"Archivio Italiano di Urologia e Andrologia" - Vol. 90 - n. 3 - 2018

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1° CONGRESSO NAZIONALE

s es i t c .

Ac i u a n a e .

Op www

ISSN 1124-3562

Vol. 90; n. 3, September 2018

9-10

NOVEMBRE 2018 FRASCATI (ROMA)

Poste Italiane S.p.A. - Spedizione in abbonamento postale - D.L. 353/2003 (conv. in L. 27/02/2004 n. 46) Art. 1, comma 1 DCB Milano

Archivio Italiano di Urologia e Andrologia / Archives of Italian Urology and Andrology - Vol. 90; n. 3 September 2018

ORIGINAL PAPERS 149

Safety and efficacy of PNL vs RIRS in the management of stones located in horseshoe kidneys: A critical comparative evaluation Bilal Eryildirim, Eyup Veli Kucuk, Gokhan Atis, Metin Ozturk, Temucin Senkul, Murat Tuncer, Ahmet Tahra, Turgay Turan, Orhan Koca, Ferhat Ates, Omer Yilmaz, Cenk Gurbuz, Kemal Sarica

155

The new Avicenna Roboflex: How does the irrigation system work? Results from an in vitro experiment Salvatore Butticè, Bahadir Sahin, Tarik Emre Sener, Laurian Dragos, Silvia Proietti, Steeve Doizi, Olivier Traxer

159

Do dental calculi predict the presence of renal stones?

163

Role of the gonadal vessels on the stone lodgment in the proximal ureter: Direct observation during laparoscopic ureterolithotomy

̧ iftçi Bulent Kati, Ergin Kalkan, Eyyup Sabri Pelit, Ismail Yagmur, Halil C

Mohammad Hadi Radfar, Reza Valipour, Behzad Narouie, Mehdi Sotoudeh, Hamid Pakmanesh

166

Ultrasound follow up: Is an undetected spontaneous expulsion of stone fragments a sign of extracorporeal shock wave treatment failure in kidney stones?

Grazia Bianchi, Diego Marega, Roberto Knez, Stefano Bucci, Carlo Trombetta

169

Comparison of an electromagnetic and an electrohydraulic lithotripter: Efficacy, pain and complications Grazia Bianchi, Diego Marega, Roberto Knez, Stefano Bucci, Carlo Trombetta

172

Effect of variant histology presence and squamous differentiation on oncological results and patient’s survival after radical cystectomy Ertugrul Sefik, Serdar Celik, Ismail Basmaci, Serkan Yarımoglu, Ibrahim Halil Bozkurt, Tarık Yonguc, Bulent Gunlusoy

176

Feasibility study for interspecialistic collaboration in active research of urothelial neoplasms of professional origin Roberta Stopponi, Enrico Caraceni, Angelo Marronaro, Andrea Fabiani, Stefania Massacesi, Anna Rita Totò, Roberto Calisti

181

Association between large prostate calculi and prostate cancer Cem Yucel, Salih Budak

184

Diabetes mellitus and prostate cancer metabolism: Is there a relationship?

Hugo Pontes Antunes, Ricardo Teixo, João André Carvalho, Miguel Eliseu, Inês Marques, Ana Mamede, Rita Neves, Rui Oliveira, Edgar Tavares-da-Silva, Belmiro Parada, Ana Margarida Abrantes, Arnaldo Figueiredo, Maria Filomena Botelho

191

Prognostic value of subclassification (pT2 stage) of pathologically organ-confined prostate cancer: Confirmation of the changes introduced in the 8th edition of the American Joint Committee on Cancer (AJCC) staging system Hugo Pontes Antunes, Belmiro Parada, João Carvalho, Miguel Eliseu, Roberto Jarimba, Rui Oliveira, Edgar Tavares-da-Silva, Arnaldo Figueiredo continued on page III

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Congresso Nazionale Urop Grand Hotel la Chiusa di Chietri - Alberobello (BA) 6 - 8 Giugno 2019 Presidente del Congresso

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Ed _Cop+Ed+fisse 2006 04/10/18 11:28 Pagina I

Official Journal of SIA, SIEUN, SIUrO and UrOP EDITORS

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ASSOCIAZIONE UROLOGI LOMBARDI EDITOR E. Montanari (Milano)

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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.

I PROSSIMI APPUNTAMENTI SIEUN La SIEUN nel 2018 sarà presente con relazioni, moderazioni e letture nei congressi delle più prestigiose Società scientifiche di Urologia, Andrologia ed Ecografia.

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XXVII CONGRESSO NAZIONALE SIUMB 2018 Napoli, Centro Congressi Stazione Marittima, 17-20 novembre 2018

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CENTRE

è a disposizione per ulteriori informazioni.

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ORIGINAL PAPERS 195

Intraoperative ultrasound in robot-assisted partial nephrectomy: State of the art Giacomo Di Cosmo, Enrica Verzotti, Tommaso Silvestri, Andrea Lissiani, Roberto Knez, Nicola Pavan, Michele Rizzo, Carlo Trombetta, Giovanni Liguori

199

Serenoa repens extracts: In vitro study of the 5α-reductase activity in a co-culture model for Benign Prostatic Hyperplasia Daniela Buonocore, Manuela Verri, Laura Cattaneo, Sara Arnica, Michele Ghitti, Maurizia Dossena

203

Hibiscus extract, vegetable proteases and Commiphora myrrha are useful to prevent symptomatic UTI episode in patients affected by recurrent uncomplicated urinary tract infections Tommaso Cai, Daniele Tiscione, Andrea Cocci, Marco Puglisi, Gianmartin Cito, Gianni Malossini, Alessandro Palmieri

208

Adolescence and andrologist: An imperfect couple Soraya Olana, Rossella Mazzilli, Michele Delfino, Virginia Zamponi, Cristina Iorio, Fernando Mazzilli

CASE REPORTS 212

Malignant mesothelioma of tunica vaginalis testis: Report of a very rare case with review of the literature Emanuela Trenti, Salvatore Mario Palermo, Carolina D'Elia, Evi Comploj, Alexander Pycha, Rodolfo Carella, Armin Pycha

215

A rare complication of ureteral stenting: Case report of a uretero-arterial fistula and revision of the literature Alois Mahlknecht, Leonardo Bizzotto, Christoph Gamper, Anton Wieser

218

Selective arterial embolization for a high-flow priapism following perineal trauma in a young gymnast Grazia Bianchi, Camilla Sachs, Irene Campo, Giovanni Liguori, Carlo Trombetta

220

Management of self-inflicted orchiectomy in psychiatric patient.

Case report and non-systematic review of the literature Marco Garofalo, Alessandro Colella, Paolo Sadini, Lorenzo Bianchi, Giacomo Saraceni, Eugenio Brunocilla, Giorgio Gentile, Fulvio Colombo

224

Primary melanoma of the bladder: Case report and review of the literature Francesco Barillaro, Marco Camilli, Paolo Dessanti, Nader Gorji, Fabio Chiesa, Alessandro Villa, Alessandro Pastorino, Carlo Aschele, Enrico Conti

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DOI: 10.4081/aiua.2018.3.149

ORIGINAL PAPER

Safety and efficacy of PNL vs RIRS in the management of stones located in horseshoe kidneys: A critical comparative evaluation Bilal Eryildirim 1, Eyup Veli Kucuk 2, Gokhan Atis 3, Metin Ozturk 4, Temucin Senkul 5, Murat Tuncer 1, Ahmet Tahra 2, Turgay Turan 3, Orhan Koca 4, Ferhat Ates 5, Omer Yilmaz 5, Cenk Gurbuz 6, Kemal Sarica

7

1 Health

Sciences University, Dr. LĂźtfi Kirdar Training and Research Hospital, Urology Clinic, Istanbul, Turkey; Sciences University, Umraniye Training and Research Hospital, Urology Clinic, !stanbul, Turkey; 3 Istanbul Medeniyet University, Goztepe Training and Research Hospital, Urology Clinic, Istanbul, Turkey; 4 Health Sciences University, Haydarpasa Numune Training and Research Hospital, Urology Clinic, Istanbul, Turkey; 5 Health Sciences University, Sultan Abdulhamid Han Training and Research Hospital, Urology Clinic, Istanbul, Turkey; 6 Medistate Hospital, Urology Department, Istanbul, Turkey; 7 Kafkas University, Faculty of Medicine, Urology Department.

2 Health

Summary

Aim: To assess the efficacy and safety of two different techniques (Percutaneous nephrolithotomy (PNL) vs Retrograde intrarenal surgery (RIRS)) in the management of stones in patients with horseshoe kidneys (HSK).

Patients and methods: Departmental files of 88 cases with radiopaque kidney stones in horseshoe kidneys undergoing two different approaches (PNL vs RIRS) were evaluated with respect to the success and complication rates of in a retrospective manner. In addition to the factors related with the procedures (success and complication rates, additional procedures), patient and stone characteristics were all well evaluated.

Findings obtained in both groups were evaluated in a comparative manner with respect to the statistical significance.

Results: Stone free rates were comparable in both groups after 1-week period (81.6% PNL vs 80% RIRS). As well as 3 months evaluation (84.2% PNL and 82.0% RIRS). The percentage of the cases with residual fragments (> 4 mm) were similar in both groups and while all PNL procedures were completed in one session, mean number of RIRS sessions was higher (1.22 Âą 0.05). Mean duration of the procedure was slightly higher in RIRS group and based on Clavien scoring system, despite a higher risk of Hb drop noted in patients treated with PNL, all complication rates were found to be similar in both groups.

Conclusion: Our results demonstrate that of the available minimally invasive treatment alternatives, both PNL and RIRS could be safe and effective alternatives for renal stone removal in patients with HSK.

KEY WORDS: Horseshoe kidney; Percutaneous nephrolithotomy; Retrograde intrarenal surgery; Renal stone; Ureteroscopy.

Submitted 8 March 2018; Accepted 29 April 2018

INTRODUCTION

Being observed in approximately 1 in 400 to 1 in 666 births, horseshoe kidney (HSK) is the most common renal fusion anomaly (1, 2). Anterior displacement of the renal pelvis and high insertion of the involved ureter cause urinary abnormal drainage with flow hinderance and

urinary stasis in the collecting system which may result in stone formation (1). The reported incidence of urolithiasis in patients with HSK varies between 20% to 60% in different series (3, 4).

On the other hand again, abnormal position of the kidney due to congenital fusion abnormality and unusual course of the ureter over the isthmus bring the management of stones in such kidneys into more challenging position. Although open surgery has been performed commonly in the past, currently all available minimal invasive treatment alternatives such as extracorporeal shock wave lithotripsy (SWL), retrograde intrarenal surgery (RIRS) and percutaneous nephrolithotripsy (PNL) are being performed with varying success rates (4).

Of these alternatives although SWL has been performed as a practical and well tolerated procedure by the majority of cases, success rates in such patients are highly variable and stone free rates (SFR) of 31-100% were reported in the literature (5-8). Although adequate fragmentation can be achieved by SWL, the anatomic abnormalities may prevent fragment passage in a substantial number of these patients.

As a second alternative, PNL has already been found to be efficient in the management of relatively large stones cases with HSK with varying success rates. Due to the relatively lower position of the kidneys most upper as well as mid renal calyces are found to be located below the twelfth rib, thereby making the supracostal puncture relatively safe in these patients. However, despite the higher success rates obtained, the invasive nature of this method and higher risk of major complications (complication rates 14.3-29.2%) led the endourologists to look for more feasible and less invasive options. Stone clearance rates after PNL in series with relatively limited number of renal units have been reported to be 7587.5% (3, 9, 10).

Last but not least, retrograde intrarenal surgery by using flexible ureterorenoscope has also been shown to be an effective management option; the success rate and associ-

No conflict of interest declared.

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149

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B. Eryildirim, E.V. Kucuk, G. Atis, M. Ozturk, T. Senkul, M. Tuncer, A. Tahra, T. Turan, O. Koca, F. Ates, O. Yilmaz, C. Gurbuz, K. Sarica

ated complications of this method have not been well documented in such patients. Despite acceptable stone free rates reported in some trials with relatively limited number of cases, due to the anatomical abnormality, a second look is usually required to render the patient completely stone free. A recent review article focusing on the management of renal stones in HSK demonstrated that RIRS may provide acceptable stone free rates (78%) (11).

In this present study we aimed to evaluate the clinical efficacy of two different approaches, RIRS combined with holmium laser lithotripter and PNL, in treating renal calculi in horseshoe kidney.

PATIENTS

the last session of PNL and RIRS with KUB and/or urinary system USG to check the degree of stone fragmentation and the presence of obstruction (hydronephrosis) if present. The ultimate success rates were defined as no stone detectable or the presence of fragments < 4 mm on low dose non-contrast CT imaging for all patients.

Statistical Analysis: The Prism 5.0 (GraphPad Software, San Diego, CA) was used for the statistical analysis. Data are presented as mean standard error of mean. Studentâ&#x20AC;&#x2122;s t test was used for both comparison of descriptive statistical methods and evaluation of quantitative data and chi-square test were used to compare the qualitative data between two groups; p < 0.05 was consider significant.

AND METHODS

The medical records of 88 cases with radiopaque renal RESULTS stones in horseshoe kidneys treated with two different Departmental files of 88 cases with kidney stones in types of procedures (PNL vs RIRS) in 7 different centers horseshoe kidneys (56 male and 32 female (M/F: 1.75) between 2007 and 2016 were reviewed. Study protocol undergoing two different approaches (PNL vs RIRS) were was approved by the Ethics Committee of the Hospital. All evaluated with respect to the success and complication steps of the study were planned and applied carefully rates of each procedure in a retrospective manner. While according to Helsinki Declaration. the age of the cases ranged from 19 to 60 years (mean Depending on the type of the procedure applied, cases 41.161.25); the overall mean size of the stones were with horseshoe kidneys were divided into two different 20.590.75 mm (7-42 mm). Patients and stone related groups; in Group 1 (n = 38) cases were treated with PNL factors are summarized in Table 1. and in Group 2 (n = 50) cases were treated with RIRS. All PNL procedures were completed in one session, but All treatment related parameters (stone free rates, numthe mean number the sessions for cases undergoing RIRS ber of sessions, treatment duration, hospitalization time, was 1.220.05 (p = 0.0064). Although mean duration presence of the residual fragments, complications as well of the procedure was slightly longer in RIRS group as the need for additional interventions) were noted and (p = 0.9075), mean radiation exposure time was higher evaluated between two groups in a comparative manner. in PNL group when compared cases undergoing RIRS Preoperative evaluation (p < 0.0001). On the other hand, while the mean duraPrior to the above mentioned procedures, in addition to tion of hospital stay was 3.150.24 days (1-10) in patients the preoperative laboratory tests including urinalysis, undergoing PNL procedure; this value was 1.580.20 renal functional parameters, complete blood count and days (1 to 7) in RIRS group (p < 0.0001) (Table 2). prothrombin concentration, urine culture and sensitivity While a nephrostomy tube (14 F) has been placed in 36 test was performed in all patients with pyuria. Patients cases (94.7%) after the PNL procedure, a double J stent with urinary tract infection (UTI) were treated before the was inserted in 42 of 50 cases undergoing RIRS proceprocedure with an appropriate antibiotic regimen. All dure (84.0%). Evaluation of the degree of hydronephropatients were given prophylactic antibiotics at the time of sis revealed a mean value of 2.050.14 dilatation in Group anesthesia induction.

1 and 1.460.16 in Group 2, there was a statistically sigIn addition to kidney-ureter-bladder (KUB) and urinary sysnificant difference on this aspect (p = 0.0087). tem ultrasonography (USG), a non-contrast abdominopelvic computed tomograTable 1. phy (NCCT) were performed for radioEvaluation of patient and stone characteristics in both groups. logic evaluation. NCCT was also applied to assess the final stone free Overall Group 1 (PNL) Group 2 (RIRS) P* rates after 3-months and/or when there n = 88 n = 38 n = 50 is any suspicion for residual fragments.

Age (year) 41.161.25 42.970.87 39.781.68 0.1434 Both procedures were performed BMI (kg/m2) 28.270.42 29.150.59 27.600.56 0.0643 under general anesthesia, a prone posiStone size (mm) 20.590.75 21.551.14 19.460.56 0.4638 tion was used for PNL and RIRS proceHU (Hounsfield unit) 97123.46 95734.29 98226.31 0.5496 dures were performed in lithotomy Degree of hydronephrosis (grade) 1.720.11 2.050.14 1.460.16 0.0087 position. While the stone disintegraStone location; n, (%) tion was performed with Ho-YAG laser Renal pelvis 30 (34.1) 12 (31.6) 18 (36.0) 0.8208 during RIRS, all stones were fragmentUpper calyx 8 (9.1) 3 (7.9) 5 (10.0) 1.0000 ed by using pneumatic lithotriptor during PNL. Middle calyx 9 (10.2) 3 (7.9) 6 (12.0) 0.7263 Postoperative evaluation Success rates in all patients were evaluated one week and 3 months after

150

Lower calyx Multiple calyces

22 (25.0) 19 (21.6)

9 (23.7) 11 (28.9)

13 (26.0) 8 (16.0)

1.0000 0.1923

* Comparison between Group 1 and Group 2.

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PNL vs RIRS in the management of stones located in horseshoe kidney

Table 2.

Evaluation of the outcomes of the procedures in terms of success rates as well as early post-operative follow-up data.

Mean duration of the procedure (min) Mean number of sessions Stone free rate; n, (%) 1. Week 3. Month Residual stone > 4 mm n, (%) Mean fluoroscopy time (sec.)

Mean drop in hb levels (g/dL) Mean hospital stay (day) Auxiliary procedures; n, (%)

Overall

Group 1 (PNL)

n = 88 77.3 42.71 1.11 0.03

n = 38 75.8 42.64 1.00 0.0

Group 2 (RIRS) n = 50 80.2 65.13 1.22 0.07

0.9075 0.0064

71 (80.7) 73 (82.9) 12 (13.6) 30.8 05.40 0.74 0.10 2.46 0.12 6 (6.8)

31 (81.6) 32 (84.2) 5 (13.2) 69.2 49.43 1.55 0.15 3.15 0.24 3 (7.9)

40 (80.0) 41 (82.0) 7 (14.0) 20.6 21.81 0.13 0.07 1.58 0.20 3 (6.0)

0.7886 0.7820 0.7559 < 0.0001 < 0.0001 < 0.0001 1.0000

the larger residual fragments ( > 4 mm) in 7 cases of RIRS group, although 1 case did pass the fragment spontaneously, fragments passed into the ureter in 3 cases and were removed again with URS during 3-months follow-up period. A double J stent was again inserted in only 1 of these 3 cases prior to URS due to the obstruction induced by ureteral stones.

PNL was unsucessful in 2 cases due to the difficulty in accessing the stones (5.3%) and RIRS was performed in these cases. On the other hand, RIRS was unsuccessful in 3 cases (6.0%) because of the difficulty in accessing to the lower pole. A mini-PNL was performed in all these 3 cases with successful stone removal. All these cases were excluded from the study program and were not included in any of these groups (Table 2).

P*

* Comparison between Group 1 and Group 2.

Table 3.

Evaluation of the type and grade of complications according to modified Clavien classification in both groups.as early post-operative follow-up data.

Gradecomplication 1

2 3a 3b

Fever > 38 0C; n, (%) Hemorrhage/hematuria not requiring blood transfusion; n, (%) Hemorrhage/hematuria requiring blood transfusion; n, (%) Double J stent placement for ureteral stone; n, (%) Endoscopic treatment for ureteral stone; n, (%)

Overall Group 1 (PNL) Group 2 (RIRS) n = 88 n = 38 n = 50 14 (15.9) 6 (15.8) 8 (16.0) 8 (9.0)

5 (1.8)

4 (4.5) 3 (3.4)

3 (7.9) 2 (5.2)

6 (6.8)

3 (7.9)

* Comparison between Group 1 and Group 2.

Evaluation of the results obtained with two different techniques revealed following findings.

Evaluation of the success as well as auxiliary procedure rates The overall percentage of the cases with no stones detectable or demonstrating fragments < 4 mm after one week period was 80.7% and the stone free rates were comparable in both groups after 1-week period (81.6% for PNL group and 80.0% for RIRS group, p = 0.7886).

This was also true during post-operative 3 months evaluation period where 84.2% of cases treated with PNL were stone free when compared with the cases undergoing RIRS procedure (82.0%) (p = 0.7820).

Evaluation of the residual fragments (RF) sizing > 4 mm demonstrated that 5 cases (13.2%) in PNL group; 7 cases in RIRS group (14.0%) had such larger residual fragments during early (1-week) follow-up evaluation.

During the 3-months follow-up period while 1 case in PNL group passed these fragments spontaneously, fragments passed into the ureter in the other 3 cases. A JJ stent have already been inserted in 2 of these 3 cases due to the severe obstruction. Fragments were removed with URS in these 3 cases. 1 case was asmptomatic with RF requiring no intervention. On the other hand, regarding

P*

Evaluation of complication rates All complications observed in both 0.2274 groups were classified by using modified Clavien scoring system (12).

3 (3.6) Based on this classification, while 11 cases (28.9%) in PNL group demon1 (2.0) 0.3113 strated grade 1 complications, this 1 (2.0) number was again 11 (22.0%) in RIRS 0.4916 group (p = 0.2274). Regarding these complications, although fever after the 3 (6.0) procedures were noted in a total of 14 cases in both groups (6 in PNL and 8 in RIRS group) none of these cases demonstrated sepsis during follow-up.

Morover, regarding the grade 3 complications while 5 cases in PNL group did show such complications, 4 cases in RIRS group had this kind of complications (p = 0.4916) (Table 3). Although evaluation of the rate of hemoglobin drop in both groups showed a statistically significant difference between two groups in (p < 0.0001); 3 cases in PNL group and 1 case in RIRS group required blood transfusion (p = 0.3113) without any significant difference between two groups. No severe (Grade IV-V) complication was noted in any case. Last but not least stone street formation due to the fragment passage into the ureter has been observed in 1 case undergoing PNL in whom a double J stent placement and ureteroscopic stone removal have been performed.

DISCUSSION

Representing the most common congenital renal fusion anomaly; HSK is mainly associated with the abnormal position of the kidney associated with the unusual course of upper ureter over the isthmus (2). Published data and clinical experience have clearly shown that these anatomical abnormalities cause impaired renal pelvic drainage due to ureteropelvic junction obstruction and resultant hydronephrosis may cause not only with Archivio Italiano di Urologia e Andrologia 2018; 90, 3

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stone formation but also makes the stone removal procedures more challenging.

Concerning the stone management principles in these patients, all available minimally invasive stone removal procedures namely SWL, PNL and RIRS have been applied as with varying stone-free rates in these patients.

Although limited, published data so far has demonstrated that while altered pyelocalyceal system anatomy and high ureteropelvic junction position may lead to relatively poor results of SWL and RIRS; similar to the kidneys with normal anatomy, PNL has been reported as an efficient treatment modality for stones located in HSK (13, 14).

Related with this issue, as a non-invasive and safe alternative, although SWL has been well tolerated by the majority of patients, stone-free rates have been reported to be significantly lower after this procedure. When compared with the patients demonstrating normal kidneys, lower efficiency of this approach could be well explained with some certain factors such as greater skin-to-stone distance (particularly for calyceal stones) value and of more importantly restricted urinary drainage. However, despite the lower stone free rates reported to be changing between 31-100% (5-8), higher risk of complications associated with PNL performed for relatively large stones in HSK (14.3-29.2%) make SWL also RIRS more feasible and safe options in selected cases (3, 9, 10).

On the other hand again, developments in instruments technology and increasing experience in minimally invasive management of stones have changed the treatment concepts of urinary calculi meaningfully over the past two decades. As a result, PNL has become the standard of care for the treatment of large (> 2 cm) stones with its evidently higher stone free rates in a single session (15, 16). However, it is well-known that these higher stonefree rates are being obtained at the expense of some certain severe complications (16).

In the light of the evident lower stone free rates after SWL due to the certain factors mentioned above however, accumulated data so far clearly demonstrate that PNL may constitute a preferred alternative in cases with HSK in experienced hands (3, 17).

Related with this issue, clinical experience showed that while access to the upper pole calyces during PNL often requires a supracostal approach with the associated risk of pleural injury in patients with normal renal anatomy, due to the relatively lower level of the upper pole, a supracostal puncture appears to be relatively safe in these kidneys. Access through the lower pole are not usually recommended due to the posterior location of these calyces. Furthermore, upper-pole access in HSK allows the surgeon to remove all stone burden in one session, as the alignment of the nephroscope with the long axis of the kidney aids manipulation of the scope into the upper calyces, renal pelvis, lower calyces, UPJ (ureteropelvic junction) and proximal ureter in a practical and safe manner. However, as mentined above despite the higher success rates obtained, the complicated nature of this method and higher risk of major complications led the endourologists to look for more feasible and less invasive options (3, 9, 10).

Evaluation of the literature with respect to the success as

152

well as complications rates of PNL reported in HSK demonstrated varying rates in studies with limited number of cases. In a single session operation using only one tract without any flexible nephroscope, Etemadian M. et al. have reported a stone free rate of 71.4% with a transfusion rate of 4.76% being encountered only in 1 patient (18). In their original study again, El Ghoneimy MN et al. treated 21 HSK renal units bearing a single pelvic stone in 52% of the cases and a staghorn calculi in 14% of the cases and 85.7% of the cases were stone free after the procedure with negligible complications (19). In a study of 24 cases with HSK again, Raj et al. performed upperpole access in the majority of the cases (63%) and reported only one pneumothorax formation. They were also able to note that the use of flexible nephroscope was usually required for a satisfactory stone clearance rate, given as 87.5% (3). Last but not least, in relatively larger series of cases Symons SJ et al. treated stones in 47 cases with HSK and demonstrated that the number of PNL sessions required for stone free status depended on both the stone configuration and the size as well. PNL was used in 60 renal units of 47 patients with a clearance rate of 77% at one session and while 12 (71%) of the 17 patients demonstrating multiple stones were stone-free in one session; 30 (86%) out of 35 with neither multiple nor staghorn stones were completely stone free (10).

An alternative to the percutaneous approaches in these cases is flexible ureteroscopy, also referred to as RIRS that has been basically used to treat the lower pole stones resistant to SWL (20). As a result of increasing experience, relatively larger renal stones have also been treated with this approach and first serie of RIRS in HSK patients was published in 2005 where a stone clearance was achieved in 3 of the 4 patients (21). Following this publication, in their original study Molimard et al. treated 17 patients with HSK and 15 patients (88.2%) with mean stone size of 16 mm were stone free in one session.

The success rate was comparable to PNL and better than SWL studies with no major complications and 7 (41.2%) patients required more than one session of RIRS (22).

In another study, 25 renal stones in 20 patients were treated with RIRS and a SFR of 70% was reported. The authors found the success rates comparable with PCNL and better than SWL with the advantage of lower complication rates (23).

Currently RIRS and holmium - YAG laser lithotripsy is being increasingly used in the treatment of stone disease particularly in HSK patients. SFR of RIRS in the management of HSK patients were reported to be 70% and 88.2 % in the two recently published studies (22, 23). As mentioned above altered orientation of the calyces and high insertion of the ureter coupled with the increased likelihood of UPJ obstruction, endourologits may face evident technical difficulties during RIRS procedure in these cases.

In a relatively higher number of cases with HSK patients (32 stones in 23 patients) undergoing RIRS, Gokce IM et al. reported a SFR of 73.9% with acceptable and comparable complication rates (4 of the 23 patients) with previously published series (24).

With the advancement of technology, smaller activelydeflectable flexible ureteroscopy (f-URS), equipped with

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PNL vs RIRS in the management of stones located in horseshoe kidney

holmium laser lithotripter and nitinol baskets or graspers increased the effectiveness of RIRS in terms of stone-free rates.

In this present study we mainly aimed to assess the efficacy and safety of two different techniques (PNL vs RIRS) in the management of renal stones in patients with horseshoe kidneys. To our knowledge our study is the first one comparing the efficacy of two different valuable alternatives in the management of renal stones in HSK cases.

Evaluation of our results clearly showed that SFRâ&#x20AC;&#x2122;s were comparable in both groups during 1-week (81.6% vs 80.0%) as well as post-operative 3 months evaluation period. The rate of larger residual fragments (> 4 mm) were again similar in both groups. However, while all PNL procedures were completed in a single session, mean number the sessions for cases undergoing RIRS was higher than PCNL group (1.220.05). Mean duration of the procedure was slightly longer in RIRS group when compared with PNL group. Regarding the mean degree of hydronephrosis in both groups, there was a statistically significant difference in favour of cases undergoing PNL and this could be best explained by the preference of the surgeons for PNL in kidneys with relatively higher degree of dilatation. Last but not least regarding the complications as evaluated on the basis of modified Clavien scoring system although they were similar in both groups; evaluation of mean fluoroscopy time as well as mean Hb drop rate in both groups clearly revealed them to be higher in cases undergoing PNL procedure.

In the light of our findings and the reported literature data as well, we may say that both PNL and RIRS procedures are equally effective treatment alternatives in the management of renal stones in patients with HSK. Although majority of the patients were stone free after a single session of PNL, taking the more invasive nature of this approach with certain complications (bleeding, extravasation), we believe that RIRS may prove itself a valuable alternative with comparable stone free rates despite possible repeated sessions. Morover, higher risk of radiation exposure as demonstrated in our cases may be another disadvantage of PNL. Depending on the experience of the surgeon and the availability of these systems, best management plan could be made in an individualized basis by considering the patient as well as stone related factors.

The major limitation of the current study may be the retrospective nature of our trial and the lack of randomization. Additionally management of the cases by 7 different surgeons with variable level of experience could constitute another drawback. However, taking the limited number of studies in small series of cases available in the literature, we believe that as the first trial on this subject comparing RIRS vs PCNL in renal stone cases with HSK into account, our findings will be contributive enough to the existing literature.

CONCLUSIONS

Management of renal stones could be challenging depending on the anatomy as well as stone related fac-

tors. Of the available minimally invasive treatment alternatives, in the light of the lower stone free rates with SWL reported in the published data; both PNL and RIRS could be safe and effective alternatives for renal stone removal in patients with HSK. However, we belive that a proper plan could be instituted by considering the experience of the surgeon and availability of the technical equipment. Further studies with larger series of cases focusing on the comparative evaluation of both procedures are certainly needed.

REFERENCES

1. Bauer S. Anomalies of the upper urinary tract. In: Walsh PC, Retic AB, Vaughan ED, et al. ed. Campbellâ&#x20AC;&#x2122;s Urology, 8th ed.

Philadelphia: Elsevier Saunders. 2002.

2. Weizer AZ, Silverstein AD, Auge BK, et al. Determining the incidence of horseshoe kidney from radiographic data at a single institution. J Urol. 2003; 170:1722-6.

3. Raj GV, Auge BK, Weizer AZ, et al. Percutaneous management of calculi within horseshoe kidneys. J Urol. 2003; 170:48-51.

4. Yohannes P, Smith AD. The endourological management of complications associated with horseshoe kidney. J Urol. 2002; 168:5-8.

5. Demirkesen O, Yaycioglu O, Onal B, et al. Extracorporeal shockwave lithotripsy for stones in abnormal urinary tracts: analysis of results and comparison with normal urinary tracts. J Endourol.

2001; 15:681-5.

6. Kirkali Z, Esen AA, Mungan MU. Effectiveness of extracorporeal shockwave lithotripsy in the management of stone-bearing horseshoe kidneys. J Endourol. 1996; 10:13-5.

7. Sheir KZ, Madbouly K, Elsobky E, et al. Extracorporeal shock wave lithotripsy in anomalous kidneys: 11-year experience with two second-generation lithotripters. Urology. 2003; 62:10-5.

8. Viola D, Anagnostou T, Thompson TJ, et al. Sixteen years of experience with stone management in horseshoe kidneys. Urol Int. 2007; 78:214-8.

9. Miller NL, Matlaga BR, Handa SE, et al. The presence of horseshoe kidney does not affect the outcome of percutaneous nephrolithotomy. J Endourol. 2008; 22:1219-25.

10. Symons SJ, Ramachandran A, Kurien A, et al. Urolithiasis in the horseshoe kidney: a single-centre experience. BJU Int. 2008; 102:1676-80.

11. Ishii H, Rai B, Traxer O, et al. Outcome of ureteroscopy for stone disease in patients with horseshoe kidney: Review of world literature. Urology Annals. 2015; 7:470-4.

12. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004; 240:205-13.

13. Stening SG, Bourne S. Supracostal percutaneous nephrolithotomy for upper pole caliceal calculi. J Endourol. 1998; 12:359-62.

14. Skolarikos A, Binbay M, Bisas A, et al. Percutaneous nephrolithotomy in horseshoe kidneys: factors affecting stone- free rate. J Urol. 2011; 186:1894-8.

15. Turk C, Knoll T, Petrik A, et al. Guidelines on urolithiasis.

European Urological Association Web site. http://www.uroweb. org/gls/pdf/ 22%20Urolithiasis_LR.pdf. Updated 2014.

16. de la Rosette JJ, Opondo D, Daels FPJ, et al. Categorisation of Archivio Italiano di Urologia e Andrologia 2018; 90, 3

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21. Weizer AZ, Springhart WP, Ekeruo WO, et al. Ureteroscopic management of renal calculi in anomalous kidneys. Urology. 2005; 65:265-9.

complications and validation of the Clavien score for percutaneous nephrolithotomy. Eur Urol. 2012; 62:246-55.

17. Al-Otaibi K, Hosking DH. Percutaneous stone removal in horseshoe kidneys. J Urol. 1999; 162:674-7.

22. Molimard B, Al-Qahtani S, Lakmichi A, et al. Flexible ureterorenoscopy with holmium laser in horseshoe kidneys. Urology.

2010; 76:1334-7.

18. Etemadian M, Maghsoudi R, Abdollahpour V, et al.

Percutaneous nephrolithotomy in horseshoe kidney: our 5-year experience. Urology Journal. 2013; 10:856-60.

23. Atis G, Resorlu B, Gurbuz C, et al. Retrograde intrarenal surgery in patients with horseshoe kidneys. Urolithiasis. 2013; 41:79-83.

19. El Ghoneimy MN, Kodera AS, Emran AM, et al. Percutaneous nephrolithotomy in horseshoe kidneys: is rigid nephroscopy sufficient tool for complete clearance? A case series study. BMC Urol. 2009; 9:17.

24. Gokce IM, TokatlÄą Z, Suer E, et al. Comparison of shock wave lithotripsy (SWL) and retrograde intrarenal surgery (RIRS) for treatment of stone disease in horseshoe kidney patients. IBJU. 2016; 42:96-100.

20. Grasso M, Ficazzola M. Retrograde ureteropyeloscopy for lower pole caliceal calculi. J Urol. 1999; 162:1904-8.

Correspondence Bilal Eryildirim, MD Associate Professor bilaleryildirim@yahoo.com Tuncer M, MD Health Sciences University, Dr. LĂźtfi Kirdar Training and Research Hospital, Urology Clinic, Tecerdagi Cad. Yakutlar Sitesi G/11 - Kartal/Istanbul, Turkey Kucuk EV, MD Tahra A, MD Health Sciences University, Umraniye Training and Research Hospital, Urology Clinic, !stanbul, Turkey Atis G, MD Turan T, MD Istanbul Medeniyet University, Goztepe Training and Research Hospital, Urology Clinic, Istanbul, Turkey Ozturk M, MD Koca O, MD Health Sciences University, Haydarpasa Numune Training and Research Hospital, Urology Clinic, Istanbul, Turkey Senkul T, MD Ates F, MD Yilmaz O, MD Health Sciences University, Sultan Abdulhamid Han Training and Research Hospital, Urology Clinic, Istanbul, Turkey Gurbuz C, MD Medistate Hospital, Urology Department, Istanbul, Turkey Sarica K, MD Kafkas University, Faculty of Medicine, Urology Department Kafkas, Turkey

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DOI: 10.4081/aiua.2018.3.155

ORIGINAL PAPER

The new Avicenna Roboflex: How does the irrigation system work? Results from an in vitro experiment Salvatore Butticè 1, 2, 6, Bahadir Sahin 3, Tarik Emre Sener 3, 6, Laurian Dragos 4, 6, Silvia Proietti 5, 6, Steeve Doizi 1, 6, Olivier Traxer 1, 6 1 Pierre

& Marie Curie University, Tenon University Hospital, Paris, France; of Urology, San Giovanni di Dio Hospital, Agrigento, Italy; 3 Department of Urology, School of Medicine, Marmara University, Istanbul, Turkey; 4 Department of Urology, Emergency County Hospital, Pius Branzeu, Timisoara, Romania; 5 Ville Turro Division, Department of Urology, IRCCS, Ospedale San Raffaele, Milan, Italy; 6 Members of PETRA UroGroup, Progress in Endourology, Technology and Research Association.

2 Department

Summary

Introduction: Since 2012 Elmed has been working on a robot specifically designed for flexible ureteroscopy. After the first version of Avicenna Roboflex, a second version was developed in 2015, with significant changes especially in the irrigation system. We consider mandatory for the endourologist that works with the Avicenna Roboflex be aware of the functioning of the irrigation system.

Materials and Methods: We connected a container to the pump’s irrigation system and measured the quantity of saline per second delivered by each speed setting, with/without the flush in five different modalities: pump on its own, pump with ureteroscope, with two laser fibers, with 1.9 Fr basket, and with a Terumo guidewire.

Results: The highest mean flow-rates were observed in the 200micrometer laser fiber, after the pump on its own. Median flowrates for all speed settings were significantly higher for the pump on its own than for the URS in both flushed and nonflushed modes (p = 0.045, p = 0.039 respectively). There was no statistically significant difference in median flow-rates between the guide wire and basket in all of the speed settings (p = 0.932 and p = 0.977). For both laser fibers there was no statistically significant difference between the median flow rate on both nonflush and flush modes. (p = 0.590 & p = 0.590). There was a linear correlation between the speed setting and the increase measured with the flush-option for pump only measurements (r = 0.602, p = 0.038). There was no statistically significant difference between laser fibers and the pump on its own on the increase of flow rate with flush mode. (p = 0.443 for the 272micrometer fiber and p = 0.219 for the 200-micrometer fiber).

Conclusion: The irrigation system of the new Avicenna Roboflex is optimized compared to the previous version.

However other more complex studies concerning the live flow/pressure relationship are needed before firm conclusions can be made.

KEY WORDS: Renal stone; Ureteroscopy; Avicenna Roboflex; Irrigation system; Flexible ureteroscopy; Intrarenal flow; Urolithiasis.

Submitted 24 March 2018; Accepted 29 April 2018

INTRODUCTION

Urolithiasis is one of the major issues in healthcare, with an incidence of around 10%, while the use of flexible ureteroscopes has increased exponentially as one of the best treatment options for renal stones (1).

The rapidly growing popularity of flexible ureteroscopy (FURS) has also been sustained by the major companies on the market, which have increased efforts to develop flexible ureteroscopes. Indeed no other endourological device has received more attention or undergone more dynamic changes than these delicate endoscopes (2).

Thus, adaptation of FURS to robotic surgery has been inevitable with all the advancements in technology. In fact, Elmed (Ankara, Turkey) has been working on a robot specifically designed for FURS since 2012 (3).

After the first version of Avicenna Roboflex in 2012, a second version was developed in 2015, with changes to the console, improved ergonomics and with significant changes in the irrigation system. Today the mechanics and electronics of Roboflex has been experienced and published but the precise flow produced by the pump in each of the different speed settings remains somewhat unexplored (4).

In fact, the first version provided 25 different speed options for the irrigation system, whereas the second one provides 12 speeds, with a dramatic change in the dynamics of intra-renal flow (5). For this reasons we consider it mandatory that the endourologists who work with the new Avicenna Roboflex be aware of the pump flow rate for each speed setting.

The irrigation system As mentioned above, the irrigation system is controlled by a 12-speed mechanical pump and can be attached to a regular rod for gravitational irrigation. The entire device is powered electronically and has two small rotors in the front part to which an infusion tube is connected; which is compatible with others on the market or with the included piece (Figure 1) The system is connected to a console with four buttons: one to start and stop, one to increase and another to decrease the flow, and the flush (Figure 2) The “flush” allows a rapid increase in flow for about one second, and is different from other mechanical systems that permit a saline adjustment; the flush can be operated approximately every 2 seconds after it has been activated; a refractory time that varies from 1.5 to 2 seconds by switching from low to high speed.

No conflict of interest declared.

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S. Butticè, B. Sahin, T. Emre Sener, L. Dragos, S. Proietti, S. Doizi, O. Traxer

Figure 1.

The pump of the irrigation system of the new Avicenna Roboflex.

used a T-flow by Rocamed which permits the addition of a manual stream via an integrated pump but the pump was not used in this case. Every measurement was performed 5 times and the mean values were taken for each modality and speed setting (Figure 3).

Figure 3.

Setting of the experiment at Tenon Hospital.

Figure 2.

The console of Avicenna Roboflex, it is possible to note on the bottom right, the part that controls the entire irrigation system electronically.

Statistical analysis Statistical analyses were performed using the original SPSS software, version 22.0 (IBM Corp, NY, USA), with significance set at p < 0.05. Baseline variables were described using means and standard deviations, or medians and minimum, maximum values as appropriate. Mann-Whitney U tests were used to evaluate the difference between quantitative measurements that have non-parametric distribution. Linear correlation between numeric variables that have a non-parametric distribution were evaluated with spearman rank coefficient. Sensitivities, specificities, and predictive values with 95% confidence intervals were calculated.

