Archivio Italiano di Urologia e Andrologia Vol. 90 - n. 2 - 2018

Ed _Cop+Ed+fisse 2006 28/06/18 16:32 Pagina I

Official Journal of SIA, SIEUN, SIUrO and UrOP EDITORS

M. Maffezzini (Genova), G. Perletti (Busto A.), A. Trinchieri (Lecco)

EDITORIAL BOARD

P.F. Bassi (Roma), F. Boccafoschi (Novara), A. Bossi (Villejuif - France), P. Caione (Roma), F. Campodonico (Genova), L. Carmignani (Milano), L. Cheng (Indianapolis - USA), L. Cindolo (Avellino), G. Colpi (Milano), G. Corona (Firenze), A. Giannantoni (Perugia), P. Gontero (Torino), S. Joniau (Leuven - Belgio), F. Keeley (Bristol - UK), L. Klotz (Toronto - Canada), M. Lazzeri (Firenze), B. Ljungberg (Umeå - Svezia), A. Minervini (Firenze), N. Mondaini (Firenze), G. Muir (London - UK), G. Muto (Torino), R. Naspro (Bergamo), A. Patel (London - UK), G. Preminger (Durham - USA), D. Ralph (London - UK), A. Rodgers (Cape Town - South Africa), F. Sampaio (Rio de Janeiro - Brazil), K. Sarica (Istanbul - Turkey), R. Schiavina (Bologna), L. Schips (Vasto), H. Schwaibold (Bristol - UK), A. Simonato (Genova), S. Siracusano (Trieste), C. Terrone (Novara), A. Timoney (Bristol - UK), A. Tubaro (Roma), R. Zigeuner (Graz - Austria)

SIA EDITOR

A. Palmieri (Napoli)

SIA ASSOCIATE-EDITORS

T. Cai (Trento), V. Favilla (Misterbianco - CT), P. Verze (Napoli)

SIA EDITORIAL BOARD

P. Capogrosso (Milano), M. Colucci (Bari), E. Conti (La Spezia), M. Paradiso (Asti), G. Paulis (Albano Laziale), N. Pavan (Trieste), M. Polito (Ancona), V. Randone (Catania), G. Romano (Arezzo), G. Sidoti (Catania), A. Vavallo (Altamura)

SIEUN EDITOR

A.B. Galosi (Ancona)

SIEUN CO-EDITOR P. Martino (Bari)

SIEUN EDITORIAL BOARD

M. Barbera (Sciacca), L. Barozzi (Bologna), M. Bertolotto (Trieste), M. Bitelli (Roma), S. Bucci (Trieste) A. D’Amelio (Lecce), M. Del Zingaro (Perugia), L. Dell’Atti (Ferrara), A. Fandella (Monastier di Treviso) R. Gunelli (Forlì), S. Palazzo (Bari), P. Pepe (Catania), V. Scattoni (Milano), C. Trombetta (Trieste)

SIUrO EDITOR

R. Valdagni (Milano)

SIUrO ASSISTANT EDITOR G.N. Conti (Como)

SIUrO EDITORIAL BOARD

V. Altieri (Salerno), B. Avuzzi (Milano), E. Bollito (Torino), M. Borghesi (Bologna), S. Bracarda (Arezzo), O. Caffo (Trento), R. Colombo (Milano), G.F. Da Pozzo (Bergamo), F. Lanzi (Siena), A. Lapini (Firenze), G. Martorana (Bologna), C. Ortega (Alba - CN), G.L. Pappagallo (Mirano - VE), M. Rizzo (Trento), R. Sanseverino (Nocera Inferiore - SA), V. Vavassori (Bergamo)

UrOP EDITOR

C. Boccafoschi (Alessandria)

UrOP EDITORIAL BOARD

R. Colombo (Milano), R. Giulianelli (Roma), M. Lazzari (Firenze), A. Porreca (Abano Terme - PD), A. Russo (Milano), M. Scarcia (Acquaviva delle Fonti - BA), N. Suardi (Milano)

ASSOCIAZIONE UROLOGI LOMBARDI EDITOR E. Montanari (Milano)

HONORARY EDITOR E. Pisani (Milano)

Ed _Cop+Ed+fisse 2006 28/06/18 16:32 Pagina II

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.

10.35-11.35

Is innovative ultrasound sensitive enough?

Moderators: V. Scattoni, Milan (IT), J. Walz, Marseille (FR)

10.15-10.50

Radiomics - C-TRUS Anna: Clinical implication T. Loch, Flensburg (DE)

10.50-11.05

Micro-ultrasound: Down to 100 microns, does it help?

To be confirmed

11.05-11.20

What’s up with elastography/shearwave?

M. Mischi, Eindhoven (NL)

11.20-11.35

Contrast enhanced ultrasound - CUDI: Fast and accurate C. Mannaerts, Amsterdam (NL)

15.45-17.00

What’s up with that?

