyosarcoma, schwannoma, epithelioid hemangioendothelioma and lymphoma as malignant clitoral tumors (1). In this presentation, an asymptomatic clitoral mass due to epidermal cyst developed following female circumcision was reported.

CASE

REPORT

A 22-year-old African female was referred to our clinic with enlarged clitoris. The enlargement had been present since early adolescence period. She had a story of traditional female circumcision in early childhood. She had no systemic disease, hirsutism and obesity. She menses regularly every 28 days and secondary sex characteristics were normal. There was a mobile, soft, non-fluctuant mass with a size of 6 cm originating from the clitoral region in physical examination. Luteinizing hormone, follicle stimulating hormone, serum prolactin, serum cortisol and 17-hydroxyprogesterone were all found

within the normal range. Bilateral ovaries and uterus were normal by pelvic ultrasonography. No structure for any male genital organ was observed. For this reason, disorders of sex development were excluded. It was reported as a massive cystic structure with no perfusion on pelvic magnetic resonance imaging. Under spinal anesthesia the clitoral mass was excised totally and labiaplasty was performed. During surgery, glans and neurovascular bundle of the clitoris were not observed. It can be associated with previous female circumcision. There was no complication at the postoperative period. Histopathologic examination was reported as a 5 x 3 x 2.5 cm epidermal cyst filled with keratinous material.

DISCUSSION

Clitoral hypertrophy may be congenital or acquired. Congenital forms are usually observed at birth and develop due to hormonal disorders. Acquired forms can be divided into two forms, hormonal or non-hormonal. Hormonal causes include hypertestosteronism, polycystic ovarian syndrome, virilizing tumors of the ovary or adrenal gland, and exogenous androgen exposure (2). Non hormonal causes are more and are associated with neoplasms. Epidermoid cyst is one of the rare causes of non-hormonal acquired clitoromegaly. The epidermoid cyst may be intradermal or subcutaneously localized and surrounded by the epidermis wall. Epidermoid cyst is formed by keratinized squamous epithelium invagination into the dermis or subcutaneous tissue spontaneously or following trauma and filled with lamine keratin (3). Epidermal cysts often occupy the vulva or labia major. Clitoral epidermoid cyst can often be observed in African girls or women following trauma caused by genital mutilation (1). Spontaneous development without trauma is rare (2). Anderson-Mueller et al. presented a 17year-old African-American girl with a painful clitoral mass. Patient had no female circumcision or any genital trauma. After the endocrinological causes were excluded, the neurovascular bundle of clitoris was preserved and the mass was excised. Pathology evaluation reported a benign squamous mucosa with submucosal edema, chronic inflammation, fibrosis, and mild vascular congestion (1). In our case, there was no trauma story and only traditional female circumcision for genital mutilia-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 2

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S. Karaci, D. Kulaksiz, C. Akin Sekerci

Figure 1. Before and after surgery.

Figure 2. Excised epidermoid cyst and its contents.

tion. Glandular structure and neurovascular bundle were not observed during surgery, while the corporal bodies were seen as a stump. Al-Ojaimi et al. reported a 19-year-old female with a giant epidermoid cyst measuring 8 x 6 cm (4). In this case, redundant skin was excised after cyst removal. In cases with very large cysts, labiaplasty following excision may be required and we performed it in our case. Clitoral enlargement during adolescence period is a very rare condition. Endocrinological evaluation should be done after carefully physical examination of internal and external genital system. If necessary, adrenal gland imaging should be included. If non-hormonal causes are diagnosed after this evaluation, biopsy and/or complete resection may be performed (1).

be considered. Imaging methods can be applied in suspicious situations. During the surgical excision, the clitoris (vascularization and innervation) should be protected as much as possible.

CONCLUSIONS

When clitoral hypertrophy is encountered, endocrinological causes should be ruled out in the first step. Subsequent malignant or benign clitoral lesions should

Correspondence Selman Karaci, MD selmankaraci@gmail.com Trabzon Kanuni Research and Training Hospital, Plastic & Reconstructive Surgery, Trabzon (Turkey) Deniz Kulaksiz, MD drdenizkulaksiz@hotmail.com Trabzon Kanuni Research and Training Hospital, Gynecology & Obstetrics, Trabzon (Turkey) Cagri Akin Sekerci, MD, FEBU (Corresponding Author) cagri_sekerci@hotmail.com Trabzon Kanuni Research and Training Hospital, Pediatric Urology, Trabzon (Turkey)

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REFERENCES

1. Schmidt A, Lang U, Kiess W. Epidermal cyst of the clitoris: a rare cause of clitoromrgaly. Eur J Obstet Gynecol Reprod Biol. 1999; 87:163-5. 2. Anderson-Mueller BE, Laudenschlager MD, Hansen KA. Epidermoid cyst of the clitoris: an unusual cause of clitoromegaly in a patient without history of previous female circumcision. J Pediatr Adolesc Gynecol. 2009; 22:e130-2. 3. Lee HS, Joo KB, Song HT, et al. Relationship between sonographic and pathologic findings in epidermal inclusion cysts. J Clin Ultrasound. 2001; 29:374-83. 4. Al-Ojaimi EH, Abdulla MM. Giant epidermoid inclusion cyst of the clitoris mimicking clitoromegaly. J Low Genit Tract Dis. 2013; 17:58-60.

Cop june ok_Layout 1 04/07/19 09:35 Pagina 2

INSTRUCTIONS Official Journal of SIA, SIEUN, UrOP and GUN EDITORIAL BOARD EDITOR

CHIEF

Alberto Trinchieri (Milan, Italy)

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

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

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

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

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

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Archivio Italiano di Urologia e Andrologia / Archives of Italian Urology and Andrology - Vol. 91; n. 2 June 2019

Vol. 91; n. 2, June 2019

ORIGINAL PAPERS 69

Increased neutrophil/lymphocyte ratio in testicular cancer Aytaç Şahin, Tuncay Toprak, Musab Ali Kutluhan, Yasin Vural, Ahmet Ürkmez, Ayhan Verit

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107