MATERIALS

RESULTS

AND METHODS

This is an in vitro study in accordance with the Helsinki Declaration, conforms to the Committee on Publication Ethics (COPE) guidelines, and was approved by the Institutional Review Board (IRB) of the University Hospitals in which the study was carried out. The design, analysis, interpretation of data, drafting, and revisions of the study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement as well as the guidelines for reporting observational studies, available through the Enhancing the Quality and Transparency of Health Research (EQUATOR) network (6).

For the study, we connected a container to the pump’s irrigation system and measured the quantity of saline solution per second delivered by each speed setting, both with and without the flush (for 30 seconds for every measurement) in five different modalities: the pump on its own, the pump with ureteroscope (Olympus URF-P5), with two laser fibers (200 and 270 μm by Rocamed), with a 1.9 Fr basket (Dakota by Boston Scientific), and with a 0.018 inch Terumo guidewire attached. The pump was fixed to a rod that is used for regular urological irrigation, at a height of 1.60 meters. As infusion tube, we

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The measured mean flow-rate values for different modalities (sets of instruments) with and without flush-mode are given in Table 1. The measured values indicate that the highest mean flow-rates were observed in the 200micrometer laser fiber, after the pump on its own.

The flow-rates for the 200-micrometer laser fiber were lower in the first four speed-settings than the flow-rates of the ureteroscope (URS). However, after the fourth speedsetting, faster flow rates were measured with the 200micrometer laser fiber. The same pattern applied to the 272-micrometer laser fiber except that faster flow-rates Table 1.

Mean flow rates.

Free pump URS Guidewire Basket 272 mm Laser fiber 200 mm Laser fiber

Without flush 52 33.9 7.8 7.1 38 41.2

With flush 54.9 34.8 8.1 7.7 39.7 42.8

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Avicenna Roboflex: How is the irrigation?

were achieved after the fifth setting instead of the fourth.

Median flow-rates for all speed settings were significantly higher for the pump on its own than for the URS in both flushed and non-flushed modes (p = 0.045, p = 0.039 respectively). There was a 33.97% drop in flowrate for the non-flush mode of the URS compared to the non-flush mode of the pump on its own.

There was no statistically significant difference in median flow-rates between the guide wire and basket in all of the speed settings, although the median flow-rate with the guide wire was slightly higher in both non-flush and flush modes (p = 0.932 and p = 0.977).

The mean decrease during non-flush mode with the guide wire was 87.2% and 81% compared to the pump on its own and the URS respectively. For the basket these drop rates were 88% and 82.1%. Instead, the median rates of increase during flush mode were 0.20 (0.101.20) and 0.30 (0.10-4.00) ml/min for the guide wire and the basket respectively. There was no statistically significant difference between the mean increase in flowrates for flush mode between the basket and the guide wire options (p = 0.378). For both laser fibers there was no statistically significant difference between mean flowrates in all of the speed settings, although the mean flow rate for the 200-micrometer fiber was markedly higher (p = 0.590 & p = 0.590). The mean decreases in nonflush mode were 32.9% and 27.2% compared to the pump on its own for the 272-micrometer and the 200micrometer laser fibers respectively. The decrease in rate compared to the pump on its own was inversely related to the speed setting for both laser fiber groups (Table 2).

Table 2.

Correlation between increase with flush mode and increase in speed setting.

Free pump URS Guidewire Basket 272 mm Laser fiber 200 mm Laser fiber

r 0.602 0.339 0.562 0.504 0.644 0.329

p 0.038 0.282 0.057 0.095 0.024 0.208

r: Spearman correlation coefficient.

There was a linear correlation between the speed setting and the increase measured with the flush-option for pump only measurements (r = 0.602, p = 0.038).

The same correlation was also observed for the 272micrometer laser fiber (p = 0.664, p = 0.024) but not for the other disposables (Figure 4).

With the use of the guide wire, basket, or URS, the median rates of increase for the flush mode were respectively 0.20 (0.10-1.20), 0.30 (0.10-4.00), 0.90 (0.4-1.30) ml/min. These values were significantly lower than the pump on its own which was 1.70 ml/min (0.80-11.90) (p < 0.001 for all three). For both laser fibers, rates of increase for flush mode were respectively 1.50 (0.403.80) and 1.35 (0.60-3.70) ml/min. There was no statistically significant difference between laser fibers and the pump on its own (p = 0.443 for the 272-micrometer fiber and p = 0.219 for the 200-micrometer fiber).

DISCUSSION

The irrigation system is a fundamental component used during FURS because it improves visualization, maintains patency of the urinary tract. Besides, pressurized irrigation is necessary to maintain sufficient distension of the lumen when accessory instruments (baskets, laser fibers, etc.) are passed through a small working channel (2). In a recent study it had been shown that with the use of 273-micrometer laser fiber flow volume decreases 53.7%. Although different sets of laser fibers are used in our study it has been showed that this new irrigation system causes minimal or no loss on flow rate with laser fibers depending on the speed setting preferred by the surgeon (7).

The mechanical irrigation systems that are currently on the market provide a continuous flow that can be integrated manually. This is the first pump on the market that allows for robotic adjustment of the flow whilst increasing it according to the needs of the endourologist.

When comparing the new irrigation system to the older one, it can immediately be seen that the new pump has a more constant flow when switching to a higher speed.

Though the â&#x20AC;&#x153;old pumpâ&#x20AC;? had more than 25 speed settings, it had a difference in flow rate of 8-10 ml/min at intermediate speed settings, which could potentially develop dangerously high intrarenal pressures. For these reasons, in our previous work we advised caution using the pump

Figure 4.

Decrease of flow rate for 272 mm laser fiber and 200 mm laser fiber compared to free pump (r = - 0.979, p = < 0.001 & r = - 0.951, p = < 0.001).

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at intermediate speed settings (5). Although this study does not assess intrarenal pressures, a profile of a safe range of kidney pressure should be developed. The only measurement of pressure using the Avicenna Roboflex was that done by Rassweiler J et al. at WCE 2015 who used an intra-pelvic sensor and reached a maximum pressure of 40 cm H2O (8). However, this pump has an important limitation; during typical FURS the endourologist or assistant who injects saline by manual pump has a pressure feedback, and is able to sense when intrarenal pressure rises.

This depends on subjective feeling and is not scientifically comparable to real intrarenal pressure, but since most centers still do not have a measurement system of renal pressure, the “tactile” sense remains the only means available to the urologist. However, even with feedback on hand, when the operator needs an additional stream and does not have an automated system, they cannot know the quantity of fluid or how fast they are injecting it, into the renal cavity. This situation may result in dangerously unrecognized high intrarenal pressures. This concept is well explained in recent work by Jung et al., who analyzed the intrarenal pressures of 20 patients undergoing FURS, using an 8 ml/min irrigation system and a 20 ml syringe as an additional irrigation system, they showed how intrarenal pressures, on average, reached 35 (± 10) mmHg and how spikes higher than 288 mmHg were not unusual using the syringe (9).

Our study also demonstrates how pump flow logically decreases with the use of higher caliber instruments that occupy the working channel of the ureteroscope.

The results are in concordance with our previous study evaluating the intrarenal pressure changes on a bench model with different instruments inside the ureteroscope (10).

However, the fact that there are no significant differences in flow between the pump on its own and the two fibers helps us understand how the system remains efficient particularly in the fragmentation phase and how, as a result, the flush should be reduced for clearer vision.

As there are no significant differences between the two fibers, the choice could switch to greater fiber size and greater power to break up the tougher stones.

Another advantage of using an automated irrigation system is connected to radiological exposure. In fact, during a standard FURS the operating urologist and the assistant that manages the manual watering system are both exposed to ionizing radiation. With an automated irrigation system instead, the operator is further away from the collimator seated in the console, and during the fragmentation phase when additional flow is often required, the assistant is not necessary since the additional flow is managed directly by the operator through the console.

CONCLUSIONS

The irrigation system of the new Avicenna Roboflex is optimized compared to the previous version, the flows developed with the ureteroscope and its various accessories appear to ensure adequate irrigation and a relatively acceptable pressure volume. However other more complex studies concerning the live flow/pressure relationship are needed before firm conclusions can be made.

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DISCLOSURE

Butticè S, Sahin B, Sener TE, Proietti S, Dragos L, Doizi S: nothing to disclose.

Traxer O: consultant for Coloplast, Rocamed, Olympus, Lumenis, Boston Scientific, Biohealth, EMS.

REFERENCES

1. Rukin NJ, Siddiqui ZA, Chedgy EC, Somani BK. Trends in upper tract stone disease in England: evidence from the hospital episodes statistics database. Urol Int. 2017; 98:391-396.

2. Somani BK, Al-Qahtani SM, de Medina SDG, Traxer O. Outcomes of flexible ureterorenoscopy and laser fragmentation for renal stones: comparison between digital and conventional ureteroscope. Urology. 2013; 82:1017-9.

3. Saglam R, Muslumanoglu AY, Tokatli Z, et al. A new robot for flexible ureteroscopy: development and early clinical results (IDEAL stage 1-2b). Eur Urol. 2014; 66:1092-100.

4. Rassweiler J, Rassweiler MC, Klein J. New technology in ureteroscopy and percutaneous nephrolithotomy. Cur Opin Urol.

2016; 26:95-106.

5. Buttice S, Proietti S, Dragos L, Traxer O. Are you familiar with the flow of the Roboflex Avicenna pump? Allow me to explain. J Endourol. 2017; 31:418-419.

6. von Elm E, Altman DG, Egger M, et al. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Int J Surg.

2014; 12:1495-9.

7. Bach T, Geavlete B, Herrmann T, Gross A. Working tools in flexible ureterorenoscopy—influence on flow and deflection: what does matter? J Endourol. 2008; 22:1639-44.

8. Seo H, Shin S, Jung N, et al. Scientific Program of 34th World Congress of Endourology & SWL Program Book and Abstracts.J Endourol. 2016; 30(S2):P1-A464.

9. Jung H, Osther PJ. Intraluminal pressure profiles during flexible ureterorenoscopy. Springerplus. 2015; 4:373 10. Sener TE, Cloutier J, Villa L, et al. Can we provide low intrarenal pressures with good irrigation flow by decreasing the size of ureteral access sheaths? J Endourol. 2016; 30:49-55.

Correspondence Salvatore Butticè, MD salvobu@gmail.com Department of Urology, San Giovanni di Dio Hospital Contrada Consolida, 92100, Agrigento, Italy Bahadir Sahin, MD drbahadirsahin@gmail.com Tarik Emre Sener, MD dr.emresener@gmail.com Department of Urology, School of Medicine, Marmara University, Istanbul, Turkey Laurian Dragos, MD lauriandragos@yahoo.com Department of Urology, Emergency County Hospital, Pius Branzeu, Timisoara, Romania Silvia Proietti, MD proiettisil@gmail.com Ville Turro Division, Department of Urology, IRCCS, Ospedale San Raffaele, Milan, Italy Steeve Doizi, MD steeve.doizi@gmail.com Olivier Traxer, MD olivier.traxer@tnn.aphp.fr Pierre & Marie Curie University, Tenon University Hospital, Paris, France PETRA UroGroup Progress in Endourology, Technology and Research Association, http://www.petraurogroup.org/

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DOI: 10.4081/aiua.2018.3.159

ORIGINAL PAPER

Do dental calculi predict the presence of renal stones?

Bulent Kati 1, Ergin Kalkan 2, Eyyup Sabri Pelit 1, Ismail Yagmur 1, Halil Ă&#x2021;iftçi 1 1 Department 2 Cagri

of Urology, Harran University Faculty of Medicine, Sanliurfa, Turkey; Dental Hospital, Dental Clinic, Elazig, Turkey.

Summary

Objective: Pathological calcifications that occur in various parts of the body may cause stone formation over time. The structure of these stones is similar in many regions of the body. We have studied the relationship between dental calculi and kidney stones.

Material and methods: A total of 183 patients with dental stone complaints or dental calculi were included between April and August 2016 in the Cagri Dental Hospital, Elazig, Turkey.

Patients were evaluated with regard to a urinary tract ultrasonography, urinalysis, oral hygiene, and stone and surgical disease history. All information was statistically investigated.

Results: The age of the patients in the kidney stones group was significantly higher than the non-kidney stone patients (p < 0.05). In the group with kidney stones, the percentage of dental calculus formation was significantly higher than the group without stones (p < 0.05). In the groups with and without kidney stones, dental stone recurrence rates did not differ significantly (p < 0.05). Urinary pH was significantly lower in the group with stones than the group without stones (p < 0.05).

Conclusions: During a physical examination, the formation of a visible stone, such as a dental calculus, may be an indicator of other types of stones, such as kidney stones, and this should be further investigated.

KEY WORDS: Renal stone; Dental calculi; Stone formation; Etiology.

Submitted 16 May 2018; Accepted 5 July 2018

INTRODUCTION

In dentistry, a calculus or tartar is a form of hardened dental plaque. These are caused by the precipitation of minerals from saliva and gingival crevicular fluid in plaque on the teeth. This precipitation process kills the bacterial cells within the dental plaque, but the rough and hardened surface that is formed provides an ideal surface for further plaque formation. This leads to a calculus build up, which compromises the health of the gingiva. A calculus can form both along the gum line (supragingival) and within the narrow sulcus between the teeth and the gingiva (subgingival) (1).

Calculus formation is associated with a number of factors including sex, age, bad breath, receding gums, and chronically inflamed gingival (2). Brushing and flossing can remove the plaque from which a calculus forms.

However, once formed, it is too hard and firmly attached to be removed with a toothbrush. Calculus buildup can be removed with ultrasonic tools or dental hand instru-

ments (such as a periodontal scaler). Calculi are composed of both inorganic (mineral) and organic (cellular and extracellular matrix) components. The mineral portion of a calculus ranges from 40-60%, depending on its location in the dentition, and consists primarily of calcium phosphate crystals organized into four principal mineral phases: octacalcium phosphate, hydroxyapatite, whitlockite, and brushite. The organic component of a calculus is approximately 85% cellular and 15% extracellular matrix (3).

Renal stones, which are part of a multifactorial disease, are some of the most common problems in modern society and may affect 12-15% of the population with observation of an increase in their prevalence. Renal stones are more common in males and are categorized into calcareous (calcium containing) stones, which make up 90% of all stones, and non-calcareous stones. Most stones (85%) primarily contain calcium oxalate (CaOx) admixed with calcium phosphate (CaP) in the form of apatite or brushite, or occasionally uric acid; however, less commonly they can be composed primarily of CaP. Although many systemic diseases, such as primary hyperparathyroidism, bowel disease, and renal tubular acidosis, can result in calcium stone formation, the majority of calcium stones are found in people with no systemic illness (4). Although many inherited and systemic diseases are associated with calcium renal stones, most stones are idiopathic (5).

In this study, we aimed to evaluate the presence of kidney stones in patients with dental calculus. This was performed according to the dental plaque density in patients who were treated at the same time in the urology clinic. We also aimed to uncover any relationships between these conditions.

MATERIALS

AND METHODS

The study group was composed of 183 patients (86 females and 97 males) with an age range from 20 to 65 years. We randomly evaluated dental patients who were diagnosed with dental calculus. Based on the amount of plaque, patients were divided into three categories. For the purposes of X-ray assessments of the jaw, panoramic, and retroalveolar region, X-rays in suspicious teeth were made. For the realization of the set objective, visual analyses of the X rays were conducted (Figure 1).

Dental calculus amounts that are generally below 25%

No conflict of interest declared.

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Figure 1.

X-ray views of dental calculi (arrows).

with a urinary tract ultrasound and urinalysis (Figure 3).

Fasting second morning specimens were collected from all individuals who had been fasting since 9:00 p.m. the preceding evening. The dental brushing habits of the patients were evaluated in terms of oral hygiene, additional disease, and stone story. All information was collected to determine the incidence of dental calculus and kidney stone in patients.

Figure 2a, b, c.

Appearance of dental calculus during a physical examination.

Statistical analysis Mean, standard deviation, median lowest and highest, frequency, and ratio values were used in the descriptive statistics of the data. The distribution of the variables was measured by the Kolmogorov-Smirnov test. The MannWhitney U test was used in the analysis of quantitative data. The chi-square test was used in the analysis of qualitative data. The SPSS 22.0 program was used for all statistical analyses.

Figure 3.

The appearance of kidney stones and crystals in the kidney ultrasound (arrows).

RESULTS

are termed as “low category,” tartar amounts from 2575% as “medium category,” and as “high category” those amounts between 75-100% (Figure 2).

After the dental examination, all patients were evaluated

The data from all patients were evaluated together (Table 1). The age of the patients in the kidney stone group was significantly higher than that of the non-kidney stone group (p < 0.05). The proportion of patients with renal stones who were males was significantly higher than the group without kidney stones (p < 0.05). The dental calculus formation was more prevalent in those without renal stones (p < 0.05). In the groups with and without kidney stones, dental stone recurrence rates did not differ significantly (p > 0.05). Urinary pH was significantly lower in the group without stones (p < 0.05) (Table 2).

In the univariate model, there was a significant difference (p < 0.05) in the age, sex, tooth stone percentage, tooth brushing habits, recurrence frequency, presence of addiTable 1.

Characteristics of patients being treated for dental calculi.

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Dental and renal calculi

Table 2.

Statistical comparisons of patient information.

Table 3.

Univariate and multivariate analyses of patient information.

tional disease, oral hygiene level, stone story, and urinary pH values. In the multivariate model, significant and independent (p < 0.05) efficacy was observed in the age of the patients, the percentage of tooth stones, and the stone story, suggesting stone formation (Table 3).

DISCUSSION

Most of the stones in our bodies can be defined as pathological calcifications. In the literature, there are thousands of articles associated with calcifications occurring in the body, however, this amount is less than the number of articles attempting to explain the relationship between them. Stones occurring in different organs resemble their structure suggesting a metabolic disorder

that underlies the process of their formation (6, 7). The components of stone formation are similar in many organs (8). Davidovich E. et al. evaluated the correlation between dental calculus and disturbed mineral metabolism in pediatric patients with chronic kidney disease.

They suggested that there is a possible association between the severity of renal dysfunction in young patients and the formation of dental calculus as an additional manifestation of disturbed calcium-phosphate homeostasis. The combination of several components in saliva including calcium, phosphate, uric acid, and magnesium plays an important role in this process (9).

Looking at the minerals that make up kidney stones, we see the same accumulation in the kidneys and teeth, suggesting similar mechanisms of stone formation (10).

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Some researchers have found that nephrolithiasis is also accepted as a predisposing factor to pulpal calcification; however, some others could not find any correlation between the presence of pulp stones and kidney stones (11, 12). Some researchers have proposed that some of the minerals found in saliva cause the formation of stones in the salivary glands. Salivary sialoliths are predominantly composed of crystals comprising calcium and phosphorous, with small amounts of magnesium, sodium, chloride, silicon, iron, and potassium (13).

Rakesh N. et al. found that, when comparing sialoliths and nephroliths, they found a high degree of elemental similarity between them. Thus, they alleged that prescription drugs used for renal stones may be of some use in the conservative management of sialoliths (14).

Shaimaa et al. evaluated idiopathic calcium renal stones and their relationship to dental calculi. They reported significant correlations between dental calculus accumulations and calcium renal stone formation, and they offered oral health preventive programs for those patients (15). Grases et al. found that salivary calcium concentrations of patients with hydroxyapatite calculi were significantly higher than that found in the saliva of healthy in their study. Therefore, their results were practically identical to those found in the hydroxyapatite renal calculi (non-infective phosphate renal calculi) (16, 17). We assessed patients based on oral hygiene, renal stone history, teeth brushing habits, dental calculus recurrence, and comorbidities. The dental calculus percentage was significantly higher in patients with kidney stones. This similarity can be seen because of the materials that make up the stone structure tend to accumulate in the body. This may be an indication that kidney stones can form in patients with a high dental calculus density. This condition, which is not related to the recurrence frequency of the dental calculi, is also directly related to oral hygiene status.

CONCLUSIONS

There are similar features in terms of the formation of stones in the body and the minerals they contain.

The height of dental calculi observed in the mouth is significant and stimulating in terms of kidney stones in patients. During physical examinations, the formation of a visible stone, such as a dental calculus, can be a predictor of stones such as kidney stones, and this relationship should be further investigated.

REFERENCES

1. Turesky SS. What is the role of dental calculus in the etiology and progression of periodontal disease? J Periodontol. 1970; 41:285-6.

2. Beiswanger BB, Segreto VA, Mallatt ME, Pfeiffer HJ. The prevalence and incidence of dental calculus in adults. J Clin Dent. 1989; 1:55-8.

3. Jin Y, Yip HK. Supragingival calculus: formation and control. Crit Rev Oral Biol Med. 2002; 13:426-41.

4. Coe FL, Worcester EM, Evan AP. Idiopathic hypercalciuria and formation of calcium renal stones. Nat Rev Nephrol. 2016; 12:519-33.

162

5. Worcester EM, Coe FL. Clinical practice. Calcium kidney stones.

N Engl J Med. 2010; 363:954-63.

6. Avogaro A, Fadini GP Mechanisms of ectopic calcification: implications for diabetic vasculopathy. Cardiovasc Diagn Ther. 2015; 5:343-52.

7. Valenzuela A, Chung L. Calcinosis: pathophysiology and management. Curr Opin Rheumatol. 2015; 27:542-8.

8. Aguilar-Ruiz J, Arrabal-Polo MA, Sierra M, Arrabal-Martin M. Application of mineralogical techniques in the study of human lithiasis. Ultrastruct Pathol. 2012; 36:367-76.

9. Davidovich E, Davidovits M, Peretz B, et al. The correlation between dental calculus and disturbed mineral metabolism in paediatric patients with chronic kidney disease. Nephrol Dial Transplant.

2009; 24:2439-45.

10. Khan SR, Pearle MS, Robertson WG, et al. Kidney stones. Nat Rev Dis Primers. 2016; 2:16008.

11. Nayak M, Kumar J, Prasad LK. A radiographic correlation between systemic disorders and pulp stones. Indian J Dent Res. 2010; 21:369-73.

12. Tarim Ertas E, Inci M, Demirtas A, et al. A Radiographic Correlation between Renal and Pulp Stones West Indian Med J. 2014; 63:620.

13. Hiraide F, Nomura Y. The fine surface structure composition of salivary calculi. Laryngoscope 1980; 90:152.

14. Rakesh N, Bhoomareddy Kantharaj YD, Agarwal M, Agarwal K. Ultrastructural and elemental analysis of sialoliths and their comparison with nephroliths. J Investig Clin Dent. 2014; 5:32-7.

15- Shaimaa KY, Mohammed SA. Dental calculus in relation to idiopathic calcium renal stone J Bagh Coll Dentistry. 2012; 24(sp. Issue 1):140-145.

16. Grases F, Santiago C, Simonet B. Sialolithiasis: mechanisim of calculi formation and etiologic factors. Clin Chim Acta. 2003; 334:131-6.

17. Grases F, Sohnel O, Villacampa AI, March JG. Phosphates precipitating from artificial urine and fine structure of phosphate renal calculi. Clin Chim Acta. 1996; 244:45-67.

Correspondence Bulent Kati, MD bulentkati@harran.edu.tr Eyyup Sabri Pelit, MD dreyyupsabri@hotmail.com Ismail Yagmur, MD dr_iyagmur@hotmail.com Halil Çiftçi, MD halilciftci63@hotmail.com Harran University, Favulty of Medicine Hospital, Urology, 63340 Sanliurfa, Turkey Ergin Kalkan, MD erginkalkan@hotmail.com Assistant Professor of Urology Cagri Dental Hospital, Dental Clinic, 23100, Elazig, Turkey

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DOI: 10.4081/aiua.2018.3.163

ORIGINAL PAPER

Role of the gonadal vessels on the stone lodgment in the proximal ureter: Direct observation during laparoscopic ureterolithotomy Mohammad Hadi Radfar 1, Reza Valipour 2, Behzad Narouie 3, Mehdi Sotoudeh 1, Hamid Pakmanesh 4 1 Department

of Urology, Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; of Urology, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran; 3 Department of Urology, Zahedan University of Medical Sciences, Zahedan, Iran; 4 Department of Urology, Shahid Bahonar Hospital, Kerman University of Medical Sciences (KMU), Kerman, Iran.

2 Department

Summary

Introduction: Previous radiological studies revealed that stones lodge more frequently in the ureterovesical junction (UVJ) as well as the proximal ureter. Factors that prevent stone passage from the proximal ureter are not well studied. Aim: To explore the site of the lodged stones in the proximal ureter with direct observation during laparoscopic ureterolithotomy.

Materials and methods: Between November 2014 and February 2015, we included 26 patients including 18 men and 8 women with stones larger than 10 millimeters in the proximal ureter who were candidate for laparoscopic ureterolithotomy. We prospectively recorded the site of the lodged stones in the ureter during laparoscopic ureterolithotomy in relation with the sites of ureteral stenosis as well as the gonadal vessels.

Results: Among 26 patients with ureteral stone, in 19 cases stone was found close to the gonadal vein compared with seven cases that stone was in other locations of the ureter (p = 0.02).

The characteristics of patients and stones were not different in cases that the stone was close to gonadal vessels compared with other locations.

Conclusions: This study showed that most of the stones lodged in the proximal ureter were in close proximity with gonadal vessels. Gonadal vessels may be an extrinsic cause of ureteral narrowing.

KEY WORDS: Ureter; Urolithiasis; Laparoscopy; Pathophysiology; Gonadal vessels.

Submitted 11 December 2017; Accepted 12 January 2018

INTRODUCTION

Ureteral stone is a common presentation of the urinary tract stone disease that usually is associated with an excruciating pain (1). Most of urinary tract stones pass spontaneously; however, some stones lodge in the ureter and require intervention (2, 3). Anecdotally, three constrictions in the ureter are told to be the potential site of stone impaction including ureteropelvic junction (UPJ), the crossing of the ureter over iliac vessels and the ureterovesical junction (UVJ) (4). In contrast with this theory, data of clinical studies did not show increased rate of stone lodgment at the level of the iliac vessels (5-7). In addition, UPJ is not a frequent location for lodged stones. Actually, studies that reviewed imaging of the patients with impacted

ureteral calculus revealed that stones lodge more frequently in two sites: UVJ and proximal ureter. UVJ is known unanimously as the narrowest part of the ureter (8); however, we have not a clear response to the question that why large stones that pass the UPJ, lodge in the proximal ureter.

Ureteroscopy (TUL) or Shock wave lithotripsy (SWL) or are the first line treatment for more ureteral stones (9).

For large stone burden or when previous options have failed, laparoscopic ureterolithotomy is a less invasive technique with excellent success rate (10). In this study, we prospectively investigated the location of the lodged stones in the proximal ureter under direct laparoscopic vision in patients who were candidate for laparoscopic ureterolithotomy. To the best of our knowledge, this is the first study that report intraoperative data of lodged ureteral stones in relation with the gonadal vessels.

MATERIALS

AND METHODS

We prospectively evaluated patients who undergo laparoscopic transperitoneal ureterolithotomy for upper ureteral stones. Between November 2014 and February 2015, we included 26 patients. The inclusion criteria was stones larger than 10 millimeters in the proximal ureter (from ureteropelvic junction to the iliac vessels) in the nonenhanced spiral abdominopelvic computed tomography scan (CT-Scan), that failed to response with Shock Wave lithotripsy (SWL). We excluded patients who had previously underwent open stone surgery. A negative urine culture and normal coagulation tests was attained. The studied variables were patient demographic data including age, gender, height, weight, body mass index as well as stone characteristics including size, number and laterality and data of previous interventions. Urology and Nephrology Research Center Board of ethical approval approved the study. All procedures 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.

Surgical technique After induction of the general anesthesia, we inserted a

No conflict of interest declared.

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Foley catheter and orogastric tube. Then, we placed the patients in flank position and flexed the operating table at umbilical level. One surgeon, trainee fellowship of laparoscopy, under supervision of one attending staff performed all operations. We inserted a 10-millimeter trocar in the umbilicus or lateral to the rectus muscle at the umbilicus level. After insufflation, we inserted two or three working ports in a rhomboid style. The ipsilateral colon was mobilized. Then, we explored the ureter based on preoperative imaging to find the stone. Then, we evaluated the location of the stone in relation with the gonadal vessels.

(Figure 1) Then, we extracted the stone through a longitudinal ureteral incision. We placed a double-J stent in all cases and repaired the ureteral incision with separate absorbable 4-0 Vicryle sutures.

Figure 1.

The location of the lodged stone in the proximal ureter in relation with the right gonadal vessels.

Statistical analysis Data are presented as mean ± standard deviation, range, numbers and percentages.

We analyzed data using nonparametric binominal test with the test proportion of 0.50 to evaluate whether the ureteral stones are randomly distributed in the ureter or not. P value less than 0.05 was considered significant.

RESULTS

We evaluated 26 patients including 18 men and 8 women with mean age of 48±14 years (25 to 75).

Table 1.

Demographic and stone characteristics of patients considering the relation of the lodged stone with gonadal vessels.

Laterality

right left Gender male female Stone size (mm) Age (years) Height (cm) BMI (Kg/m2)

Close to gonadal vessels (n = 19) 12 (63.2) 7 (36.8) 13 (68.4) 6 (31.6) 16.3 ± 6.1 47.8 ± 13.8 167.7 ± 7.2 25.9 ± 3.4

Location of stone Other locations (Nn = 7) 4 (57.1) 3 (42.9) 5 (71.4) 2 (28.6) 15 ± 2.9 50 ± 14.1 170.7 ± 9.8 26.7 ± 3.5

Data are presented as count (column percent) or mean ± standard deviation.

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P value 0.78 0.88 0.59 0.74 0.48 0.6

Mean BMI was 26 ± 3 kg/m2 (21 to 32). Regarding previous history of intervention, two patients had previous history of percutaneous nephrolithotomy. In sixteen cases (61%), stone was located in the right side.

Considering the location of the stone in relation with gonadal vessels, among 26 patients with ureteral stone, in 19 cases stone was found close to the gonadal vein compared with seven cases that stone was in other locations of the ureter (p = 0.02). The characteristics of patients and stones were not different in cases that the stone was close to gonadal vessels compared with other cases (Table 1).

DISCUSSION

To the best of our knowledge, this is the first report that consider the gonadal vessels as a cause of stone lodgment in the proximal ureter. UPJ is told to be one of the three constrictions of the ureter; however, there is large body of evidence that shows many stones pass the UPJ but lodge in the proximal ureter (5, 3, 11, 7). Nevertheless, no one has explained an etiological factor for this finding yet. Actually, stones that lodge in the proximal ureter are less likely to pass spontaneously with Medical Expulsive Therapy (MET) compared with lower ureter stones (12). We think that, presence of gonadal vein as an extrinsic compression against ureteral peristalsis may explain these findings.

There are some examples that a vessel can compress the ureter and produce obstruction in the upper urinary tract.

Ureterovascular hydronephrosis is an example of upper tract obstruction secondary to the pressure effect on the ureter by the lower pole arterial branches. This obstruction leads to hydronephrosis resembling uretero-pelvic junction obstruction especially in children (13, 14).

This obstruction may be successfully resolved by laparoscopic transposition of the lower pole crossing vessels (15). Likewise, thrombosis of the ovarian vein may compress the ureter, a condition known as ovarian vein syndrome (16, 17).

The aforementioned conditions corroborate our finding that gonadal vessels may cause extrinsic narrowing in the ureter sufficient to prevent spontaneous stone expulsion.

Ordon et al. reviewed kidney-ureter-bladder (KUB) and CT-scan of the patients referred for SWL. They found that in this group of patients most stones were lodged at the level of the lower L2 and upper L3 vertebra followed by at the level of the iliac spine. Larger stones and stones in female patients were located more proximally (6).

They concluded that the stones at the level of the L2-L3 vertebra is compatible with the UPJ. They did not considered that the gonadal vessels traverse the ureter at the same level of the vertebra. Gonadal arteries arise from the abdominal aorta at the L2 vertebral level (18) and traverse laterally and cross the ureter at L3 vertebral level. Namely, stone lodgment at the L2-L3 level may be a consequence of the extrinsic pressure of the gonadal vessels rather than functional narrowing of the UPJ. Additionally, some other studies have shown that stones usually lodge at the upper ureter rather than UPJ. Eisner et al. retrospectively reviewed CT-Scan imaging data of 94 patients referred to the emergency department and reported that upper ureter (23%) stone was the second most frequent site of the stone lodgment after UVJ

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Location of the lodged proximal ureter stones

(60%). In their study, stone lodged at the UPJ level in 10 percent of cases (5). Similarly, Jong Song et al. reviewed CT-Scan imaging of 95 patients with acute renal colic and found that UPJ stone was present in only 5% of patients. In contrast, 30% of stones were detected in the proximal ureter. Interestingly, only in one case in both aforementioned studies stone was detected in the level of ureter crossing iliac vessels (5, 7). This data confirms that UPJ itself is not the leading cause of stone lodgment, the stones lodge in the proximal ureter instead.

El-Barky et al. published result of their prospective study on ureteral stone location in cases that were candidate for intervention due to failed MET. They reported that UVJ followed by proximal ureter were the more frequent sites of stone lodgment in this cohort. Twenty two percent of the stones were at the level of the L3-L4 vertebra in the proximal ureter whereas only 10% of stones were in the UPJ level (3). Recently, Moon et al. reviewed the finding of the computed tomography scans of the patients with ureteral stone that failed to pass the ureteral calculi after two weeks of MET. This study showed that 37% of patients that failed to response with two weeks of MET had stone in the proximal ureter, 36% in the UVJ and 2% in the UPJ. Further, stones lodged in the upper ureter were larger than the lower ureter stones and showed lower response rate to MET (11). These findings more attest our theory that some pathophysiological factor should be present that create a constriction on the proximal ureter that interfere with stone passage.

Our finding may explain this difference likewise.

In this study, for the first time we introduce the gonadal vessels as an extrinsic factor that induce stone lodgment in the proximal ureter. Previous studies evaluated imaging studies of the patients whereas this is the first report that investigate the real place of the stone lodged in the ureter by direct laparoscopic vision. In addition, results of this study may help during laparoscopy of the ureteral stone to find the stone by focusing on the site that gonadal vessels traverse the ureter. Further studies including more patients is needed to validate our findings in the present study.

CONCLUSIONS

This study showed that most of the stones lodged in the proximal ureter were in close proximity with gonadal vessels. Gonadal vessels may be a cause of extrinsic ureteral narrowing.

5. Eisner BH, Reese A, Sheth S, Stoller ML Ureteral stone location at emergency room presentation with colic. J Urol. 2009; 182:165-168.

6. Ordon M, Schuler TD, Ghiculete D, et al. Stones lodge at three sites of anatomic narrowing in the ureter: clinical fact or fiction? J Endourol. 2013; 27:270-276.

7. Song HJ, Cho ST, Kim KK. Investigation of the location of the ureteral stone and diameter of the ureter in patients with renal colic.

Korean Journal Urol. 2010; 51:198-201.

8. Abdel Razzak OM. Ureteral anatomy. In: Smith AD B, G BD, et al, eds. Smithâ&#x20AC;&#x2122;s Textbook of Endourology., 2nd ed. Lewiston: BC Decker Inc, pp 213-216.

9. Porpiglia F, Fiori C, Poggio M, et al. Ureteroscopy: is it the best?

Urologia. 2014; 81:99-107.

10. Wu T, Duan X, Chen S, et al. Ureteroscopic lithotripsy versus laparoscopic ureterolithotomy or percutaneous nephrolithotomy in the management of large proximal ureteral stones: a systematic review and meta-analysis. Urol Int 2017 doi:10.1159/000471773.

11. Moon YJ, Kim HW, Kim JB, et al. Distribution of ureteral stones and factors affecting their location and expulsion in patients with renal colic. Korean J Urol. 2015; 56:717-721.

12. Choi T, Yoo KH, Choi SK, et al. Analysis of factors affecting spontaneous expulsion of ureteral stones that may predict unfavorable outcomes during watchful waiting periods: What is the influence of diabetes mellitus on the ureter? Korean J Urol. 2015; 56:455-460.

13. Stephens FD. Ureterovascular hydronephrosis and the "aberrant" renal vessels. J Urol. 1982; 128:984-987.

14. Pesce C, Campobasso P, Costa L, et al. Ureterovascular hydronephrosis in children: is pyeloplasty always necessary? Eur Urol. 1999; 36:71-74.

15. Gundeti MS, Reynolds WS, Duffy PG, Mushtaq I. Further experience with the vascular hitch (laparoscopic transposition of lower pole crossing vessels): an alternate treatment for pediatric ureterovascular ureteropelvic junction obstruction. J Urol. 2008; 180(4 Suppl):1832-1836.

16. JC C. The right ovarian vein syndrome. Clinical urography: an Atlas end Texbook of Roentgenologic Diagnosis 2ÂŞ ed, 1964, pp.1227-1236.

17. Derrick FC Jr., Turner WR, House EE, Stresing HA. Incidence of right ovarian vein syndrome in pregnant females. Obst Gynecol.

1970; 35:37-38.

18. Ahlberg NE, Bartley O, Chidekel N. Right and left gonadal veins. An anatomical and statistical study. Acta radiologica: diagnosis. 1966; 4:593-601.

Correspondence

REFERENCES

1. Basiri A, Shakhssalim N, Khoshdel AR, et al. Drinking water composition and incidence of urinary calculus: introducing a new index. Iranian journal of kidney diseases. 2011; 5:15-20.

2. Deliveliotis C, Chrisofos M, Albanis S, et al. Management and follow-up of impacted ureteral stones. Urol Int. 2003; 70:269-272.

Mohammad Hadi Radfar, MD Mehdi Sotoudeh, MD Department of Urology, Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Reza Valipour, MD Department of Urology, Zahedan University of Medical Sciences, Zahedan, Iran

3. El-Barky E, Ali Y, Sahsah M, et al. Site of impaction of ureteric calculi requiring surgical intervention. Urolithiasis. 2014; 42:67-73.

Behzad Narouie, MD Departement of Urology, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran

4. AI D. Anatomy and surgical approach to the urogenital tract in the male. In: Campbell M (ed) Urology. WB Saunders Company, Philadelphia/London 1954, (1st edn.), p.12

Hamid Pakmanesh, MD (Corresponding Author) h_pakmanesh@yahoo.com; h_pakmanesh@kmu.ac.ir Department of Urology, Shahid Bahonar Hospital, Kerman University of Medical Sciences (KMU), Kerman, Iran Archivio Italiano di Urologia e Andrologia 2018; 90, 3

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DOI: 10.4081/aiua.2018.3.166

ORIGINAL PAPER

Ultrasound follow up: Is an undetected spontaneous expulsion of stone fragments a sign of extracorporeal shock wave treatment failure in kidney stones?

Grazia Bianchi, Diego Marega, Roberto Knez, Stefano Bucci, Carlo Trombetta Department of Urology, University of Trieste, Cattinara Hospital, Trieste, Italy.

Summary

Introduction. After extracorporeal lithotripsy (SWL), a spontaneous expulsion of fragments is often reported. The aim of this study is to demonstrate the presence of a stone free status or the presence of clinically insignificant residual fragments (CIRFs, defined as “asymptomatic, noninfectious, ≤ 3 mm fragments”) in people with undetected spontaneous expulsion.

Materials and methods. Between May and September 2017, we performed a total of 87 treatments. The device used was a Storz Medical Modulith® SLK. All the patients were treated in prone position to reduce respiratory movements and underwent sonography before and four to eight weeks after the treatment.

An in line ultrasound targeting was possible with all the stones.

People lost to follow up or with ureteral stones were excluded.

Patients were divided in groups according to gender, previous treatments, stone diameter and position.

Results. We enrolled 73 patients. 57 patients had a single stone and 16 multiple stones. A mean number of 3044 shock waves was administered with a maximum average energy of 0.68mj/mmq. At follow up, 41 patients (56.2%) were found stone free or with CIRFs. The association between undetected expulsion and the presence of CIRFs is considered to be not statistically significant (p = 0.89). Among patients with CIRFs, 25/41 didn’t report expulsion. Taking in account the groups our population was divided in, according to gender (p = 0.36), previous treatments (p = 0.44), stone diameter (p = 0.28) and stone position (p = 0.35), the association between undetected spontaneous expulsion and presence of CIRFs was never statistically significant.

Conclusions. An undetected spontaneous expulsion of stone fragments could not be considered a sign of SWL treatment failure. The association between undetected expulsion and presence of CIRFs is never statistically significant if gender of the patients, previous treatments, stone diameter and stone position are considered.

KEY WORDS: Lithotripsy; Fragment expulsion; Clinically insignificant fragments; SWL. Submitted 6 June 2018; Accepted 19 August 2018

INTRODUCTION

After extracorporeal shock waves lithotripsy (SWL), a spontaneous expulsion of fragments is often reported.

During the first medical examination after the treatment, the patient is always asked if he had a renal colic or hematuria and fragment expulsions were seen. We won-

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dered if fragment expulsion could be considered a good indicator of a successful treatment. In many patients, reporting that they had not expelled fragments, we actually noticed that insignificant lithiasis was present.