Moderators: P. Martino, Bari (IT), M. Ritter, Mannheim (DE)

15.45-16.00

Dual energy analysis: Useful tool or waste of money To be confirmed

16.00-16.15

Fluorescence diagnostics in cystoscopy M. Ritter, Mannheim (DE)

16.15-16.30

Contrast enhanced ultrasound for the kidney: Any helpfull for diagnostic of reflux To be confirmed

16.30-16.45

mpCystoscopy for bladder cancer M.C. Kriegmair, Mannheim (DE)

16.45-17.00

Question and answers

Società Italiana di Diagnostica Integrata in Urologia, Andrologia, Nefrologia

Board EAU Section of Urological Imaging (ESUI) G. Salomon Chairman M.C. Kriegmair Member B.M. Carey Member M. Ritter Member M. Mischi Member H.U. Ahmed Member L. Budäus Member V. Scattoni Member P. Martino Member A. Villers Member J.J. Futterer Ex-Officio

Hamburg (DE) Mannheim (DE) Leeds (GB) Mannheim (DE) Eindhoven (NL) London (GB) Hamburg (DE) Milan (IT) Bari (IT) Lille (FR) Nijmegen (NL)

CORSO SIEUN-SIUT Corso Teorico-Pratico su Ecografia Urologica ed Andrologica Ancona, 29-30 novembre 2018 Per informazioni ed iscrizioni: www.sieun.eu

NUOVO SITO WEB La SIEUN, con il suo nuovo sito www.sieun.eu, volge lo sguardo all’Europa.

La segreteria della Società

QUOTE ASSOCIATIVE 2018 Socio ordinario - Euro 100,00 Socio Junior - Euro 50,00 Per la modalità di pagamento della quota sociale collegarsi al sito della Società www.sieun.eu.

I PUNTI SIEUN (una possibilità di incontro tra Soci SIEUN e di contatto con altri specialisti) Presso i punti SIEUN i nostri soci potranno essere continuamente informati su tutte le attività e le iniziative della Società e rinnovare il pagamento della quota associativa.

ELLERRE

CENTRE

è a disposizione per ulteriori informazioni.

Via Orfeo Mazzitelli 47/G - 70124 BARI Tel. 080.5045353 - Fax 080.5045362 E-mail: ellerre@ellerrecentre.com www.ellerrecentre.com

Ed _Cop+Ed+fisse 2006 28/06/18 16:32 Pagina III

ORIGINAL PAPERS 130

Clinical comparison between conventional and microdissection testicular sperm extraction for non-obstructive azoospermia: Understanding which treatment works for which patient Elia Maglia, Luca Boeri, Matteo Fontana, Andrea Gallioli, Elisa De Lorenzis, Franco Palmisano, Stefano Paolo Zanetti, Gianluca Sampogna, Liliana Restelli, Edgardo Somigliana, Mariapia Serrago, Franco Gadda, Emanuele Montanari

136

Predictive factors of successful salvage microdissection testicular sperm extraction (mTESE) after failed mTESE in patients with non-obstructive azoospermia: Long-term experience at a single institute Cem YĂźcel, Salih Budak, Mehmet Zeynel Keskin, Erdem Kisa, Zafer Kozacioglu

CASE REPORTS 141

Skin flap squamous cell carcinoma developed after urethroplasty Danilo Abate, Giuseppe Giusti, Nicola Caria, Giuseppe De Vita, Marco Lucci Chiarissi, Antonello De Lisa

143

Rupture of the cavernous body diagnosed by contrast-enhanced ultrasound: Presentation of a clinical case Lucio Dell’Atti, Simone Scarcella, Giulio Argalia, Lorenzo Montesi, Gian Marco Giuseppetti, Andrea Benedetto Galosi

145

Surgical approach to adrenal ganglioneuroma: Case report and literature review Danilo Abate, Giuseppe Giusti, Nicola Caria, Marco Lucci Chiarissi, Antonello De Lisa

Archivio Italiano di Urologia e Andrologia 2018, 90, 2

III

Ed _Cop+Ed+fisse 2006 28/06/18 16:32 Pagina IV

Perletti_Stesura Seveso 28/06/18 16:33 Pagina 85

DOI: 10.4081/aiua.2018.2.85

REVIEW

Resistance of uropathogens to antibacterial agents: Emerging threats, trends and treatments Gianpaolo Perletti 1, 2, Vittorio Magri 3, Tommaso Cai 4, Konstantinos Stamatiou 5, Alberto Trinchieri 6, Emanuele Montanari 7 1 Department

of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, Università degli Studi dell'Insubria, Varese, Italy; 2 Faculty of Medicine and Medical Sciences, Ghent University, Ghent, Belgium; 3 Urology Secondary Care Clinic, ASST-Nord, Milan, Italy; 4 Department of Urology, Santa Chiara Regional Hospital, Trento, Italy; 5 Department of Urology, Tzaneio General Hospital of Piraeus, Piraeus, Greece; 6 Urology Unit, A. Manzoni Hospital, Lecco, Italy; 7 Department of Urology, University of Milan - Ca' Granda Foundation - Ospedale Maggiore Policlinico, Milan, Italy.

Summary

Urinary tract infections are among the most common infectious diseases in humans.

Today, resistance to nearly all antimicrobial classes is dramatically growing, and extremely drug-resistant or even pan-drug resistant pathogens are increasingly isolated around the world.

It is foreseen that in the next decades the world will be facing a major medical emergency generated by the rapid spread of pathogens carrying resistance determinants of unprecedented power. Carbapenemase-producing Enterobacteriaceae, multidrug-resistant Enterococci and fluoroquinolone resistance determinants in both Gram-negative and Gram-positive uropathogens are among the greatest emergencies. In this article, the major emerging threats of particular interest to urologists are reviewed, worldwide resistance trends are illustrated, and novel and older – but still active – recommended drugs are summarized.

KEY WORDS: Urinary tract infections; Resistance; Antibacterial agents; Antibiotics; Carbapenemase; Carbapenem resistance.

EMERGING

RESISTANCE THREATS

In 2013, the Centers for Disease Control and Prevention (USA) included carbapenem-resistant Enterobacteriaceae (CREB) among the three microorganisms posing an urgent threat to public health, due to the extensive resistance shown by these pathogens to a wide array of antibacterial agents, and to the very high mortality rates reported in patients with bloodstream infections caused by organisms like carbapenem-resistant KP. Several international programs are now aimed at fostering research, development and awareness about the threat of pathogen resistance. Pivotal European trials are for example EURECA (European prospective cohort study on Enterobacteriaeae Showing Resistance to Carbapenems), and REVISIT (Revisiting serious bacterial infection with innovation), promoted in the frame of the European COMBACTE-CARE project, an initiative of the combacte.com collaboration.

Submitted 11 April 2018; Accepted 11 April 2018

INTRODUCTION

Urinary tract infections (UTIs) are among the most common bacterial-borne diseases in humans. Although antibacterial agents have been the mainstay of treatment for UTIs for decades, today routine antibiotic therapy is seriously threatened by worldwide outbursts of infections involving multidrug-resistant (MDR), extremely drug-resistant (XDR) or even pan drug-resistant pathogens. Gramnegative Enterobacteriaceae like Klebsiella pneumoniae (KP) and Escherichia coli (EC), and Gram-positive cocci like Enterococcus faecalis and Enterococcus faecium are at the same time the most common uropathogens and the bacteria carrying the most powerful resistance determinants.

On the basis of a general assessment of the major resistance threats, the present review will focus on worldwide susceptibility trends resulting from large international surveillance studies, and will present some available therapeutic options -either novel or old but still effective- for the management of resistant infections of urological interest.

Carbapenem resistance For several decades, extended-spectrum beta-lactamases (ESBL) of TEM and SHV lineage, conferring resistance to a variety of penicillins and third-generation cephalosporins, have represented a worrisome problem for physicians treating patients affected by infectious diseases. In these cases, carbapenem therapy was a useful therapeutic resource against ESBL-producing pathogens.

However, today the usefulness of carbapenems is decreasing rapidly, and the global spread of carbapenemase-producing Enterobacteriaceae (the etiological agents of lung, soft tissue and urinary tract infections) has undoubtedly become the most important threat in the field of infectious diseases. The speed of such spread is alarming: for example, whereas in 2009 the spread of the Klebsiella pneumoniae carbapenemase (KPC) in the USA was classified as ‘sporadic’ in half of the federal states and ‘less than sporadic’ in the remaining states (1), in 2014 the entire USA territory has been defined as affected by an ‘endemic’ presence of KPC (2).

The concern raised by this mounting trend is due to the

No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

85

Perletti_Stesura Seveso 28/06/18 16:33 Pagina 86

G. Perletti, V. Magri, T. Cai, K. Stamatiou, A. Trinchieri, E. Montanari

fact that the spectrum of enzymatic activity of carbapeneclass-A carbapenemases, but at present is isolated less fremases is not restricted to drugs like imipenem, ertapenem, quently than KPC, being in almost all cases restricted meropenem or doripenem, but extends to almost all beta-lactams.

Table 1.

Moreover, resistance to carbapenCarbapenem resistance determinants in pathogens involved in UTIs. ems and other beta-lactams is in most cases facilitated by horizontal-transfer of genetic elements like transposons and plasmid-borne integrons, invariably containing multiple resistance determinants which often confer multidrugresistant, extensively drug-resistant or even pan drug-resistant properties to pathogens.

K. pneumoniae is the most prevalent pathogen among carbapenem-resistant Enterobacteriaceae according to a recent surveillance report by the European Centre for Disease Prevention and Control (3).

Infection with carbapenemase-producing KP (CPKP) can double the mortality rate of affected patients (from 21% to 42%, all infections), and can triplicate the mortality of non-intensive care patients with UTIs from 13% to 43% in intensive care unit (ICU) cases (4).

The carbapenemases that have been characterized so far belong to all four Ambler classes of beta-lactamases (Table 1). Among the enzymes of concern for urologists, the class-A, plasmid-borne K. pneumoniae serine carbapenemase (KPC) is today the most common transmissible resistance determinant in Enterobacteriaceae. KPC includes more than 20 variants (the most prevalent being KPC-2 and -3), who can hydrolyze virtually all beta-lactam agents including carbapenems, penicillins, broad spectrum cephalosporins and monobactams. KPCs are only weakly inhibited by clavulanate and tazobactam (1, 5), and the encoding blaKPC gene, predominantly present in IncF plasmids (with FIIK replicons, and often associated with a Tn4401 trasposon-like structure), is very often coexpressed with cotrimoxazole, fluoroquinolone and aminoglycoside resistance determinants (6).

Notably, today KPC is no longer exclusively expressed in KP (mainly the ST258 strain) or other CREB, but is also found in other species such as Pseudomonas aeruginosa (7).

The SME enzyme also belongs to

86

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

Perletti_Stesura Seveso 28/06/18 16:33 Pagina 87

Uropathogen resistance threats, trends and treatments

to the Serratia marcescens species, a member of the Enterobacteriaceae family (8).

Class B metallo beta-lactamases/carbapenemases (MBLs) require zinc for their catalytic activity. These enzymes are expressed in Enterobacteriaceae but also in P. aeruginosa, and can hydrolyze carbapenems, penicillins and cephalosporins, but not monobactams. Importantly, MBLs are not affected by beta-lactamase inhibitors.