The aim of this study is to demonstrate the presence of a stone free status or the presence of clinically insignificant residual fragments (CIRFs, defined as “asymptomatic, noninfectious, ≤ 3 mm fragments”) in people with undetected spontaneous expulsion.

MATERIALS

AND METHODS

Between May and September 2017, we performed a total of 87 treatments. The device used for ESWL was Storz Medical Modulith® SLK. In this electromagnetic system, the shock waves are generated through a cylindrical coil with a metallic membrane in a water-filled cushion. The magnetic field of the coil causes an expansion of the membrane and the shock wave in water, which is focused by a parabolic reflector. The plastic membrane of the cushion is coupled to the patient by an ultrasound gel. The ultrasound probe is placed in line, allowing continuous monitoring of the treatment. All the patients were treated in prone position to reduce respiratory movements of the stone. They underwent sonography before treatment and four to eight weeks after treatment.

No patients had radiographic targeting of stones, because of far better performance of ultrasound targeting in our hands and to avoid X-ray exposure. People lost to follow-up and with ureteral stones were excluded. Every patient was given potassium citrate and no one was given expulsive therapy after the treatment. Patients were divided into groups according to gender, previous treatments, stone diameter and position. We retrospectively reviewed the data collected and compared the results obtained using chi-square test, with significance considered at p < 0.05.

RESULTS

We enrolled 73 consecutive patients, 53 males and 20 females. 57 patients had a single stone (mean 9,5 ± 3.12 mm) and 16 multiple stones. The mean age was 59 ± 12 years. A mean number of 3044 shock waves was administered with a maximum average energy of 0.68mj/mmq.

No conflict of interest declared.

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Ultrasound follow up: Is an undetected spontaneous expulsion of stone fragments a sign of extracorporeal shock wave treatment failure in kidney stones?

Table 1 describes the main characteristics, evaluating, for each considered aspect, the presence of reported spontaneous expulsion of fragments and the presence of clinically insignificant residual fragments.

At follow up, 41 patients (56.2%) were found stone free or with CIRFs. Among 73 patients we considered, 28 reported spontaneous expulsion, in particular, among them, 16 were stone free or with CIRFs and 12 had stones clinically significant. The association between undetected spontaneous expulsion and the presence of CIRFs (primary outcome) is considered to be not statistically significant (p = 0.89). Patients without CIRFs required further treatments and this is considered a treatment failure (Table 2).

Among 42 patients where CIRFs were diagnosed, 25 didn’t report expulsion and were divided into groups according to gender, previous treatments, stone diameter and stone position.

According to gender, 19 males and 6 females didn’t report expulsion (p = 0.36). Patients who underwent Table 1.

Presence of reported spontaneous expulsion of fragments and presence of clinically insignificant residual fragments in relation to different conditions.

Males Females Previous treatments No previous treatments Stones ≤ 10 mm Stones > 10 mm or multiple Lower calyx Middle and superior calyx Renal pelvis

Reported No CIRFs no CIRFs spontaneous expulsion expulsion 22 31 33 20 6 14 8 12 15 22 20 17 13 23 21 15 23 34 33 24 5 11 8 8 13 17 15 15 7 22 20 9 8 6 6 8

Table 2.

Association between undetected spontaneous expulsion and the presence of CIRFs (primary outcome).

Reported spontaneous expulsion Clinically insignificant residual fragments (CIRFs) Lithiasis that requires further treatments

16 12

Table 3.

Association between undetected spontaneous expulsion and presence of CIRFs.

Males Females Previous treatments No previous treatments Stones ≤ 10 mm Stones > 10 mm or multiple Lower calyx Middle and superior calyx Renal pelvis

Reported spontaneous expulsion 14 2 9 7 5 6 5 13 3

No expulsion

P

19 6 11 14 8 14 3 17 8

0.36 0.44 0.28 0.35

Taking in account the groups our population was divided in, according to gender (p = 0.36), previous treatments (p = 0.44), stone diameter (p = 0.28) and stone position (p = 0.35), the association between undetected spontaneous expulsion and presence of CIRFs is never statistically significant (Table 3).

DISCUSSION

Although different definitions (1, 2) of CIRFs (clinically insignificant residual fragments) could be found (3) and taking in account that some authors consider CIRFs a risk factor for future stone growth (2-4), they are still considered a good indicator of successful ESWL fragmentation.

The CT scan is believed to be the gold standard for residual fragments detection (5, 6), but we tried to avoid xray exposure, especially in recurrent stone-formers (7).

The available studies about residual fragments deal mostly with medical therapy (8, 9), but studies about spontaneous expulsion after ESWL could not be found.

CONCLUSIONS

No expulsion

P

25 20

0.89

previous treatments (stenting was not considered a treatment because it does not involve fragmentation) were 11 and 14 had no previous treatments or any kind of stone fragmentation (p = 0.44).

According to stone diameter, 17 patients with stones ≤ 10 mm and 8 with stones > 10 mm or multiple didn’t report expulsion (p = 0.28) and according to stone position, 8 with stones in lower calyx, 14 in middle and superior calyx, 3 in renal pelvis didn’t report expulsion (p = 0.35).

An undetected spontaneous expulsion of stone fragments could not be considered a sign of ESWL treatment failure.

The association between undetected expulsion and presence of CIRFs is never statistically significant if gender of the patients, previous treatments, stone diameter and stone position are considered.

REFERENCES

1. Sarica K, Yuruk E. What should we do with residual fragments.

Arch Esp Urol. 2017; 70:245-250.

2. Osman MM, Alfano Y, Kamp S, et al. 5-year-follow-up of patients with clinically insignificant residual fragments after extracorporeal shockwave lithotripsy. Eur Urol. 2005; 47:860-4.

3. Chung VY, Turney BW. The success of shock wave lithotripsy (SWL) in treating moderate-sized (10-20 mm) renal stones.

Urolithiasis. 2016; 44:441-4.

4. Khaitan A, Gupta NP, Hemal AK, et al. Post-ESWL, clinically Archivio Italiano di Urologia e Andrologia 2018; 90, 3

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insignificant residual stones: reality or myth? Urology. 2002; 59:20-4.

7. Elkoushy MA, Andonian S. Lifetime radiation exposure in patients with recurrent nephrolithiasis. Curr Urol Rep. 2017; 18:85.

5. Cicerello E, Merlo F, Maccatrozzo L. Management of Clinically Insignificant Residual Fragments following Shock Wave Lithotripsy.

Adv Urol. 2012; 2012:320104.

8. Yang TX, Liao BH, Chen YT, et al. A network meta-analysis on the beneficial effect of medical expulsive therapy after extracorporeal shock wave lithotripsy. Sci Rep. 2017; 7:14429.

6. Skolaris A, Papatsoris AG. Diagnosis and management of post percutaneous nephrolithotomy residual stone fragments. J Endourol.

2009; 23:1751-1755.

9. Janane A, Hamdoun A, Hajji F, et al. Usefulness of adjunctive alpha1-adrenergic antagonists after single extracorporeal shock wave lithotripsy session in ureteral stone expulsion. Can Urol Assoc J. 2014; 8:E8-E11.

Correspondence Grazia Bianchi, MD (Corresponding Author) graziuccia88@libero.it Diego Marega, MD Roberto Knez, MD Stefano Bucci,MD Carlo Trombetta, MD trombcar@units.it UniversitĂ degli Studi Trieste, Urology Department â&#x20AC;&#x201C; Cattinara Hospital, Strada di Fiume 447, Trieste, Italy

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DOI: 10.4081/aiua.2018.3.169

ORIGINAL PAPER

Comparison of an electromagnetic and an electrohydraulic lithotripter: Efficacy, pain and complications Grazia Bianchi, Diego Marega, Roberto Knez, Stefano Bucci, Carlo Trombetta Department of Urology, University of Trieste, Cattinara Hospital, Trieste, Italy.

Summary

Introduction. We analyzed efficacy and complications of extracorporeal shock wave lithotripsy (SWL) and analgesia requirement during the treatment in two groups of patients treated with different lithotripters.

Materials and methods. The patients treated were 189, 102 between September 2016 and April 2017 with HMT Lithotron® LITS 172, electrohydraulic, and 87 between May and September 2017 with Storz Medical Modulith® SLK, electromagnetic. The main differences between the lithotripters are: type of energy source, patient position, frequency and number of shock waves. All the patients underwent sonography before and four to eight weeks after the treatment. The targeting was sonographic for renal stones and X-ray for ureteral stones.

All the patients received Ketorolac before the treatment with a supplement of Pethidine if needed. People lost to follow-up and with incomplete data were excluded.

Results. We enrolled 173 patients, 94 treated with the electrohydraulic lithotripter and 79 with the electromagnetic one.

43 patients (54%) in the electromagnetic group and 31 (33%) in the electrohydraulic group were stone free or presented clinically insignificant residual fragments (CIRFs), defined as asymptomatic, noninfectious, ≤ 3 mm. The association between CIRFs and the kind of lithotripter was statistically significant (p = 0.004).

An increased need for analgesia was found in 14.9% of patients in the electromagnetic group and in 81% of patients in the electrohydraulic group (p < 0.001). The access to emergency room (intractable pain, kidney failure, fever, Steintrasse) after the treatment was similar in the two groups (p = 0.37).

Conclusions. The best results in stones fragmentation and less analgesia requirement were demonstrated in the electromagnetic lithotripter group. No differences were demonstrated considering the need for emergency room after the treatment.

KEY WORDS: Lithotripter; Stones; Extracorporeal shock wave lithotripsy; Electromagnetic; Electrohydraulic.

Submitted 5 June 2018; Accepted 3 August 2018

INTRODUCTION

Shock wave lithotripsy was introduced in the 1980s for the treatment of urinary stones and became a first line treatment option (1). Since the introduction of the Dornier HM3 lithotripter, there have been many changes to produce machines that were easier and more practical to use. Three shock wave generating principles have been used in clinical lithotripters: electrohydraulic, electromagnetic and piezoelectric, but they work substan-

tially the same way (2). Many studies compare different lithotripters or different energy source in order to evaluate efficacy (3, 4). In our institution, we used an electrohydraulic lithotripter and when it was no longer available, we used an electromagnetic one.

MATERIALS

AND METHODS

We retrospectively reviewed the data collected and compared the results obtained with the two lithotripters, using chi-square test, with significance considered at p < 0.05.

The patients collected were 189. Between September 2016 and April 2017 we treated with HMT Lithotron® LITS 172, an electrohydraulic lithotripter, 102 patients and when it was no longer available we use, between May and September 2017, a Storz Medical Modulith® SLK, electromagnetic, with 87 patients.

All the patients underwent sonography before and four to eight weeks after the treatment, performed by the same urologists. The targeting during the treatment was sonographic for renal stones and X-ray for ureteral stones. All the patients received Ketorolac (30 mg) before the treatment or Paracetamol (1g) in case of allergy with a supplement of Pethidine, according to weight, if needed. When we evaluated complications after the treatment, patients who visited the emergency room within 48 hours were included (5). People lost to follow-up and with incomplete data were excluded.

RESULTS

We enrolled 173 patients, 129 males and 44 females with a mean age of 58 ± 12 years. 94 were treated with the electrohydraulic lithotripter, 23 females and 71 males, and 79 with the electromagnetic one, 21 females and 58 males.

In the group treated with the electromagnetic lithotripter the mean diameter of the stones was 9.59 ± 3.04mm and 16 patients had multiple stones. 73 had stones in the kidney and 6 in the ureter.

The mean number of shock waves was 3079 (3043 in the kidney and 3516 in the ureter) with a 3-4Hz frequency.

In the group treated with the electrohydraulic one, the mean diameter of the stones was 10.39 ± 3.41 mm and 18 patients had multiple stones. 73 had stones in the kidney and 21 in the ureter. The mean number of shock

No conflict of interest declared.

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waves was 2228 (2139 in the kidney and 2500 in the ureter) with a 1-2Hz frequency (Table 1).

43 patients (54%) in the electromagnetic group and 31 (33%) in the electrohydraulic group presented clinically insignificant residual fragments, defined as asymptomatic, noninfectious, ≤ 3 mm fragments (CIRFs).

The data were compared using chi-square test, demonstrating that the association between presence of CIRFs or stone free status and kind of lithotripter was statistically significant (p = 0.004).

An association between the kind of lithotripter and the need for more analgesia during the treatment was evaluated. 14.9% of people treated with electromagnetic (13 patients) and 81% of people treated with electrohydraulic (83 patients) asked for Pethidine. People treated with electromagnetic lithotripter needed less analgesia (p < 0.001).

The causes of access to the emergency room were intractable pain, kidney failure, fever (> 38°C) and Steintrasse. 10 patients treated with electromagnetic an 8 treated with electrohydraulic went to emergency room within 48 hours and the difference was not statistically significant (p = 0.37) (Table 2).

Table 1.

Characteristics of stones and treatments.

Mean diameter of the stones Patients with multiple stones kidney stones ureteral stones Mean number of shock waves

Frequency of shock waves

Electromagnetic lithotripter 9.59 ± 3.04 mm 16 73 6 3079 (3043 kidney and 3516 ureter) 3-4Hz

Electrohydraulic lithotripter 10.39 ± 3.41 mm 18 73 21 2228 (2139 kidney and 2500 ureter) 1-2Hz

Table 2.

Success rate,complications and analgesia requirement.

Electromagnetic lithotripter CIRFs 43 Lithiasis > 3 mm 36 Access to emergency room 10 No complications 69 Analgesia requirement 13 Asymptomatic patients 74

Electrohydraulic P lithotripter 31 0.004 63 8 0.37 86 83 0.00001 19

DISCUSSION

The electrohydraulic lithotripter has a source that generates a shock wave that is focused by an ellipsoidal reflector. The pressure pulse originates as a shock wave and remains a shock wave at all times. During shooting, there can be significant variation in the amplitude of the shock wave and there can be some shift in the position of the focal zone at the target.

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The electrodes wear out and must be replaced because this can affect their acoustic output. The electromagnetic lithotripter uses an electrical coil in proximity to a metal plate as an acoustic source. When the coil is excited by a short electrical pulse, an acoustic wave is generated.

Focusing is very reproducible and the variation in measured pressure waves is less than 10%.

The shock waves generated by electromagnetic lithotripters are inherently more consistent than in electrohydraulic. An additional advantage is that there are no electrodes to replace (2).

As seen above, there are inherent differences between the two kinds of lithotripter, but each brand has its own features (6-8).

The position of the patient is different. With Lithotron®, the patient is supine, with his flank lying on the therapy head and sometimes must be fixed to the bed to avoid involuntary movements (9). With Modulith®, the patient is prone and the respiratory movements are smaller.

In both, the therapy head is filled with water, covered by a thin rubber membrane pressed against the patient and through which the shock wave passes and gel is used as coupling agent (10).

The number of the shock waves depends on the stone fragmentation. The frequency depends on the configuration of the lithotripter. For the Lithotron® the frequencies available are 1 or 2 shock waves per second. For the Modulith® the frequency depends on the energy delivered and with higher energy the frequency is 3 or 4 shock waves per second.

In literature there are many studies that compare different lithotripters. Some studies evaluate, as we did, the differences between electrohydraulic and electromagnetic lithotripters, however, the results are discordant (3, 4).

In our series electromagnetic lithotripter has better results.

Another important argument about SWL is pain management (11).

Discomfort during shock wave treatment is due primarily to the sensation of cutaneous pain over the area of shock wave entry at the surface of the body (2). Analgesics used include opioids, NSAIDs and local analgesia, however, there is no consensus on standard analgesia for pain during SWL (12).

In our series, pain is better managed in patients treated with electromagnetic lithotripter.

Many complications after ESWL are reported. The most dangerous are renal hematomas and injuries to adjacent organs, but the most frequent are flank pain, hematuria, fever, nausea with vomiting and acute urinary retention (5). We had no severe complication and in the two groups, the access to the emergency room was similar.

CONCLUSIONS

All the treatments and the follow up were performed by the same group of urologists with years of experience.

In the series we considered, the best results in stones fragmentation (p = 0.004) and less analgesia requirement (p < 0.001) were demonstrated in the electromagnetic lithotripter group. No differences were demonstrated considering the need for emergency room after the treatment (p = 0.37).

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Comparison of an electromagnetic and an electrohydraulic lithotripter: Efficacy, pain and complications

REFERENCES 1. Tailly GG. Extracorporeal shock wave lithotripsy today. Indian J Urol. 2013; 29:200-7.

2. Cleveland RO, McAteer JA. The physics of shock wave lithotripsy.

In: Smith AD, Badlani GH, Preminger GM, et al., editors. Smith’s Textbook on Endourology 3. Vol. 1. Hoboken: Wiley-Blackwell; 2012; pp. 529-558.

3. Matin SF, Yost A, Streem SB. Extracorporeal shock-wave lithotripsy: a comparative study of electrohydraulic and electromagnetic units. J Urol. 2001; 166:2053-6.

4. Bhojani N, Mandeville JA, Hameed TA, et al. Lithotripter outcomes in a community practice setting: comparison of an electromagnetic and an electrohydraulic lithotripter. J Urol. 2015; 193:875-9.

5. Lu CH, Kuo JY, Lin TP, et al. Clinical analysis of 48-h emergency department visit post outpatient extracorporeal shock wave lithotripsy for urolithiasis. J Chin Med Assoc. 2017; 80:551-557.

6. Ng CF, Thompson TJ, McLornan L, Tolley DA. Single-center experience using three shockwave lithotripters with different generator designs in management of urinary calculi. J Endourol. 2006; 20:1-8.

Correspondence Grazia Bianchi, MD (Corresponding Author) graziuccia88@libero.it Diego Marega, MD Roberto Knez, MD Stefano Bucci,MD Carlo Trombetta, MD trombcar@units.it Università degli Studi Trieste, Urology Department – Cattinara Hospital, Strada di Fiume 447, Trieste, Italy

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DOI: 10.4081/aiua.2018.3.172

ORIGINAL PAPER

Effect of variant histology presence and squamous differentiation on oncological results and patientâ&#x20AC;&#x2122;s survival after radical cystectomy Ertugrul Sefik, Serdar Celik, Ismail Basmaci, Serkan YarÄąmoglu, Ibrahim Halil Bozkurt, TarÄąk Yonguc, Bulent Gunlusoy Bozyaka Training and Research Hospital, Department of Urology, Izmir, Turkey.

Summary

Objective: To evaluate the effect of variant histology on pathological and survival findings in patients undergoing radical cystectomy due to muscle invasive bladder cancer.

Materials and methods: Data from 146 patients with radical cystectomy performed due to muscle-invasive urothelial carcinoma between January 2006 to November 2016 at our clinic were investigated. The preoperative and postoperative data of patients with variant histology were compared with nonvariant urothelial carcinoma patients. Then of patients with variant histology only those with squamous differentiation (SqD) were compared with nonvariant urothelial carcinoma patients in terms of preoperative, postoperative and survival data.

Results: Of the 146 patients, 23 had carcinoma with variant histology. Of these, 17 had SqD, 4 had glandular differentiation, 1 patient had plasmocytoid variant and 1 patient had sarcomatoid variant. In patients with variant histology, postoperative T stage and upstaging was higher, with no difference observed in terms of overall and cancer-specific survival compared with nonvariant urothelial cancer patients. SqD patients were observed to have higher postoperative T stage compared to nonvariant urothelial cancer patients, with no significant difference observed in terms of survival.

Conclusions: In cystectomy pathologies, patients with variant histology (especially SqD patients) were observed to have proportionally higher T stage compared to nonvariant urothelial carcinoma; however there were no significant differences for overall survival and cancer-specific survival.

KEY WORDS: Bladder cancer; Radical cystectomy; Squamous differentiation; Variant histology; Survival.

Submitted 26 March 2018; Accepted 7 May 2018

INTRODUCTION

The most common histologic type observed in bladder cancers is urothelial carcinoma. Urothelial carcinoma is known to sometimes display extraordinary characteristics (variants) differentiated from normal morphology (1). The histologic variant differentiation rate for bladder urothelial carcinoma is reported as 7-81% in radical cystectomy series (2). There are some studies stating that oncologic results and especially survival results are worse for bladder cancers with variant histology (3, 4).

The most commonly observed among histologic variants

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of urothelial carcinoma is squamous differentiation (SqD), though other non-SqD variants may be observed (5).

There are studies reporting that the survival for non-SqD histologic variants is lower (6).

In our study in patients with radical cystectomy performed due to muscle-invasive bladder cancer, firstly we aimed to assess the effect of the presence of variant histology on oncologic results and survival results, and secondly we aimed to compare oncologic data and survival data between the most commonly observed histologic variant of SqD with nonvariant urothelial carcinoma.

MATERIALS

AND METHODS

The data belonging to 178 patients with radical cystectomy performed for bladder tumors from January 2006 to November 2016 at our clinic were retrospectively investigated. Patients who undergone radical cystectomy due to high risk non-muscle-invasive bladder, patients with non-urothelial carcinoma pathology and patients who had missed data were excluded from the study.

Finally the study included 146 patients who undergone radical cystectomy operation due to muscle-invasive urothelial bladder carcinoma. Pathologic staging of patients was performed according to the 2002 Union for International Cancer Control (UICC) TNM staging system.

All patients provided informed consent before the procedure. Before radical cystectomy, patients had preoperative clinical staging with examination, transurethral resection (TUR) and computed tomography.

The age, gender, preoperative data (presence of hydronephrosis, clinical stage and tumor grade and presence of carcinoma in situ (CIS) in TUR pathology data, postoperative data (postoperative T stage, tumor grade, surgical margin positivity, lymph node metastasis, presence of prostate and urethra invasion and lymphovascular invasion), upstaging and overall and cancer-specific survival data were assessed.

Additionally patients with variant histology on radical cystectomy pathology and the histologic type of this variant were noted. Patients with variant histology observed were called Group 1, with patients with nonvariant histology called Group 2. Patients in Group 1 with SqD were separately assessed.

No conflict of interest declared.

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Variant histology and survival after radical cystectomy

A total of 23 patients had variant histology; 17 had SqD, 4 had glandular differentiation, 1 patient had plasmocytoid variant and 1 patient had sarcomatoid variant.

The preoperative, postoperative and survival data and comparison between Group 1 (n = 23) and Group 2 (n = 123) are given in Table 1. When the comparison results are investigated, in the preoperative data, age, gender and clinical T stage and TUR pathology tumor grade and CIS presence were similar in Group 1 and Group 2.

In the postoperative data, tumor grade, surgical margin positivity, prostate invasion, urethral invasion and presence of lymphovascular invasion were similar in both groups. However, the postoperative pathologic T stage and pathologic upstaging were significantly higher in RESULTS Group 1. There were no significant differences observed There were 13 females and 133 males with radical cysbetween the groups in terms of overall and cancer-spetectomy performed due to muscle-invasive bladder cancific survival. cer. The mean age of all patients was 64.4 ± 9 years.

Data for patients with urothelial carcinoma with the The mean follow-up time was 31.7 ± 31.8 months. most commonly observed variant histology of SqD along with Group 2 patient data were compared and results are given in Table 2.

Table 1.

Patients with SqD had significantly Preoperative and postoperative patient characteristics and survival higher rates of preoperative tumor results for Group 1 and Group 2. grade (p = 0.020) and postoperative pathologic T stage (p = 0.040) comVariant Variant P* pared with Group 2. When survival histology (+) histology (-) n: 23 n: 123 data were examined, though patients Age 63.7 ± 10.4 64.5 ± 8.7 0.119 with SqD had lower overall survival (52.3 ± 4.7 and 49.6 ± 10.4 months, Gender Female 4 9 0.136 Male 19 114 respectively) and cancer-specific surPreoperative hydronephrosis Positive 11 40 0.158 vival times (64.7 ± 5.3 and 58.4 ± 10.7 Negative 12 83 months, respectively) compared to Preoperative T stage T2 23 118 0.325 Group 2, no statistically significant difT3 0 5 ference was found between the two Preoperative tumor grade Grade 1 1 0 0.065 groups.

Statistical analysis Patient data was first compared between Group 1 and Group 2 and then between patients with SqD and Group 2 using the Mann-Whitney U test and the Pearson X2 test. The cancer-specific survival and overall survival times in the groups were assessed with the Kaplan-Maier survival analysis. Statistical analysis was completed using the Statistical Package for the Social Sciences (SPSS) Version 20.0 (SPSS, Chicago, Illinois, USA). Data are presented as mean and standard deviation, with statistical analysis calculated on the median values. The analysis results with p value < 0.05 were accepted as significant.

CIS Postoperative T stage

Postoperative tumor grade

Grade 2 Grade 3

1 21

4 119

Positive Negative

5 18

≤ T1 T2 T3 T4

0 10 10 3 1 1 21

37 83 19 61 17 26

1 2 3 Positive Negative

3 20

Lymph node metastasis

Positive Negative

7 16

Invasion of prostate

Positive Negative

Invasion of urethra

0.380 0.035

4 4 104

0.967

0.416

2 20

25 98 23 93 15 100

Positive Negative

2 21

8 108

0.760

Lymphovasculer invasion

Positive Negative

7 16

18 100

0.081

Perineural invasion

Positive Negative

3 17 14 9 52.3 ± 4.70 64.8 ± 5.3

17 101

0.864

45 78 0.816 0.824

0.029

Surgical margin

Upstaging Overall survival Cancer spesific survival

Positive Negative 47.1 ± 8.6 52.8 ± 4.8

DISCUSSION

In our study, the rate of patients with variant histology on radical cystectomy pathology was 16%, while the SqD rate was 12%. In the literature, different studies show different rates for variant histology, with these rates reported between 7 and 81% (2).

This large difference in variant histology rates may be explained by not using defined criteria for evaluation. SqD is reported to be most common among observed histologic variants, in fact in our study the rate of SqD among all histologic variants is 74% (17/23). Though SqD is characterized by histologic intercellular bridges and keratinization, the World Health Organization (WHO) defines it is a urothelial carcinoma variant (7). Among non-urothelial bladder cancers, squamous cell carcinoma and adenocarcinoma are known for their aggressive nature and low survival rates (8). However there is no consensus on the prognostic importance of histologic

0.160 0.606

*Mann-Whitney U test CIS:carcinoma in situ.

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E. Sefik, S. Celik, I. Basmaci, S. Yarımoglu, I. Halil Bozkurt, T. Yonguc, B. Gunlusoy

Table 2.

Patient characteristics and survival results of urothelial carcinoma with squamous differentiation and nonvariant urothelial cancer patients.

Age Gender Preoperative hydronephrosis Preoperative T stage Preoperative tumor grade

CIS Postoperative T stage

Postoperative tumor grade

Surgical margin Lymph node metastasis Upstaging Overall survival Cancer specific survival

Female Male Positive Negative T2 T3 Grade 1 Grade 2 Grade 3 Positive Negative ≤ T1 T2 T3 T4 1 2 3 Positive Negative Positive Negative Positive Negative

Squamous differantiation n: 17 66.9 ± 10 3 14 7 10 17 0 1 0 16 4 13 0 8 6

Nonvariant urothelial cancer n: 123 64.5 ± 8.8 9 114 40 83 118 5 0 4 119 37 83 19 61 17

3 1 1 15 3 14 4 13 10 7 49.6 ± 10.4 58.4 ± 10.7

26 4 4 104 25 98 23 93 45 78 52.3 ± 4.7 64.7 ± 5.3

variants of urothelial carcinoma. Studies of variant histologies and their clinical importance are examined, have generally heterogeneous populations and small scale.

A study by Monn et al. observed that generally patients with variant histology have high pathologic T stage.

When subtypes are investigated, while plasmocytoid and micropapillary variants have high mortality, SqD and sarcomatoid variants were identified to have similar survival to nonvariant urothelial carcinoma (9).

In our study, patients with variant histology had higher postoperative pathologic T stage and upstaging rate compared to nonvariant urothelial carcinoma patients, while survival rates were similar in accordance with the literature.

There are studies showing that bladder cancers with variant histology forms are aggressive tumors with high tumor stage and high lymph node metastasis rates (10-12).

Xylinas et al. reported that patients with variant histology on radical cystectomy pathology were correlated with high tumor stage, high lymph node metastasis, lymphovascular invasion (LVI) presence, high recurrence risk and increased cancer-specific mortality.

Furthermore, they stated the patients with non-squamous differentiation were the worst prognostic group. In spite of this, they reported that variant histology was not an

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independent risk factor in terms of prognosis (13).

In the present study, though the preoperative tumor grade and postoperative tumor stage were high among patients with SqD, the overall survival and cancer-specific survival were similar to nonvariant urothelial carcinoma.

Our findings support the report of Moschini et al. who assessed 1067 radical cystectomy cases, observing SqD in 10.2% of patients with no effect of SqD on survival (14).

Our study has some limitations.

The most important of these are that it is a retrospective study and the low number of patients.

P*

0.219 0.154 0.479 0.397 0.020

0.538

CONCLUSIONS

0.040

Patients with variant histology on cystectomy pathology were observed to have high T stage compared to those with nonvariant urothelial cancer; however there were no significant differences in overall survival and cancerspecific survival.

When the most commonly observed histologic variant of SqD is investigated, though there was higher stage disease compared to nonvariant urothelial cancers, there was no effect shown on overall survival and cancer-specific survival.

0.802

0.796 0.723 0.078 0.626 0.743

REFERENCES

1. Shah RB, Montgomery JS, Montie JE, Kunju LP. Variant (divergent) histologic differentiation in urothelial carcinoma is underrecognized in community practice: impact of mandatory central pathology review at a large referral hospital. Urol Oncol. 2013; 31:1650-55.

2. Chalasan i V, Chin JL, Izawa JI. Histologic variants of urothelial bladder cancer and nonurothelial histology in bladder cancer. Can Urol Assoc J. 2009; 3(6 Suppl.4):S193-8.

3. Cai T, Tiscione D, Verze P, et al. Concordance and clinical significance of uncommon variants of bladder urothelial carcinoma in transurethral resection and radical cystectomy specimens. Urology.

2014; 84:1141-6.

4. Wasco MJ, Daignault S, Zhang Y, et al. Urothelial carcinoma with divergent histologic differentiation (mixed histologic features) predicts the presence of locally advanced bladder cancer when detected at transurethral resection. Urology. 2007; 70:69-74.

5. Gluck G, Hortopan M, Stanculeanu D, et al. Comparative study of conventional urothelial carcinoma, squamous differentiation carcinoma and pure squamous carcinoma in patients with invasive bladder tumors. J Med Life. 2014; 7:211.

6. Soave A, Schmidt S, Dahlem R, et al. Does the extent of variant histology affect oncological outcomes in patients with urothelial carcinoma of the bladder treated with radical cystectomy? Urol Oncol.

2015; 33:21.e1-21.e9.

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Variant histology and survival after radical cystectomy

7. Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference committee. Am J Surg Pathol. 1998; 22:1435.

8. Rogers CG, Palapattu GS, Shariat SF, et al. Clinical outcomes following radical cystectomy for primary nontransitional cell carcinoma of the bladder compared to transitional cell carcinoma of the bladder. J Urol 2006; 175:2048-53.

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

12. Hautmann RE, dePetriconi RC, Pfeiffer C, Volkmer BG. Radical cystectomy for urothelial carcinoma of the bladder without neoadjuvant or adjuvant therapy: long-term results in 1100 patients. Eur Urol. 2012; 61:1039-47.

9. Monn MF, Kaimakliotis HZ, Pedrosa JA. Contemporary bladder cancer: variant histology may be a significant driver of disease. Urol Oncol. 2015; 33:18.e15-18.e20.

13. Xylinas E, Rink M, Robinson BD. Impact of histological variants on oncological outcomes of patients with urothelial carcinoma of the bladder treated with radical cystectomy. Eur J Cancer. 2013; 49:1889-97.

10. Shariat SF, Karakiewicz PI, Palapattu GS, et al. Outcomes of radical cystectom y for transitional cell carcinoma of the bladder: a contemporary series from the Bladder Cancer Research Consortium.

J Urol. 2006; 176:2414-22.

14. Moschini M, Dell'Oglio P, Luciano' R, et al. Incidence and effect of variant histology on oncological outcomes in patients with bladder cancer treated with radical cystectomy. Urol Oncol. 2017; 35:335-41.

Correspondence Ertugrul Sefik, MD (Corresponding Author) sefikanamur@yahoo.com Serdar Celik, MD Ismail Basmaci, MD Serkan YarÄąmoglu, MD Ibrahim Halil Bozkurt, MD TarÄąk Yonguc, MD Bulent Gunlusoy, MD Bozyaka Training and Research Hospital, Department of Urology, Izmir, Turkey

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DOI: 10.4081/aiua.2018.3.176

ORIGINAL PAPER

Feasibility study for interspecialistic collaboration in active research of urothelial neoplasms of professional origin Roberta Stopponi 1, Enrico Caraceni 2, Angelo Marronaro 2, Andrea Fabiani 3, Stefania Massacesi 1, Anna Rita Totò 1, Roberto Calisti 1 1 Servizio

Prevenzione e Sicurezza Ambienti di Lavoro, ASUR Marche AV3, Civitanova Marche, Italy; ASUR Marche AV3 - Ospedale Civitanova Marche, Italy; 3 Urologia ASUR Marche AV3 - Ospedale Macerata, Italy.

2 Urologia

Summary

Introduction: In Italy only a small fraction of cancer is reported to the supervisory body and recognised as professional by the insurance institution.

Among the causes of this sub-notification, especially for lowgrade etiologic fractional cancers such as bladder cancers are the lack of knowledge of carcinogenicity in the occupational field and the consequent incomplete medical history collections.

Objectives: Diagnosis of occupational bladder neoplasms and activation of systematic surveillance of tumors of professional origin through an "active research" program.

Methods: From July 2010 to July 2017, all patients diagnosed with Bladder Cancer in the departments of Urology of Area Vasta 3 ASUR Marche underwent a first interview and a further anamnestic study in selected cases.When an occupational exposure was recognised, more information for preventive, social security and criminal justice has been acquired.

Results: The study highlighted 18 cases of bladder tumors due to occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons, which are the most important risk factor for BC after tobacco smoking.

Conclusions: Our study confirmed that active research is an useful tool both for the activation of epidemiological surveillance and for the regional registration of professional tumors.

In addition active research of occupational exposure allow obtaining information that can be used for preventive purposes, for criminal justice and for the initiation of medico-legal actions and improvement of working conditions aimed at guaranteeing workers' rights.

KEY WORDS: Bladder Cancer; Occupational Exposure; Epidemiology.

Submitted 2 July 2018; Accepted 19 July 2018

INTRODUCTION

The contribution of occupational exposures to cancers has been clearly identified. However, occupational exposures in many cancers still remain under-reported.

Identification of occupational diseases can result in both a worker’s compensation by insurance companies and a reimburse for medical assistance related to the specific condition.

Knowledge of both insurance system and occupational cancer are the main factors that contribute to the request of worker’s compensation. Prevalence of occupational cancers vary according to studies design and type of

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tumor. The first epidemiological study on occupational cancers was conducted in the USA in the 1980s and attributed 4% of all cancers to occupational exposures (8% for men and 1% for women) (1); a more recent Finnish epidemiological study (2) considers 8% of neoplasms (14% for men and 2% for women) as of possible professional origin. According to data from AIRTUM 2009 (3), bladder cancer is the 4th most common cancer in Italy, accounting for an estimated 17,000 new cases diagnosed each year. It affects men more frequently than women. Over the years there has been both a reduction in the incidence and mortality of bladder cancer (5-year cancer specific survival of 70% and 72%, in men and women respectively). Cigarette smoking is the primary risk factor for bladder cancer and several epidemiological studies describe the impact of tobacco smoking on its development. In the developed countries cigarette smoking accounts for 60-66% of all new cases of bladder cancer. Occupational exposure still remains the second most important risk factor for bladder cancer (4-6).

Correlation between bladder cancer and work environment it is well known since 50ths. Occupational exposure accounts for about 5 to 15% of all cases (7), depending on the criteria adopted and the geographical areas in which the epidemiological studies have been conducted.

The most notable occupational agents which act as the main factors for the development of bladder cancer are the aromatic amines, in particular, followed by polycyclic aromatic hydrocarbons (8). This type of occupational exposure occurs mainly in industrial plants which process paints, dyes, metal and petroleum products, as well as in rubber, cosmetic and print industries. Some studies have shown an increased bladder cancer risk among footwear manufacturers.

Despite the clear evidence of correlation between cancer and occupational exposure, the identification of occupational cancer and, consequently, the insurance compensation of workers, are still lacking, in particular in tumors with a low etiologic fraction such as the bladder cancer. This under-reporting is often caused by the confusion between professional exposure and other determinants at the individual level (9). There are many interventions aimed at improving the obligation of notification by doctors.

No conflict of interest declared.

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Professional urothelial neoplasms

A publication by Cochrane (10) says that there is no single intervention that has proven to be effective in improving notifications of professional tumors. On the contrary authors conclude by saying that it is important to create a network that allows a better knowledge of professional tumors. It is also important that this network helps to raise awareness among doctors in the clinical setting and contributes to active case research, to patient information and care facilities.

With the aim of improving notification of professional tumors it is also important their identification by recordlinkage method (11) or the active research of patients affected by professional diseases by questionnaire of occupational history when the patient is admitted to the hospital or after discharge.

Finally, for the sake of completeness, other risk factors involving in the development of bladder cancer are infection by Schistosoma haematobium responsible for a chronic endemic cystitis, frequent use of cyclophosphamide and phenacetine and consumption of water contaminated by arsenic (12, 13), that is well known in some italian regions (14).

In the Marche region (OCCAM - OCCupational CAncer Monitoring research 2001-2005), 1629 cases of bladder carcinoma were detected (out of a total of 1,560,785 inhabitants), which is equivalent to 326 cases each year.

The professional etiological fraction attributable to the bladder neoplasm is 5-15%, but considering that during the same period (2001-2005) the insurance certification was made only in 13 patients with professional bladder cancer, it is clear that it is sufficient notification of the bladder of the tumor due to occupational exposure. that notification of the bladder tumors due to occupational exposure is not sufficient.

For this reason, considering that in the “Occupational Prevention and Safety Service” - Asur Marche AV3 - of Civitanova Marche, there is the regional registry of tumors with a low etiological fraction (regional resolution of 29 December 2009), we decide to start a research program on the professional origin bladder cancer among patients admitted to two urological departments (Civitanova Marche and Macerata).

METHODS

the questionnaires referring to cases of transitional cell urothelial carcinoma accepting/validating only the cases of bladder carcinoma with histological diagnosis of the most typically urothelial or epidermoid form (representing the latter the expression of a carcinogenic process with "chronic irritative" component associated with DNA damage). This selected cases have been subjected to specific occupational anamnesis using a standardised questionnaire called "questionnaire on work, life habits and health" based on the questionnaires used in the the National Register of Nose-Sinus Tumors and the National Registry of Mesotheliomas (ReNaM and ReNaTuns) studies.

Collaterally, was conducted an informative campaign about the occupational bladder neoplasia, about the presence of an "active research of professional neoplasies" and about the possibility for workers and former workers to ask, directly or through a medical request, specific information. The standardised anamnestic questionnaire was directly submitted to the cases reached through this channel.

The diagnoses of occupational disease and the attributions of exposure and cause were based on coherence between the professional history, technological knowledge, epidemiological evidence and, in the absence of other efficient causes, on the etiopathogenetic model.

After the medical history, the Occupational doctor proceeded in the: • acquisition of company documentation useful for the legal medical investigation • inspection of the work places if still existing • assignment of an exposure matrix based on the work history • expression of a certain, probable or possible judgment on the professionalism or otherwise of the disease • identification of any responsibility on the part of the company.

RESULTS

The cases reported by the Departments of Urology and assessed with a brief history were 164 (Figure 1). A further nine cases came to the Service through other channels: five workers, one of whom was advised by his General Practitioner, presented directly to the Medical Department of the PSAL Service, 3 were sent by the Judicial Authority represented by two other PSAL Services of the ASUR Marche and the Judicial Authority

The Urologists of the Departments involved in the study enrolled urinary bladder cancer patients from August 2010 through a “short” anamnestic questionnaire, preceded by an explanation of the motivation of this "anamnestic supple- Figure 1. ment". All subjects with bladder Sources of the cases studied. neoplasia were included: there were no recruitment restrictions on age, gender, ethnicity or cancer-stage.

Subsequently the Occupational doctors selected the subjects who, on the basis of the medical history, according to a preliminary postexposure attribution, could have been professionally exposed to bladder carcinogens.

The Occupational doctors validated

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R. Stopponi, E. Caraceni, A. Marronaro, A. Fabiani, S. Massacesi, A.R. Totò, R. Calisti

Figure 2.

Work activities.

(through a request for investigation) competent for the territory and one through the National Institute for Accident Insurance at Work (INAIL) channel (through reporting) (Figure 1).

Overall, 173 cases were evaluated: 27 females and 146 males. In two cases the bladder lesions were benign, while one case showed inflammation.

The average age at the first diagnosis is 71.09 years (for the female) and 70.2 years (for the man): the youngest patient is 30 years old and the oldest is 93 years old).

The 21% of cases are smokers at the time of the questionnaire administration and the 53% claimed to be an ex-smoker.

The medical staff of SPSAL evaluated the professional

exposures of all the cases reported based on the analysis of the short questionnaires administered by Urologists deciding to contact about a third (50 workers) for a more detailed professional history: of these seven refused further investigations.

After an anamnestic study, an exposure to bladder professional carcinogens was confirmed in more than half of the cases of hospital origin (n = 24); exposure has been revealed for all nine cases that have reached the Service through the other channels.

From the further anamnestic analysis it was possible to diagnose a professional illness with a certain “attribution of exposure and cause” in 19 cases, all of them male. The insurance process was started for 5 footwear workers, 1 cast-iron founder, 1 aluminum production employee, 2 dyers, 2 paint/varnish production workers, 2 hairdressers, 1 steel worker, 1 metalworker, 1 galvanic worker, 1 plastic rubber production assistant, 1 disinfection worker, 1 ceramic production worker (Figure 2).

The carcinogenic occupational substances for the bladder are predominantly the aromatic amines (12 cases), the polycyclic aromatic hydrocarbon (4 cases), the tetrachlorethylene (1 case) and the arsenic (1 case) (Figure 3).

The average of exposure to this substances is 23 years.

In two workers, other occupational diseases were diagnosed: namely a tumor of the nasal and paranasal sinuses from exposure to leather powder and asbestosis and pleural plaques from exposure to asbestos.

Only two companies are still active in which the exposure of workers to the bladder carcinogens has reasonably occurred.

Figure 3.

Prevalent exposures in cases for which the insurance process has been launched (aromatic amines AA, polycyclic aromatic hydrocarbons PAHs, tetrachlorethylene TCE and arsenic AS).

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Professional urothelial neoplasms

DISCUSSION

In our target group of 173 patients affected by bladder cancer, occupational exposure accounts for about 10% of all cases which is, on average, the worldwide percentage of professional urothelial neoplasms. We expected this result considering the production of local industry.

Tobacco smoking is not relevant for the certification of occupational disease when carcinogenic occupational exposure has been clearly established. Half of the workers for whom a certification request of occupational disease were made to stop smoking (average 36.8 year of smoking) and 20% were still smoking (30.8 years, on average).

We couldn’t find any definitive correlation between occupational exposure and multifocality, grading and histology because our data are insufficient on this purpose.

There are some evidences on the literature that occupational exposure could influence prognosis of bladder cancer so it is advisable to further analyse this aspect with a larger amount of data (15) . Otherwise, the correlation between occupational exposure and prognosis does not influence certification of professional disease and workers’ compensation.

Only in one patient after the diagnosis of bladder cancer the medical procedure for the certification of professional disease had been started. Therefore we made a request for certification of a professional disease in every patient where occupational exposure was identified except for a patient that needed a further investigation from territorial competent service.

Nowadays, this study confirms that the most important carcinogenic occupational factors for urothelial neoplasm are aromatic amines and polycyclic aromatic hydrocarbons.

In particular we found five patients affected by bladder cancer in leather and footwear industries. Processing of leather and footwear are well known to be an important cause of professional bladder cancer due to exposure to aromatic amines in painting processes.

We also confirm association between bladder cancer and industrial plants which process metal, in particular steel and iron foundries.

This association has been found in other studies too but at the moment there is not significant epidemiological evidence in order to certainly establish a higher risk of bladder cancer in this working context.

Industrial plants which involves aluminium production are also represented. In the literature aluminium industries are associated with the main carcinogens present in the processing and represented by the volatile derivatives of tar pitch.

In our study, in addition to cases of bladder cancer in workers of industrial plants which process paint and dye, association between urothelial neoplasms of the bladder and dyes production which involves use of aromatic amines is also represented.

Exposure to arsenic was the reason why we judged bladder cancer as a professional origin in a disinfestation worker. In fact arsenic was used to produce pesticides in the past (16).

We found a case of bladder cancer in a worker in the galvanic sector. In this case bladder neoplasm is not includ-

ed in the list of disease to be denounced according to the Italian legislation. Despite this the first certificate of occupational disease was completed because some studies have showed that exposure to tetrachlorethylene is reasonable associated with an increase of risk of bladder cancer (17).

We managed to found two companies still existing in which the exposure of workers to professional bladder carcinogens reasonably existed.

One was not a local factory and is based outside Marche region. For this reason data was sent to the competent territorial office. Instead the other factory is located in the Marche region so we were able to identify and characterise carcinogens in the work environment and proceed with action aimed at remove them. In addition another target was searching for responsibilities of the company.

The assessment of the presence of clusters is underway in a third company (currently not active) in the Marche region and in a company outside the region.

CONCLUSIONS

Active research of professional bladder neoplasms is a valid and simple tool able to identify cases of cancer of professional origin that otherwise would have remained unknown. Active research of professional cancer should be based on the careful clinical history of the patient, the knowledge of production cycles and information on risks obtained from the scientific literature.

In this contest certification of tumors of professional origin is also important to obtain workers’ compensation, to activate the systematic epidemiological surveillance of professional bladder neoplasms, to start the regional registration of these diseases, to certificate effects of occupational carcinogens useful for implementing data that can be used for preventive purpose and to evaluate effectiveness of preventive measures adopted to reduce incidence of these neoplasms.

Our experience confirms that it is fundamental to improve knowledge of bladder carcinogenic risks including professional ones and to implement preventive measures linked not only to life habits but to work environment also.

Apart from competent medicals, it is also important to involve other professional figures like family physicians and specialists pointing out the necessity of collecting a detailed medical history and to report diseases that could be of professional origin because of an exposition to occupational carcinogens in the past.

In addition, Occupational Physicians need to pay attention, promote and control to the establishment of registers of people who have been exposed to occupational carcinogens (ex art 248 D.lgs 81/08 smi). In the same time they have to improve professional prevention by monitoring the application of the legislation regarding the safety of work environment (art 224 e 225 del DlgS 81/08 smi). It is also crucial to promote the demise of artificial rubber extended to aromatic oils, by substitution with materials (paraffinic oils and naphthenic oils) without IPA or with a significantly reduced content of the same.

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R. Stopponi, E. Caraceni, A. Marronaro, A. Fabiani, S. Massacesi, A.R. Totò, R. Calisti

REFERENCES

1. Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst 1981; 66:1191-1308 2. Nurminen M, Karjalainen A. Epidemiologic estimate of the proportion of fatalities related to occupational factors in Finland. Scand J Work Environ Health. 2001; 27:161-213.

3. AIRTUM, Associazione Italiana Registro Tumori, “I trend dei tumori negli anni duemila”, 2009, http://www.registritumori.it/ cms/?q=Rapp2009Indice.

4. Letašiová S, Medve’ová A, Šovcíková A, et al. Bladder cancer, a review of the environmental risk factors. Environ Health 2012; 11(Suppl 1):S11.

5. Burger M, Catto JWF, Dalbagni G, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013; 63:234-241.

of occupational carcinogens]. G Ital Med Lav Ergon. 2008; 30:3925. (Article in Italian).

10. Curti S, Sauni R, Spreeuwers D, et al. Interventions to increase the reporting of occupational diseases by physicians. Cochrane Database Syst Rev. 2015;(3):CD010305. doi: 10.1002/14651858.

CD010305.pub2.

11. www.occam.it 12. Silverman DT, Devesa SS, Moore LE, Rothman N. Bladder cancer In Schottenfeld D, Fraumeni JF Jr (eds) Cancer Epidemiology and Prevention, 3rd ed, New York, NY 2006, Oxford University Press, pp 1101-1127.

13. Nuckols JR, Freeman LE, Lubin JH, et al. Estimating water supply arsenic levels in the New England Bladder Cancer Study.

Environ Health Perspect. 2011; 119:1279-85.

6. Miyazaki J, Nishiyama H. Epidemiology of urothelial carcinoma.

Int J Urol. 2017; 24:730-734.

14. Di Lorenzo G, Federico P, De Placido S, Buonerba C. Increased risk of bladder cancer in critical areas at high pressure of pollution of the Campania region in Italy: A systematic review”. Crit Rev Oncol Hematol. 2015; 96:534-41.

7. Olfert SM, Felknor SA, Delclos GL. An updated review of the literature: risk factors for bladder cancer with focus on occupational exposures. South Med J. 2006; 99:1256-63.

15. Selinski S, Bürger H, Blaszkewicz M, et al. Occupational risk factors for relapse-free survival in bladder cancer patients. J Toxicol Environ Health A. 2016; 79:1136-1143.

8. Cumberbatch MG, Cox A, Teare D, Catto JW. Contemporary occupational carcinogen exposure and bladder cancer: a systematic review and meta-analysis. JAMA Oncol. 2015; 1:1282-90.

9. Crosignani P, Amendola P, Audisio R, et al. [Confounding and confusion: recognition of causative relation and identification of victims

16. Boulanger M, Tual S, Lemarchand C, et al. Agricultural exposure and risk of bladder cancer in the AGRIculture and CANcer cohort. Int Arch Occup Environ Health. 2017; 90:169-178.)

17. Vlaanderen J, Straif K, Ruder A, et al. Tetrachloroethylene exposure and bladder cancer risk: a meta-analysis of dry-cleaning-worker studies. Environ Health Perspect. 2014; 122:661-6.

Correspondence Stopponi Roberta, MD (Corresponding Author) Massacesi Stefania, MD Totò Anna Rita, MD Calisti Roberto. MD Servizio Prevenzione e Sicurezza Ambienti di Lavoro, ASUR Marche AV3, Civitanova Marche, Italy Caraceni Enrico, MD Marronaro Angelo, MD ang6marr@yahoo.it Urologia ASUR Marche AV3 - Ospedale Civitanova Marche (Italy) Fabiani, MD Urologia ASUR Marche AV3 - Ospedale Macerata (Italy)

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DOI: 10.4081/aiua.2018.3.181

ORIGINAL PAPER

Association between large prostate calculi and prostate cancer Cem Yucel 1, Salih Budak 2 1 Department 2 Department

of Urology, Tepecik Training and Research Hospital, Izmir, Turkey; of Urology, Sakarya Training and Research Hospital, Sakaraya, Turkey.

Summary

Objective: We investigated the relationship between large prostate calculi and prostate

cancer (PCa) risk.

Materials and methods: The medical records of 340 patients who received a prostate biopsy at our institution between January 2015 and August 2016 were reviewed retrospectively.

Of the patients, 82 had large prostatic calculi visualised by transrectal ultrasonography and 88 did not or had scarce prostatic calculi. We divided these patients into two groups: patients with large prostatic calculi (group 1) and patients without prostatic calculi (group 2). These groups were compared according to age, total prostate specific antigen (PSA) level, prostate volume, and final pathological diagnosis.

Results: The mean age of all patients was 61.4 ± 6.2 years, the mean total PSA was 12.3 ± 17.4 ng/mL, the mean prostate volume was 41.7 ± 17.6 mL, and the overall cancer detection rate was 31.5%. The cancer detection rates were 41.3% and 22.6% in groups 1 and 2, respectively (p = 0.018). No significant differences in mean age, mean total PSA, or mean prostate volume were observed between the groups.

Conclusions: In the present study, large prostatic calculi were associated with PCa. However, more study is needed to examine the relationship between large prostatic calculi and PCa in more detail. The effects of particularly large prostate calculi in the development of PCa will be a necessary focus of future research.

KEY WORDS: Prostatic calculi; Prostate cancer; Ultrasound; Risk factors.

Submitted 21 January 2018; Accepted 21 February 2018

INTRODUCTION

Prostatic calculi are presumed to form by precipitation of prostatic secretions and desquamated acinar cells under inflammatory conditions (1). However, the clinical significance of prostatic calculi for evolution of cancer is unknown, immunological and inflammatory reactions may contribute to the carcinogenic process (2).

Histopathological and molecular biology studies have shown that inflammation of the prostate gland may contribute to the development of prostate cancer (PCa) (3).

Inflammation may affect the development of PCa in patients with prostate calculi compared to patients without prostate calculi (4). Two kinds of calculi exist in the prostate. Type 1 are discrete, multiple small echoes and are usually diffusely distributed throughout the gland,

whereas type 2 calculi are larger, multifaceted, and situated mainly in the prostatic ducts (5, 6). Larger prostate calculi are reportedly related to clinical prostatitis (5).

Transrectal ultrasonography (TRUS)-guided prostate biopsy remains the gold-standard method for diagnosing PCa, and prostatic calculi are frequently diagnosed by TRUS (1, 7). Although prostatic calculi are commonly seen in TRUS-guided prostate biopsy, the relationship between PCa and prostatic calculi is unclear. In the present study, we investigated the relationship between large prostate calculi and PCa risk.

MATERIALS

AND METHODS

The medical records of 340 patients who received a prostate biopsy at our institution between January 2015 and August 2016 were reviewed retrospectively.

Indications for prostatic biopsy included an abnormal digital rectal examination and/or an elevated serum prostate specific antigen (PSA) concentration (≥ 4.0 ng/mL). After informed consent was obtained from patients, all biopsies were taken transrectally with ultrasonographic guidance using a 25 cm, 18 gauge, sidenotch cutting (Tru-cut) needle. The biopsy was obtained from patients in the lateral decubitus position with periprostatic nerve blockage. Prostatic calculi and prostate volume were measured by TRUS. Prostate volume was calculated using the prostate ellipse formula (0.52 × length × width × height). We defined large prostatic calculi as multiple (≥ 3) or large (≥ 3 mm largest diameter) hyperechoic zones.

In the present study, among 340 patients, we included only patients who have large prostate calculi or have not prostate calculi. We excluded patients who have fewer than three prostatic calculi or < 3 mm prostatic calculi (67 cases). We also excluded patients who have chronic diseases (diabetes, hyperlipidemia, hypertension, cardiovascular disease) (49 cases), malignancy (9 cases), psychiatric disorders (9 cases), acute infections (8 cases), a history of urinary tract surgery (15 cases), a prior diagnosis of Pca (11 cases) and a history of irradiation (2 cases). A total number of 170 patients were enrolled in this study.

Patients were divided into two groups, group 1 included 82 patients with large prostatic calculi visualised by TRUS, whereas group 2 included 88 patients without

No conflict of interest declared.

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prostatic calculi. These groups were compared according to age, total PSA level, prostate volume, and final pathological results. We identified the PCa detection rates and Gleason scores of the two groups. We also compared the patients according to their final pathological diagnosis.

Statistical Analysis The conformity of variables to a normal distribution was assessed with the Kolmogorov-Smirnov test. Descriptive statistics for variables with a normal distribution and categorical variables are shown as means ± standard deviations and percentages, respectively. Student’s t test and the chi-square test were used for intergroup analyses of continuous variables. More than two independent averages were compared using analysis of variance and the Kruskal-Wallis test. Data were analysed using SPSS ver.

22.0 (SPSS Inc., Chicago, IL, USA), and a p-value < 0.05 was considered significant.

RESULTS

A total of 170 patients participated in this study.

The mean age of all patients was 61.4 ± 6.2 years, the mean total PSA was 12.3 ± 17.4 ng/mL, the mean prostate volume was 41.7 ± 17.6 mL, and the overall cancer detection rate was 30%. The clinical and demographic characteristics of the study patients are listed in Table 1.

According to the final pathological diagnosis, in group 1, 18 patients (21.9%) had prostatitis, 31 patients (37.8%) had benign pathology, 33 patients (40.2%) had PCa; in group 2, 34 patients (38.6%) had prostatitis, 36 patients (40.9%) had benign pathology and 18 patients (20.5%) had PCa (Table 2). The Gleason score was 6 in 23 (69.7%), 7 in three (9.1%) and ≥ 8 in seven (21.2%) patients in group 1 who were diagnosed with PCa; it was 6 in 16 (88.9), 7 in one (5.6%) and ≥ 8 in one (5.6%) patients who were diagnosed with PCa in group 2 (Table 2).

The cancer detection rates were 40.2% and 20.5% in groups 1 and 2, respectively (p = 0.018). No differences in mean age, mean total PSA, or mean prostate volume were observed in group 1 compared to group 2.

The comparisons of the patients according to their final pathological diagnosis, is summarized in Table 3.

Table 1.

Clinical and biological characteristics of all patients (n = 170).

Variables Age (years) PSA (ng/mL) Prostate volume (ml) Pathology (n, %) Prostatitis BPH PCa Gleason score (n, %) 6 7 ≥8

Mean (SD) 61.4 (± 6.2) 12.3 (± 17.4) 41.7 (± 17.6) 52 (30.6) 67 (39.4) 51 (30.0) 39 (76.4) 4 (7.6) 8 (15.6)

PSA: prostate specific antigen, BPH: benign prostatic hyperplasia, PCa: prostate cancer

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Table 2.

Clinical variables for patients with and without prostatic calculi.

Variables Age (years) PSA (ng/mL) Prostate volume (ml) Pathology (n, %) Prostatitis BPH Pca Gleason score (n, %) 6 7 ≥8

Group 1 (n = 82) Group 2 (n = 88) (with calculi) (without calculi) 60.5 (± 8.1) 61.8 (± 7.2) 12.8 (± 15.1) 11.3 (± 7.8) 42.5 (± 10.7) 39.2 (± 18.5)

P value 0.946 0.439 0.345

18 (21.9) 31 (37.8) 33 (40.2)

34 (38.6) 36 (40.9) 18 (20.5)

0.438 0.790 0.018

23 (69.7) 3 (9.1) 7 (21.2)

16 (88.9) 1 (5.6) 1 (5.6)

0.289 0.302 0.041

PSA: prostate specific antigen, BPH: benign prostatic hyperplasia, PCa: prostate cancer

Table 3.

Comparisons of patients according to the final pathologic diagnosis.

Variables Age (years) PSA (ng/mL) Prostate volume (ml) Large prostate calculi (n, %) Absent prostate calculi (n, %)

Prostatitis BPH PCa (n = 52) (n = 67) (n = 51) 58.8 (± 7.3) 60.2 (± 6.6) 65.2 (± 7.2) 8.7 (± 9.1) 7.9 (± 8.5) 21.7 (± 12.3) 40.2 (± 9.4) 43.6 (± 11.2) 40.7 (± 8.1)

P value 0.686 < 0.01 0.867

18 (34.6)

31 (46.2)

33 (64.7)

< 0.01

34 (65.3)

36 (53.7)

18 (35.2)

< 0.01

PSA: prostate specific antigen, BPH: benign prostatic hyperplasia, PCa: prostate cancer

DISCUSSION

Prostatic calculi are generally detected while performing TRUS (8). Prostate calculi occur during the aging process and may not produce any symptoms (9). The definition of prostatic calculi has not been well described in the literature, so the incidence of prostatic calculi may differ by definition; it is about 30% in histological studies and increases to 71% in radiological-histological correlational studies. Prostatic calculi exist in about 99% of autopsy specimens (10). In our study, large prostate calculi were found in 48.2% of participants.

A limited number of studies are available on the correlation between PCa and calculi (4, 8, 11, 12). Griffiths et al. analysed the ultrasound images of 221 patients with diagnosed PCa and observed a 63% association between PCa and prostatic calculi (11). Hwang et al. reviewed the medical records of 417 patients who underwent a TRUSguided prostate biopsy and reported that prostatic calculi were found more often in patients diagnosed with PCa (4). They also reported that prostatic calculi are correlated with a higher Gleason score when PCa is proven.

In another study, Smolski et al. found that 78.1% of peripheral zone calculi were associated with PCa (8).

This percentage was higher than in our study. We did not assess the prostate zones separately. A specific zone assessment of the prostate may be more useful for detect-

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ing PCa. Contrary to the aforementioned studies, Woods et al. analysed the histological material of 266 radical prostatectomy and 10 cystoprostatectomy cases and suggested that prostatic microcalculi were less commonly associated with PCa (12). In our study we observed that PCa was more common in patients with large prostatic calculi, and, similar to Hwang et al., we found that prostatic calculi were correlated with high-grade PCa. Chronic inflammation damages the prostate cells and promotes proliferation, so PCa can develop from the damaged cells. Mutations in prostate cells also contribute to the development of PCa. Although the relationship between inflammation and PCa remains unclear, antiinflammatory drugs (e.g., aspirin) potentially reduce the incidence of PCa and PCa-specific mortality (13).

A meta-analysis of 11 studies revealed a 60% increased risk of PCa in patients with prostatitis (14). Contrary to the aforementioned studies, the Reduction by Dutasteride of Prostate Cancer Events trial reported that patients with inflammation in an initial negative biopsy had a lower risk of PCa than those who received a repeat prostate biopsy. Inflammation can elevate PSA levels, and these patients are selected more often for repeat prostate biopsy; thus, these patients have a lower risk of being diagnosed with PCa (15). In our study, patients with large prostatic calculi tended to have higher PSA levels than patients who had no prostatic calculi, but this difference was not significant. The Prostate Cancer Prevention Trial (PCPT) found that PCa, in particular high-grade PCa, was more common in patients with chronic inflammation (16). In the present study, we observed that PCa was more common in patients with large prostatic calculi.

Although our study had a small sample size, we achieved similar results to those reported in the PCPT trial.

2. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002; 420:860-867.

CONCLUSIONS

13. Liu Y, Chen JQ, Xie L, et al. Effect of aspirin and other nonsteroidal anti-inflammatory drugs on prostate cancer incidence and mortality: A systematic review and meta-analysis. BMC Med. 2014; 12:55.

Prostate calculi are a common finding on ultrasonographic evaluation of the prostate, but their role in the development of PCa is not fully understood. In the present study, large prostatic calculi were associated with PCa. However, more work is needed to examine the relationship between large prostatic calculi and PCa in more detail. The effects of particularly large prostate calculi in the development of PCa will be a focus of further research.

REFERENCES

1. Park SW, Nam JK, Lee SD, et al. Are prostatic calculi independent predictive factors of lower urinary tract symptoms? Asian J Androl. 2010; 12:221-226.

3. Palapattu GS, Sutcliffe S, Bastian PJ, et al. Prostate carcinogenesis and inflammation: Emerging insights. Carcinogenesis. 2005; 26:1170-1181.

4. Hwang EC, Choi HS, Im CM, et al. Prostate calculi in cancer and BPH in a cohort of Korean men: Presence of calculi did not correlate with cancer risk. Asian J Androl. 2010; 12:215-220.

5. Geramoutsos I, Gyftopoulos K, Perimenis P, et al. Clinical correlation of prostatic lithiasis with chronic pelvic pain syndromes in young adults. Eur Urol 2004; 45:333-338.

6. Peeling WB, Griffiths GJ. Imaging of the prostate by ultrasound. J Urol. 1984; 132:217-224.

7. Lee SE, Ku JH, Park HK, et al. Prostatic calculi do not influence the level of serum prostate specific antigen in men without clinically detectable prostate cancer or prostatitis. J Urol. 2003; 170:745-748.

8. Smolski M, Turo R, Whiteside S, et al. Prevalence of prostatic Calculi subtypes and association with prostate cancer. Urology.

2015; 85:178-81.

9. Hong CG, Yoon BI, Choe HS, et al. The prevalence and characteristic differences in prostatic calculi between health promotion center and urology department outpatients. Korean J Urol. 2012; 53:330-334.

10. Suh JH, Gardner JM, Kee KH, et al. Calculis in prostate and ejaculatory system: A study on 298 consecutive whole mount sections of prostate from radical prostatectomy or cystoprostatectomy specimens. Ann Diagn Pathol. 2008; 12:165-170.

11. Griffiths GJ, Clements R, Jones DR, et al. The ultrasound appearances of prostatic cancer with histological correlation. Clin Radiol. 1987; 38:219-227.

12. Woods JE, Soh S, Wheeler TM. Distribution and significance of microcalculis in the neoplastic and nonneoplastic prostate. Arch Pathol Lab Med. 1998; 122:152-155.

14. Dennis LK, Lynch CF, Torner JC. Epidemiologic association between prostatitis and prostate cancer. Urology. 2002; 60:78-83.

15. Moreira DM, Nickel JC, Gerber L, et al. Baseline prostate inflammation is associated with a reduced risk of prostate cancer in men undergoing repeat prostate biopsy: results from the REDUCE study. Cancer. 2014; 120:190-196.

16. Gurel B, Lucia MS, Thompson IM, et al. Chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the prostate cancer prevention trial.

Cancer Epidemiol Biomarkers Prev. 2014; 23:847-856.

Correspondence Cem Yucel, MD meclecuy@hotmail.com Department of Urology, Tepecik Training and Research Hospital, Izmir, Turkey Salih Budak, MD salihbudak1977@gmail.com Sakarya Training and Research Hospital, Sakaraya, Turkey

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DOI: 10.4081/aiua.2018.3.184

ORIGINAL PAPER

Diabetes mellitus and prostate cancer metabolism: Is there a relationship?

Hugo Pontes Antunes 1, Ricardo Teixo 2, 3, 5, João André Carvalho 1, Miguel Eliseu 1, Inês Marques 2, 3, 5, Ana Mamede 2, 3, 4, 5, Rita Neves 2, 3, 5, Rui Oliveira 3, 6, Edgar Tavares-da-Silva 1, 3, 5, Belmiro Parada 1, 5, Ana Margarida Abrantes 2, 3, 5, Arnaldo Figueiredo 1, 5, Maria Filomena Botelho 2, 3, 5 1 Urology

and Transplantation Department, Coimbra Hospital and University Centre, Coimbra, Portugal; University of Coimbra, Coimbra, Portugal; 3 Institute of Biophysics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; 4 CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal; 5 Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO) Faculty of Medicine University of Coimbra, Portugal; 6 Pathology Department, Coimbra Hospital and University Centre, Coimbra, Portugal.

2 CNC.IBILI,

Summary

Objective: Our aim was to evaluate the effects of glucose levels and diabetes mellitus in prostate cancer (PCa) biology.

Materials and methods: Two PCa cell lines (LNCap and PC3) were cultured in RPMI medium with different glucose concentrations [5mM (LG) and 25mM (HG)]. Expressions of androgen receptor, Her2/neu and glucose transporters (GLUT1, 3, 5 and 12) were evaluated by flow cytometry. Proliferation rate was assessed by colorimetric assay MTT and cellular characterization was performed by haematoxylin and eosin staining.

Additionally, we performed a cross sectional analysis of 704 patients undergoing radical prostatectomy who were divided into two groups (diabetic and non-diabetic). An analysis of clinical and histological data seeking to identify the differences on tumor aggressiveness between the two groups was performed.

Results: In LNCaP cell line, when the glucose concentration in the medium increased, there was an increased in AR expression. Regarding expression of Her2/neu receptor, medium’s glucose concentration significantly changed the expression of this receptor in both PC3 and LNCaP cell lines. Growth rate was higher on the HG medium for both cell lines. The clinical study of patients undergoing radical prostatectomy revealed no relationship between the presence of diabetes and the development of more aggressive tumours. Diabetic patients had significantly higher prostatic volumes, however, no significant difference was found between the relapse risk classification or the ISUP classification between the two groups.

Conclusions: Our results showed that medium glucose concentration could influence prostate cancer cells growing but not the aggressiveness.

KEY WORDS: Diabetes; Glucose; Prostate cancer; Hormonal receptors; 18F-FDG. Submitted 20 July 2018; Accepted 27 July 2018

INTRODUCTION

Diabetes mellitus (DM) and prostate cancer (PCa) are two diseases that affect a large number of men in adulthood (1, 2). Several studies show how DM can be a risk factor for the development of several neoplasms (1-4) or even to its progression (5).

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The relationship between the DM and the PCa is still not well studied, as with other neoplasms. Populational studies have shown conflicting results (6, 7).

The REDUCE study showed no association between the DM and the risk of PCa (6). On the other hand, the Prostate Cancer Prevention Trial (PCPT) shows an increased risk of PCa in diabetic patients (7). Reviews from studies of the pre-PSA era have shown a negative association between PCa and DM (8, 9). Latest reviews show that there may be an increased risk for high-grade tumours in diabetic patients, despite a negative association between DM and all forms of PCa (10-12).

Diabetic disease’s parameters as hyperglycaemia (proven

by HbA1c or by fasting blood glycaemia) show a linear risk association with high-grade tumours (11, 13). PCa diagnosis in diabetic patients may be more difficult because diabetics presents lower PSA values, lower serum testosterone and higher prostatic volumes (14).

Finally, some therapies for DM seem to have effect also on PCa, as for example metformin, which has been associated with reduction in cancer-specific mortality, as well as less recurrences after curative treatment in PCa (15).

Molecular mechanisms involved in the relationship between DM and neoplasms have been the focus of several works.

The main study points were the molecular pathways associated with hyperinsulinemia (16, 17), insulin growth factor-1 (IGF-1) and inflammation (18). Concerning PCa and DM, scientific work at the molecular level is scarce.

In addition to the pathways referred above, hyperglycaemia per se seems to have an effect on the androgen receptor (AR) expression (19).

The aim of our study was to evaluate the effects of high glucose level, one aspect of the diabetic disease, in PCa tumour biology. For this purpose, we evaluated the various molecular expression in PCa cell lines, when incubated in different glycaemic environments, simulating normal blood glucose and hyperglycaemia concentrations.

To complement the study in cell lines, we performed a revision of our patients’ data subjected to radical prostate-

No conflict of interest declared.

This work was supported by Strategic Projects PEst-C/SAU/UI3282/ 2013 and FEDER-COMPETE (POCI01-0145-FEDER-007440).

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ctomy and compared clinical and histological data of diabetic and non-diabetic patients.

MATERIALS

AND METHODS

Cell culture Prostate cancer cell lines used in this study – LNCaP (hormone-dependent) and PC3 (hormone-independent) – were obtained in American Type Culture Collection (ATCC, USA). Cell lines were thawed and propagated in adherent cultures in Roswell Park Memorial Institute medium (RPMI), pH 7.4, supplemented with 10% fetal bovine serum (Sigma F7524), 1% antibiotic/antimycotic (Sigma A5955) and 1% sodium pyruvate (Gibco 11360).

We used two different formulations of RPMI medium: high glucose (25mM, SIGMA R4130) or low glucose (5mM).

The low glucose (LG) medium resembles normal glycaemia. To obtain 5mM glucose medium, we used a medium without glucose (SIGMA R1383) to which we added the appropriate amount of glucose (SIGMA G7528). Cells were maintained at 37ºC with 5% CO2.

Expression of androgen receptor (AR) and Her2/neu To evaluate the expression of AR and Her2/neu, 106 cells were washed with phosphate buffered saline [PBS: 137mM NaCl (Sigma, S7653), 2.7mM KCl (Sigma, P9333), 10mM Na2HPO4.2H2O (Merck, 6580), 2mM KH2PO4 (Sigma, P0662), pH=7.4] by centrifugation at 209×G during 5 minutes. Cells were stained with anti-AR antibody (Abcam AB9474) and with anti-Her2/neu-APC (APC, alophycoerythrin) antibody (BD BioSystems 340554) for 15 minutes at room temperature in the absence of light.

After cells were washed and resuspended in 400μL of PBS. Stained cells with anti-AR were washed as described above and stained with a secondary antibody conjugated with phycoerythrin (PE, Santa Cruz Biotechnology sc3818) for 20 minutes at room temperature in the absence of light, and after were washed with PBS by centrifugation at 209×G for 5 minutes and resuspended in 400μL of PBS. The expression of AR and Her2/neu were analyzed by flow cytometry. The results obtained are expressed as mean intensity fluorescence (MIF).

Proliferation rate To analyse PCa cells growth, 50000 cells/mL were plated in 24 multiwell plates. After 24 and 96 hours, the colorimetric test MTT was performed as described elsewhere 20. The proliferation rate is given by the ratio of the absorbance measured at 96h (AD4) and measured at 24h (AD1).

Cellular characterization and immunocytochemistry Cell lines used in this experiment were morphologically characterized using cytospin centrifugation, on a Shandon Cytospin II Cytocentrifuge at 471×G for 3min and then stained using haematoxylin and eosin (H&E).

The remaining material was then centrifuged at 471×G for 5 min. After, paraffin inclusion of the pellet was performed for immunocytochemistry, on a Ventana Marker Platform Bench Mark ULTRA IHC/ISH.

Immunocytochemical analysis was performed using formalin-fixed, paraffin-embedded sections. The avidinbiotin peroxidase complex technique was employed.

Ki67 antigen (MIB-1 clone, 1:50, Ultra CC1 antigen retrival, Darko) was tested as representative of proliferation index, and evaluated by percentage of expression – it was chosen for each condition a hot spot and counted the percentage of cells with nuclear expression/without expression of Ki67 in a high-power field (40x objective – 0.3mm2). The samples were observed under a light microscope – Nikon Eclipse 50i, and images were obtained using a Nikon-Digital Sight DS-Fi1 camera.

Glucose transporters (GLUTs) quantification To evaluate the membrane expression of glucose transporters previously referred, 106 cells were washed by centrifugation with PBS at 209×G during 5 minutes.

Cells were stained with anti-GLUT1-PE (R&D Systems FAB1418P), anti-GLUT3 (R&D Systems MAB1415), antiGLUT5 (R&D Systems MAB1349) and anti-GLUT12 (Santa Cruz Biotechnology sc-161659) for 15 minutes at room temperature and in the absence of light. After, cells stained with monoclonal antibody anti-GLUT1-PE were washed with PBS by centrifugation at 209×G during 5 minutes and resuspended in 400μL of PBS. Stained cells with the antibodies anti-GLUT3, anti-GLUT5 and antiGLUT12 were washed with PBS by centrifugation at 209×G for 5 minutes and stained with a secondary antibody conjugated with PE (Santa Cruz Biotechnology sc3818) for 20 minutes at room temperature in the absence of light. After incubation, cells were washed with PBS by centrifugation at 209×G during 5 minutes and resuspended in 400μL of PBS. The expression of GLUTs was analysed by flow cytometry. The results obtained are expressed as MIF. 18F-Fluorodeoxyglucose (18F-FDG)

uptake studies A cell suspension of 2x106 cells/mL was prepared to perform the uptake studies. Obtained the suspension, it was left to rest at 37ºC in 25cm2 flasks. After 60 minutes, 25μCi/mL of 18F-FDG was added to cell suspension.

At 5, 30, 60, 90 and 120 minutes, 200μL of cell suspension were collected for microtubes with iced PBS. The samples were centrifuged at 209×G for 1 minute to separate the pellet from the supernatant, having this been collected to an identified tube. After the separation of pellets and supernatants, the 18F-FDG uptake was determined by counting both fractions in a well counter (CAPINTEC CRC-15W) in counts per minute (CPM). The uptake studies were performed in normoxia (95% O2 and 5% CO2), as well as in hypoxia (93% N2, 2% O2 and 5% CO2) conditions. Studies in hypoxia were performed in a controlled environment chamber (PlasLabs Lamsing, Mich. 800-866-7527).

Clinical study A cross sectional analysis of all patients undergoing radical prostatectomy between January 2009 and December 2016 in urology department was performed. We evaluated 704 patients who were divided into two groups (diabetic and non-diabetic). We assessed clinical and histological parameters such as age at PCa diagnosis, preArchivio Italiano di Urologia e Andrologia 2018; 90, 3

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operative PSA, diagnostic biopsy results and surgical specimen pathology. All patients classified as diabetic were already diagnosed prior to radical prostatectomy.

The diagnosis was in all cases performed by endocrinologists or general practitioners, with all patients being followed up on a specific diabetes mellitus consultation. All patients underwent open radical prostatectomy.

Statistical analysis Statistical analysis was performed using the IBM® SPSS® software v. 22.0 (IBM Corporation, Armonk, New York, USA). The normality distribution of the variables was confirmed through Shapiro-Wilk. Student t-test (parametric) was used in case of normal distribution and homogeneity of variance, otherwise, Mann-Whitney test (nonparametric) was used. In order to compare cell lines, one-factor analysis of variance (ANOVA) parametric test was used in case of normal distribution and homogeneous variances of the variables, otherwise KruskalWallis nonparametric test was used. Multiple comparisons were obtained after Games-Howell correction. The Chi-Square test was used to analyse categorical variables.

A significant level of 5% was adopted for all comparisons.

RESULTS

Results showed that PC3 cell line has a higher growth rate than LNCaP in both media considered in our work.

PC3 cell line presents an AD4/AD1 ratio of 9.2 when cultured in high glucose condition and an AD4/AD1 ratio of 6.1 when cultured in low glucose. Thus, it presents a significantly higher proliferative rate in high glucose conditions (p < 0.001). The same observation is valid for LNCaP cells, presenting an AD4/AD1 ratio of 3.1 when cultured in high glucose condition a significant different value when compared with the AD4/AD1 ratio of 1.5 when cultured in low glucose conditions (p = 0.003).

We can also observe that proliferative rate is significantly higher in PC3 cells than in LNCaP cells, in both glucose conditions, high (p < 0.001) and low (p < 0.001).

Cellular characterization and immunocytochemistry Percentage of positive Ki67 cell of prostate cancer cell lines in high and low glucose are, respectively, 38.7% and 9.9% in PC3 cell lines and 11.2% and 3.6% in LNCaP cell lines. The percentage of Ki67 positive cells is significantly higher in cells cultured in high glucose medium, in both LNCaP and PC3 cell lines. Moreover, we observed a higher expression of Ki67 in the PC3 cell line in both culture media.

Glucose transporters (GLUTs) quantification Expression of AR and Her2/neu Glucose transporters expression is resumed in Figure 3.

To characterize both PC3 and LNCaP cell lines we evalOur results showed that there are differences in the uated hormonal androgen receptor and Her2/neu with expression of glucose transporters between the two cell high and low glucose concentration medium. Results are lines under study. LNCaP cell line presented a higher presented in Figure 1. expression of GLUT12 than PC3 cells when cultured in According to Figure 1A, PC3 cell line does not express low glucose condition (p = 0.013). androgen receptor in both conditions, as for this receptor, we only consider a Figure 1. positive staining when MIF values are higher than 10. On the other hand, Expression of androgen receptor in PC3 (A) and LNCaP (B) in high glucose (HG) LNCaP cell line (Figure 1B) expresses and low glucose (LG). Expression of her2/neu receptor in PC3 (C) and LNCaP (D) in high glucose (HG) and low glucose (LG), expressed as mean intensity this receptor in both culture conditions fluorescence (MIF). For each condition, results were obtained with a minimum of but show a significantly higher expres- eight experiments. Graphs represent mean±standard error. sion of AR when cultured in high glu- Statistical significance: *p < 0.05; ***p < 0.001. cose concentration medium (p < 0.05).

Regarding expression of Her2/neu receptor in prostate cancer cell lines, it is possible to observe that glucose concentration in the medium significantly alter the expression of this receptor in both PC3 (Figure 1C, p = 0.036) and LNCaP (Figure 1D, p < 0.001) cell lines, with an increased expression in high glucose medium. Our results also highlight that androgen-dependent cell line LNCaP presents a higher expression of this receptor compared to androgen-independent cell line PC3, both in HG (p < 0.001) and in LG (p < 0.01) medium.

Proliferation rate To evaluate the proliferation rate of PCa cell lines, the ratio AD4/AD1 was calculated and is represented in Figure 2.

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18F-Fluorodeoxyglucose (18F-FDG)

Figure 2.

Results represent the ratio between the measured absorbance after 96h (day 4, AD4) and after 24h (day 1, AD1) for PC3 (A) and LNCaP (B). Results were obtained with six independent experiments. Values represent mean±standard error Statistical significance: **p < 0.01; ***p < 0.001.

uptake studies In our work the uptake profile of 18FFDG was determined in prostate cancer cell lines when cultured in high and low glucose media. Our results (Figure 4) showed that there are no alterations in 18F-FDG uptake over time when PC3 and LNCaP cell lines are cultured in high glucose medium. Moreover, when cells are culture in low glucose concentration, 18F-FDG uptake significantly increases with time when compared with cells cultured in high glucose concentration. On PC3 cell line, we observed a significantly higher uptake on cells culture on LG compared with HG after 5 minutes (1.46% ± 0.06% vs.

0.76% ± 0.07%, p < 0.001), 30 minutes (5.02% ± 0.58% vs. 1.15% ± 0.07%, p = 0.010), 90 minutes (11.83% ± 2.01% vs. 2.09% ± 0.33%, p = 0.026) and 120 minutes (13.60% ± 1.33% vs. 2.31% ± 0.22%, p = 0.005).

On LNCaP cells, we observed a significantly higher uptake on cells culture on LG compared with HG after 5 minutes (1.92% ± 0.37% vs. 0.51% ± 0.09%, p < 0.045), 30 minutes (4.10% ± 0.10% vs. 0.76% ± 0.02%, p < 0.001), 60 minutes (6.80% ± 0.18% vs. 1.02% ± 0.17%, p < 0.001), 90 minutes (9.46% ± 2.01% vs. 1.28% ± 0.14%, p < 0.001) and 120 minutes (11.78% ± 0.51% vs. 1.41% ± 0.12%, p < 0.001).

Figure 3.

Expression of GLUTs in prostate cancer cell line LNCaP (A) and PC3 (B) in high and low glucose media presented as mean intensity fluorescence. Results are expressed as mean±standard error of a minimum of three independent experiments Statistical significance: **p < 0.01.

Figure 4.

18F-FDG uptake in PC3 (A) and LNCaP (B) prostate cancer cells cultures in high and low glucose media, expressed as percentage of uptake. Results are presented as mean±standard error of a minimum of four independent experiments Statistical significance: *p < 0.05; **p < 0.01; ***p < 0.001.

Clinical study Demographic and clinicopathological data of patients undergoing radical prostatectomy are shown in Table 1.

The rate of diabetic patients was 21.2%.

Diabetic patients had higher prostatic volumes. However, the diagnosis of DM did not show relationship with the development of tumours with more aggressive histology or staging.