The most powerful and most diffuse MBLs are the New Delhi MBL (NDM), the Verona-Integron-Encoded MBL (VIM) and the IMP imipenemase (9). The blaNDM gene variants are harbored by a variety of broad-host-range Inc plasmids like IncA/C, IncF, IncR, IncN, IncM, IncX, which are in turn expressed within various pathogen isolates, including the highly prevalent ST11 KP clone.

Pathogens harboring the NDM are often residually susceptible to a single last-resort agent like polymixin E, since NDM is very frequently co-expressed with other carbapenemases (OXA-48, VIM and/or KPC) and with multiple resistance determinants such as ESBL, AmpC beta-lactamases, aminoglycoside-modifying enzymes, fluoroquinolone resistance enzymes (e.g., Qnr), macrolide esterases, as well as determinants conferring resistance to trimethoprim-sulphametoxazole.

Among class C beta-lactamases, the CMY enzymes (e.g., ACT-1, CMY-1, CMY-2, and CMY-4, often transferred via pYMG plasmids) were originally expressed in Enterobacter spp. but now are being carried by several other Enterobacteriaceae, including KP (CMY-10). ACT-1 and CMY-1 show moderate carbapenemase activity, are not significantly inhibited by clavulanic acid, and highlevel resistance to carbapenems is often the result of combined drug hydrolysis and impaired drug permeability (e.g., involving OmpK35/36 porins) (10, 11).

Class D OXA beta-lactamases can efficiently hydrolyze penicillins like oxacillin. Some OXA enzymes, such as OXA-23, OXA-48, OXA-51 and OXA-58, carried mainly by highly transferable IncL group plasmids like pOXA48a, have a weak carbapenemase activity. Nevertheless, in pathogens like ST-11 KP, high-MIC carbapenem resistance may result from the concomitant activity of efflux pumps or low-permeability porins (12).

As far as carbapenem-resistance in Gram-positive pathogens is concerned, three mechanisms of reduced beta-lactam susceptibility have been reported in Enterococci: (i) beta-lactamase production as well as (ii) overproduction or (iii) inactivation (by point-mutation) of penicillin-binding proteins like PBP4 or PBP5.

Notably, carbapenem resistance is mainly caused by point-mutations in PBP4. For example, resistance to faropenem in E. faecalis is due to decreased affinity of the drug for PBP4, due to the acquisition of one or two point mutations in the PBP4-encoding gene (13).

gyrase and topoisomerase IV in Gram-negative and -positive pathogens. Mutations occurring in the quinolone resistance determining regions of genes encoding these type II topoisomerases (e.g., in gyrA, gyrB, parC or parE subunits) are the most common chromosomal determinants of FQ resistance (16). For example, in Enterococci resistance to fluoroquinolones is mainly caused by mutations in the GyrA and ParC genes in gyrase and topoisomerase IV, respectively (17). Other mechanisms of resistance to FQ are the qepA-encoded efflux pumps, the OqxAB-encoded efflux pumps -very common in plasmids carried by K. penumoniae-, the qnr-encoded proteins, impeding the interaction of FQ with DNA gyrase, and a mutant aminoglycosyde acetyl-transferase (aac (6’)-Ib-cr) which acetylates the piperazine ring of FQ like norfloxacin and ciprofloxacin (18-21).

Determinants of PMQR are horizontally transferable. For example, qnrA1, A3, A6, B2, B4, B6 and B10 are associated with the mobilizing element insertion sequence ISCR, whereas qnrB1 and B20 are associated with IS26 and Orf1005. The aac (6’)-Ib-cr enzyme-encoding gene is often found in association with qnrB and blaCTX in a cassette within an IS26 transposon. In addition, qepA and OqxAB are also often mobilized by IS26 transposons (22).

Plasmid-mediated fluoroquinolone resistance Plasmid mediated fluoroquinolone resistance (PMQR) is increasing to the point that international guidelines no longer recommend drugs like ciprofloxacin, ofloxacin or levofloxacin as first-choice agents for treatment of urinary tract infections, when resistance is assessed in at least 10% of pathogen isolates (14, 15).

Fluoroquinolones (FQ) inhibit the activity of bacterial

WORLDWIDE

Polymyxin resistance Polymyxins (polymyxin B and colistin/polymyxin E) are antibiotics produced by the Gram-positive species Paenibacillus polymyxa. The plasmidic mcr-1 colistin resistance gene, expressed in Klebsiella spp. and other Enterobacteriaceae, encodes for a phosphatidylethanolamine transferase enzyme, lessening the affinity of colistin towards the lipid-A on bacterial cell membranes via enzymatic modification (23). This resistance determinant, rapidly spreading worldwide (24), represents a major threat since polymyxins are considered last-resource antibiotics against CREB. Glycopeptide resistance Together with Enterobacteriaceae, Enterococci are the most common etiological determinants of urinary tract infections. Acquired resistance to glycopeptide antibiotics in Enterococci is given by five gene clusters: vanA, vanB, vanD, vanE and vanG, leading to the expression of peptidoglycal pentapeptide precursors (PPP) characterized by poor affinity for vancomycin and other glycopeptides.

Interestingly, vanA Enterococci are resistant to the lastgeneration glycopeptide dalbavancin but are susceptible to oritavancin, possibily due to the unique dual mechanism of action of the latter (25). Horizontal transfer of Van genes may occur via Tn-1546 transposons, which are found in conjugative and non-conjugative plasmids (26).