DISCUSSION

We also observed that GLUT1, GLUT3 and GLUT5 expression is not different between the two prostate cancer cell lines.

Moreover, in LNCaP cells, an increased expression of GLUT3 were observed when cells were cultured in low glucose medium (p = 0.016). In PC3 cell line, this differential expression due to culture media is observed only for GLUT1 (p = 0.013).

As mentioned before, the correlation between DM and some neoplasms, like lung, colorectal or breast cancer, is already known (1-3), however, the relationship with PCa was not established yet. Similarly, populational studies are not clear on establishing an association between this two diseases (68). The diabetic disease has several aspects capable of exerting influence on PCa, like hyperinsulinemia (16), IGF-1, inflammation and also its treatment (18).

In our work, we evaluated another aspect of DM, the hyperglycaemia, and its action on PCa behaviour at a molecular level, by using an in vitro model of two PCa Archivio Italiano di Urologia e Andrologia 2018; 90, 3

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Table 1.

Demographic and clinicopathological features of patients undergoing radical prostatectomy.

and a down-regulation of M2PK (M2 pyruvate kinase isoenzyme) (29). This down regulation of M2PK leads to an accumulation of glycolytic metabolites, providing Diabetic group Non-diabetic group P value substrates for synthetic processes (29). (n = 149) (n = 555) Thus, as we mentioned before, PCa cells Age (years), mean ± SD 64.5 ± 5.6 62.8 ± 6.7 0.003 also stimulates glycolysis for a synthetic PSA preoperative (ng/mL), mean ± SD 9.2 ± 6.3 9.9 ± 12.0 NS purpose (25), may the process seen in Preop. fasting glycaemia (mg/dL), mean ± SD 114.0 ± 25.4 93.9 ± 12.6 0.001 breast cancer cells also happens with them.

Prostatic volume (cc), mean ± SD 54.2 ± 21.3 47.7 ± 18.1 0.001 18F-FDG is an analogous of glucose radiolaRisk groups, n (%) NS belled with Fluor-18. In the uptake studies Low-risk 50 (33.6%) 208 (37.5%) we verified that the uptake of the 18F-FDG Intermediate-risk 80 (53.5%) 261 (47.0%) glucose analogous depends of the medium High-risk 17 (11.4%) 63 (11.4%) composition.

Besides this it is important to ISUP of RP specimen, n (%) NS have in account the uptake mechanism in ISUP Grade 1 31 (20.8%) 118 (21.2%) which 18F-FDG enters in the cell by faciliISUP Grade 2 96 (64.4%) 364 (65.6%) tated diffusion mediated by membrane gluISUP Grade 3 13 (8.7%) 54 (9.7%) cose transporters, and after it is phosphoryISUP Grade 4 3 (2.1%) 12 (2.2%) ISUP Grade 5 6 (4.0%) 7 (1.3%) lated by hexokinase to FDG-6-phosphate.

Further the phosphorylation concerning Perineural invasion, n (%) 116 (83.5%) 456 (86.4%) NS the very strict structural and geometric TNM staging, n (%) NS demands of the reaction, the phosphoglupT2 85 (57.0%) 328 (59.1%) pT3 64 (43.0%) 227 (40.9%) cose isomerase does not recognize FDG-6pN0 93 (62.4%) 357 (64.3%) phosphate and consequently there will be pN1 12 (8.1%) 37 (6.7%) accumulation on the cytoplasm, which pNx 44 (29.5%) 161 (29.0%) means that 18F-FDG-6-P remains inside the Positive margins, n (%) 41 (27.5%) 138 (24.9%) NS cell capable of being detected during the NS = not significant; SD = standard deviation; RP = radical prostatectomy. time that remains radioactive. The distribution of radiolabelled FDG reflects not the glycolytic pathway but the exaggerated cell lines incubated with different glucose concentraneed of glucose according to the Warburg effect (30). tions, resembling a normal glycaemia (LG) and hyperThe 18F-FDG uptake by the cells was higher with low glycaemia (HG). glucose concentration medium. This can be explained by Our results showed that PC3 cell line do not significantthe absence of competitor in the transporter, which is the ly express AR, while LNCaP cell line have a higher glucose present in the medium. Since PCa cells are metaexpression of this receptor, as was proved by Tilley (21) bolically very active, they are greedy to glucose and the in 1990. For LNCaP cell line we observed that when lower the content of glucose, the higher is the 18F-FDG medium’s glucose concentration increased, there was an uptake. This has clinical relevance because the better the increased in AR expression. This may be explained, in glucose control is, the better will be the images of the part, by the AR role on the glucose uptake and glycolyPET scan with 18F-FDG. As we determined by the prolifsis regulation (22). It seems that AR stimulates glycolysis eration rate, we verified interesting results, as the PC3 via the metabolic sensor 5′-AMP activated protein cell line is the one who present a higher growth rate and kinase (AMPK) not only for adenosine 5’-triphosphate for both cell lines we saw that the HG medium had the (ATP) production (23, 24) but also for de novo lipid synshorter doubling time. Moreover, the fact that cells culthesis (25). This is consistent with the typical Warburg tured in LG presented a higher 18F-FDG uptake even effect for cancer cells metabolism (26), which is an inefhaving a lower proliferation rate highlights the clinical ficient way to generate ATP in order to acquire nutrients relevance of a good glucose control when a PET scan (26). This effect appears to take place in prostate cancer with 18F-FDG is performed. under the AR regulation (22).

GLUT proteins facilitate glucose transport across biologHer2/neu has been indicated as a factor of cancer aggresical membranes. Different expressions of GLUTs have siveness in other types of cancer (27) and in PCa was been related with different kinds of cancer and with canalso related with AR activation in castration resistant cer specific survival (31-35). GLUTs 1, 3 and 12 are prostate cancer (28). Our results showed that Her2/neu known for being expressed in PCa (31). In our work we receptor expression was also significantly different with observed a similar expression of the investigated glucose both media glucose concentrations in the two cell lines. transporters in both culture media, exception for GLUT1 There was an increased Her2/neu receptor expression in PC3 cells and GLUT3 in LNCaP cells. With the LG with the HG medium. As far as we know, this association medium we observed a significant increase GLUT1 was not studied until today in prostate cancer cells, but expression in the PC3 cells and an increase GLTU3 in breast cancer cells was identified a relationship expression in the LNCaP cells. Also, in LNCaP cells, between Her2/neu and the glycolytic phenotype (29). It there is a higher expression of GLUT1, GLUT3 and appears that Her2/neu overexpression increases activaGLUT12 compared with PC3 cells when both cell lines tion of Akt, which leads to an up-regulation of GLUT1 are cultured in HG conditions, showing that maybe these

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transporters could be related with the AR (24). Despite the results in cell lines, our clinical sample did not show significant differences between tumour development in diabetic and non-diabetic patients. Diabetic patients had higher prostatic volumes. In terms of oncologic staging we did not find significant differences, however, we found that the rate of patients with grade 5 of the ISUP classification is higher in diabetic patients (4.0% vs.

1.3%), although this difference did not reach statistical significance. This result is in agreement with other studies that have reported that DM mainly decreases the risk of low-grade tumors and, to a lesser degree, the risk of high-grade tumors. Consequently, it is plausible to assume that DM changes the proportions of PCa grades favoring high-grade tumors (7, 11). Some series of patients undergoing RP have shown that DM is associated with a higher PCa grade (36). However, a previous analysis of the CaPSURE database found no association between DM and PCa aggressiveness (37). Thus, more studies in this area will be necessary to really clarify the relationship between DM and PCa aggressiveness.

CONCLUSIONS

Our results showed that glucose levels could influence prostate cancer cells behaviour. In the HG medium PCa cells had a more aggressive pattern, with higher expression of AR (only for LNCaP) and Her2/neu (for both cell lines) and a higher proliferation rate demonstrated by Ki67 staining and ratio AD4/AD1. GLUT expression had slight variations in both culture conditions, but its expression is significantly higher in LNCaP cells. Thus, incubation of cells in hyperglycaemia-like conditions induced a more aggressive molecular phenotype. This could be one of the link aspects between DM and PCa.

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Correspondence Hugo Manuel Pontes Antunes, MD (Corresponding Author) hugoantunes4@gmail.com Urology and Transplantation Dpt, Coimbra Hospital and University Centre Rua Padre Sebastião, nº12 – 2C, 3040-376 Coimbra, Portugal Ricardo Teixo, MD rcardoteixo@gmail.com João André Carvalho, MD jccarvalho@gmail.com Miguel Eliseu, MD migeliseu3@gmail.com Inês Marques, MD Ana Mamede,MD Rita Neves, MD Rui Oliveira, MD Edgar Tavares-da-Silva, MD Belmiro Parada, MD Ana Margarida Abrantes, MD Arnaldo Figueiredo, MD Maria Filomena Botelho, MD

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DOI: 10.4081/aiua.2018.3.191

ORIGINAL PAPER

Prognostic value of subclassification (pT2 stage) of pathologically organ-confined prostate cancer: Confirmation of the changes introduced in the 8th edition of the American Joint Committee on Cancer (AJCC) staging system Hugo Pontes Antunes 1, Belmiro Parada 1, JoĂŁo Carvalho 1, Miguel Eliseu 1, Roberto Jarimba 1, Rui Oliveira 2, Edgar Tavares-da-Silva 1, Arnaldo Figueiredo 1 1 Department 2 Department

of Urology and Renal Transplantation, Coimbra University Hospital Center, Portugal; of Pathology, Coimbra University Hospital Center, Portugal.

Summary

Objective: The last edition of the AJCC staging system eliminated the pT2 subclassification of prostate cancer (PCa). Our objective was to evaluate the association of pT2 subclassification with the oncological results of patients with PCa who underwent radical prostatectomy (RP).

Material and methods: We evaluated 367 patients who underwent RP between 2009 and 2016, with pT2 disease in the final pathological evaluation. We assessed differences in rates of biochemical recurrence (BCR), metastasis and mortality between T2 substages (pT2a/b vs pT2c).

Results: Fifty-three (14.4%) patients presented pT2a/b disease and 314 (85.6%) pT2c disease. The mean follow-up time was 4.9 Âą 2.6 years. Grade group scores (p = 0.1) and prostate specific antigen (PSA) (p = 0.2) did not differed between pT2 substages. The rate of BCR in pT2a/b and pT2c patients was 11.3% and 18.2%, respectively (p = 0.2). Five (9.4%) patients with pT2a/b and 45 (14.3%) with pT2c substage underwent salvage radiotherapy (p = 0.3). The rate of positive surgical margins did not differ between groups (p = 0.2). Seven (2.2%) patients with pT2c had lymph nodes or distant metastases.

The overall survival was 92.5% and 93.6% in pT2a/b and pT2c, respectively (p = 0.2).

Conclusion: Our results are in accordance with the changes introduced in the 8th edition of the AJCC staging system in which the pT2 subclassification was eliminated.

KEY WORDS: Prostatic neoplasms; Biochemical recurrence; Prostatectomy; Neoplasm staging.

Submitted 16 August 2018; Accepted 19 August 2018

INTRODUCTION

The TNM system is an established tool for classification of solid tumors by means of tumor size and extent, the involvement of local lymph nodes, and the presence of distant metastases. The classification was established in order to visualize prognostic implications and to allow establishment of systematic therapeutic algorithms.

Successive editions from the most common staging sys-

tem for prostate cancer, the American Joint Committee on Cancer (AJCC) system, have been published reflecting progress in our understanding of prostate cancer biology and prognosis (1).

The 8th edition of AJCC staging system, implemented in January 2018, has set some changes (2, 3). The major anatomic-based change is in the classification of organconfined disease. All organ-confined disease is now pathologically staged as T2 without further subcategorization by extent of involvement or laterality (3).

This change was assigned a Level of Evidence III, meaning that available evidence was not strong. In fact, there is no consensus whether pT2 subclassification has prognostic value in patients who underwent radical prostatectomy (4). Nonetheless, the collective reasoning and data were deemed sufficient to support this change in pathologic stage.

It is unknown how this updated staging classification will perform in different populations. Given these changes have the potential to influence treatment decisions, and thus patient outcomes, independent validation is necessary to confirm the prognostic accuracy and to ensure generalizability across different settings (5, 6).

The aim of this study was to assess the prognostic association of pT2 subclassification with the probability of biochemical recurrence (BCR), metastasis, cancer specific survival (CSS) and overall survival (OS) in patients who had organ-confined disease in radical prostatectomy (RP) specimens.

MATERIALS

AND METHODS

We performed a cross-sectional analysis of patients who underwent RP between 2009 and 2016 in a single urology department with pT2 disease. Patients with missing data and/or neoadjuvant treatments were excluded.

The final study population consisted of 367 patients.

Surgeries were performed by different surgeons. Patients who received previous treatments or had measurable

No conflict of interest declared.

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PSA values immediately after surgery Table 1. were excluded. Patients were followed Demographics and disease characteristics by pT2 subclassification. with serum PSA at 4-6 weeks, every 6 pT2a/b pT2c p Value1 months for 5 years and annually therePatients (%) 53 (14.4%) 314 (85.6%) after. Data were collected through the PSA pre-RP, ng/ml (mean ± SD) 7.4 ± 4.9 8.3 ± 8.3 n.s. clinical information recorded in the Age at RP, years (mean ± SD) 62.9 ± 6.9 63.0 ± 6.8 n.s. database of our hospital. BCR was RP specimen Grade group (%) defined as the presence of a confirmed Grade Group 1 17 (32.1%) 104 (33.1%) n.s.

PSA value of 0.2 ng/ml or greater.

Grade Group 2 32 (60.4%) 190 (60.5%) Recurrence was based on clinical, laboGrade Group 3 2 (3.8%) 17 (5.4%) ratorial and radiological findings.

Grade Group 4 1 (1.9%) 3 (1.0%) Data are expressed as mean ± standard Grade Group 5 1 (1.9%) 0 (0%) deviation, number (%), or median with Prostate size, cc (median) 45 (16-105) 45 (20-163) n.s. interquartile range as appropriate. IBM Perineural invasion, n (%) 31 (58.5%) 245 (78.0%) 0.01 SPSS 24.0 software was used for all staPositive surgical margins (%) 5 (9.4%) 50 (15.9%) n.s. tistical analyses. Normality of numeriBCR rate (%) 6 (11.3%) 57 (18.2%) n.s. cal variables was accessed with Time to BCR, years (mean ± SD) 2.6 ± 1.8 2.3 ± 2.0 n.s.

Kolmogorov-Smirnov test, and Student t test or Mann-Whitney U test were Salvage radiotherapy (%) 5 (9.4%) 45 (14.3%) n.s. properly used to assess differences in Lymph node metastases (%) 0 (0%) 5 (1.6%) n.s. numerical variables. The chi-square or Distant metastases (%) 0 (0%) 2 (0.6%) n.s.

Fisher exact probability tests were used 1Statistical significances: p < 0.05; Abbreviations: BCR, biochemical recurrence; n.s., not significant; for categorical data as appropriate. CSS PSA, prostate specific antigen; SD, standard deviation. and OS were calculated using KaplanMeier analysis and tested for differences with the Mantel-Cox log-rank test. Multivariate analysis pT2a/b and pT2c patients (p = 0.7). Five (9.4%) patients was performed with a binary logistic regression. Results with pT2a/b and 45 (14.3%) with pT2c substage underwere considered statistically significant if the P value was went salvage radiotherapy (p = 0.3, Table 1). No patient 0.05. For methodological reasons, we decided to focus with pT2a/b disease developed lymph node or distant the comparison between patients with unilateral metastases (Table 1). In contrast, in the pT2c group 5 (pT2a/b) and bilateral (pT2c) disease. patients developed lymph node metastases and 2 pre-

RESULTS

Fifty-three (14.4%) patients presented pT2a/b disease and 314 (85.6%) pT2c disease. The mean age of our study population was 63.0 ± 6.8 years.

Demographics and disease characteristics by pT2 subclassification are shown in Table 1. The mean follow-up time was 4.9 ± 2.6 years. We found no significant difference between the preoperative PSA values of the two groups (p = 0.2, Table 1). Approximately twothirds of patients with pT2a/b and pT2c stage had a grade group 2 PCa or higher (p = 0.1, Table 1). The prostate volume did not show significant differences between the groups (p = 0.5, Table 1). The rate of perineural invasion in RP specimens was higher in pT2c patients (p = 0.01, Table 1). Patients with pT2c substage showed no higher rates of positive surgical margins (p = 0.2, Table 1). Sixty-three (17.2%) patients had BCR in the entire cohort during follow-up. The rate of BCR in pT2a/b and pT2c patients was 11.3% and 18.2%, respectively (p = 0.2, Table 1). There was no significant difference in time from RP to BCR between

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Figure 1.

Overall survival of patients with pT2a/b and pT2c prostate cancer in radical prostatectomy specimens.

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Subclassification of pT2 stage prostate cancer

sented bone metastases during follow-up. The overall survival was 92.5% and 93.6% in pT2a/b and pT2c, respectively (p = 0.2, Figure 1).

No cancer related deaths were identified in both groups.

One (1.9%) patient in the pT2a/b group did androgendeprivation therapy. In the pT2c group, 7 (2.2%) patients were treated with androgen-deprivation.

No patient was treated with docetaxel, abiraterone, enzalutamide or another new drug.

In addition, we performed a binary logistic regression to access a multivariate analysis between ISUP grade, pT2 sub staging and surgical margins status from one side and survival or BCR on the other side. There was no association between these pathological variants and survival (p = 0.564; p = 0.748; p = 0.345) or BCR (p = 0.180; p = 0.246; p = 0.288), respectively.

The pT2 subclassification showed no prognostic value in patients with PCa who underwent RP. Our results are in accordance with the changes introduced in the 8th edition of the AJCC staging system in which the pT2 subclassification was eliminated.

DISCUSSION

REFERENCES

PCa grading has undergone significant evolution in the past half century (7, 8) and the AJCC staging system has been repeatedly revised with the current 2017 system eliminating the 3-tiered pT2 subclassification (4, 9).

Since the adoption of the 1992 AJCC/UICC TNM prostate cancer staging system, the pT2 subclassification has remained controversial due to the lack of robust evidence that it adds meaningful prognostic value (10).

Our results confirm the 8th edition AJCC staging system for PCa. We confirmed that pT2 subclassification offers limited prognostic value, which supports its elimination.

We found that the pT2 subclassification did not add prognostic information to the outcomes of BCR, distant metastases and overall survival. The subclassification of pT2 disease has been previously evaluated (4, 11-14).

Multifocal cancer has been noted in up to 80% of prostatectomy specimens and thus subclassification into pT2a/b/c may depend more on detection than underlying biology (5, 15).

Freeland et al. evaluated the rate of BCR in patients with unilateral and bilateral organ confined PCa. They found no significant difference between both groups (16).

Other studies have observed results similar to those of our study (12, 13, 17, 18).

Nguyen et al. in a long follow-up study with 15.305 patients showed that the rates of metastases and cancer specific death at 10 years were relatively low in the pT2 population (4). The authors validate in their work the elimination of the pT2 subclassification and argue that the preoperative serum PSA level and pathological grade remain the strongest prognostic factors in patients with pT2 disease.

Our results are similar to these previous studies.

We observed higher rates of perineural invasion and positive surgical margins in patients with pT2c disease.

However, these results had no significant impact on the development of BCR, metastases or survival. In agreement with the study of Nguyen, we found a very low overall metastases rate (0.5%) (4).

Our study showed no cancer-specific deaths. This finding may be justified by a relatively short follow-up for a disease with a long natural history. However, other studies with longer follow-up time also show rates of cancer-

specific death below 0.5% (4, 19). Our work presents some limitations. First, it is a retrospective study which may introduce mis-classification or information bias.

Some data regarding patients were missing. Another limitation is related to the sample size and duration of follow-up. A larger sample and length of follow-up would allow a further understanding of the prognostic value of the pT2 subclassification.

CONCLUSIONS

1. Abdel-Rahman O. Assessment of the prognostic value of the 8 th AJCC staging system for patients with clinically staged prostate cancer; A time to sub-classify stage IV. PLoS One. 2017; 12:e0188450.

2. Paner GP, Stadler WM, Hansel DE, et al. Updates in the Eighth Edition of the Tumor-Node-Metastasis Staging Classification for Urologic Cancers. Eur Urol. 2018; 73:560-569.

3. Fine SW. Evolution in prostate cancer staging: pathology updates from AJCC 8th edition and ppportunities that remain. Adv Anat Pathol. 2018; 25:327-332.

4. Nguyen DP, Vertosick EA, Sharma V, et al. Does Subclassification of Pathologically Organ Confined (pT2) Prostate Cancer Provide Prognostic Discrimination of Outcomes after Radical Prostatectomy?

J Urol. 2018; 199:1502-1509 5. Bhindi B, Karnes RJ, Rangel LJ, et al. Independent Validation of the American Joint Committee on Cancer 8th Edition Prostate Cancer Staging Classification. J Urol 2017; 198:1286-94.

6. Bleeker SE, Moll HA, Steyerberg EW, et al. External validation is necessary in prediction research: A clinical example. J Clin Epidemiol. 2003; 56:826-32.

7. Bailar JC, Mellinger GT, Gleason DF. Survival rates of patients with prostatic cancer, tumor stage, and differentiation--preliminary report. Cancer Chemother Reports 1966; 50:129-36.

8. Gleason DF, Mellinger GT. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol. 1974; 111:58-64.

9. Brierley JD, Gospodarowicz MK, Wittekind C (editors) TNM classification of malignant tumours - 8th edition. Union Int Cancer Control. Wiley Blackwell, Oxford 2017.

10. Eichelberger LE, Cheng L. Does pT2b prostate carcinoma exist?

Critical appraisal of the 2002 TNM classification of prostate carcinoma. Cancer. 2004; 100:2573-6.

11. Van Der Kwast TH, Amin MB, Billis A, et al. International society of urological pathology (ISUP) consensus conference on handling and staging of radical prostatectomy specimens. working group 2: T2 substaging and prostate cancer volume. Mod Pathol. 2011; 24:16-25 12. Chun FKH, Briganti A, Lebeau T, et al. The 2002 AJCC pT2 substages confer no prognostic information on the rate of biochemical recurrence after radical prostatectomy. Eur Urol. 2006; 49:273-8.

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13. Hong SK, Han BK, Chung JS, et al. Evaluation of pT2 subdivisions in the TNM staging system for prostate cancer. BJU Int. 2008; 102:1092-6.

14. May F, Hartung R, Breul J. The ability of the American Joint Committee on Cancer Staging system to predict progression-free survival after radical prostatectomy. BJU Int. 2001; 88:702-7.

15. Andreoiu M, Cheng L. Multifocal prostate cancer: biologic, prognostic, and therapeutic implications. Hum Pathol. 2010; 41:781-93.

16. Freedland SJ, Partin AW, Epstein JI, Walsh PC. Biochemical failure after radical prostatectomy in men with pathologic organ-con-

fined disease: pT2a versus pT2b. Cancer. 2004; 100:1646-9.

17. Kordan Y, Chang SS, Salem S, et al. Pathological stage T2 subgroups to predict biochemical recurrence after prostatectomy J Urol.

2009; 182:2291-5 18. Caso JR, Tsivian M, Mouraviev V, et al. Pathological T2 subdivisions as a prognostic factor in the biochemical recurrence of prostate cancer. BJU Int. 2010; 106:1623-7.

19. Hruza M, Bermejo JL, Flinspach B, et al. Long-term oncological outcomes after laparoscopic radical prostatectomy. BJU Int. 2013; 111:271-80.

Correspondence Hugo Antunes, MD (Corresponding Author) hugoantunes4@gmail.com Department of Urology and Renal Transplantation, Coimbra University Hospital Center, Coimbra, Portugal Belmiro Parada, MD Department of Urology and Renal Transplantation, Coimbra University Hospital Center, Coimbra, Portugal JoĂŁo Carvalho, MD Department of Urology and Renal Transplantation, Coimbra University Hospital Center, Coimbra, Portugal Miguel Eliseu, MD Department of Urology and Renal Transplantation, Coimbra University Hospital Center, Coimbra, Portugal Roberto Jarimba, MD Department of Urology and Renal Transplantation, Coimbra University Hospital Center, Coimbra, Portugal Rui Oliveira, MD Department of Pathology, Coimbra University Hospital Center, Coimbra, Portugal Edgar Tavares-da-Silva, MD Department of Urology and Renal Transplantation, Coimbra University Hospital Center, Coimbra, Portugal Arnaldo Figueiredo, MD Department of Urology and Renal Transplantation, Coimbra University Hospital Center, Coimbra, Portugal

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DOI: 10.4081/aiua.2018.3.195

ORIGINAL PAPER

Intraoperative ultrasound in robot-assisted partial nephrectomy: State of the art Giacomo Di Cosmo, Enrica Verzotti, Tommaso Silvestri, Andrea Lissiani, Roberto Knez, Nicola Pavan, Michele Rizzo, Carlo Trombetta, Giovanni Liguori UniversitĂ degli Studi Trieste, Urology Department - Cattinara Hospital, Strada di Fiume 447, Trieste, Italy.

Summary

Introduction: Nephron-sparing surgery (NSS) is of one of the most studied fields in urology due to the balancing between renal function preservation and oncological safety of the procedure. Aim of this short review is to report the state of the art of intra-operative ultrasound as an operative tool to improve localization of small renal masses partially or completely endophytic during robotassisted partial nephrectomy (RAPN).

Material and methods: We performed a literature review by electronic database on Pubmed about the use of intra-operative US in RAPN to evaluate the usefulness and the feasibility of this procedure.

Results: Several studies analyzed the use of different US probes during RAPN. Among them some focused on using contrastenhanced ultra sonography (CEUS) for improving the dynamic evaluation of microvascular structure allowing the reduction of ischemia time (IT). We reported that nowaday the use of intraoperative US during RAPN could be helpful to improve the preservation of renal tissue without compromising oncological safety. Moreover, during RAPN there is no need for assistant to hand the US probe increasing surgeon autonomy.

Conclusions: The use of a robotic ultrasound probe during partial nephrectomy allows the surgeon to optimize tumor identification with maximal autonomy, and to benefit from the precision and articulation of the robotic instrument during this key step of the partial nephrectomy procedure. Moreover US could be useful to reduce ischemia time (IT).

The advantages of nephron-sparing surgery over radical nephrectomy is well established with a pool of data providing strong evidence of oncological and survival equivalency. With the progressive growth of robot-assisted partial nephrectomy (RAPN) techniques, the use of several tools has been progressively developed to help the surgeon in the identification of masses and its vascular net. In this short review we tried to analyze the current use of intra-operative ultrasound as an operative tool to improve localization of small renal masses partially or completely endophytic during RAPN.

KEY WORDS: Robotic surgery; Nephron-sparing surgery; Intraoperative ultrasound; Contrast-enhanced ultrasonography .

Submitted 6 July 2018; Accepted 12 July 2018

INTRODUCTION

Renal cell carcinoma (RCC) is the seventh most common urological neoplasm with an incidence of approximatively 270.000 new cases diagnosed each year worldwide. The rising incidence of kidney cancer is related to the improv-

ing of imaging techniques such as contrast-enhanced ultrasonography (CEUS), magnetic resonance imaging (MRI) and computed tomography (CT) that are capable to incidentally diagnose small renal masses (SRM). In past decades SRM have been treated by radical nephrectomy with increased risk of chronic kidney disease (1). For this reason thereâ&#x20AC;&#x2122;s been increasing interest in using nephron-sparing surgery (NSS) techniques and nowadays NSS is the standard of care for T1a renal masses and several retrospective series as well as one prospective randomized controlled trial (RCT) including patients with organ-confined RCC of limited size, low T-stage (pT1a), have demonstrated a comparable cancer specific survival (CSS) for NSS versus radical nephrectomy (RN) (2, 3).

Several studies focused on the ischemia time as a predictor of renal function reduction. In this context, in recent years we have seen an increasing use of intraoperative ultrasound (IOUS) probes and contrast-enhanced ultrasonography (CEUS). The use of ultrasound in the intraoperative renal surgery is able to provide indications regarding the parenchyma and vascularization of the kidney. In this paper we describe the different operative approaches and we also performed a short review to focus on the actual application of intraoperative ultrasound in robot-assisted partial nephrectomy (RAPN).

TECNIQUE Instrumentation and technical characteristics The frequency normally used for laparoscopy or robotic ultrasound guidance is between 7.5 and 10 MhZ. Especially probes with 7.5 Mhz can surely provide excellent images for distances between 1 and 4 centimeters. In this context ultrasound is able to detect tumors up to 34 mm diameter (4). Probe may be linear (with multiple longitudinal transductors) or convex. Linear probe is generally more effective to scan organs with large flat surfaces as liver or spleen while convex probes are usually better for curved surfaces as kidney. To obtain better resolution is sometimes useful to irrigate the surface with saline solution (5).

During laparoscopic or robot-assisted procedure, both the assistant or the surgeon can control the laparoscopic ultrasound probe. In this second case the laparoscopic

No conflict of interest declared.

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probe might require adjustment of probe positioning with also a robotic instrument to reduce probe slippage from tumor surface (6, 7). There’s also the possibility of using ultrasound probes directly related to the robotic arm through a grooved ridge on its ventral aspect that fits the robotic grasping instrument allowing control by the surgeon himself.

In different series of laparoscopic or robot-assisted partial nephrectomy (LAPN and RAPN) with laparoscopic ultrasonography, it has been described some difficulty during the identification of tumor borders because the transducer may be not perpendicular to the surface of the kidney. The robotic ultrasound probe, instead, can be handled independently by the surgeon, achieving difficult angles while maintaining perpendicular contact of the probe with kidney surface (7).

Intraoperative CEUS CEUS plays a key role in the characterization of malignant renal lesions (8). RAPN may be carried out by clamping of hilar vessels or by selective clamping of tumor vessels that aloud to reduce ischemia effects on the whole kidney. Several techniques have been described to perform partial ischemia by identifying tumor vessels and clamping or ligating those who feed the tumor (9).

Finally the intraoperative ultrasonography (IOUS) can be used for surgery of renal neoplasms, associated with the presence of venous thrombus. In case the thrombus extension is not visible or palpable, ultrasounds may be essential to identify the distal portion of the thrombus itself (10).

The contrast agent used during the CEUS procedure enhances the kidneys for about 2 minutes in real-time post-injection of contrast. In case of chronic kidney disease renal parenchyma could be enhanced for a shorter period and with lower intensity (11). A second-generation contrast agent, SonoVue (Bracco, Milan, Italy) is widely used for the CEUS procedure. Each milliliter of this contrast agent contains stabilized microbubbles of sulfur hexachloride gas (12). The recommended dose for renal imaging using a single intravenous injection of SonoVue is 1-2.4 ml. The ultrasound contrast agent can actually be seen to flow into the renal parenchyma usually within 15-20 seconds after an intravenous injection of SonoVue. This contrast enhancement of the renal parenchyma starts with the medulla and spreads to the renal cortex as the kidney is perfused with ultrasound contrast agent. Intravenous aliquots of SonoVue may be repeated as necessary and most importantly, this contrast agent is not nephrotoxic, as it is excreted by the lungs.

Thus, it can be used safely in patients with compromised renal functions.

The intra-operative CEUS technique uses two images: a conventional B-mode or 2D mode (brightness mode) image of the tissue using low acoustic power that produces a two-dimensional image on the screen and a contrast-enhanced mode (a contrast-specific) image which displays the reflection made by the spatial distribution of bubbles (Figure 1).

When an ultrasound wave falls on the microbubbles, they expand to almost double their original size and con-

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Figure 1.

Intra-operative contrast-enhanced ultrasonography (CEUS) technique: conventional B-mode or 2D mode (brightness mode) image and contrast-enhanced mode image which displays the reflection made by the spatial distribution of bubbles.

Courtesy of Prof. Michele Bertolotto, Trieste.

tract simultaneously, producing an oscillatory movement. This movement further results in the transmission of return signals to the US machine transducer (13), resulting in successful enhancement of the renal microvasculature and accurate tumor marking. A technique, which we are still developing, is sequential occlusion angiography. In this technique we capitalize on the ability to rapidly destroy or “rupture” the SonoVue microbubbles by increasing the ultrasound scanning frequency. This effectively clears the renal parenchyma or tissue being scanned of microbubbles and allows a second or subsequent intravenous injection of SonoVue to be administered immediately. In our hands, this is the real advantage of CEUS, which undoubtedly, seems to offer a better intra-operative imaging in comparison to power Doppler and Firefly.

The combination of CEUS and microbubble contrast agents allows a definite enhancement of contrast resolution, and inhibition of signals from stationary tissues.

Although, SonoVue is more widely used for CEUS in most countries except the United States, there are a number of other alternative contrast agents available for this purpose.

Technical procedures and our experience In our center we perform RAPN or LAPN for tumors sized < 4 cm with average PADUA score of 7, most of times at lower pole of the kidney. Most of times, transperitoneal approach is used. Pre-operative staging is completed by chest and abdomen computed tomography (CT) to assess tumor morphology and vascular anatomy of the hilum. After identification and exposure of hilum, the surgeon release the Gerota’s fascia (in case of posterior mass and transperitoneal approach, full mobilization of kidney is required). After giving patient 12.5 mg mannitol, warm ischemia is induced by bulldog clamping on the principal arteria. In this moment intraoperative ultrasound helps to localize the mass, the depth of penetra-

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Intraoperative ultrasound

tion inside the parenchyma and its relationship with the collecting system. Moreover, IOUS helps in delineation of tumor margins and peritumoral vascularization: especially a contrast-enhanced ultrasound can enhance the visualization of the tumor and its vascularization during RAPN or LAPN with more precision consequently increasing the diagnostic accuracy of the surgeon and aloud selective clamping.

Review of studies We performed as well a comprehensive literature search by electronic bibliographic databases in PubMed up to March 2018 using the following keywords: “contrast enhanced ultrasound”, “intra-operative ultrasound”, “nephron-sparing surgery”, “partial nephrectomy” and “robotic-assisted partial nephrectomy”. The list of all electronically identified bibliographies and articles was then reviewed to distinguish potentially relevant studies including experiments, case reports, and reviews and preliminary clinical studies. We selected studies in the field of intra-operative ultrasound in laparoscopic and RAPN.

DISCUSSION

RAPN is performed with different techniques based on surgeon preferences, tumor characteristics, patient factors and available technology. According to AUA and EAU guidelines partial nephrectomy should be offered to all patients with organ confined disease, with mass equal or lass than. Although several nephrometric scoring system have been developed (14, 15) to help the surgeon in planning surgical best approach and CT or MRI clearly show the relationship between the lesion and renal sinus fat and pyelocaliceal system or involvement of renal vessels, IOUS can provide more detailed real-time guidance in the operating room for selected T1 lesions. Moreover, IOUS helps determine whether the distance between a main or segmental blood vessel and the tumor is greater 3-5 mm (16, 17). Therefore, there is a perceived need for IOUS especially if the tumor is intraparenchymal and complex according to the nephrometry score. First reports of IOUS to help identify renal cell carcinoma in patients with poorly visualized and non-palpable disease have been described in 1988 (18). IOUS could also reduce operative time and ischemia time because it increase mass delimitation in those cases with particularly dense perirenal adipose tissue with highly represented fibrous components. Assimos et al. reported using of intraoperative ultrasonography for tumor identification to obtain negative surgical margins during partial nephrectomy (19). Great attention has also been given to IOUS use in the identification of extrarenal venous extension, multifocality and associated renal cysts and has also been reported that the use of intraoperative ultrasonography influenced the choice of surgical approach in 13% of cases (20, 21).

In recent years, there has been a progressive shift from laparoscopic partial nephrectomy and RAPN due to the ability to reduce the warm ischaemia time (WIT) and learning curve during nephron-sparing surgery in robotic surgery (22). A prolonged WIT has been demonstrat-

ed to be potentially dangerous for renal functions post partial nephrectomy, especially in patients with high risk factors, or underlying disorders such as hypertension, diabetes, and small vessel disease (23-25). Surgeons are motivated to avoid global ischemia and consequently reduce the WIT by ligating or clamping selective arteries that supply blood to the segment of the kidney containing the tumor helps achieve a lower WIT. Intra-operative ultrasound seems to be highly useful for this purpose, as it can demonstrate real-time imaging of the renal vasculature. CEUS is capable of further reducing the WIT by aiding the process of selective clamping, since it permits real-time scanning of the macrovasculature and microvasculature of the kidneys without the need for removing the perinephric fat.

Kaczmarek et al. (7) performed RAPN using a robotic US probe for tumor identification in 22 patients. The Gerota’s fascia was opened to expose the renal capsule around the tumor, hilar blood vessels were isolated and clamped in preparation for excision of the tumor under warm ischemia and renoraphy was performed by “sliding clip suture” technique (26). The ultrasound probe was introduced through the assistant port to help the recognition of the border between tumor pseudo-capsule and normal renal parenchyma. The location and extent of the tumor were visualized through the medium of real-time images, obtained from intra-operative ultrasound techniques. Images were produced and visualized by the surgeon using the TilePro feature of the da Vinci surgical system to produce a picture-on-picture image in the console screen to view the images. Finally In some studies have been described intra-operative ultrasound scan using a fourth robotic arm with ProART robotic drop-in probe (6, 27).

CONCLUSIONS

IOUS has been demonstrated as one of the most important tool to help surgeon in maximize the loss of nephrons and it can be performed both by using assistant port or robotic probe with surgeon directly handling the probe with sensible benefit from the precision and articulation of robotic instrument. Intraoperative CEUS can further reduce global WIT and thus may improve recovery of renal function. By facilitating selective arterial clamping during RPN and avoiding global ischemia it may decrease the risk of permanent loss of nephrons.

Most importantly, CEUS can help us image the renal microvasculature, without affecting renal function. In addition, CEUS is capable of dynamic evaluation and quantification of microvasculature blood (capillary perfusion) in real time. When used in conjunction with a robotic ultrasound probe, CEUS can facilitate better visualization of renal vasculature and tumor and ultimately improving acumen and precision.

REFERENCES

1. Hollenbeck BK, Taub DA, Miller DC, et al. National utilization trends of partial nephrectomy for renal cell carcinoma: a case of underutilization? Urology. 2006; 67: 254-9.

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2. Gratzke C, et al. Quality of life and perioperative outcomes after retroperitoneoscopic radical nephrectomy (RN), open RN and nephron-sparing surgery in patients with renal cell carcinoma. BJU Int. 2009; 104:470.

15. Ficarra, et al. Preoperative aspects and dimensions used for an anatomical (PADUA) classification of renal tumours in patients who are candidates for nephron.sparing surgery. Eur Urol. 2009; 56:786-793.

3. Van Poppel H, et al. 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.

16. Li QL, et al. Significance of margin in nephron sparing surgery for renal cell carcinoma of 4 cm or less. Chine Med J (Engl). 2008; 121:1662-1665.

4. Polascik TJMF. Intraoperative sonographic evaluation of the Kidney. AUA Update Series. 1997; 16:137.

17. Lam, et al. Importance of surgical margin in nephron sparing surgery in the management of renal cell carcinoma. Nat. Clin Pract Urol. 2008; 5:308-317.

5. Lirici, et al. Laparoscopy ultrasonography: limits and potential of present technologies. Endosc Surg Allied Technol. 1994; 2:127-133.

18. Gilbert BR, et al. Intraoperative sonography: application in renal cell carcinoma. J Urol. 1988; 139:582-284.

6. Rogers CG et al. Maximizing console surgeon independence during robot-assisted renal surgery by using the Fourth Arm and Tile Pro. J Endourol. 2009; 23:115-121.

19. Assimos D, et al. Intraoperative renal ultrasonography: a useful adjunct to partial nephrectomy. J Urol 1991; 146:1218-1220,

7. Kaczmarek BF, et al Robotic ultrasound probe for tumor identification in robotic partial nephrectomy; initial series and outcomes.

Int J Urol, 2013; 20:172-176, 8. Bertolotto M, et al. Renal masses as characterized by ultrasound contrast. Ultrasound Clin. 2013; 8:581-592.

9. Gill IS, Eisenberg MS, Aron M, et al. Zero ischemia partial nephrectomy: novel laparoscopic and robotic technique. Eur Urol.

2011; 59:128-134.

10. Hsu et al. Laparoscopic radical nephrectomy incorporating intraoperative ultrasonography for renal cell carcinoma with renal vein tumor thrombus. Urology 2003; 61:1246-1248.

11. Piscaglia F, et al. The EFMBSU Guidelines and Recommendations on the clinical practice of Contrast enhanced ultrasound (CEUS): update 2011 on non-hepatic applications.

Ultraschall Med. 2012; 33:33-59.

12. Greis C. Technology overview: SonoVue (Bracco, Milan) Eur Radiol. 2004; 14(supp 8):11-15.

13. Uhlendorf V, et al Acoustic behavior of current ultrasound contrast agents. Ultrasonics. 2000; 38:81-86.

14. Kutikov, et al. The R.E.N.A.L. nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth. J Urol. 2009; 182:844-853.

20. Polascik TJ, et al. Intraoperative sonography for the evaluation and management of renal tumors: experience with 100 patients. J Urol 1995; 154:1676-1680.

21. Marshall, et al. Intraoperative sonography of renal tumor. J Urol 1992; 148:1393-1396.

22. Mottrie A, De Naeyer G, Schatteman P, et al. Impact of the learning curve on perioperative outcomes in patients who underwent robotic partial nephrectomy for parenchymal renal tumoursâ&#x20AC;? Eur Urol. 2010; 58:127-132.

23. Clark MA, et al. Chronic kidney disease before and after partial nephrectomy. J Urol. 2011; 185:43-48.

24. Thompson RH, et al. Every minute counts when the renal hilum is clamped during partial nephrectomy. Eur Urol. 2010; 58:340345.

25. Campbell SC, et al. Guideline for management of the clinical T1 renal mass. J Urol, 2009; 182:1271-1279.

26. Benway BM, et al. Robotic partial nephrectomy with sliding-clip renorrhaphy: technique and outcomes. Eur Urol. 2009; 55:592-599.

27. Rao AR, Gray R, Mayer E, et al. Occlusion angiography using intraoperative contrast-enhanced ultrasound scan (CEUS): a novel technique demonstrating segmental renal blood supply to assist zero-ischaemia robot-assisted partial nephrectomy. Eur Urol. 2013; 63:913-9.

Correspondence Giacomo Di Cosmo, MD (Corresponding Author) giacomo.dicosmo@gmail.com Enrica Verzotti, MD enrica.verzotti@gmail.com Tommaso Silvestri, MD tommaso.silve@gmail.com Andrea Lissiani, MD a_lissiani@gotmail.com Roberto Knez, MD r.knez@libero.it Nicola Pavan, MD nicpavan@gmail.com Michele Rizzo, MD mik.rizzo@gmail.com Carlo Trombetta, MD trombcar@units.it Giovanni Liguori, MD gioliguori33@gmail.com UniversitĂ degli Studi Trieste, Urology Department - Cattinara Hospital, Strada di Fiume 447, Trieste, Italy

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DOI: 10.4081/aiua.2018.3.199

ORIGINAL PAPER

Serenoa repens extracts: In vitro study of the 5α-reductase activity in a co-culture model for Benign Prostatic Hyperplasia Daniela Buonocore 1, Manuela Verri 1, Laura Cattaneo 1, Sara Arnica 1, Michele Ghitti 2, Maurizia Dossena 1 1 University

of Pavia, Pavia (Italy), Department of Biology and Biotechnology “L. Spallanzani”; of Pavia, Pavia (Italy), Department of Earth and Environmental Sciences (DSTA) - Unit of Statistical Analyses (UNISTAT).

2 University

Summary

Objectives. Benign Prostatic Hyperplasia (BPH) is a form of benign tumor that occurs in humans mainly with ageing. It affects more than 50% of over 50 years old males and it is characterized by an increased synthesis of dihydrotestosterone (DHT), due to the 5α-reductase activity. The BPH therapeutic approach mainly uses 5α-reductase inhibitors, such as the active compounds present in the extracts deriving from species Serenoa repens. Many lipidosterolic extracts are available on the market, which are obtained with different solvents, among them ethanol is recognized as non-toxic and has less handling risks than hexane.

The purpose of the present experimental study was to investigate in-vitro the potency of an ethanol extract of S. repens comparing it with an n-hexane one.

Materials and methods. Two different lipido-sterolic extracts of S. repens have been tested: ethanol extract and n-hexane extract, two batches for each one. The inhibitory action of the extract was evaluated estimating in-vitro the activity of enzyme 5α-reductase type I (5α-RI), which was mainly active under the experimental condition of pH 7.5. DHT amount, synthesized from testosterone (1 μM), was evaluated in a co-culture model of epithelial cells and fibroblasts resulting from prostatic biopsy of a patient with BPH. Results. The analysis of the resulting dose-response curves showed that the entire S. repens extracts inhibited the 5α-RI showing no difference between the two kinds of extract or between the batches. The resulting IC50 values were the following: 8.809 (95% CI = 5.133-15.56) and 9.464 (95% CI = 5.09418.27) for ethanol extracts; 11.08 (95% CI = 6.389-19.98) and 12.72 (95% CI = 7.758-21.53) for n-hexane extracts.

Conclusions. The potency of ethanol extracts of S. repens was comparable with the one of n-hexane extracts.

KEY WORDS: Benign Prostatic Hyperplasia; Dihydrotestosterone; Ethanol extracts; In-vitro study; 5α-reductase; Serenoa repens.

Submitted 7 May 2018; Accepted 12 July 2018

INTRODUCTION

Benign Prostatic Hyperplasia (BPH) is a form of benign tumor that occurs in humans mainly with ageing. In fact, it affects more than 50% of over 50 years old males, with an incidence rate directly proportional to age (1). It is characterized by an increased synthesis of dihydrotestosterone (DHT) starting from testosterone, due to the

action of enzyme 5α-reductase, which leads to an increase of the prostate size and causes various disorders, especially in the lower urinary tract (1, 2). The approach for the treatment and therapy of BPH is mainly based on the use of inhibitors of 5α-reductase enzyme, in particular natural inhibitors, such as the active compounds present in the alcoholic extracts deriving from species Serenoa repens, a typical palm common in the Subtropical sandy soils and in the southern coasts of the United States. Although the sure mechanism of action of S. repens is not yet fully understood, numerous mechanisms have been proposed (3) and the presence of specific fatty acids (saturated and unsaturated fatty acids) and phytosterols in its alcoholic extracts confers upon S. repens an anti-inflammatory and above all antiproliferative action on prostatic tissue (4). Both a systematic Cochrane review of the literature (5) and a meta-analysis (6) assessed the safety profile and the clinical efficacy of S. repens in the treatment of symptoms in patients with BPH. These studies have shown an improvement of urinary tract disorders, with a mild to moderate effect and, therefore, a lack of therapeutic equivalence between S. repens extracts of different brands and between extracts of a single brand, but belonging to different manufacturing batches (5, 6). Many lipido-sterolic extracts are commercially available, which were obtained with different solvents, among them ethanol is recognized as non-toxic and it has less handling risks than hexane (7, 8). The purpose of the present experimental study was to investigate in-vitro the potency of an ethanol extract of S. repens comparing it with an n-hexane one. In particular, the activity of enzyme 5α-reductase was estimated invitro concerning the inhibitory action of the extracts, using co-cultures of epithelial cells and fibroblasts resulting from prostatic biopsy of a patient with BPH.

MATERIALS

AND METHODS

Samples Two extracts, belonging to commercial brands SABA® (Lampugnani Farmaceutici) and PERMIXON® (Pierre Fabre Pharma), supplied with marketing authorization in

No conflict of interest declared.

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several EU Member States (including Italy) and belonging to the class of drugs employed to counter the increase in prostatic volume in males with BPH, have been tested.

The two branded drugs contained the lipid-sterolic extract of S. repens (320 mg/soft capsule) as active ingredient and particularly, ethanol extract (SABA®) and hexane extract (PERMIXON®). Two different batches of each brand were tested: SABA® (G08363 and G08364); PERMIXON® (F 11917 and G07340), mentioned below as “samples”.

The content of one soft capsule was weighed (10 mg) and dissolved in N-hexane; then the solvent was evaporated to leave the solid extract that was dissolved in ethanol (70%) to give a concentration of 10 mg/ml.

This stock solution was further diluted in appropriate media to provide a working solution of 1 mg/ml (9).

Co-culture cell model Two types of primary cells were used: epithelial cells and fibroblasts, previously isolated from prostatic tissue obtained during a biopsy from a patient with established BPH. Informed consent of the patient was obtained.

Primary cultures of fibroblast and epithelial cells were obtained as previously described (2). Both the epithelial and fibroblast cells were cultured separately in flasks with culture medium, complete with fetal bovine serum (10%), DMEM and RPMI 1640 respectively, and kept in an incubator in a humidified atmosphere (37°C and 5% CO2). Corresponding to the third generation step, both the epithelial cells and fibroblasts, were transferred into multiwell plates of 12 wells provided with Transwell® (3470 Clear-Corning), or supports consisting of a microporous polystyrene membrane. This enabled to keep the two cell populations separate but, at the same time, to allow their interactions.

In particular: epithelial cells were sown in the number of 50,000 on the bottom of each well; on the contrary, fibroblasts were sown in the number of 5,000 on the microporous polystyrene membrane. Co-cultures were maintained in DMEM:RPMI-1640 (1:1 v/v) media + 10% fetal calf serum at 37°C in 5% CO2 (10).

Furthermore, in order to verify that the fibroblasts were correctly adhering to the membrane, the quantitative technique TEER (Transepithelial Transendothelial Electrical Resistance) was applied; this technique enabled to examine the integrity of the cell junctions (tight junctions) by measuring the resistance that the monolayer of fibroblasts opposed to the passage of electric current (11).

Measurement of the trans-epithelial resistance value, expressed in Ohms and normalized for the polystyrene membrane area (Ω/cm²), was performed using a voltmeter (Millicell® ERS-2, Merck Millipore) equipped with two electrodes of different length (data not reported).

5α-reductase activity assay The co-culture cells were pre-treated for a period of four days with a non-toxic concentration (10 μg/ml) of each sample (SABA®: G08363 and G08364; PERMIXON®: F 11917 and G07340). Afterwards the cells were harvested by trypsinization, centrifuged and the pellet was suspended in RPMI-1640, supplemented with 10% fetal calf serum, and then counted. The pH value of the medium

200

solution was 7.85, an optimum value for the activity of 5 α-reductase type I (12). Cell suspensions were added into tubes containing testosterone (1 μM) as substrate, a NADPH-regenerating system (0.5 mM glucose-6-phosphate, 0.06 U glucose-6-phosphate dehydrogenase, 50 μM NADPH) (H+ donor) (13) and different concentrations of each sample: 1 mg/ml, 100 μg/ml, 10 μ /ml, 5 μg/ml, 1 μg/ml, 0.1 μg /ml, 0.01 μg/ml; these concentrations were chosen basing on the cytotoxicity results, previously obtained in laboratory applying the MTT test (14)) and in agreement with data present in the literature (9, 10).

The tubes were then incubated at 37° C for 30 min in a stirring water bath. The reaction was stopped by dipping the tubes into liquid nitrogen (9, 10, 12).

The 5α-reductase type I activity was assessed by measuring the conversion of testosterone to dihydrotestosterone (DHT) applying a qualitative/quantitative Enzyme-Linked Immunosorbent Assay (Abnova KA1886), as previously described (15).

Enzyme activity is expressed as a percentage of the control. The conversion of 1 μM of testosterone in the absence of inhibitors is defined as 100% activity (2.953.63 nmol of DHT/106 cells/min for type I isoenzyme).

Dose-effect response curves were analyzed using a sigmoid maximum-effect model with a variable slope (Graphpad, Prism7).

Inhibitory potency was assessed by estimating the IC50 value that represented the concentration (μg / ml) capable of determining the 50% of the maximal effect (enzymatic inhibition). The highest IC50 value was then divided by the IC50 values obtained for each sample for the relative potency (RP) (the relative potency value = 1 was considered the lowest value).

Statistical analysis The nonlinear-regression curves were analyzed applying two different Linear Mixed Models, one to analyze the commercial brands (SABA® vs PERMIXON®) and one for the batches. The analyses were performed with software R.

RESULTS

All the samples of S. repens extracts (F 11917; G07340; G08363; G08364) were found to be capable of inhibiting 5α-reductase (5α-RI) in a prostatic co-cultured epithelial and fibroblast cells, as shown by dose-effect curves in Figure 1 (enzyme activity (%) as a function of the logarithm of concentrations).

Regarding the potency of each sample, evaluated by IC50 value (Table 1) and highlighted by the relative potency (Table 2), SABA® (IC50 = 8.809 and 9.464) showed a higher efficacy on 5α-RI than PERMIXON® (IC50 = 11.08 and 12.72), but there were non-significant differences between the two brands and batches, as mentioned below.

Regarding the comparison between the two brands (SABA® vs PERMIXON®), the analysis of deviance (Type III tests) for 5α-RI data set showed that the model was non-significant (Response: enzyme; Chisq Df Pr (> Chisq); (Intercept) 28.3600 1 1.007e-07 ***; Brand 2.9228 1 0.08734; Signif. codes: 0 ‘***’ 0.001 ‘**’ 0.01 ‘*’ 0.05 ‘.’

0.1 ‘ ’ 1).

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S. repens inhibits 5α-reductase

Figure 1.

Inhibition of 5α-reductase type I. Enzyme activity, depending on the logarithm of concentrations, is expressed in percentage as compared with the positive control (100% of enzyme activity converting testosterone 1μM, in the absence of inhibitors).

Regarding the comparison between the batches (F 11917; G07340; G08363; G08364), the analysis of deviance (Type III tests) showed that the model was non-significant [Response: enzyme; Chisq Df Pr (> Chisq); (Intercept) 28.0176 1 1.202e-07 ***; Batch 2.9326 3 0.4021; Signif. codes: 0 ‘***’ 0.001 ‘**’ 0.01 ‘*’ 0.05 ‘.’

0.1 ‘ ’ 1].

Regarding the relative potency (Table 2), both SABA® and PERMIXON® showed comparable potencies between the two batches and PERMIXON® showed the lowest values.

G07340), have shown to inhibit enzyme 5α-reductase in a co-culture model of human prostatic cells (epithelial and fibroblasts), as reported also in the literature (9, 10).

Even though the potency of SABA samples of inhibiting the activity of enzyme 5α-reductase type I showed higher values than PERMIXON’s values, there were no significant statistical differences between the two brands or the batches. These in-vitro results pointed out that the S. repens ethanol extract (SABA®) was equivalent to the nhexane one (PERMIXON®).

This conclusion is important because basing on the equivalence of efficacy for both tested extracts, obtained with different extraction methods, it would be better to DISCUSSION use organic solvents (ethanol) recognized as environAll the extracts of S. repens that we tested, SABA® mentally safer and alternative to hexane, which is a sol(G08363 and G08364) and PERMIXON® (F 11917 and vent obtained from petrochemical sources that can remain in potential traces in edible oils after refining and can be emitted during extraction and recovery and that has been identified as Table 1. an air pollutant since it can react with other Comparative potency of the two extracts on 5α-reductase type I, pollutants to produce ozone and photochemgiven by IC50 value and related 95% CI. ical oxidants (7, 8, 16).

PERMIXON SABA Moreover, data that we obtained allow us to F11917 G07340 G08363 G08364 speculate on the possible effects of the ethanol IC50 (5α-RI)1 11.08 12.72 8.809 9.464 extract from S. repens on the pathology of 95% CI2 6.39 to 19.98 7.76 to 21.53 5.13 to 15.56 5.09 to 18.27 BPH: it is known that clinical benefits are gen15α-RI: 5α-reductase type I. 2CI: Confidence Interval. erally associated with the free fatty acid content, along with a small contribution from unsaponifiable components (17, 18).

Particularly, the relative inhibitory efficacy of Table 2.

Relative potency of the various extracts on 5α-reductase type I the various free fatty acids seems to depend (considering RP = 1 as the lowest potency). on the length of the carbon chain and its saturation state (17). For example, lauric acid 5α-RI1 (short saturated, C12 chain) inhibits both 5 SABA SABA PERMIXON PERMIXON α-reductase type I and II, while oleic acid Batch G08363 G08364 F11917 G07340 with a C18 unsaturated chain (C18 ∆9) and RP2 1.444 1.344 1.148 1 linoleic acid (C18 ∆9, 12) have a good activ15α-RI: 5α-reductase type I. 2RP: relative potency. ity on type I but not on type II (15). SABA® and PERMIXON® (19) were analyzed in Archivio Italiano di Urologia e Andrologia 2018; 90, 3

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terms of concentration in free fatty acids, methyl and ethyl esters, long-chain esters and glycerides. These analyses revealed that each of the individual FFAs analyzed was found in similar proportions in the tested products, with lauric and oleic acids present at the highest concentrations in every tested sample and similar concentrations of methyl and ethyl esters were found.

Instead, glyceride content was particularly high (420%) in SABA® and not in PERMIXON®.

Generally, a similar content composition was observed between SABA® and PERMIXON® (19). So, our results are explained by data reported above: similar content composition is associated with the same potency of ethanol and hexane extracts.

CONCLUSIONS

Ethanol extract of S. repens has shown in vitro a potency of inhibiting the activity of enzyme 5α-reductase comparable with potency of n-hexane extract of S. repens.

REFERENCES

1. Rył A, Rotter I, Grzywacz A, et al. Molecular analysis of the SRD5A1 and SRD5A2 genes in patients with benign prostatic hyperplasia with regard to metabolic parameters and selected hormone levels. Int J Environ Res Public Health. 2017; 14:1318.

2. Bayne CW, Donnely F, Chapman K, et al. A Novel coculture model for benign prostatic hyperplasia expressing both isoforms of 5α-reductase. JCEM. 1998; 83:206.

3. Buck AC. Is there a scientific basis for the therapeutic effects of Serenoa repens in benign prostatic hyperplasia? Mechanisms of action. J Urol. 2004; 172:1792.

4. Capasso F, De Pasquale R, Grandolini G. Droghe contenenti lipidi. In: Farmacognosia. Botanica, chimica e farmacologia delle piante medicinali. Italia: Ed. Springer Verlag, 2014.

7. Johnson LA & Lusas EW. Comparison of alternative solvents for oils extraction. J Am Oil Chem Soc. 1983; 60:229.

8. Ferreira-Dias S, Valente DG, Abreu JMF. Comparison between ethanol and hexane for oil extraction from Quercus suber L. fruits.

Grasas y Aceites. 2003; 54:378.

9. Scaglione F, Lucini V, Pannacci M, et al. Comparison of the Potency of Different Brands of Serenoa repens Extract on 5αReductase Types I and II in Prostatic Co-Cultured Epithelial and Fibroblast Cells. Pharmacology. 2008; 82:270.

10. Bayne CW, Donnely F, Ross M, Habib FK. Serenoa repens (Permixon®): A 5α-reductase Types I and II Inhibitor-New evidence in a Coculture Model of BPH. Prostate. 1999; 40:232.

11. Srinivasan B, Kolli Reddy A, Esch MB, et al. TEER measurement techniques for in vitro barrier model systems. J Lab Autom. 2015; 20:107.

12. Smith CM, Ballard SA, Worman N, et al. 5 alpha-reductase expression by prostate cancer cell lines and benign prostatic hyperplasia in vitro. J Clin Endocrinol Metab. 1996; 81:1361.

13. Weisser H, Tunn S, Behnke B, Krieg M. Effects of the sabal serrulata extract IDS 89 and its subfractions on 5 alpha-reductase activity in human benign prostatic hyperplasia. Prostate. 1996; 28:300.

14. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983; 65:55.

15. Di Silverio F, D'Eramo G, Lubrano C, et al. Evidence that Serenoa repens extract displays an antiestrogenic activity in prostatic tissue of benign prostatic hypertrophy patients. Eur Urol. 1992; 21:309.

16. Wan PJ, Pakarinen DR, Hron RJSr, et al. Alternative hydrocarbon solvents for cottonseed extraction. J Am Oil Chem Soc. 1995; 72:653.

17. Paubert-Braquet M, Cousse H, Raynaud JP, et al. Effects of the lipido-sterolic extract of Serenoa repens (Permixon ®) and its major components on basic fibroblast growth factor-induced proliferation of cultures of human prostate biopsies. Eur Urol. 1998; 33:340.

5. Wilt T, Ishani A, MacDonald R. Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev. 2002; CD001423.

18. Raynaud JP, Cousse H, Martin PM. Inhibition of type 1 and type 2 5alpha-reductase activity by free fatty acids, active ingredients of Permixon®. J Steroid Biochem Mol Biol. 2002; 82:233.

6. Boyle P, Robertson C, Lowe F, Roehrborn C. Updated metaanalysis of clinical trials of Serenoa repens extract in the treatment of symptomatic benign prostatic hyperplasia. BJUI. 2004; 39:751.

19. Habib FK & Wyllie MG. Not all brands are created equal: a comparison of selected components of different brands of Serenoa repens extract. Prostate Cancer Prostatic Dis. 2004; 7:195.

Correspondence Daniela Buonocore, MD (Corresponding Author) daniela.buonocore@unipv.it Manuela Verri, MD manuela.verri@unipv.it Laura Cattaneo, MD laura.cattaneo02@universitadipavia.it Sara Arnica, MD sara.nica90@gmail.com Maurizia Dossena, MD maurizia.dossena@unipv.it Via Ferrata, 9-27100 Pavia, Italy Michele Ghitti, MD ghitti.michele@gmail.com Via Ferrata, 1-27100 Pavia, Italy

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DOI: 10.4081/aiua.2018.3.203

ORIGINAL PAPER

Hibiscus extract, vegetable proteases and Commiphora myrrha are useful to prevent symptomatic UTI episode in patients affected by recurrent uncomplicated urinary tract infections Tommaso Cai 1, Daniele Tiscione 1, Andrea Cocci 2, Marco Puglisi 1, Gianmartin Cito 2, Gianni Malossini 1, Alessandro Palmieri 3 1 Department

of Urology, Santa Chiara Regional Hospital, Trento, Italy; of Urology, University of Florence, Florence, Italy; 3 Department of Urology, University of Naples, Federico II, Naples, Italy.

2 Department

Summary

Objective: To evaluate the efficacy of a combination of Hibiscus extract, vegetable proteases and Commiphora myrrha extract in the prophylaxis of symptomatic episode in women affected by recurrent urinary tract infections (rUTIs).

Materials and methods: In this phase II clinical trial, all patients with history and diagnosis of rUTI were enrolled. All patients underwent the following treatment schedule: 1 tablet in the morning and 1 tablet in the evening for 7 days and, then, 1 tablet in the evening for 10 days (1 cycle every each month, for 6 months) of a combination of Hibiscus extract, vegetable proteases and Commiphora myrrha extract. At the baseline, all patients underwent urologic visit with quality of life (QoL) questionnaires and mid-stream urine culture. After 3 and 6 months, all patients underwent urologic visit, urine culture and QoL questionnaires evaluation.

Results: Fifty-five women were enrolled (mean age 49.3; range: 28-61). At the enrollment time, the most common pathogen was Escherichia coli (63.7%). The median number of UTI per 6 months was 5 (IQR: 4-9). At the end of the second follow-up evaluation, 25 women did not reported any symptomatic episode of UTI (49%), 18 reported less than 2 episodes (35.3%), while 8 reported more than 2 episodes (15.7%). However, at the first and second follow-up evaluation the clinical statistically significant improvement (QoL) was reported by 38/51 (74.5%) (p < 0.001 from baseline) and 43/51 (84.3%) (p < 0.001 from baseline) women, respectively. The median number of UTI decreased to 2 (IQR: 0-3). At the end of the follow-up period, 30/51 had sterile urine (58.8%), while 21/51 (41.2%) reported a transition from symptomatic UTI to asymptomatic bacteriuria.

Conclusions: In conclusion, this treatment, in motivated patients, is able to prevent symptomatic UTI symptomatic episode and improve patient’s QoL.

KEY WORDS: Urinary tract infection; Ellirose; Protelix; Serrazimes; Myrliq; Plant extracts; Antibiotic stewardship; treatment.

Submitted 11 August 2018; Accepted 24 August 2018

INTRODUCTION

Urinary tract infections (UTIs) represent the most frequently reported community-acquired infection and carry a significant burden for patients’ quality of life and

healthcare costs (1). Overall, more than 50% of women report having had at least one UTI at some point in their lifetime, and it is estimated that almost 11% of women aged over 18 suffer from a UTI each year (2-3). In particular, UTIs recur approximately in 20-30% of women within 6 months after their first episode (1, 4) and in around 35 to 53% of women within 12 months (5). The management of recurrent uncomplicated UTIs in women is still object of great discussion. To date, there are not well-established recommendations for a ‘standard’ prophylactic protocol to prevent recurrent UTI (6). Since the mainstay for the management of recurrent UTI still remains a short course of oral antimicrobial therapy, on the other hand the frequent use of antibiotics has led to the spread of multidrug-resistant microorganisms (710). Possible side effects, although rare, increasing healthcare costs, and rising bacterial resistance have progressively marked the downfall of classic antibiotic prophylaxis and, over years, paved the way to consider alternative prophylactic methods (4). In this regard nonpharmacological oral supplements, including the phytotherapy and nutraceuticals, seem to be an attractive alternative to antibiotic therapy to ameliorate symptoms related to UTIs and lower the rate of symptomatic recurrences. These considerations led us to conduct a prospective non-randomized phase II clinical trial in order to evaluate the efficacy of a combination of Ellirose®, Protexil®, Serrazimes® and Myrliq® (AVIUR® retard) in the prophylaxis of symptomatic episode in women affected by recurrent UTIs focusing on both the capability to reduce the number of symptomatic recurrences and the efficacy in improving QoL.

MATERIALS

AND METHODS

Study design From September to December 2017, we enrolled in a prospective, non-randomized phase II study, all women affecting by recurrent uncomplicated UTI and attending our Centre. Written informed consent was obtained

No conflict of interest declared.

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Figure 1.

from all subjects before proceeding with the enrollment.

Preliminary evaluation was performed by administering QoL questionnaires and by performing a preliminary mid-stream urine culture, in line with Cai T et al. (11).

Before enrolment all patients were treated with antibiotics in line with trialist’s choice in order to obtain the infection free condition at baseline. The last isolated bacterial strain before the antibiotic treatment was collected and consider for this analysis. The main outcome measure was, then, the recurrence-free condition at the follow-up visit. All enrolled patients underwent the following treatment schedule: AVIUR retard® 1 tablet in the morning and 1 tablet in the evening for 7 days and, then, 1 tablet in the evening for 10 days (1 cycle each month, for 6 months). After 30 days from the beginning of the treatment, all patients have been contacted by phone in order to ensure compliance to the treatment. Subsequent follow up schedule included urologic visit with QoL questionnaires and mid-stream urine culture performed after 3 and 6 months from the beginning of the therapy.

In case of acute symptomatic UTI episode all patients were treated with antibiotics in line with European Association of Urology (EAU) guidelines on urological infections (12) and in line with the antibiogram.

The Figure 1 shows the study schedule.

Clinical and microbiological considerations In accordance with the EAU guidelines, the diagnosis of UTI was defined according to the following parameters: patient reported symptoms and patient interview, physical examination, bed-side dip-stick urinalysis and urine culture (12). All microbiological and laboratory analyses have been described previously (13). In brief, all cleancatch midstream urine samples collected at room temperature were immediately taken to the laboratory under refrigerated conditions and analyzed. All urine samples were analyzed for common bacteria and yeasts, aliquoted for DNA extraction and polymerase chain reaction testing for Chlamydia trachomatis, Neisseria gonorrhoeae, and urogenital Mycoplasma. Microbiological culture was performed according to the procedure described by Hooton et al. (14). All other microbiological procedures and DNA extraction have been performed in line with Mazzoli et al. (15). For microbiological diagnosis, a colony count ≥ 105 units/mL was considered the cutoff for significant bacterial growth.

Inclusion and exclusion criteria We included in this study all patients with recurrent

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UTI, defined as ≥ 2 infections in six months or ≥3 infections in one year. Relevant exclusion criteria comprised: evidence of overactive bladder; anatomical abnormalities or previous surgery of the urinary tract; complicated UTI; pregnancy; urinary catheterization. Moreover, we excluded all patients with active infection by STD pathogens. We did not include any other exclusion criteria in order to make the results clinically relevant.

Composition and characterization of the extracts used All patients who were treated in line with the manufacturer’s instructions (Anatek Health Italia s.r.l. Via A. Caroncini, 5 - 20137 Milano; www.anatekhealth.com). Each administration contained a combination of 200 mg Ellirose™, 100 mg Protexil®SP750, 100 mg Serrazimes®, 60 mg Myrliq®PWD. Outcome measures and statistical analysis The primary outcome of this study was the rate of recurrence at the end of the study period. A good response to treatment was defined as a significant reduction of recurrences (< 2 in six months). Treatment failure was defined as the absence of recurrence reduction at the end of the study period. Transition from symptomatic UTI to asymptomatic bacteriuria was not considered as treatment failure. In order to obtain significant results to analyze, sample size calculation was based on the following assumptions: difference in terms of recurrence between baseline and follow-up visit: -3 ± 1; α error level, 0.05 two-sided; statistical power, 80%; anticipated effect size, Cohen’s d = 0.5. The calculation yielded 43 individuals.

Taking into account a drop-out rate of 10%, the final sample size has been set to 49 patients in the both groups. Statistical analysis was performed by using SPSS.

RESULTS

Fifty-five women were enrolled (mean age 49.3; range: 28-61). At the time of enrollment,the most common isolated pathogen was Escherichia coli (63.7%). All patients obtained sterile urine after antibiotic before enrollment.

The median number of UTI per 6 months was 5 (IQR 49). Demographic, microbiological and clinical characteristics at the time of enrollment are reported in Table 1.

Clinical and microbiological data at the first follow-up evaluation (3 months) After 3 months from the beginning of the treatment, 43 out of 51 patients (84.3%) reported a clinical improvement in terms of QoL form the baseline (p < 0.001),

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Hibiscus extract, vegetable proteases and Commiphora myrrha are useful to prevent symptomatic UTI episode

25 (45.5) 30 (54.5) 48 (87.3)

sterile urine samples (58.8%) and 21/51 (41.2%) reported a transition from symptomatic UTI to ABU. The Table 2 shows all clinical and microbiological data at the second follow-up evaluation.

Adherence results and treatment related adverse effects At the end of the study period, the adherence to the therapy was very high.

Only one patient (1.8%) discontinued the prescribed therapy because of the onset of drug-related adverse effects, nausea in this particular case.

21 (38.2) 34 (61.8)

DISCUSSION

Table 1.

Patient’s sociodemographic anamnestic, clinical characteristics at enrolment time.

No. of total patients Median age (range) Educational level Primary school Secondary school Post-secondary education Sexually active (past month) Current smoker No Yes Number of sex partners 1 ≥1 Number of UTI in the past 6 months 2 ≥2 Hormonal status Pre-menopausal Post-menopausal Isolated strains before ABT treatment Escherichia coli Klebsiella spp.

Enterococcus spp.

Others

55 49.3 (28-61)

49 (89.1) 6 (10.9) 39 (70.9) 16 (29.1) 35 (63.7) 20 (36.3) 35 (63.7) 10 (18.2) 7 (12.7) 3 (5.4)

while 42 out of 51 patients (82.3%) reported a restore to pre-UTI situation. From a microbiological point of view, 40 patients (78.4%) showed sterile urine and 11 (20%) showed a transition from UTI to ABU (from Escherichia coli to Enterococcus Faecalis).

Clinical and microbiological data at the second followup evaluation (6 months) At the end of the second follow-up evaluation, 25 women did not reported any acute episode of UTI (49%), 18 reported less than 2 episodes (35.3%), while 8 reported more than 2 episodes (15.7%).

However, at the first and second follow-up evaluation the clinical statistically significant improvement (QoL) was reported by 38/51 (74.5%) (p < 0.001 from baseline) and 43/51 (84.3%) (p < 0.001 from baseline) women, respectively. Moreover, the median number of UTI decreased to 2 (IQR 0-3). From a microbiological point of view, at the end of the follow-up period, 30/51 Table 2.

All patient’s sociodemographic anamnestic, clinical characteristics at enrolment time. ABT: antibiotic treatment.

Outcomes variable Clinical improvement No episode of UTI < 2 episodes of UTI > 2 episodes of UTI QoL (questionnaire) Microbiological improvement Sterile urine Transition to ABU from UTI

Baseline

Follow-up 180 days

0/51 0/51 51/51 91.3

25/51 (49) 18/51 (35.3) 8/51 (15.7) 99.0

0/51 0/51

30/51 (58.8) 21/51 (41.2)

P

< 0.001 < 0.001 < 0.001 < 0.001

The inappropriate use of antibiotics during last years has been paralleled by the growing onset of multidrug-resistant pathogenic strains among community-acquired isolates. The evolution of antimicrobial resistances has resulted into a global public health challenge, with rising costs and greater risk of poorer patient outcomes.

Nowadays antibiotic stewardship protocols represent a precise imperative need. Unfortunately, to date there is not a “gold standard” prophylactic management to prevent recurrent UTI. Actually, European Association of Urology guidelines report several non-antibiotic measures for preventing recurrent UTIs but only a few are based on well-designed randomized clinical trials (13).

However it cannot be denied that during last years research in non-antibiotic prophylaxis of recurrent UTIs has gradually grown. Particularly the use of phytotherapy and nutraceuticals might represent a feasible alternative approach for reducing the use of antibiotics and decreasing the rate of symptomatic recurrences (4, 1617). In this light, in this phase II clinical trial we evaluated the efficacy and safety of a new nutraceutical agent named containing Ellirose®, Protexil®, Serrazimes® and Myrliq® in the prophylaxis of symptomatic episodes in women affected by recurrent UTIs. In our experience AVIUR® retard was well tolerated, resulting in optimal compliance since only one patient experienced adverse drug related effect which forced the discontinuation of the therapy. Moreover a statistically significant improvement in QoL was reported in almost 74.5% of patients and in 84% at first and second follow up visit respectively. Also from a microbiological point of view AVIUR® retard showed promising results since almost 60% of patients at the end of the follow-up period showed sterile urine and more than 40% reported a transition from symptomatic UTI to ABU. To this regard, a significant body of evidence advocated that ABU could play a protective role in preventing symptomatic UTI recurrences, interfering with the establishment of many enteric pathogens, such as E. coli (8). Noteworthy the fact that AVIUR® retard is able to establish an ABU is a tangible proof of the absence of its effects on the normal microbiota. In this sense, the use of non-antibiotic approach should be preferred since it doesn’t interfere with the normal commensal bowel flora. AVIUR® retard is made of a combination of several nutraceutical agents playing different roles in the prevention of symptomatic UTI recurrences. Ellirose®, an Ibiscus dry extract, is a phytocomplex containing Sambubiosides, which seem to have an anti-inflammatory activity by reducing the levels of Archivio Italiano di Urologia e Andrologia 2018; 90, 3

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inflammatory mediators such as iNOS, NO, IL-6, MCP1, and TNF-α induced by LPS (18). Protexil® is a form of concentrated protease derived as an exogenous production from controlled fermentation of maltodextrins through the Aspergyllus oryzae.

The protease, once absorbed into the blood stream, effectively performs anti-inflammatory and anti-edema functions (19-20). Particularly, the proteases from Protexil® are bound to alpha 2-macroglobulines, which are thus modified into an activated form. Once activated, the alpha-2-macroglobulines bind the citokines TNFalpha (tumor necrosis factor alpha) and TGF-beta (transformative growth factor beta), modulating their activity in an anti-inflammatory way. Similarly, Serrazimes® is a proteolytic blend composed of enzymes derived from non-pathogenic enterobacteria belonging to genus Serratia species E-15. Serrazimes® contributes to the maintenance of a balanced immune system response by regulating protein-based immune cell inflammation mediators. It seems that Serrazimes® has also an additional analgesic activity due to its capability to block the release of biogenic amines. (19) Finally, Myrliq® is a Commiphora myrrha extract with a standardized content of curzerene, furanoeudesma-1,3-diene, and lindestrene and a high total furanodiene content (20) Recent evidence showed that myrrh extract inhibits the production of interluchin-6 (IL-6) and interluchin-8 (IL-8) in human fibroblast cells. In addition it is involved in the blockage of the proteins involved in the inflammatory process such as Cox and also inhibits the formation of NO, ROS, TNF-α, PGE2, NF-kB and MAPK (21-22).

Our results showed that AVIUR® retard can be taken into consideration as a potential effective prophylactic agent for symptomatic recurrent UTIs. However, the present study was not devoid of several limitations. Possible shortcomings of the study lie in the lack of randomization as well as in the small cohort size. Each of these variables might have introduced statistical bias and weaken the overall reliability of the reported findings.

Acknowledged the limitations, the present study represents the largest series so far evaluating the prophylactic effect of Ellirose®, Protexil®, Serrazimes® and Myrliq® in women suffering from recurrent uncomplicated UTIs. Although antimicrobials remain the mainstay of treatment for acute UTI, the spread of multidrug resistant microorganisms among community-acquired isolates is worryingly increasing and needs for stronger surveillance and new preventing approaches. Only advancing our understandings about alternative treatments, such as phytotherapty and nutraceuticals, will enable us to develop appropriate non-antibiotic approaches and prevention strategies for recurrent UTIs. To this regard, further phase III randomized studies and larger series will certainly be needed to confirm and validate our preliminary results.

CONCLUSIONS

Recurrent urinary tract infections afflict a large number of young women nowadays, with a high impact on patient’s quality of life. Currently, several strategies have been purposed and used in order to reduce the number

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of recurrence and improve QoL, without any significant achievement.

Here, considering the available evidence, the use of phytotherapy seems a feasible antibiotic-sparing approach for reduce the number of recurrence.

In our experience, the treatment with AVIUR retard®, in motivated patients, is able to prevent symptomatic UTI episode and improve patient’s QoL. Moreover, the use of AVIUR retard® is be able to improve the antibiotic stewardship, reducing the use of antibiotic prophylaxis in these patients. However, further prospective studies are needed to validate our results in larger series.

REFERENCES

1. Silverman JA, Schreiber HL 4th, Hooton TM, Hultgren SJ. From physiology to pharmacy: developments in the pathogenesis and treatment of recurrent urinary tract infections. Curr Urol Rep. 2013; 14:448-56.

2. Foxman B, Brown P. Epidemiology of urinary tract infections: transmission and risk factors, incidence, and costs. Infect Dis Clin North Am 2003; 17:227-241.

3. Jennifer A. Silverman, Ph.D., Henry L. et al. From physiology to pharmacy: developments in the pathogenesis and treatment of recurrent urinary tract infections. Curr Urol Rep. 2013; 14:448-56.

4. Cai T, Tamanini I, Kulchavenya E, et al. The role of nutraceuticals and phytotherapy in the management of urinary tract infections: What we need to know? Arch Ital Urol Androl. 2017; 89:1.

5. Bojana Kranjcˇec, Dino Papesˇ, Silvio Altarac. D-mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. World J Urol. 2014; 32:79-84.

6. Tandogzu Z, Wagenlehner FM. Global epidemiology of urinary tract infections. Curr Opin Infect Dis. 2016; 29:73-79.

7. Kostakioti M, Hultgren SJ, Hadjifrangiskou M. Molecular blueprint of uropathogenic Escherichia Coli virulence provides clues toward the development of anti virulence therapeutics. Virulence.

2012; 3:592-594.

8. Cai T, Mazzoli S, Mondaini N, et al. The role of asymptomatic bacteriuria in young women with recurrent urinary tract infections: to treat or not to treat? Clin Infect Dis. 2012; 55:771.

9. Gupta K, Scholes D, Stamm WE. Increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in women. JAMA 1999; 281:736-8.

10. Naber KG, Bergman B, Bishop MC, et al. Urinary Tract Infection (UTI) Working Group of the Health Care Office (HCO) of the European Association of Urology (EAU). EAU guidelines for the management of urinary and male genital tract infections. Eur Urol.

2001; 40:576-88.

11. Cai T, Cocci A, Tiscione D, et al. L-Methionine associated with Hibiscus sabdariffa and Boswellia serrata extracts are not inferior to antibiotic treatment for symptoms relief in patients affected by recurrent uncomplicated urinary tract infections: Focus on antibiotic-sparing approach. Arch Ital Urol Androl. 2018; 90:97-100.

12. Grabe M, Bjerklund-Johansen TE, Botto H et al. Antibiotics.

In:Grabe M, Bjerklund-Johansen TE, Botto H, et al. (Editors) Guidelines on urological infections. Arnhem: European Association of Urology. 2010; p. 69.

13. Cai T, Nesi G, Mazzoli S, et al. Asymptomatic bacteriuria treatment is associated with a higher prevalence of antibiotic resistant

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strains in women with urinary tract infections. Clin Infect Dis. 2015; 61:1655-61.

14. Hooton TM, Scholes D, Gupta K, et al. Amoxicillin-clavulanate vs ciprofloxacin for the treatment of uncomplicated cystitis in women: a randomized trial. JAMA. 2005; 293:949-55.

15. Mazzoli S, Cai T, Rupealta V, et al. Interleukin 8 and antiChlamydia trachomatis mucosal IgA as urogenital immunologic markers in patients with C. trachomatis prostatic infection. Eur Urol. 2007; 51:1385-93.

16. Stange R, Schneider B, Albrecht U, et al. Results of a randomized, prospective, double-dummy, double-blind trial to compare efficacy and safety of a herbal combination containing Tropaeoli majoris herba and Armoraciae rusticanae radix with cotrimoxazole in patients with acute and uncomplicated cystitis. Res Rep Urol. 2017; 9:43-50.

17. Ledda A, Belcaro G, Dugall M, et al. Highly standardized cranberry extract supplementation (AnthocranÂŽ) as prophylaxis in young healthy subjects with recurrent urinary tract infections. Eur Rev Med Pharmacol Sci. 2017; 21:389-393.

18. Sogo T, Terahara N, Hisanaga A, et al. Anti-inflammatory activity and molecular mechanism of delphinidin 3-sambubioside, a Hibiscus anthocyanin. Biofactors. 2015; 41:58-65.

19. Bhagat S, Agarwal M, Roy V. Serratiopeptidase: a systematic review of the existing evidence. Int J Surg. 2013; 11:209-17.

20. Germano A, Occhipinti A, Barbero F, et al. A pilot study on bioactive constituents and analgesic effects of MyrLiqÂŽ, aCommiphora myrrha Extract with a High Furanodiene Content. Biomed Res Int. 2017; 2017:3804356.