RESISTANCE TRENDS

Beta-lactam antibiotic resistance Information about worldwide trends in pathogen resistance is not frequently published, due to the fact that global epidemiological studies are difficult to perform, and most studies focus on a single nation or region.

Nevertheless, quality works like for example the 2016 Archivio Italiano di Urologia e Andrologia 2018; 90, 2

87

Perletti_Stesura Seveso 28/06/18 16:33 Pagina 88

G. Perletti, V. Magri, T. Cai, K. Stamatiou, A. Trinchieri, E. Montanari

systematic review by Lee et al. (27), or some global surveillance studies, which are occasionally performed, give access to evidence concerning global trends of pathogen chemoresistance.

The Study to Monitor Antimicrobial Resistance Trends (SMART) is among the largest global surveillance programs aimed at monitoring longitudinal antimicrobial resistance patterns worldwide. Over 200,000 clinical samples have been collected since 2002 from patients with complicated intra-abdominal infections, whereas isolates from patients with UTIs have been acquired since 2009.

Among other surveillance actions, susceptibility testing to 12 commonly used antibacterial agents has been performed in different regions of the world. One-hundred ninety-four hospital sites in countries located within the macro-regions of Asia/Pacific, Latin America, Middle East/Africa, North America, and Europe have taken part in the project. Within the SMART program, the ESKAPE group of pathogens (Enterococcus spp, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) is of main interest to urologists and accounts for the vast majority of resistance encountered in nosocomial settings.

Global trends. Data from the SMART project provide an excellent overview of global resistance trends for uropathogens. In the frame of SMART, the 2009-2010 susceptibility analysis of E. coli isolates from UTI specimens of hospitalized patients in countries worldwide showed an overall 17.9% prevalence of extended-spectrum beta lactamase (ESBL) resistance determinants (28), whose rate varied depending on the region considered (Asia/Pacific, 27.7%, Latin America, 23.3%, Europe, 18.8%, Middle East/Africa, 16.2%, Northern America, 7.4%).

Only imipenem and ertapenem demonstrated > 90% susceptibility in ESBL-positive E. coli at that time (99.7% and 98% isolates susceptible, respectively), whereas susceptibility to amikacin and piperacillin-tazobactam was lower (87.1% and 84.4%, respectively). The least active agents were ampicillin-sulbactam, all cephalosporins except cefoxitin, and the fluoroquinolones (28). In the discussion of their data, Hoban et al. emphasized the relevance of intermediate susceptibility in the treatment of UTIs, as certain antibacterial agents concentrate physiologically in the urine (28). This suggests that in specific infections showing intermediate susceptibility towards certain agents, high-dose treatment may be attempted in the absence of more suitable options.

As far as the geographic distribution of carbapenemases is concerned, the overall mortality due to CREB reported in studies from Northern America, Southern America, Europe, and Asia was 33.2%, 46.7%, 50%, and 44.8%, respectively (all infections) (4).

KP carbapenemases (KPC) are endemic in the USA, China, Greece, Italy, Poland, Israel, Brazil, Argentina, Colombia and Taiwan, whereas sporadic spread of KPC-producing KP has been observed in virtually all Asian, European and American countries (summarized in: 27).

The New Delhi metallo beta-lactamases (NDM) confer resistance to most beta-lactams including carbapenems, as well as co-resistance to aminoglycosides, tetracyclines, fluoroquinolones and other antibacterials, due to the comp-

88

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

resence of various resistance determinants within the same mobile genetic elements. NDM are endemic India, Pakistan and Bangladesh (27). An analysis of the prevalence of NDM in the in the frame of the SMART program for years 20082012 – published in 2015 – showed that isolates of nine different species of NDM-expressing Enterobacteriaceae were disseminated in India, Serbia, the Philippines, Saudi Arabia, Guatemala, Vietnam and Georgia, and that different variants of the NDM gene were compresent with CTX-M cephalosporinases (29). Moreover, Enterobacteriaceae producing the VIM and IMP carbapenemases (alone or coexpressed) have been found in Greece, Italy, Spain, the Philippines, Turkey, Australia, Mexico, USA and India, with most isolates concomitantly nonsusceptible to one or more agents like ampicillin-sulbactam, ceftriaxone, cefepime, ceftazidime, piperacillin-tazobactam, ciprofloxacin, amikacin, tigecycline and colistin (30).

Importantly, KP isolates produced IMP-26 together with various VIM variants (VIM-1, 5, 26 or 27), whereas E. coli expressed IMP-1 alone (30). Class-D OXA carbapenemases are endemic in India, Turkey, Morocco, Libya, Egypt and Tunisia, and sporadic spreads have been documented throughout Europe and the Middle-East (summarized in: 27). OXA enzymes have been recently isolated in all continents.

Asia-Pacific. In the Asia-Pacific region, 60 centers from 31 countries provided susceptibility data, which were collected in years 2010-2013 and published in 2016 (31). Uropathogenic E. coli (UPEC) and KP were the most prevalent isolates. China showed the highest rates of ESBL, both in UPEC and KP (66.4% in 2010 and 59.9% in 2013 for UPEC; 60% in 2010 and 54.5% in 2013 for KP). Besides China, dramatic increases of ESBL-expressing UPEC were observed for example in Thailand (54.2% in 2013 vs. 36.8% in 2010) and Hong Kong (41.7% in 2013 vs. 25% in 2010), while ESBL-KP were substantially increased in New Zeland (45.5% in 2013 vs. 23.1% in 2010), South Korea (55.6% in 2013 vs. 37.5% in 2010) and the Philippines (61.3% in 2013 vs. 37.9% in 2010).

In the same region, Jean et al. reported a significant increase of the annual rates of carbapenemase prevalence between year 2008 (0.07%) and year 2014 (1.1%), with the blaNDM-1 allele becoming more prevalent than the IMP-26 gene (32).

Latin America. In 11 Latin American countries, analysis of resistance trends in years 2013-2015, published in 2017, showed that ESBL-positive KP accounted for 46.6% of UTI isolates, substantially higher than the values assessed in SMART 2003 (14%). ESBL-positive rates of KP were higher (52.9%) in isolates from intensive care unit (ICU) compared to non-ICU patients (44.4%) (33). Ertapenem and imipenem showed slightly lower rates of resistance, compared to other beta-lactams (37.4% and 24.1%, respectively, versus, e.g., > 38% for cephalosporins and piperacillin-tazobactam). Among other antimicrobials tested, the aminoglycoside amikacin continues to show high rates of susceptibility (92.3%) for isolates of KP (33).

Northern America. The SMART program provided 24655 isolates from Europe and North America, obtained from ICU (17.8%) and NON-ICU (82.2%) wards. Data from

Perletti_Stesura Seveso 28/06/18 16:33 Pagina 89

Uropathogen resistance threats, trends and treatments

90 hospitals in Canada, in the USA and in 18 European countries were collected. By comparing these regions, in 2015 Lob and coworkers found that resistance among Enterobacteriaceae in Europe was largely driven by KP expressing high rates of ESBLs (41.2% in intensive care units; mostly CTX-M) and carbapenemases (13.2%; mostly KPC and OXA-types). For all Enterobacteriaceae combined, only ertapenem and amikacin inhibited > 90% of ICU isolates in both regions. In Northern America, ertapenem, imipenem and amikacin inhibited > 90% of KP, whereas in Europe only amikacin attained such levels, according to Lob et al. (34).

In 2016, the same research group also focused on susceptibility patterns of ESBL in E. coli from UTIs, representing the 52% of Gram-negative pathogens collected.

A significant increase in ESBL prevalence was seen in the US (from 7.8% in 2010 to 18.3% in 2014, P < 0.0001), whereas in Canada an increase from 10.4% to 13.0% was not statistically significant (35). Moreover, isolates from hospital-acquired UTIs increased considerably in the US (9.4% in 2010 to 27.7% in 2014). The steepest increases over the five-year study period were found among US males (from 7.1% to 26.2%) and older US patients (from 8.8% to 26.6%) (34).

Europe. National surveillance programs worldwide have reported extensive spreads of carbapenemase-producing uropathogens. Logan and Weinstein have edited maps showing the spread of CREB throughout Europe and the world (6). According to the 2017 survey published by the European Centre for Disease Prevention and Control (ECDC), 25% to 50% isolates of KP are carbapenemresistant in Italy, Romania and Greece, the latter showing rates beyond the upper limit (36). In Europe, the diffusion of KPC is â&#x20AC;&#x2DC;endemicâ&#x20AC;&#x2122; in Greece, Poland and Italy (1).

From a study involving 3324 non-replicate isolates of Enterobacteriaceae from Italian hospitals, it was found that 4.3% of isolates were non-susceptible to carbapenems, K. pneumoniae being the most prevalent carrier of the blaKPC carbapenemase gene (in 25.1% and 7.7% inpatients and outpatients, respectively) (37).

A recent ECDC report focusing on Italy, pointed to dramatically increasing resistance trends in this country. For example, the proportion of CPKP blood isolates increased from 1.3% in 2006 to 33.5% in 2015, whereas combined resistance to third-generation cephalosporins, fluoroquinolones and aminoglycosides increased from 2.8% in 2005 to 29.7% in 2015. However, in E. coli the proportion of carbapenem-resistant blood isolates remained low: 0.1% in 2007 to 0.2% in 2015, though combined resistance increased from 0.8% in 2002 to 14.6% in 2015 (38).

In Germany, a very low incidence of carbapenemase-producing isolates has been documented, as a multicenter study published in 2016 demonstrated an incidence of 0.047 cases per 1000 hospital admissions (39). Low prevalence has also been reported in Belgium, with 3.5% of Enterobacteriaceae being carbapenem non-susceptible through expression of OXA-48, OXA-427, KPC and NDM (40). A steep growth of carbapenem resistance has been reported in France. The OXA-48 and NDM resistance determinants increased from 23.1% in 2012 to 36.2% in 2014 (41).

Non-beta-lactam antibiotic resistance As far as non-beta-lactam antibiotic susceptibility trends are concerned, certain African countries show dramatic prevalences of pan-resistant infections. For example, it has been reported that in Nigeria uropathogenic E. coli (UPEC) is pan-resistant to cotrimoxazole (100% isolates), and highly resistant to ofloxacin (70%), gentamycin (92%) and tetracycline (88%) (42).

In various Asia-Pacific countries, the SMART program reported that the rates of susceptibility to levofloxacin among hospital isolates of E. coli ranged from 83% in New Zeland, to 39% in Singapore, to 15% in India (cited in: 43). The overall prevalence of fluoroquinolone resistance in UPEC is dramatically increasing worldwide, with increasing trends in Brazil (63.53% increase for ciprofloxacin and 66.50% for norfloxacin from 2010 to 2015)(44), and with values up to 17% in Italy and 38% in Turkey (summarized in: 45), whereas in the US a 10year study reported an increase from 3% to 17% between 2000 and 2010 (46).