21. Su S et al. Evaluation of the anti-inflammatory and analgesic properties of individual and combined extracts from Commiphora myrrha, and Boswellia carterii.. J Ethnopharmacol. 2012; 139:649-56.

22. Bellezza I, et al. Furanodien-6-one from Commiphora erythraea inhibits the NF-kB signalling and attenuates LPS-induced neuroinflammation. Mol Immunol. 2013; 54:347-54.

Correspondence Tommaso Cai, MD ktommy@libero.it Daniele Tiscione, MD Marco Puglisi, MD Gianni Malossini, MD Department of Urology, Santa Chiara Hospital Largo Medaglie d'Oro 9, Trento, Italy Andrea Cocci, MD Gianmartin Cito, MD Department of Urology, University of Florence, Florence, Italy Alessandro Palmieri, MD Department of Urology, University of Naples, Federico II, Naples, Italy

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DOI: 10.4081/aiua.2018.3.208

ORIGINAL PAPER

Adolescence and andrologist: An imperfect couple Soraya Olana, Rossella Mazzilli, Michele Delfino, Virginia Zamponi, Cristina Iorio, Fernando Mazzilli Andrology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, University of Rome "Sapienza", Rome, Italy.

Summary

Objective: The aims of this research were to study: a) the prevalence of male adolescents, aged between 10 and 19 years of age, referred to our Unit for an andrological assessment; b) the reasons (stated and subsequently modified) for referral; c) the prevalence of clinically diagnosed diseases.

Materials and methods: A total of 2.855 subjects, referred to the Andrology Unit for a first examination, were retrospectively studied. For each adolescent, a medical history was taken and an andrological physical examination was carried out.

Results: Prevalence was found to be 6.9% (197/2855). Subjects were divided into two groups according to age (A: ≤ 14 and B: ≥ 15 years). The original reason stated for their consultation was corrected by 11.7% of the subjects (23/197); this correction concerned almost all the Group B subjects (21/23 (91.3%) vs 2/23 (8.7%) of Group A; p < 0.01). Regarding sexual dysfunctions, a simple explanation of certain conditions reassured the subject in about 15% of the cases. Furthermore, the physical examination proved extremely useful, revealing clinical alterations in more than 60% of subjects.

Conclusions: In conclusion, to date in Italy, the prevalence of adolescents among males referred to an Andrology Unit for assessment is very low. It is important to encourage adolescents to undergo andrological examination to enable identification of reproductive function and psycho-sexual disorders.

KEY WORDS: Adolescence; Andrological examination; Prevention; Sexual dysfunctions; Varicocele; Cryptorchidism; Dysmorphophobias.

Submitted 11 June 2018; Accepted 19 August 2018

INTRODUCTION

Adolescence is understood to be a transitional phase of growth between childhood and adulthood. The World Health Organization (WHO) defines an adolescent as being between 10 and 19 years of age (1).

In addition, studies show that only 13% of the age group in question are aware of the professional role that andrologists play (2).

Screening for teenage pathologies should be an important part of general health management. In many countries, this used to be linked to routine physical examinations associated with military service.

The abolition of compulsory military service, in Italy, has meant that an important screening opportunity has been lost and this has led to a lower level of preventive care and treatment related to male reproductive and sexual diseases (3). Undiagnosed pathologies no longer picked up by such routine screening would affect pre-pubertal,

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pubertal and post-pubertal subjects, and a different approach would be needed for each age range.

The reports in the literature concerning this period are not numerous and they are mainly regarding single issues (such as varicocele, infections, anatomical anomalies and pubertal delay), or they report the results of campaigns for prevention, rather than spontaneous referrals requesting a medical examination (4-11).

The aims of this work were to evaluate: a) The prevalence of adolescent subjects in a large population of men referred to our Andrology Unit for an andrological assessment; b) The reasons given for first referral (subsequently modified); c) The prevalence of clinically diagnosed diseases.

MATERIALS

AND METHODS

A total of 2,855 subjects, referred to our Andrology Unit (Sant'Andrea Hospital - “Sapienza” University of Rome) from September 2012 to December 2017 for a first examination, were retrospectively studied. For each adolescent aged between 10 and 19 years, the following were carried out: a) a full medical history; b) an andrological physical examination [Body Mass Index, hair distribution, scrotum, testis, varicocele (grade I-III), epididymis, penis and breast].

The diagnosis of erectile dysfunction and premature ejaculation were evaluated using the International Index of Erectile Function - 5 (IIEF-5) and Premature Ejaculation Diagnostic Tool (PEDT) questionnaires (total score ≤ 21 and ≥ 11 respectively). The clinical study was conducted according to the Hospital Ethics Committee Guidelines.

Statistical analysis Continuous data were described as absolute values, mean ± standard deviation and range. Categorical data were described as absolute, percentage frequency, and 95% Confidence Intervals. Student t-test and Fisher's exact test were used for continuous and categorical data, respectively. P < 0.05 was considered statistically significant.

RESULTS

The prevalence of male adolescents was found to be 6.9% (197/2855). The distribution, according to age, is shown in Figure 1.

No conflict of interest declared.

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Adolescence and andrologists

Figure 1.

Prevalence based on adolescent’s age. Group A: Age 10-14 years.

Group A: Age 10-14 years; Group B: Age 15-19 years.

According to the WHO definition, the subjects were divided into two age groups: – Group A (n = 49; age ≥ 10 ≤ 14), which included subjects in pre-pubertal or peri-pubertal period; BMI 21.8 ± 2.0 kg/m2 (range 18.2-26.3).

– Group B (n = 148; age ≥ 15 ≤ 19), which included subjects generally in the post-pubertal period; BMI 21.7 ± 2.1 kg/m2 (range 18.3-28.1) (p = NS).

R eported and actual reasons for andrological consultation The most common reasons given for the andrological consultation were: a preventive andrological check-up, suspected varicocele and other organic diseases.

A preventive andrological examination regarded mainly Group A (36.7%) rather than Group B (12.2%); p < 0.05).

While giving information for the medical history, 23/197 (11.7%) subjects corrected the original reason stated for the consultation. This correction concerned almost all the Group B subjects (21/23, 91.3%) compared with a minority in Group A (2/23, 8.7%) (p < 0.01) (Table I).

In particular, 8/36 subjects, who had come for a preventive check-up, said they actually needed a consultation for sexual dysfunction. Likewise, 10/56 subjects who had initially claimed that they were worried about an organic disease, afterwards admitted that they were instead concerned about sexual dysfunction or dysmorphophobia.

Finally, we found that 5/9 subjects, who were initially referred to us for a suspected infection, were really suffering from dysmorphophobia or sexual dysfunction.

Clinical evidence in groups and subgroups (Table I) 1. Andrological examination: clinical alterations were observed in 17/28 subjects who originally attended for a preventive andrological examination. This concerned mainly Group A (13/18 subjects: 1/13 varicocele, 5/13 phimosis or sub-phimosis, 3/13 short

Table 1.

Referred, effective reasons of the requested of andrological examination and clinical confirmation in total and subgroups A and B.

Reasons

Firstly referred (n, %, 95%CI)

Andrological examination Varicocele Pain testis Other organic diseases Dysmorphophobias Infections and contraception Sexual dysfunctions Other: trauma, testicular torsion, etc

36/197 (18.3) 13.5-24.3 39/197 (19.8) 14.8-26.0 11/197 (5.6) 3.0-9.8 56/197 (28.4) 22.6-35.1 17/197 (8.6) 5.4-13.5 9/197 (4.6) 2.3-8.6 24/197 (12.2) 8.3-17.5 5/197 (2.5) 0.9-6.0

Total n = 197 Effective (n, %, 95%CI) 28/197 (14.2) 10.0-19.8 39/197 (19.8) 14.8-26.0 11/197 (5.6) 3.0-9.8 46/197 (23.4) 18.0-30.0 33/197 (16.8) 12.2-22.6 4/197 (2.0) 0.6-5.3 31/197 (15.7) 11.3-21.5 5/197 (2.5) 0.9-6.0

Clinical evidence Firstly referred (n, %, 95%CI) (n, %, 95%CI) 17/28 (60.7) 18/49 (36.7)* 42.4-76.5 24.6-50.8 37/39 (94.9) 9/49 (18.4) 82.2-99.5 9.8-31.6 10/11 (90.9) 2/49 (4.1) 60.1-99.9 0.4-14.5 42/46 (91.3) 16/49 (32.7) 79.1-97.1 21.2-46.7 5/33 (15.2) 3/49 (6.1) 61.7-31.4 1.5-17.5 4/4 (100) 45.4-100 26/31 (83.9) 66.9-93.4 5/5 (100) 1/49 (2.0) 51.1-100 < 0.1-11.7

GROUP A n = 49/197 (24.9%) Effective (n, %, 95%CI) 18/49 (36.7)* 24.6-50.8 9/49 (18.4) 9.8-31.6 2/49 (4.1) 0.4-14.5 14/49 (28.6) 17.8-42.5 5/49 (10.2) 4.0-22.2 -

Clinical evidence (n, %, 95%CI) 13/18 (72.2) 48.8-87.8 9/9 (100) 65.5-100 2/2 (100) 29.0-100 12/14 (85.7) 58.8-97.2 1/5 (20.0) 2.0-64.0 -

-

-

1/49 (2.0) < 0.1-11.7

1/1 (100) 16.8-100

Firstly referred (n, %, 95%CI) 18/148 (12.2) 7.6-18.5 30/148 (20.3) 14.5-27.5 9/148 (6.1) 3.1-11.3 40/148 (27.0) 20.5-34.7 14/148 (9.5) 5.6-15.4 9/148 (6.1) 3.1-11.3 24/148 (16.2) 11.1-23.1 4/148 (2.7) 0.8-7.0

GROUP B n= 148/197 (75.1%) Effective Clinical evidence (n, %, 95%CI) (n, %, 95%CI) 10/148 (6.8) 4/10 (40.0) 3.6-12.1 16.7-68.8 30/148 (20.3) 28/30 (93.3) 14.5-27.5 77.6-99.2 9/148 (6.1) 8/9 (88.9) 3.1-11.3 54.3-99.9 32/148 (21.6) 30/32 (93.8) 15.7-29.0 78.8-99.3 28/148 (18.9) 4/28 (14.3) 13.4-26.0 5.1-32.1 4/148 (2.7) 4/4 (100) 0.8-7.0 45.4-100 31/148 (21.0) 26/31 (83.9) 15.3-28.2 66.9-93.4 4/148 (2.7) 4/4 (100) 0.8-7.0 45.4-100

Group A: Age 10-14 years; Group B: Age 15-19 years. CI: Confidence Intervals. *p<0.05 vs Group B.

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2.

3.

4.

5.

6.

7.

8.

frenulum, 3/13 retractile testis, 1/13 hypospadias) compared with Group B (4/10 subjects: 1/4 varicocele, 1/4 sub-phimosis, 2/4 short frenulum).

Varicocele: 9/49 subjects in Group A and 30/148 subjects in Group B referred to us for a suspected varicocele. During the andrological examination we observed varicocele in all the Group A subjects (6/9 of grade I, 3/9 of grade II), and in 28/30 Group B subjects (9/28 of grade I, 16/28 of grade II, 3/28 of grade III).

Testis pain: this problem was observed in 2/49 subjects in Group A and 9/148 subjects in Group B. Specifically, two subjects in Group A showed epididymal hypertrophy; regarding Group B, 8/9 subjects had epididymal hypertrophy, while the remaining subject had grade II varicocele.

Other organic diseases: in 12/14 Group A subjects, we observed clinical evidence of organic disease (4/12 phimosis, 3/12 gynaecomastia, 3/12 retractile testis, 1/12 cryptorchidism and 1/12 pubertal delay). Moreover, in 30/32 Group B subjects, we observed clinical confirmation of organic disease (6/30 short frenulum, 5/30 sub-phimosis, 3/30 gynaecomastia, 4/30 retractile testis, 2/30 cryptorchidism, 4/30 hypogonadotropic hypogonadism, 2/30 penis recurvatum, 3/30 phimosis and 1/30 adrenogenital syndrome).

Dysmorphophobias: in Group A, only 1/5 subject showed adipomastia. Moreover, in Group B, only 4/28 subjects showed any clinical evidence of a condition (3/4 penis in peri-pubic fat and 1/4 adipomastia).

Infections and contraception: these problems only concerned Group B. In particular, 1/4 subjects showed gland inflammation, 1/4 secretion in the urethral meatus, 1/4 condylomas; finally, 1/4 subjects needed information about contraception.

Sexual dysfunction: these problems only concerned Group B. The diagnosis was made by using specific questionnaires (IIEF-5 and PEDT). In particular, premature ejaculation was observed in 16/26 subjects, erectile dysfunction in 8/26 subjects and anejaculation and/or anorgasmia in 2/26 subjects.

Other: in Group A we observed a reduced testicular volume (post trauma) in one subject; in Group B we observed a reduced testicular volume post testicular torsion (1/4), post orchitis (1/4), post trauma (2/4).

All subjects were directed to the appropriate and specific diagnostic/therapeutic pathways.

tant factors may prompt the decision to undergo such an examination.

Critical analysis of our results showed that 11.9% of all subjects included in this study corrected the stated motivation for their andrological assessment during the anamnestic interview. This concerned mainly Group B subjects, aged â&#x2030;Ľ 15 years. This is perhaps because parents reported the problems of the younger subjects.

We noted that subjects found some difficulties in explaining to the andrologist their worries regarding sexual dysfunctions and dysmorphophobias.

These problems were first reported in the context of a preventive andrological examination or organic disease or a suspicion of infection, but it would seem that a different worry could be the real prompt for an examination in many cases.

An interesting finding concerned sexual dysfunctions. In fact, in about 15% of the cases, it was necessary only to explain the real definition of a condition to reassure a subject that there was no real problem. For example, some subjects reported premature ejaculation (PE), with sexual intercourse lasting about 10 minutes. Instead, PE can be defined as being Intravaginal Ejaculation Latency Time (IELT) of less than 1 minute), which is quite different from the subject's perception. Furthermore, no problem was observed in 84% of subjects who had reported dysmorphophobia.

A very important point to underline is that the andrological check-up showed itself to be extremely useful in detecting clinical alterations (such as phimosis, gynaecomastia, retractile testis, cryptorchidism and pubertal delay) in more than 60% of subjects. It is for this reason that every effort should be made to ensure that adolescent males get a chance to undergo an andrological screening.

The limit of the present work is the single-centre retrospectively based form.

In conclusion, in Italy, the prevalence of adolescents among the males referred to an Andrology Unit for assessment is very low. This may be due to the fact that here the professional figure of the andrologist is little known among young males and it is therefore essential to promote awareness of andrological examinations through mass media and school campaigns for prevention (2, 5, 12). Early diagnosis of andrological diseases is crucial so as to prevent later problems in reproductive function. Finally, sexual education during adolescence is also very important because it could help to reduce many psycho-sexual problems.

DISCUSSION

This study considered the prevalence of male adolescents referred to our Andrology Unit.

The subjects of this study were divided into two groups, according to age.

Of the 6.9% of adolescents found, 5.2% were regarded subjects of post-pubertal age while only 1.7% were regarded subjects of pre- and peri-pubertal age.

According to the literature (6-8), the main reasons that prompt adolescents to carry out this kind of examination are: suspicion of organic diseases (28.4%), varicocele (19.8%) and preventive andrological check-up (18.3%). However, our study found that other impor-

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AUTHORSâ&#x20AC;&#x2122;

ROLE

FM and RM conceived the study. SO and RM analysed the data drafted the manuscript. All authors contributed to the data collection and/or interpretation, and provided a critical revision of the manuscript.

REFERENCES

1. Sixty-fourth World Health Assembly. Resolution WHA 64.28: Youth and health risks. Geneva, World Health Organization, 2011.

2. Mondaini N, Silvani M, Zenico T, et al. Genital diseases aware-

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Adolescence and andrologists

ness in young male students: Is information necessary to protect them? Arch Ital Urol Androl. 2013; 85:14-9.

3. Campodonico F, Michelazzi A, Capurro A, Carmignani G. Andrologic disease detected during army medical visit. Arch Ital Urol Androl. 2003; 75:205-7.

4. Hadziselimovic F, Herzog B. Andrological problems in adolescence. Ther Umsch. 1994; 51:305-13.

5. Foresta C, Garolla A, et al. Anthropometric, penile and testis measures in post-pubertal Italian males. J Endocrinol Invest. 2013; 36:287-92.

6. Pereira NM. Phimosis, hydrocele and varicocele. 3 frequent pathologies in the male child and adolescent. Acta Med Port. 1999; 12:137-43.

7. Serefoglu EC, Saitz TR, La Nasa JA Jr, Hellstrom WJ. Adolescent varicocoele management controversies. Andrology. 2013; 1:109-15.

8. Fast AM, Deibert CM, Van Batavia JP, et al. Adolescent varicocelectomy: does artery sparing influence recurrence rate and/or catch-up growth? Andrology. 2014; 2:159-64.

9. Maggi M, Buvat J. Standard operating procedures: pubertas tarda/delayed puberty--male. J Sex Med. 2013; 10:285-93.

10. Foresta C, Garolla A, Zuccarello D, et al. Human papillomavirus found in sperm head of young adult males affects the progressive motility. Fertil Steril. 2010; 93:802-6.

11. Delfino M, Elia J, Imbrogno N, et al. Testicular adrenal rest tumors in patients with congenital adrenal hyperplasia: prevalence and sonographic, hormonal, and seminal characteristics. J Ultrasound Med. 2012; 31:383-8.

12. Valkenburg PM, Peter J. Online communication among adolescents: an integrated model of its attraction, opportunities, and risks.

J Adolesc Health. 2011; 48:121-7.

Correspondence Soraya Olana, MD soraya.olana@gmail.com Rossella Mazzilli, MD (Corresponding Author) rossella.mazzilli@uniroma1.it Michele Delfino, MD micheledelfino@libero.it Virginia Zamponi, MD virginia22.zamponi@gmail.com Cristina Iorio, MD cristina.iorio90@gmail.com Fernando Mazzilli, MD fernando.mazzilli@uniroma1.it Sant'Andrea Hospital, University of Rome "Sapienza", Rome, Italy

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DOI: 10.4081/aiua.2018.3.212

CASE REPORT

Malignant mesothelioma of tunica vaginalis testis: Report of a very rare case with review of the literature Emanuela Trenti 1, Salvatore Mario Palermo 1, Carolina D'Elia 1, Evi Comploj 1, 2, Alexander Pycha 3, Rodolfo Carella 4, Armin Pycha 1, 5 1 General

Hospital of Bolzano, Department of Urology, Bolzano, Italy; of Research, College of Health Care Professions Claudiana, Bolzano, Italy; 3 Kantons Hospital Luzern, Department of Urology, Luzern, Switzerland; 4 General Hospital of Bolzano, Department of Pathology, Bolzano, Italy; 5 Chair of Urology, Sigmund Freud University Medical School, Vienna, Austria.

2 Department

Summary

Introduction: Mesothelioma of the tunica vaginalis testis is a extremely rare tumor and represents 0.3 to 0.5% of all malignant mesotheliomas.

Exposure to asbestos often precedes illness. Because of its low incidence and nonspecific clinical presentation, it is mostly diagnosed accidentally during surgery for other reasons and the prognosis is usually poor. We present a case of a patient with a mesothelioma of tunica vaginalis testis, diagnosed secondarily during hydrocele surgery, with long-term survival after radical surgery.

Materials and methods: a 40 years old patient was admitted to our department for routine surgery of a left hydrocele. During the operation a frozen section analysis was requested because of the unusual nodular thickening of the tunica vaginalis: the examination revealed a diffuse malignant mesothelioma with epithelioid structure and tubular-papillary proliferation.

Therefore a left hemi-scrotectomy with left inguinal lymph node dissection was performed.

Results: The definitive histology confirmed the previous report of diffuse malignant mesothelioma with angio-invasion but normal testicle findings and negative lymph nodes. No metastases were found on the CT-scan. For the first 2 years a CT was repeated every 4 months, for other 3 years every 6 months and then yearly. Six years after surgery the patient is classified as no evidence of disease.

Conclusions: malignant mesothelioma of the tunica vaginalis testis is a rare entity, often initially thought to be a hydrocele or an epididymal cyst. An aggressive approach with hemiscrotectomy with or without inguinal and retroperitoneal lymphadenectomy can reduce the risk of recurrence.

KEY WORDS: Mesothelioma; Tunica vaginalis testis; Asbestos exposure.

Submitted 11 June 2018; Accepted 5 July 2018

INTRODUCTION

Mesothelioma of the tunica vaginalis testis is an extremely rare tumor and the most unusual type, representing 0.3% to 5% of all malignant mesotheliomas. To date only a limited number of cases (about 300) have been reported worldwide in the literature (1, 2). Exposure to asbestos is a well-known risk factor for development of mesothelioma with a long latency between exposure and diagnosis, however, in most cases of mesothelioma of

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tunica vaginalis testis no asbestos exposure can be documented (2-4). It occurs mostly in middle-aged men but the range of age at presentation can be wide. Because of its low incidence and nonspecific clinical presentation, it is mostly diagnosed accidentally during surgery and the prognosis is usually poor.

We present a case of a patient with a malignant mesothelioma of tunica vaginalis testis, diagnosed secondarily during hydrocele surgery, with long-term survival after radical surgery.

CASE

REPORT

A 40 years old patient was admitted to our department for routine left hydrocele surgery. The patient reported progressive scrotal enlargement with discomfort in the left testis and strong groin pain after extended periods of sitting. His past medical history was not significant. No cigarette smoking, trauma or infections were reported.

The ultrasonography showed a simple left hydrocele with 350 ml in volume and normal testicular parenchyma. The contralateral testis was normal. The patient underwent resection of the hydrocele; the hydrocele fluid was citrine but the surgeon noted a strange fibrotic thickening of the tunica vaginalis and a frozen section was requested. The patient was discharged one day after the operation, waiting for the definitive histology.

The histologic examination revealed a diffuse malignant mesothelioma with epithelioid structure and tubularpapillary proliferation. The computed tomography (CT) showed absence of distant metastases with modest enlargement of the left inguinal lymph nodes up to 22 mm. The patient agreed to a left hemiscrotectomy with left inguinal lymph node dissection, which was thereafter performed. The definitive histology confirmed a diffuse malignant mesothelioma with multiple areas of residual tumors in the tunica vaginalis testis with angioinvasion and stromal infiltration (Figures 1, 2) but normal testicular findings and negative lymph nodes.

The immunohistochemical study was positive for calretinin, cytocheratin 5/6, Thrombomodulin, WT1 and D240 while carcinoembryonic antigen and cytocheratin 20 were negative. After consultation with medical and No conflict of interest declared.

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Mesothelioma of the testis

Figure 1.

Neoplastic cells with epithelioid structure and tubular-papillary proliferation with parietal and stromal infiltration (hematoxillin and eosin staining and cytocheratin 5 staining 4 x magnification).

Figure 2.

Mitosis and nuclear polymorphism (hematoxylin and eosin staining - 10 x magnification).

radiation oncologists and in absence of evidence of residual disease, adjuvant therapy was not indicated in our patient. A CT was repeated every 4 months for the first 2 years and every 6 months for the next 3 years, thereafter annually. Six years after surgery the patient shows no signs of recurrent disease. The occupational physician couldnâ&#x20AC;&#x2122;t demonstrate an exposure to asbestos of this patient.

DISCUSSION

Mesothelioma is an extremely rare malignant tumor, which develops from the internal surface of the pleura, pericardium, peritoneum and tunica vaginalis testis. Less then 5% of cases of malignant mesothelioma occur in the tunica vaginalis (5).

The first case was described by Barbera and Rubino in 1957 (6).

Exposure to asbestos is a well-known risk factor for development of pleural and peritoneal mesothelioma with a very long latency between exposure and diagnosis, however, exposure is less frequently associated with pericardium and tunica vaginalis testis. Due to its low incidence, it is unknown whether asbestos exposure plays a role in its etiology: less than half of reported mesothelioma of tunica vaginalis testis are associated with asbestos exposure (7). The first case of malignant mesothelioma of the tunica vaginalis testis, associated with asbestos exposure, was reported by Fliegel in 1976 (8). In a general review of 223 cases in 2010, Bisceglia et al. found an association with asbestos exposure in only 30-40% of the patients (3). Nevertheless in the series of Spiess et al. (5) the correlation with asbestos was docu-

mented in 80% of the cases and in a recent Italian study, based on the data from the Lombardy Mesothelioma Registry, Mensi found an asbestos exposure in 67% of the patients with mesothelioma of the tunica vaginalis testis: here the author underlines the importance to collect the occupational history, the living habits, the residential history and the hobbies of the patients (9).

In our opinion the investigation of the exposure history should be conducted by an experienced occupational physician (2, 3).

Other suspected causes of this kind of mesothelioma are scrotal trauma, long-term hydrocele, herniorraphy and exposure radiotherapy (2-10-11). The age at presentation varies from 7 to 87 years in different reports (2, 4).

Because of the lack of characteristic symptoms, these tumors could be confused on clinical assessment with hydrocele or an epididymal cyst and could initially be treated conservatively, delaying the diagnosis.

The patient consults his physician usually for scrotal enlargement, scrotal/inguinal mass or scrotal pain and undergoes surgery with preoperative diagnosis of hydrocele, testicular tumors, inguinal hernia or epididymal cyst. Preoperative testicular ultrasonography could show a nodular thickening of the tunica vaginalis testis and a dense fluid inside but it is mostly negative. Thus, the diagnosis usually occurs secondarily during surgery and the patient needs further surgical treatment: one third of patients, who underwent only hydrocelectomy, experienced local recurrence compared to approximately 11% of patients, who underwent radical orchiectomy (12-13).

Inguinal orchiectomy or hemiscrotectomy with inguinal and retroperitoneal lymph node dissection in case of lymph node enlargement and appears to be the preferred treatment for these patients. It is associated with better prognosis and should be proposed when possible.

Radiotherapy and chemotherapy have failed to yield significant results and their role is still controversial; however adjuvant radiotherapy could be considered to prevent local disease recurrence while adjuvant chemotherapy with combination of permetrexed and cisplatin, which have had a proven efficacy in pleural mesothelioma, should be considered in cases with unfavorable prognosis (4).

Approximately one third of tumors is locally invasive when diagnosed (1) and more than 50% of patients develop local or distant recurrence with more than 60% Archivio Italiano di Urologia e Andrologia 2018; 90, 3

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recurrences within the first 2 years (4, 5, 12, 14). The disease specific survival ranges in different studies between 20 and 30 months with 40% of the patients dying from their disease (5, 12, 14) though the last recent series of Recabal et al., with a cohort of 15 patients treated with aggressive surgical management, shows better results: after a median follow-up of 42 months the median overall survival has not been reached (4).

Because of the high rate of recurrence a close follow up for the first 2 years is paramount; however a local recurrence may occur up to 15 years after surgery, which is why also a long-life follow up has to be considered (15).

CONCLUSIONS

Malignant mesothelioma of the tunica vaginalis testis is a very rare entity, often initially misinterpreted as a hydrocele or an epididymal cyst. Our case shows the importance of a correct diagnosis, even if intraoperatively.

A mesothelioma of tunica vaginalis testis should always be suspected in patients with asbestos exposure and rapid enlargement of hemiscrotum and must always be considered in case of fibrotic or nodular thickening of the tunica vaginalis or in case of hemorrhagic or yellow hydrocele fluid. An aggressive surgical approach with hemiscrotectomy with or without inguinal and retroperitoneal lymphadenectomy can reduce the risk of recurrence and improve the poor prognosis of these patients.

A close and life-long follow up is recommended.

REFERENCES

1. Jankovichova T, Jankovich M, Ondrus, et al. Extremely rare tumor â&#x20AC;&#x201C; malignant mesothelioma of tunica vaginalis testis. Bratisl Med J. 2015; 116:574-576.

2. Mrinakova B, Kajo K, Ondrusova M, et al. Malignant mesothelioma of the tunica vaginalis testis. A clinicopathologic analysis of two cases with a review of the literature. Klin Onkol. 2016; 29:369-374.

3. Bisceglia M, Dor DB, Carosi I, et al. Paratesticular mesothelioma.

Report of a case with comprehensive review of literature. Advances in anatomic pathology 2010; 17:53-70.

4. Recabal P, Rosenzweig B, Bazzi WM, et al. Malignant mesothelioma of the tunica vaginalis testis: outcomes following surgical management beyond radical orchiectomy. Oncology. 2017; 107:166-170.

5. Spiess PE, Tomasz T, Kassouf W, et al. Malignant mesothelioma of the tunica vaginalis. Urology. 2005; 66:397-401.

6. Barbera V. Rubino M. Papillary mesothelioma of the tunica vaginalis. Cancer. 1957; 10:183-189.

7. Alesawi AM, Levesque J, Fradet V. Malignant mesothelioma of the tunica vaginalis testis: comprehensive review of literature and case report. J Clin Urol. 2015; 8:147-152.

8. Fliegel Z, Kaneko M. Malignant mesothelioma of the tunica propria testis in a patient with asbestos exposure. A case report. Cancer.

1976; 37:1478-1484.

9. Mensi C, Pellegatta M, Sieno C, et al. Mesothelioma of tunica vaginalis testis and asbestos exposure. BJU Int. 2012; 110:533-537.

10. GĂźrdal M, Erol A. Malignant mesothelioma of tunica vaginalis testis associated with long-lasting hydrocele: could hydrocele be an etiological factor? Int Urol Nephrol. 2001; 32:687-9.

11. Peterson JT, Greenberg SB, Buffier PA. Non-asbestos-related malignant mesothelioma. Cancer. 1984; 54:951-960.

12. Plas E, Riedl CR, Pflueger H. Malignant mesothelioma of the tunica vaginalis: review of the literature and assessment of prognostic parameters. Cancer. 1998; 83:2437-2446.

13. Esen T, Acar O, Peker K, et al. Malignant mesothelioma of the tunica vaginalis: presenting with intermittent scrotal pain and hydrocele. Case Rep Med. 2012; 2012:189170.

14. Jones MA, Young RH, Scully RE. Malignant mesothelioma of the tunica vaginalis: a clinicopathologic analysis of 11 cases with review of the literature, Am J Surg Pathol. 1995; 9:815-825.

15. Brimo F, Illei PB, Epstein JI. Mesothelioma of the tunica vaginalis: a series of eight cases with uncertain malignant potential, Mod Path. 2010; 23:1165-1172.

Correspondence Emanuela Trenti, MD (Corresponding Author) emanuela.trenti@sabes.it Salvatore Mario Palermo, MD salvatore.palermo@sabes.it Carolina D'Elia, MD carolina.delia@sabes.it Evi Comploj, MD evi.comploj@sabes.it Rodolfo Carella, MD rodolfo.carella@sabes.it Armin Pycha, MD armin.pycha@sabes.it Ospedale di Bolzano, via L. Boehler n. 5, 39100, Bolzano, Italy Alexander Pycha, MD alexander.pycha@sabes.it Luzerner Kantonsspital, Spitalstrasse 6000, Luzern 16, Switzerland

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CASE REPORT

A rare complication of ureteral stenting: Case report of a uretero-arterial fistula and revision of the literature Alois Mahlknecht 1, Leonardo Bizzotto 1, Christoph Gamper 1, Anton Wieser 2 1 Department 2 Department

of Urology, Azienda Sanitaria dell’Alto Adige, Merano, Italy; of Radiology, Azienda Sanitaria dell’Alto Adige, Merano, Italy.

Summary

Introduction: Uretero-arterial fistulas are a rare condition. The most frequent clinical sign is hematuria. Since these bleedings occur intermittently, the diagnosis is very difficult. If not discovered, uretero-arterial fistulas involve a very high rate of mortality or even results in loss of kidney function.

Case report: The clinical case we describe is an unusual one.

After a radical hysterectomy and a subsequent radiotherapy, a hydronephrosis caused by ureteral fibrosis occurred on both sides. Therefore, the patient received bilateral ureteral stents.

During a change of the ureteral stents 18 months later, a massive bleeding appeared in the right ureter. Initially, a clear evidence of a fistula was not possible - neither through CT scan nor through selective angiography. There were some indicators of a uretero-arterial fistula, so an endoluminal vessel stent was placed. Subsequently the fistula probably led to an erosion of the vessel stent.

Discussion: A fistula between the ureter and the iliac artery (UAF) is a rare complication. The increase in known cases during the last years is linked to the possibility of ureteral stenting since 1978. Until now only 140 cases have been described in literature. The mortality rate through UAF has decreased from 69% in 1980 to 7-23% today. Its development can be traced through the pulsation of the artery and the pressure on the ureter. The most important clinical symptom is bleeding.

Diagnosis is generally difficult and represents the real problem.

The sensitivity of the standard angiography examination is 2341%; it can be improved to 63% using the “provocative” method, which means mobilizing the ureteral stent during examination. The therapy in course of the angiography consists of a simultaneous endovascular stent and/or a co-embolisation.

Conclusion: Arterial or uretero-arterial fistulas (UAF) are a rare condition; the diagnosis is very difficult and most of the time the treatment requires a multidisciplinary team.

KEY WORDS: Ureteral stenting; uretero-arterial fistula.

Submitted 18 June 2018; Accepted 5 July 2018

INTRODUCTION

Uretero-arterial fistulas are a rare condition that can be critical in case of bleeding. Since these bleedings occur intermittently, the diagnosis is very difficult. If not discovered, uretero-arterial fistula involve a very high rate of mortality or even results in the loss of kidney function.

CASE

REPORT

In 2004, the patient was 79 years old. Because of a welldifferentiated endometrial carcinoma, the patient under-

went a radical hysterectomy, adnexectomy and a lymphadenectomy. Histological examination was a pT2b, N1, (2/19 positive lymph nodes), Mo, Gr I, Ro stage.

Consequently, the patient underwent radiotherapy.

During a control visit in September 2009, a fibrosis plate in the lower pelvis had become visible on the CT and MRI scans. This plate compressed both ureters and subsequently caused a hydronephrosis on both sides.

The hydronephrosis was more evident on the right side and caused a chronic kidney failure. Therefore, the kidney was drained. Silicon TU-stents of Opti-Med, 7 Ch, 28 cm were used.

The hydronephrosis never receded entirely and a recurrent urinary tract infection with fever occurred.

Furthermore, the patient suffered from several additional pathologies, e.g. diabetes mellitus type II, a chronic cardiomyopathy and a diffuse vasculopathy.

During a programmed change of the ureteral stent in March 2011, a massive bleeding in the right ureter suddenly arose. Through the quick change of the stent a spontaneous tamponade was made. After stabilizing the cardiovascular system and correcting the heavy loss of blood, a CT scan followed by a selective intra-arterial angiography in digital technique were carried out.

Both examinations showed an ureteroarterial fistula between the right common iliac artery and the ureter; however, a clear evidence could not be found. During the examination, the common and the external iliac artery were successfully repaired. Additionally, the internal iliac artery was closed.

Eight months later, an intermittent macrohematuria occurred again and this time, the “provocative” angiography clearly showed a fistula and also the retrograde pyelography also confirmed a contrast medium leakage (Figures 1, 2).With high probability, the fistula was caused by the erosion of the ureteral endoluminal stentgraft. A covering through a second stent was made.

In May 2012, a definitive, percutaneous nephrostomy was placed on the right side as additional changes of the ureteral stents would surely have increased the risk of new bleedings.

Four months later, a severe macrohematuria occurred again. Therefore, another endografting of the right common iliac artery with a Fluency 10x100 covered stent was placed (Figure 3).

The patient died two months later - probably due to pulmonary embolism.

No conflict of interest declared.

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Figure 1.

The “provocative” angiography clearly showed a fistula and also the retrograde pyelography also confirmed a contrast medium leakage.

Figure 2.

This image shows the contrast medium leakage even more distinctly.

Please note the endovascular stent in the right common iliac artery.

Figure 3.

Four months later a Fluency 10x100 covered stent was placed.

DISCUSSION

A fistula between the ureter and the iliac artery (UAF) is a rare complication. The first presentation took place in New York in 1908 when Moschcowitz presented a case in which a patient underwent a ureterostomy on both sides and postoperatively developed an erosion on both sides in the external iliac artery caused by a ureteral stone. Both vessels were ligated above and below the lesions (1).

The increase in known cases during the last years is linked to the possibility of ureteral stenting since 1978 (2).

However, uretero-arterial fistulas are a rare condition (3).

Until now only 140 cases have been described in literature. The mortality rate through UAF has decreased from 69% in 1980 to 7-23% today.

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The uretero-arterial fistula (UAF) arises where the ureter and the common or external iliac artery meet. Its development can be traced through the pulsation of the artery and the pressure on the ureter. Above, the edema develops into a necrosis to the ureter wall and eventually into a fistula (5, 6). With an intact wall and mucosa a fistula will not develop. There must be predisposal factors and/or risk factors. Indeed, inflammatory reactions after surgery to the ureter wall, local fibrosis of the retroperitoneum after radiotherapy or vascular surgery in the pelvic area can lead to adhesions between the ureter and artery, which then will cause the formation of a fistula (7). However, most of the time fistulas arise after the placement of ureteral stents (8). Especially when they lie for a long time, fistulas can develop; even the harder polyethylene stents, which are easier to position, seem to cause fistulas more easily. Generally, the period between the positioning of a stent and the formation of a fistula can last between 1 up to 8 years (9). Additionally, oncological surgeries in the pelvis (cervix, uterus, and bladder), radiotherapy and vascular surgeries are risk factors for the formation of fistulas (10). A rupture of the vasa vasorum and the weakening of the tunica media and the adventitia of the bigger arteries could be probable causes (11).

Other factors are rare exceptions - for example the surgical drainage after an appendectomy or ureterotomy, where the mechanical pressure of the drain creates a simultaneous inflammatory reaction; or the spontaneous rupture of an aneurysm in the ureter (12, 13). Several other factors play a significant role, e.g. in the case description of Taylor and Reinhard, in which a mycotic aneurysm of the common iliac artery ruptured into the ureter which had a ureteral stent lying for 24 days (14).

The most important clinical symptom is bleeding. In most cases, it is intermittent bleeding, in which the thrombosis closes the fistula in the meantime.

Diagnosis is generally difficult and represents the real problem. Through sonogram, urography and CT scan the uretero-arterial fistula cannot be shown. The CT scan has low sensitivity and it is not sufficient as the only imaging technique (8). Furthermore, the results of the antegrade or retrograde pyelography are questionable.

The cystoscopy with retrograde pyelography has a sensitivity of 45-60% (15). Only angiography is relatively suitable for diagnosis. The sensitivity of standard angiography examination is 23-41%; it can be improved to 63% using the “provocative” method, which means mobilizing the ureteral stent during examination (16).

The angiography shows evidence of fistulas only during the bleeding phase. If a sonogram or urography shows blood coagula in the renal pelvis-calyceal system in a patient with a lying stent, a uretero-arterial fistula could be the cause (17). Therefore, the sonography can give first diagnostic indication.

First of all, the therapy depends on the quality of the preoperative diagnosis. If not made correctly and carefully, 32% of the patients consequently suffer from the loss of the kidney through nephrectomy or embolisation (16).

With certain diagnosis the therapy consists of supplying the arterial lesion. The ureter does not necessarily have to be repaired (5, 6). The surrounding circumstances are decisive for the choice of therapy: stitching over the

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A rare complication of ureteral stenting: Case report of a uretero-arterial fistula and revision of the literature.

lesion, embolising or rather ligating the iliac artery with or without bypass, and interpositioning of a vascular prosthesis. When embolising, the danger of inadequate blood supply of the lower extremities has to be kept in mind; therefore, a vascular surgery to create a bypass is absolutely necessary. In some circumstances, fibrotic changes after preceding surgery and/or radiotherapy as well as recurrent tumours can militate against reconstruction. If these factors do not exist, a direct supply of the artery should be favoured. Alternatively, the arterial embolisation of the common iliac artery is recommended.

Since 1996 endovascular methods have been at hand they are less invasive and are nowadays therapeutic standard (18-20). Indeed, in the course of angiography a simultaneous endovascular supply of the fistula through implantation of a covered stent and/or co-embolisation should be favoured. Its advantages are obvious: interventional application without surgery and a low operative risk with physiological maintenance of the arterial bloodstream. The only disadvantage is the risk of infection.

5. Keller FS, Barton RE, Routh WD, Gross GM. Gross hematuria in two patients with ureteral-ileal conduits and double-J stents. J Vasc Intervent Radiol. 1990; 1:69.

CONCLUSIONS

13. Rennick JM, Link DP, Palmer JM. Spontaneous rupture o fan iliac artery aneurysm into an ureter: a case report and review of the literature. J Urol. 1976; 116:111.

Arterial or uretero-arterial fistulas (UAF) are a rare condition. Until now, about 140 cases have been described.

Through the increase of gynecological, urological and vascular surgeries in the lesser pelvis and, above all, through the introduction of ureteral stents in 1978, an exponential increase of the cases has been recorded. Therefore, for stenting it is recommended to use soft stents and stents that are smaller in diameter when stenting (21, 22).

The leading symptom is the massive, mostly intermittent hematuria. If untreated, mortality comes up to 100%.

A careful anamnesis and diagnosis are preconditions for a successful therapy. Uretero-arterial fistulas arise only when predisposal risk factors like ureteral stents and pelvic pre surgeries occur, or after radiation. Through selective selective angiography as digital subtraction technique, clear evidence of the cause of the bleeding can be obtained in the majority of the cases. Furthermore, in the course of the same examination an endovascular therapy can be made The case of an uretero-arterial fistula after ureteral stenting on the right side has been described above. The fistula had been successfully treated three times.

The very high mortality rate of 67% until 1978 decreased to 17% in 1996 through the introduction of endovascular treatment. In view of the good results as well as the patient’s limited life expectancy because of a malign underlying disease, the endovascular treatment should be the therapy of choice.

REFERENCES

1. Moschcowitz AV. Simultanous ligation of both external iliac arteries for secondary hemorrhage following bilateral ureterolithotomy.

Ann Surg. 1908; 48:872.

2. Finney RP. Experience with new double J ureteral catheter stent.

J Urol. 1978; 120:678.

3. Bettman MA, Murray PD, Perlmutt LM, et al. Uretero-iliacal anastomotic leaks: percutaneous treatment. Radiology. 1983; 148:95.

4. Batter SJ, McGovern FJ, Cambria RP. Uretroarterial fistula: case report and review of the literature. Urology 1996; 48:481.

6. Toolin E, Pollack HM, Mc Lean GK, et al. Uretero-arterial fistula: a case report. J Urol. 1984; 132:553.

7. Reiner RJ, Conway GF, Threlkeld R Ureteroarterial fistula J Urol.

1975; 116:111.

8. Krambeck AE, DiMarco DS, Gertman MT, et al. Ureteroiliac artery fistula: diagnosis and treatment algorithm. Urology. 2005; 66:990.

9. Puppo P, Perachino M, Ricciotti G, et al. Ureteroarterial fistula: a case report. J Urol. 1992; 148:863.

10. Vandersteen DR, Saxon RR, Fuchs E, et al Diagnosis and management of ureteroiliac artery fistula: value of provocative arteriography followed by common iliac artery embolization and extraanatomic arterial bypass grafting. J Urol. 1997; 158:748.

11. Dervanian P, Castaigne D, Travagli JP, et al. Arterioureteral fistula after extendet resection of pelvic tumors: report of three cases and review of the literature. Ann Vasc Surg. 1992; 6:362.

12. Martinez VMB, Gomez AEM. Postappendectomy aretrio-ureteral fistula. Actas Urol Esp. 1980; 4:331.

14. Taylor WN, Reinhart HL. Mycotic aneurysm of common iliac artery with rupture into right ureter: report of a case. J Urol. 1939; 42:24.

15. Quillin SP, Darcy MD, Picus D. Angiographic evaluation and therapy of arterioureteral fistulas. Am J Roentg 1994; 162:873.

16. Vandersteen DR, Saxon RR, Fuchs E, et al. Diagnosis and management of uretroureteral fistula: value of provocative arteriography followed by common iliac artery embolization and extraanatomic arterial bypass grafting. J Urol. 1997; 158:748.

17. Hausegger von KA, Sonnleitner J, Uggowitzer M, et al. Iliakouretrale Fistel, eine seltene Komplikation bei Ureterschienung.

Fortschr Roentgenstr. 1996; 164:525.

18. Bilbao JI, Cosin O, Bastarrika G, et al. Treatment of ureteroarterial fistulae with covered vascular endoprothesis and ureteral occlusion. Cardiovasc Intervent Radiol. 2005; 28:159.

19. Araki T, Nagata M, et al. Endovascular treatment of ureteroarterial fistulas with stent-grafts. Radiat Med. 2008; 26:372.

20. Krenzien J, Zimmermann HB, Schott H. Die iliaco-ureterale Fistel und ihre Behandlung mit einem Stent-Graft Der Chirurg.

1998; 69:977-980.

21. Zweers HMM, Driel van MF, Mensink HJM. Iliac artery- ureteral fistula associated with an indwelling ureteral stent. Urol Int. 1991; 46:213.

22. Sparwasser C, Kugler A, Gilbert P, et al. Bilaterale uretero-iliakale Fisteln in Zusammenhang mit Radiatio und ureteraler Splintung. Urologe A. 1994; 33:85.

Correspondence Alois Mahlknecht, MD alois.mahlknecht@sabes.it Leonardo Bizzotto, MD Christoph Gamper, MD Department of Urology, Azienda Sanitaria dell’Alto Adige, Merano, Italy Anton Wieser, MD Department of Radiology, Azienda Sanitaria dell’Alto Adige, Merano, Italy Archivio Italiano di Urologia e Andrologia 2018; 90, 3

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DOI: 10.4081/aiua.2018.3.218

CASE REPORT

Selective arterial embolization for a high-flow priapism following perineal trauma in a young gymnast Grazia Bianchi 1, Camilla Sachs 2, Irene Campo 2, Giovanni Liguori 1, Carlo Trombetta 1 1 Department 2 Department

of Urology, University of Trieste, Cattinara Hospital, Trieste, Italy; of Radiology, University of Trieste, Cattinara Hospital, Trieste, Italy.

Summary

Introduction. High-flow priapism is a rare condition in children, usually due to a

perineal trauma.

Materials and methods. We present a case of traumatic highflow priapism investigated by Doppler ultrasound and managed by angiography and selective embolization of a branch of the internal pudendal artery.

Results. A 13-year-old gymnast underwent perineal trauma during training and developed a high-flow priapism. The first ultrasound (immediately after the trauma) showed the presence of an inhomogeneous area of 3 x 2 cm associated with an anechoic vascularized area (pseudoaneurysm) in the right corpus cavernosum. On the left side there was a similar finding, but of smaller size. After 3 weeks the pseudoaneurysm on the left was completely obliterated while the right one was still present.

Angiography and superselective catheterization of a branch of the left pudendal artery and its embolization with microspheres and with metal microcoils were performed. After the procedure, ultrasound showed that the right pseudoaneurysm was completely obliterated and there were no more branches reaching it. The cavernous arteries were both pervious.

Conclusions. Selective arterial embolization is a safe treatment that can also be used in pediatric patients.

KEY WORDS: High-flow priapism; Perineal trauma; Embolization.

Submitted 5 June 2018; Accepted 26 July 2018

INTRODUCTION

and his penis was not completely rigid. The first ultrasound (immediately after the trauma) showed, in the right corpus cavernosum, the presence of an inhomogeneous area of 3 x 2 cm, associated with an anechoic vascularized area (pseudoaneurysm) (2). On the left side there was a similar finding, but of lesser magnitude. After 3 weeks, the patient came to our attention and we performed another Doppler ultrasound using linear 5-12 and 5-17 MHz transducers. During the exam, a modest degree of erection could be appreciated. In correspondence to the palpatory finding in the crura, a 1.2 x 0.4 cm cavernous pseudoaneurysm was recognized on the right, fed by a small fistula with turbulent flows and with high velocities. No other vascular afferents were recognized. With compression, we could stop the flow in the pseudoaneurysm with immediate resumption of the pathological stream at the end of compression. After 3 weeks, the pseudoaneurysm on the left was completely obliterated. After retrograde guidewire puncture of the left common femoral artery, we proceeded to selective catheterization of the right hypogastric artery and the right pudendal artery, which were found to be pervious. Angiography showed the presence of an arteriocavernosal fistula at the root of the penis with an afferent arterial branch originating from the pudendal artery.

We proceeded to superselective catheterization of the branch of the right pudendal artery and its embolization with microspheres (Embozene 250 Îźm) and with metal microcoils (Striker 2 x 40 mm).

The final angiographic check demonstrated the complete occlusion of the embolized arterial branch (Figure 1).

High-flow (non-ischaemic, arterial) priapism is a nonsexual, persistent erection caused by unregulated cavernous arterial inflow. Cavernous blood gases are not hypoxic or acidotic. Typically the penis Figure 1. is neither fully rigid nor painful. In children Angiography before and after embolization. this is a rare condition, usually due to a perineal trauma and does not require emergent treatment (1).

CASE

REPORT

We present the case of a 13-year-old prepubertal gymnast. He was performing an exercise on parallel bars. During a jump he hit a wooden bar with his genitalia, underwent perineal trauma and developed a high flow priapism. He had a scrotal hematoma, but he had no pain

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No conflict of interest declared.

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Embolization for a high-flow priapism

Afterwards, selective catheterization of the left hypogastric artery and of the left pudendal artery were performed and the angiography did’t show any arteriocavernosal fistula on this side (3).

Ultrasound performed after the procedure showed that the right pseudoaneurysm was completely obliterated and there were no more branches reaching it. The cavernous arteries were both pervious.

CONCLUSIONS

Selective arterial embolization is a safe and painless treatment that can also be used in young patients.

REFERENCES

Ta D

1. Hacker HW, Schwoebel MG, Szavay PO. Nonischemic priapism in childhood: a case series and review of literature. Eur J Pediatr Surg. 2018; 28:255-260.

2. Vega-Vigo C, Márquez-Moreno AJ, Rojo-Carmona LE, Castillo Gallardo E. High-flow priapism caused by a pseudoaneurysm and an arteriocavernosal fistula: clinical and radiological approach of 3 cases. Arch Esp Urol. 2014; 67:642-5.

3. Bertolotto M, Quaia E, Mucelli FP, et al. Color Doppler imaging of posttraumatic priapism before and after selective embolization.

Radiographics 2003; 23:495-503.

Correspondence Grazia Bianchi, MD (Corresponding Author) graziuccia88@libero.it Giovanni Liguori, MD gioliguori33@gmail.com Carlo Trombetta, MD trombcar@units.it Università degli Studi Trieste, Urology Department – Cattinara Hospital, Strada di Fiume 447, Trieste, Italy Camilla Sachs, MD cami_sachs@hotmail.it Irene Campo, MD irenecampo11@gmail.com Università degli Studi Trieste, Radiology Department – Cattinara Hospital, Trieste, Italy

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DOI: 10.4081/aiua.2018.2.220

CASE REPORT

Management of self-inflicted orchiectomy in psychiatric patient. Case report and non-systematic review of the literature Marco Garofalo 1, Alessandro Colella 1, Paolo Sadini 1, Lorenzo Bianchi 1, Giacomo Saraceni 2, Eugenio Brunocilla 1, Giorgio Gentile 3, Fulvio Colombo 3 1 Department

of Urology, Sant’Orsola Hospital - University of Bologna, Bologna, Italy; Pelvic Surgery Unit, Department of Gynecology and Urology, Sant'Orsola-Malpighi Hospital, Bologna, Italy; 3 Andrology-Unit, Sant’Orsola Hospital - University of Bologna, Department of Gynecology and Urology, Bologna, Italy. .

2 Complex

Submitted 15 May 2018; Accepted 26 July 2018

no mental illness history (8, 9). Risk factors for GSM include: commanding hallucinations, religious delusions, substance abuse and social isolation (5, 10, 11).

It has been reported a correlation between schizophrenia (or its acute state induced/flared by drugs abuse and acute psychotic states induced by recreational drugs consumption) and major self-mutilations (12, 13); sometimes genital mutilation can also be the presenting sign of schizophrenia (14). Auto-castration in a setting of drugs abuse alone, especially of a single drug (mainly methamphetamine and cannabinoids) and within absence of a certified mental illness history, has also been described (15-17).

The vast majority of reported cases have occurred among single, white males in their 20s and 30s (18).

Usually, patients report all the common signs in traumatic amputation of the testis (namely, exposed lacerated wound, avulsion, etc). In addition, very few other cases show genital auto-mutilation of one or both testicles without involving the penile shaft. We show a case of unilateral self-orchidectomy performed in a “surgical fashion”, resulting in a closed wound acute scrotum presentation. The aim of our study it to present the management of a patient who performed a self-orchiectomy; we also propose a non-systematic review of literature about self-orchiectomy.

INTRODUCTION

MATERIALS

Summary

Introduction: Self-inflicted orchidectomy and auto-castration, also known as “Eshmun complex” is a rare phenomenon. The aim of our study it to present the management of a patient who performed a self orchiectomy and propose a non-systematic review of literature about self-orchiectomy.

Material and method: A 27-years old male Patient with psychiatric disorder was admitted to our ward to have been cutted his scrotum with scissors and cut away his left testicle causing active bleeding from the left spermatic artery. The patient underwent emergency surgery with clamping of the spermatic cord and hemostasis of the wound.

Results: After surgery the clinical condition of the patient remained good during whole hospitalization. Urgent psychiatric evaluation was performed in order to administer proper therapy for acute management. To best of our knowledge, only 11 cases of self-orchidectomy are reported in literature and all of them except 1 case, underwent surgical exploration.

Conclusions: Self-orchidectomy is an extremely rare phenomenon, often associated with psychiatric disorders, compounded by the use of drugs. In our opinion, emergency surgery should be the first choice of treatment, offering diagnostic and hemostatic purpose in a single act, aimed to prevent acute and postacute complications.

KEY WORDS: Self orchiectomy; Genital mutilation; Self castration.

Self-inflicted testicular injury is a rare phenomenon, with less than 200 cases reported in literature (1). Scrotal traumas are included in a different genital self-mutilation (GSM) setting, with lesions varying from tissues laceration to ablation of the whole external genitals (2). Most self-inflicted testicular injuries have been reported in trans-sexual patients who desire emasculation (3) or by psychotic patients with either functional or organic brain disease (4, 5).

Self-inflicted orchidectomy and auto-castration, also known as “Eshmun complex” (6, 7) is a type of major-selfmutilation (MSM) common among young individuals affected by psychiatric disorders, especially during acute psychotic state (1). This traumatic injury is less common in delusional and depressed individuals or in subject with

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AND METHODS

21.03.2017. 03:12 p.m. A 27-years old male Patient, voluntarily admitted to St. Orsola Malpighi Hospital’s Casualty Ward, asking for medical assistance for referred “scrotal bleeding and self-orchidectomy”. Patient was already admitted before, since he was followed by a psychiatric clinic due to schizophrenia, not properly adherent to Fluphenazine prescription. The patient lucidly reported his psychiatric disorder at beginning of medical consultation and he reported that he incised his scrotum with scissors and cut away his left testicle, then he sutured his scrotum by himself. He had no mention of local anesthesia or analgesic usage.

Genital examination revealed globally swollen and round scrotum (approximately 15 cm). Scrotal skin, looking stretched, dehydrated and clean, was involved by a large No conflict of interest declared.

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Management of self-inflicted orchiectomy in psychiatric patient

Figure 1.

Preoperative picture of the scrotum, with the surgical suture made by the patient.

B.

A. Figure 2.

Ultrasound of scrotum: a) right scrotum with regular right testis b) left scrotum, without the testis.

B.

A. Figure 3.

Intraoperative picture: the cut funiculus.

Basing on this preliminary data, in absence of major bleeding, considering the regular Glasgow Coma Scale (GCS) and mental status, himself showing a calm and cooperative behavior, we aimed firstly to determine the entity of lesion, the extent of active bleeding and the need of acute management by surgical exploration.

Examination was extended through palpation and manipulation of external genitals, revealing a scrotal fistula covered by uneven wire stitching on the left scrotal sack. By applying progressive non-traumatic digital pressure, the left scrotum was evacuated from an approximate amount of 400 ml of blood clots and serous/hematic material through the un-sutured scrotal breech.

This maneuver allowed palpation of scrotal content.

Therefore, surgical scrotal exploration was planned in emergency, with the consent of the informed patient.

Antibiotic prophylaxis was administered by endovenous infusion of cefuroxime 2 gr. First, we removed some black cotton double-wired single-suturing stitches overlapping each other in the left scrotum, assumed to be placed with a sewing needle. So, an irregular circular area of excision of 4 cm involving all scrotal wall tissues, appeared. Scrotal incision margins presented as neat as a single or few scissor section lines. Evacuation of approximately 100 ml of blood clots revealed an empty left hemiscrotum. An active bleeding sprouting was individuated from the left spermatic artery; this revealed the distal portion of the left spermatic chord (Figures 3a, 3b), suggesting that the spermatic chord incision has been conducted by the patient above the testicular veins; no testicular or epididimal remnants were found. Didymus and epididymis were missing: in fact, the patients referred in follows consultation, that he threw the testis into the toilet.

After clamping and dissection of distal amputated spermatic chord, the vessels and the vas deferens were sutured separately with 2-0 Vicryl®. After washing the cavity, the hemostasis check showed no further bleeding and no other trauma. A percutaneous suction drainage has been placed in the left scrotal cavity. Finally, the scrotum has been repaired by suturing the Dartoic plane and the skin in 4-0 SafilQuick® absorbable single stitches.

B.

A.

ecchymosis more evident on the lower-left side. Indeed, on the left side, at lower-middle third, a cutaneous suturing measuring approximately 1 x 0.5 cm appeared as repaired by suturing stitches made of common cotton thread (Figures 1a, 1b).

Ultrasound evaluation by scrotal eco-color-Doppler (ECD) has been performed, according to the casualty ward’s dedicated acute scrotum diagnostic protocol. The ECD showed a normal, despite dislocated, right testicle (Figure 2a) and an extensive hematoma of the left scrotum cavity with a modest color-Doppler signal within its content, but no evaluable left testicle (Figure 2b).

Blood exams were indicative for acute infection and inflammation (White blood cells: 19.01 x 10^9/L; Neutrophils: 16.13 x 10^9/L); toxicological screening found high amounts of plasmatic cannabinoids (69 ng/mL). Total hemoglobin was 13.8 g/dL. within normality ranges of Hematocrit and Red Blood Cells total amount.

RESULTS

After surgery, the clinical condition of the patient remained good during whole hospitalization. Intravenous fluids, anti-inflammatory drugs and analgesic have been administered. The day after the surgical intervention, the vital signs were good and stable; Hemoglobin values of 11.0 g/dL in the first postoperative day, lined with the blood loss before the hemostasis in the operating theatre (Estimating Blood Loss: 150 cc) and the inflammation signs were considerably reduced (White Blood Cells 8.92 x 10^9/L).

There was no fever, no local or systemic infection and good status of the surgical wound.

Urgent psychiatric evaluation was performed in order to administer proper therapy for acute management.

The patient referred during the Psychiatric evaluation that his act was impelled by voices inside his head, and probably this escalated quickly with chronic and acute abuse of cannabinoids. Moreover, he said that he felt no pain during the mutilation. Since the surgical postoperaArchivio Italiano di Urologia e Andrologia 2018; 90, 3

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M. Garofalo, A. Colella, P. Sadini, L. Bianchi, G. Saraceni, E. Brunocilla, G. Gentile, F. Colombo

Table 1.

Review of literature on penile trauma and anterior urethral rupture: characteristic of studies, population and management.

Authors

Study

Years

Sutchin R. Patel et al.

Case report

2007

N° patients (total) 1

Helen Stunell et al.

Ugur LoK et al.

A.A. Ajape et al.

Moudif K. et al.

Wade C. Myers M.D., et al.

Eugene F. Simopoulos, M.D., et al.

Case report Case report Case report Case report Case report Case report

2006 2014 2010 2004 2001 2012

1 1 1 1 1 1

Abdurakhmanov RA, et al.

Rehan Ahmed Siddiquee, et al.

Jacek S. Anand et al.

Case report Case report Case report

2016 2007 2014

1 1 1

Mustapha Ahsaini TOTAL

Case report

2011 11

1 160

tive convalescence elapsed without complication, the patient was transferred to a psychiatric ward.

DISCUSSION

GSM is a rare phenomenon. The most common self-mutilating behavior is cutting one’s own wrist, which is usually committed by adolescents or by the mentally retarded for attention-seeking purposes. Rarely, self-mutilation has a serious scenario that leads the patient to attempt to amputate his penis, to castrate himself, to extract his eye or to amputate his hand (19). The instruments that have been used include kitchen knives, blades, scissors, a chainsaw and an axe. Most of cases reported in the literature, consist of patients with psychosis or psychiatric disorders with either functional or organic brain disease.

Such cases have been observed in schizophrenia or depression, and it is sometimes difficult to diagnose these conditions because such a behavior is usually the only presenting symptom of the psychiatric disorder. However, few cases have been described in non-psychotic persons.

It has been suggested that there is no difference in the severity of the self-inflicted injuries between psychotic and non-psychotic patients. In our case report, the reason for self-mutilation of the testis was the status of schizophrenia compounded by the use of drugs.

As the degree of mutilation varies, so does the treatment, which can be complex and quite challenging; it often consists of a multidisciplinary management between the urologist, psychiatrist, psychologist and primary care physician. Early diagnosis and fast treatment can reduce the acute and post-acute complications (blood loss, infections, hemorrhagic shock…). To best of our knowledge, only 11 cases of self-orchidectomy are reported in literature and all of them except 1 case, underwent surgical exploration (Table 1).

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Psychiatric/neurologic pathology Gerstmann-Straüssler-Scheinker syndrome Paranoid schizophrenia Unknown Depression Unknown Schizophrenia Major depression, Social anxiety disorder, gender identity disorder, and complex Post-traumatic stress disorder Unknown Schizophrenia Polydrug abuse Borderline personality disorder Cannabis abuse

Drugs

Management

_

Surgery

_ _ _ Unknown Lorazepam, ramelteon

Surgery Surgery Surgery Surgery Conserevative/medical Surgery

Unknown Methamphetamine (up to 500 mg per day) Cannabinoids

Surgery Surgery Surgery Surgery

The main goal of surgical treatment includes restoration of the anatomy and function of mutilated organs, as much as possible. A superficial laceration may require no more than simple suturing; a serious injury with selfmutilation of organ or part of it, as we reported in the present case report, needs an emergency intervention.

Complications resulting from GSM vary according to the severity of the injury inflicted and the extent of surgical repair undertaken.

CONCLUSIONS Self-orchidectomy is an extremely rare phenomenon, often associated with psychiatric disorders, compounded by the use of drugs. In our opinion, emergency surgery should be the first choice of treatment, offering diagnostic and hemostatic purpose in a single act, aimed to prevent acute and post-acute complications. However, a multidisciplinary approach is essential and includes a careful psychiatric evaluation to avoid recurrences and to more extensively support these patients through their mental and physical integrity recovery.

REFERENCES

1. Veeder TA, Leo RJ. Male genital self-mutilation: a systematic review of psychiatric disorders and psychosocial factors. Gen Hosp Psychiatry. 2017; 44:43-50.

2. Stunell H, Power RE, Floyd M, Quinlan DM Genital self-mutilation. Int J Urol. 2006; 13:1358-60.

3. Simopoulos EF, Trinidad AC. Two cases of male genital self-mutilation: an examination of liaison dynamics. Psychosomatics. 2012; 53:178-80.

4. Patel SR, Thavaseelan S, Handel LN, et al. Bilateral manual

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Management of self-inflicted orchiectomy in psychiatric patient

externalization of testis with self-castration in patient with prion disease. Urology. 2007; 70:590.e15-6.

ital self-mutilation: an update of case reports. Riv Psichiatr. 2015; 50:148-50.

5. Ozan E, Deveci E, Oral M, et al. Male genital self-mutilation as a psychotic solution. Isr J Psychiatry Relat Sci. 2010; 47:297-303.

13. Siddiquee RA, Deshpande S. A case of genital self-mutilation in a patient with psychosis. Ger J Psychiatry. 2007; 10:25-8.

6. Kushner AW. Two cases of auto-castration due to religious delusions. Br J Med Psychol. 1967; 40:293-8.

14. Myers WC, Nguyen M. Autocastration as a presenting sign of incipient schizophrenia. Psychiatr. Serv. 2001; 52:685-6.

7. Eke N. Genital self-mutilation: there is no method in this madness. BJU Int. 2000; 85:295-298.

15. Ahsaini M, Tazi F, Khalouk A, et al. Bilateral testicular self-castration due to cannabis abuse: a case report. J Med Case Rep. 2011; 5:404.

8. Ajape AA, Issa BA, Buhari OI, et al. Genital self-mutilation. Ann Afr Med. 2010; 9:31-4.

9. Mareko GM, Othieno CJ, Kuria MW, et al. Body dysmorphic disorder: case report. East Afr Med J. 2007; 84:450-2.

10. Rao KN, Bharathi G, Chate S. Genital self-mutilation in depression: a case report. Indian J Psychiatry. 2002; 44:297-300.

11. Charan SH, Reddy CM. Genital self mutilation in alcohol withdrawal state complicated with delirium. Indian J Psychol Med. 2011; 33:188-90.

12. Vender S, Bianchi L, Callegari C, et al. Cannabis use and gen-

16. Anand JS, Habrat B, Barwina M, Waldman W. Repeated self-mutilation of testicles in the context of methamphetamine use e A case report and brief review of literature. J Forensic Leg Med. 2015; 30:1-3.

17. Large M, Babidge N, Andrews D, et al. Major self-mutilation in the first episode of psychosis. Schizophr Bull. 2009; 35:1012-21.

18. Lok U, Gulacti U, Benlioglu C, et al. Self mutilation of genitaliausing teeth. J Clin Diagn Res. 2014; 8:179-80.

19. Nerli RB, Ravish IR, Amarkhed SS, Manoranjan UD, Prabha V, Koura A. Genital self-mutilation in nonpsychotic heterosexual males: Case report of two cases. Indian J. Psychiatry 2008;50:285–7

Correspondence Marco Garofalo, MD marco.garofalo@unibo.it Alessandro Colella, MD alessandro.colella@studio.unibo.it Paolo Sadini, MD sadini@libero.it Lorenzo Bianchi, MD lorenzo.bianchi3@gmail.com Eugenio Brunocilla, MD eugenio.brunocilla@unibo.it Department of Urology, Sant’Orsola Hospital - University of Bologna, Bologna, Italy Giacomo Saraceni, MD giacomo.sareceni@libero.it Complex Pelvic Surgery Unit, Department of Gynecology and Urology, Sant'Orsola-Malpighi Hospital, Bologna, Italy Giorgio Gentile, MD (Corresponding Author) dr.giorgio.gentile@gmail.com Fulvio Colombo, MD fulvio.colombo@aosp.bo.it Andrology-Unit, Sant’Orsola Hospital - University of Bologna, Department of Gynecology and Urology, Bologna, Italy

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DOI: 10.4081/aiua.2018.3.224

CASE REPORT

Primary melanoma of the bladder: Case report and review of the literature Francesco Barillaro 1, Marco Camilli 1, Paolo Dessanti 2, Nader Gorji 2, Fabio Chiesa 3, Alessandro Villa 3, Alessandro Pastorino 4, Carlo Aschele 4, Enrico Conti 1 1 Department of Urology, ASL 5 Spezzino. Sarzana - La Spezia, Italy; 2 Department of Pathology, ASL 5 Spezzino. La Spezia, Italy; 3 Department of Radiology, ASL 5 Spezzino. Sarzana - La Spezia, Italy; 4 Department of Oncology. ASL 5 Spezzino. La Spezia, Italy.

Summary

Skin melanoma represents one of the most common and lethal solid tumor. It usually develops on the skin but it can occur in any tissues with melanine-containing-cells (extracutaneous malignant melanoma).

Only 4-5% of malignant melanomas originate in extracutaneous tissues, and they have an extremely lethal behavior (1).

These non-skin malignant melanomas are rare but extremely aggressive. Primary melanoma of the genitourinary tract accounts for less than 0.2% of all melanomas. To date only 28 cases of primary bladder melanoma (PMM) are described. We report a rare case of PMM of the bladder in a 72 years old man treated with radical cystectomy and immunotherapy with Nivolumab.

KEY WORDS: Bladder melanoma.

Submitted 16 April 2018; Accepted 29 April 2018

CASE

REPORT

A 72 year-old caucasian man presented to the Emergency Room of our Hospital with gross asymptomatic haematuria. A cystoscopy showed a solid mass with red and brown spots in the surface, consequently the diagnosis of solid bladder tumor was posed. After obtaining informed consent, we performed a trans urethral resection of the bladder tumor (TURBt) without a radical debulking of the whole mass due to the aspect of extensive muscle invasion.

The histological exam confirmed the diagnosis of PMM of the bladder. Patient denied an history of nevi-excision or other surgery.

A multiparametric Magnetic Resonance (mpMR) scan confirmed a solid tumor of 7x6 cm.

The lesion extended through all the bladder wall with suspicious iliac nodal metastasis. A fluorodeoxyglucose positron emission tomography computed tomography (FDG PET-CT) scan showed hypermetabolic capitation of the right ilar lymph-nodes and of the mesenteric tissue.

A single capitation in para-vertebral region of the low portion of left lung was not clearly identified as metastasis. Dermatological exam, gas-

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troscopy,colonscopy and a ophthalmologic exam ruled out the suspicious of a secondary lesion from a primitive malignant melanoma elsewhere. Patientâ&#x20AC;&#x2122;s case was discussed by the institutional multidisciplinary uro-oncologic disease management team that stated a multimodal treatment. A radical cystectomy with a simple urinary diversion (UCS) and immunotherapy protocol were planned. Patient underwent surgery and the final histological exam reported a pT4 N0 Mx R0 melanoma of the bladder (Figure 1). Immunoistochemical exam was positive for S-100, and SOX-10 and slightly positive for HMB45 while was negative for Cytocheratines CAM5.2, AE/1/AE3, 7, 20; Actine, CD34, Desmin,DOG-1, EMA, GATA-3, Myogenine, Chromoreanine, PSA and P63 (Figure 1).

Two months after surgery patient underwent contrast enhancement computed tomography (CeCT) without showing progression of the chest nodes. Three months

Figure 1.

Pathological specimens.

No conflict of interest declared.

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Primary melanoma of the bladder

after surgery patient underwent immunotherapy with Nivolumab as for skin melanoma. A 14 day course of intravenous injections of 3 mg/kg of Nivolumab in 100 ml of saline solution was completed. A new FDG PET-CT scan six months after surgery showed a complete response of the nodal and mesenteric lesions while reported a decrease in size of the pulmonary lesion (17 mm vs 21 mm). Thirteen months after surgery, a new FDG PET-CT showed a 4 mm small right inguinal nodal recurrence and a steady situation of the pulmonary lesion. Fifteen months after surgery patient is alive with Karnofsky score of 90 and ECOG 1-2.

DISCUSSION

Primary melanoma of the urinary bladder is an extremely rare neoplasm and to date only 28 cases including this case are reported to medical literature (Table 1).

The diagnosis of primary melanoma of the bladder is not always easy. Ainsworth et al. (2) and Siroy and MacLennan (3) established some diagnostic criteria for primary bladder tumours: (1) absence of any previous skin lesion, or (2) cutaneous malignant melanoma, or (3) primary visceral malignant melanoma, (4) recurrence pattern showing

consistency with the primary tumour diagnosis, (5) atypical melanocytes at the tumour margin on microscopic examination.

Primary melanoma of the urinary bladder usually affects people over fifty and there is a slight prevalence in male sex (60%). Our literature review presents few cases over a wide range of time with extremely different treatments and behavior. In addition, the follow up is extremely heterogeneous and only 12/28 patients (42%) were alive at time of the report with different follow-up (3-144 months; median 20.7 months). First choice treatment is surgery. The treatment can be conservative as trans urethral resection of the bladder tumor (TURBt) associated or not with endovesical Immunotherapy with Bacillus of Calmette Guerin (BCG); partial cystectomy can be considered as alternative conservative treatment. Radical Cystectomy can be carried out based on the staging of tumor and in patients with better performance status. Chemotherapy can be a possibility as unique therapy for patients who are poor surgical candidates and options include platinum-based chemotherapy as cisplatin/carboplatin plus paclitaxel.

Immunotherapy can be considered optional. Interferon and interleukin (IL)-2 are used for metastatic melanoma but the high tossicity and the low response rate reported in literature considerably limited the use.

Table 1.

Primary malignant melanomas reported in literature.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

References Wheelock 1942 Su and Prince 1962 Ainsworth et al. 1976 Willis et al. 1980 Anichkov and Nikonov 1982 Anichkov and Nikonov 1982 Ironside et al. 1985 Goldschmidt et al. 1988 Goldschmidt et al. 1988 Philippe et al. 1989 Van Ahlen et al. 1992 Lund et al. 1992 Kojima et al. 1992 Lange-Welker et al. 1993 Mourad et al. 1993 Niederberger and Lome 1993 De Torres et al. 1995 Tainio et al. 1999 Garcia Montes et al. 2000 Khalbuss et al. 2001 T. Hsu and Y. Hsu 2002 Baudet et al. 2005 Pacella et al. 2006 Sundersingh et al. 2011 El Ammari et al. 2011 Truong et al. 2013 Otto et al. 2017 Barillaro et al. 2018

Age (y) 67 61 65 57 48 46 56 53 56 77 81 81 63 75 34 53 44 52 44 82 73 7 82 56 71 84 52 72

Sex F F F F M M M F F M M F F M M M M M F F M F M M M F M M

Treatment Follow up (months) Outcome Partial cystectomy 36 Died None 2 Died Radical cystectomy 17 Alive Radical cystectomy 36 Died Partial cystectomy 12 Died Radical cystectomy 3 Alive None 8 Died Partial cystectomy 7 Died None 6 Alive TURB n.r. n.r.

Radical cystectomy, radiotherapy, interferon-alpha 24 Died Local excision, radiotherapy chemotherapy 15 Alive Chemotherapy 18 Died Partial cystectomy 3 Died Radical cystectomy 12 Alive Radical cistectomy 18 Alive Radical cystectomy 14 Died TURB 8 Died TURB 144 Alive Radiotherapy + cistectomy 16 Died TURB + intravesical BCG and ReTURB at 2-7-9 months 16 Alive Partial cystectomy 84 Alive TURB 9 Died Radical cystectomy and pelvic excision four months later 10 Alive TURB 5 Died TURB + Ipilimumab n.r n.r.

TURB + Interferon/dacarbazine 18 Died Radical cystectomy + Nivolumab 16 Alive

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F. Barillaro, M. Camilli, P. Dessanti, N. Gorji, F. Chiesa, A. Villa, A. Pastorino, C. Aschele, E. Conti

The fully human IgG4 PD-1 immune checkpoint inhibitor antibody Nivolumab has received the FDAapproval in March 2015 for squamous lung cancer treatment. In addition, antibodies targeting PD-1 or PD-L1 have demonstrated their efficacy and safety in additional tumors, including non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), bladder cancer, and Hodgkin's Lymphoma. Nivolumab plus Ipilimumab or Nivolumab alone, blocking the interaction between the programmed cell death PD1 and his ligand PD-L1 have been reported to be effective in antitumor response in melanoma (4, 5). Other treatment as radiation therapy might be only considered for palliative treatment in bladder melanoma. Based on our review TURBt or other conservative treatments were carried out in 14 patients (50%) with a survival rate of 28.5% (4/14) in an average follow up of 14 months. One patient was treated with conservative treatment (TURBt) along with a combination of Interferon plus Dacarbazine and died after 18 months. In one case treated with TURBt and Ipilimumab survival was not reported.

Three cases did not receive any treatment and the reported follow up showed a death in 2 months and 8 months and a survival at 6 months. One case was treated with chemotherapy alone and died after 18 months. Radical cystectomy was carried out in 10 patients with median age of 59 y/o; survival rate was 60% (6/10) at a median follow up of 15.5 months. Among patients treated with cystectomy, one received also radiotherapy and died 16 months after primary treatment. One patient received a multimodal treatment combined of cystectomy, radiotherapy and immunotherapy with interferon alpha and died 24 months after. In our case, Nivolumab was started as first line treatment after surgery based upon the BRAF, NRAS and c-KIT wild type molecular pattern. At time of this literature review is the only one reported with clinical and metabolic remission 15 months after primary treatment without relevant toxicities.

ACKNOWLEDGMENTS

All authors contributed equally to the manuscript drafting. The authors are the only ones responsible for the content and writing of the paper.

CONCLUSIONS

The best treatment of primary bladder melanoma is not univocally recognized due to the small number of cases reported in literature. While a bladder resection can be an option for localized small tumors, radical cystectomy may be the treatment of choice for invasive muscle disease.

As for metastatic skin melanoma, immunotherapy with Nivolumab seems representing a feasible therapy for this rare neoplasm.

The role of the surgical treatment versus only immune or chemotherapy is not known. According to literature review, radiation therapy seems not to be the treatment of choice.

According to other cases reported, an almost total remission after 15 months after surgery and immunotherapy, can be considered a good therapeutic choice.

REFERENCES

1. Hussein MR. Extracutaneous malignant melanomas. Cancer Invest. 2008; 26:516-34.

2. Ainsworth AM, Clark WH, Mastrangelo M, Conger KB. Primary malignant melanoma of the urinary bladder. Cancer. 1976; 37:1928-36.

3. Siroy AE1, MacLennan GT. Primary melanoma of the bladder. J Urol. 2011; 185:1096-7.

4. Mahoney KM, Freeman GJ, McDermott DF. The Next ImmuneCheckpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma. Clin Ther. 2015; 37:764-82.

5. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015; 372:320-30.

Correspondence Francesco Barillaro, MD francesco.barillaro@asl5.liguria.it Marco Camilli, MD marco.camilli@asl5.liguria.it Fabio Chiesa, MD fabio.chiesa@asl5.liguria.it Alessandro Villa, MD dr.willaav@gmail.com Enrico Conti, MD enrico.conti@asl5.liguria.it Osp. S. Bartolomeo via Cisa, 19038 Santa Caterina, Sarzana (SP), Italy Paolo Dessanti MD paolo.dessanti@asl5.liguria.it Nader Gorji, MD nader.gorji@asl5.liguria.it Alessandro Pastorino, MD alessandro.pastorino@asl5.liguria.it Carlo Aschele, MD carlo.aschele@asl5.liguria.it Osp. S. Andrea Via Vittorio Veneto 197, 19121 La Spezia (SP), Italy

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segreteria dell'Associazione all'indirizzo: segreteria@urop.it

Cop settembre_Layout 1 04/10/18 11:34 Pagina 1

1° CONGRESSO NAZIONALE

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ISSN 1124-3562

Vol. 90; n. 3, September 2018

9-10

NOVEMBRE 2018 FRASCATI (ROMA)

Poste Italiane S.p.A. - Spedizione in abbonamento postale - D.L. 353/2003 (conv. in L. 27/02/2004 n. 46) Art. 1, comma 1 DCB Milano

Archivio Italiano di Urologia e Andrologia / Archives of Italian Urology and Andrology - Vol. 90; n. 3 September 2018

ORIGINAL PAPERS 149

Safety and efficacy of PNL vs RIRS in the management of stones located in horseshoe kidneys: A critical comparative evaluation Bilal Eryildirim, Eyup Veli Kucuk, Gokhan Atis, Metin Ozturk, Temucin Senkul, Murat Tuncer, Ahmet Tahra, Turgay Turan, Orhan Koca, Ferhat Ates, Omer Yilmaz, Cenk Gurbuz, Kemal Sarica

155

The new Avicenna Roboflex: How does the irrigation system work? Results from an in vitro experiment Salvatore Butticè, Bahadir Sahin, Tarik Emre Sener, Laurian Dragos, Silvia Proietti, Steeve Doizi, Olivier Traxer

159

Do dental calculi predict the presence of renal stones?

163

Role of the gonadal vessels on the stone lodgment in the proximal ureter: Direct observation during laparoscopic ureterolithotomy

̧ iftçi Bulent Kati, Ergin Kalkan, Eyyup Sabri Pelit, Ismail Yagmur, Halil C

Mohammad Hadi Radfar, Reza Valipour, Behzad Narouie, Mehdi Sotoudeh, Hamid Pakmanesh

166

Ultrasound follow up: Is an undetected spontaneous expulsion of stone fragments a sign of extracorporeal shock wave treatment failure in kidney stones?

Grazia Bianchi, Diego Marega, Roberto Knez, Stefano Bucci, Carlo Trombetta

169

Comparison of an electromagnetic and an electrohydraulic lithotripter: Efficacy, pain and complications Grazia Bianchi, Diego Marega, Roberto Knez, Stefano Bucci, Carlo Trombetta

172

Effect of variant histology presence and squamous differentiation on oncological results and patient’s survival after radical cystectomy Ertugrul Sefik, Serdar Celik, Ismail Basmaci, Serkan Yarımoglu, Ibrahim Halil Bozkurt, Tarık Yonguc, Bulent Gunlusoy

176

Feasibility study for interspecialistic collaboration in active research of urothelial neoplasms of professional origin Roberta Stopponi, Enrico Caraceni, Angelo Marronaro, Andrea Fabiani, Stefania Massacesi, Anna Rita Totò, Roberto Calisti

181

Association between large prostate calculi and prostate cancer Cem Yucel, Salih Budak

184

Diabetes mellitus and prostate cancer metabolism: Is there a relationship?

Hugo Pontes Antunes, Ricardo Teixo, João André Carvalho, Miguel Eliseu, Inês Marques, Ana Mamede, Rita Neves, Rui Oliveira, Edgar Tavares-da-Silva, Belmiro Parada, Ana Margarida Abrantes, Arnaldo Figueiredo, Maria Filomena Botelho

191

Prognostic value of subclassification (pT2 stage) of pathologically organ-confined prostate cancer: Confirmation of the changes introduced in the 8th edition of the American Joint Committee on Cancer (AJCC) staging system Hugo Pontes Antunes, Belmiro Parada, João Carvalho, Miguel Eliseu, Roberto Jarimba, Rui Oliveira, Edgar Tavares-da-Silva, Arnaldo Figueiredo continued on page III

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18-Oct-2018 Posizione 1

11:08:35