In Europe, the areas showing the highest rates of PMQR are the Mediterranean countries. This distribution extends to the whole Mediterranean basin, and the affected countries are Croatia, Slovenia, Greece, Italy, Spain, France, Morocco, Algeria, Tunisia, Egypt, and Turkey (47, 48). Resistance to cotrimoxazole in community-acquired UPEC is high in Southern America (64% in Nicaragua and up to 58% in pediatric cases in Brazil), Turkey (up to 43%) and Greece (27.3%) whereas in the USA a percentage of 24.2 has been reported (45).

The prevalence of vancomycin-resistant Enterococci (VRE) causing symptomatic or asymptomatic infections in Europe ranges between 1 and 30%, whereas in the USA, VRE are about the 30% of all nosocomial isolates (49).

Encouragingly, Toner et al. reported that the proportion of VRE has remained stable between 2006 (13.9%) and 2014 (11.5%), whereas a worrisome increase of resistance to nitrofurantoin has been documented in frame of the same study (just above zero in 2005 to over 40% in 2009 to about 20% in 2014). Notably, in that study the prevalence of vancomycin resistance was substantially higher in E. faecium (51.2%) compared to E. faecalis (1.6%)(49).

Despite the data mentioned above, uropathogens worldwide seem to retain sensitivity against agents like nitrofurantoin and fosfomycin. For example, the prevalence of resistance to nitrofurantoin in UPEC isolates has been reported to be 2.9% in Brazil (year 2007, 50), < 2% in Europe and 1.6 in the US (45, 49, 50). The figures concerning fosfomycin appear to be as low, with a prevalence in several European countries inferior to 2% (51, 52).

As far as infections of urological concern in the pediatric population are concerned, resistance to ciprofloxacin in E. coli UTIs increased 10-fold between 2002 and 2009 both in young boys and girls, as shown in a study performed in 195 US pediatric hospitals (1% to 10% and 0.6% to 4% of isolates, respectively) (53).

AVAILABLE

AND EMERGING THERAPEUTIC STRATEGIES

Few randomized controlled studies concerning novel or improved therapeutic protocols against drug-resistant Archivio Italiano di Urologia e Andrologia 2018; 90, 2

89

Perletti_Stesura Seveso 28/06/18 16:33 Pagina 90

G. Perletti, V. Magri, T. Cai, K. Stamatiou, A. Trinchieri, E. Montanari

infections have been performed so far. Thus, the available evidence is mainly observational and sometimes limited to case reports. In most cases, studies focusing on Enterobacteriaceae are based on complicated cases of pneumonia or bacteremia. Despite these limitations, this section will focus on selected therapeutic options -novel or old but still efficacious- for treatment of infections caused by resistant pathogens of concern to urologists.

Carbapenems It is known that certain carbapenemase enzymes can decrease the susceptibility of pathogens to carbapenems to a limited extent, and PK/PD data suggest that T > MIC targets can be met with high probability of attainment with high-dose continuous infusions of carbapenems (e.g. 6 g/day meropenem) when MICs are ranging between 4 and 16 mg/L (summarized in: 54).

These experimental data are encouraging, though experts suggest that monotherapy with these agents is not advisable, and that combination therapy including a carbapenem (when MICs are ≤ 8 mg/L) can result in lower mortality rates (54). importantly, the efficacy of combined therapies including a carbapenem appears to be MIC-dependent, as mortality rates in sepsis patients infected with KPCproducing KP were up to 35% for MICs > 16 mg/L, but as low as 13.3% if the MICs of meropenem (2g, > 3h infusion thrice daily) were below or equal to 4 mg/L (55).

Interestingly, combination of two carbapenems might become a last-resort regimen for treating pandrug-resistant and colistin-resort KPC-producing KP infections (bacteremia, pneumonia, and UTIs). The rationale for such approach is based on the fact that KPC appears to have higher affinity for ertapenem compared to other carbapenems. Thus, while KPC would be “engaged” by ertapenem, a co-administered different carbapenem could exert its bactericidal activity. Although recent quality observational data are encouraging (56-58), additional, adequately powered studies are urgently warranted. Moreover, such evidence may ideally foster the development of ertapenem analogues characterized by higher affinity for KPC compared to the founder compound, in order to optimally exploit such “engagement” activity on carbapenemases.

Aztreonam Monobactam therapy may be considered as an option against Enterobacteriaceae expressing class B or D carbapenemases when these determinants are not coexpressed with class A enzymes, which are able to efficiently hydrolyze aztreonam (59). In all cases, susceptibility testing is necessary, due to variable monobactamase activity shown by different subclasses of class-B enzymes.

Avibactam The novel non-beta-lactam beta-lactamase inhibitor avibactam (Figure 1) has been approved in 2016 in the European Union for treatment of soft tissue infections, pneumonia and urinary tract infections in combination with the third-generation cephalosporin ceftazidime.

Avibactam inhibits a broad spectrum of beta-lactamases including A-class, C-class and some D-class carbapene-

90

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

mases (60). In vitro assessments performed in the frame of the INFORM global surveillance study demonstrated that 98% of CREB isolates containing KPC or OXA-48 enzymes were susceptible to this combination, even when the isolates expressed ESBLs or AmpC enzymes (61, 62). However, ceftazidime/avibactam was ineffective against carbapenem-hydrolyzing metallo-beta-lactamases like NDM. In vitro activity of this combination was also demonstrated in the frame of a phase 3 trial involving ceftazidime-resistant UTIs (63). Recently, Jayol et al. investigated the in vitro activity of ceftazidime/avibactam, alone (for class A and D carbapenemase producers) or in combination with aztreonam (for class-B carbapenemase Figure 1.

Chemical structure of the novel non-beta-lactam beta-lactamase inhibitors avibactam, relebactam and vaborbactam. Structures were drawn using the PubChem NIH public repository database (93).

Perletti_Stesura Seveso 28/06/18 16:33 Pagina 91

Uropathogen resistance threats, trends and treatments

producers), against a collection of colistin-resistant and carbapenemase-producing KP isolates (64).

It was shown that ceftazidime/avibactam was effective against colistin-resistant and KPC-producing or OXA48-producing KP, and was also efficient against KP isolates co-expressing two carbapenemases. Interestingly, the combination of ceftazidime/avibactam with aztreonam was synergic against NDM-producing KP. Investigators suggested that such synergic activity could be explained by the neutralization of the ESBL activity by avibactam, which can in turn restore the susceptibility of KP to aztreonam (64). These data warrant urgent clinical investigation.

The clinical efficacy of the ceftazidime/avibactam combination (2g/0.5g, intravenous q8h) was demonstrated by recent phase 3 studies in patients with complicated UTIs, including acute pyelonephritis (65, 66). Further studies are urgently needed to investigate the clinical cure rates of this combination in UTIs caused by CREB. Relebactam The SMART program provided isolates from the USA, which were used for testing the activity of imipenem combined with the newly developed, renally excreted carbapenemase inhibitor relebactam. Relebactam is structurally related to avibactam, differing only by the presence of an amide functional group bound to a piperidine ring (Figure 1). For KP, 99% and 96.1% of isolates were susceptible to imipenem-relebactam and imipenem alone, respectively, and 74.1% of imipenem-resistant isolates were rendered susceptible to the carbapenem by addition of relebactam (67). In vitro assays showed that the combination imipenem/relebactam decreased the MICs of KPC-producing KP compared to imipenem alone (MIC50: 0.25/4 mg/L, MIC90: 1/4 mg/L), but was not as effective against pathogens expressing class D enzymes (e.g., OXA-48 in KP) (68). To date, phase II clinical trials have reported that imipenem/relebactam is as effective as imipenem alone for treatment of complicated UTIs, including acute pyelonephritis (69).

Imipenem-relebactam is currently investigated in the frame of phase III clinical trials for the treatment of imipenem-resistant infections.

Vaborbactam Vaborbactam (VB) is a boronic acid-based non-beta lactam beta-lactamase inhibitor, registered by FDA in 2017 for therapy of complicated urinary tract infections, combined with meropenem (2g/2g, intravenous q8h, to be adjusted in patients with renal impairment). Its chemical structure is not related to the ones of avibactam or relebactam (Figure 1).

Similar to meropenem, VB is renally excreted, and up to 60% of a dose is found unchanged in the urine within 24 hours. VB inhibits class A beta-lactamases (including KPC) and class C AmpC β-lactamases.

The meropenem/VB combination decreases the MICs of most resistant Enterobacteriaceae (2-fold to > 1024-fold decrease), though it appears that the addition of VB does not improve the activity of meropenem against P. aeruginosa (70).

Meropenem/VB is active against CREB isolates and

against Enterobacteriaceae showing multidrug-resistant and extensively drug-resistant phenotypes (MIC50/90: 0.5/32, 0.03/1, and 0.5/32 mg/L, respectively), though this drug combination showed limited activity against isolates expressing metallo-β-lactamases (e.g., NDM-1, VIM) and oxacillinases (e.g., OXA-48, OXA-163) detected in Asia-Pacific and in certain European countries (71).

The TANGO-1 phase III clinical trial has reported superiority of meropenem/VB over piperacillin/tazobactam for the treatment of complicated UTIs, including acute pyelonephritis (72). The TANGO-2 randomized, openlabel phase III clinical trial of meropenem/VB versus “best available therapy” in patients with complicated urinary tract infections, bacteremia or pneumonia, was stopped early due to a benefit-risk ratio in favor of meropenem/VB (73).

Polymyxins The polymyxin antibiotics colistin (poliymyxin E) and poliymyxin B have become a mainstay in the treatment of CREB infections. The EUCAST breakpoint for resistance is 2 mg/L. Recent studies resulted in the recommendation to prescribe high doses of the antibiotic (up to 10 million international units), divided into twice- or thrice-daily administrations (74). Importantly, combination therapy including colistin and rifampin was shown to be effective against colistin-resistant, KPC-producing KP (75). Though new polymyxin derivatives with decreased toxicity are under development, nephrotoxicity occurring in about 40% of cases and neurotoxicity are limiting factors to the extensive administration of colistin for treatment of CREB-induced infections. A possible limiting factor to the full exploitation of polymyxins for UTIs may also be the limited renal clearance of these drugs, though pharmacokinetic studies seem to confirm that the urinary recovery of colistin may be sufficient to attain concentrations above the MICs shown for example

by XDR P. aeruginosa (76).

Aminoglycosides Plazomicin is a novel aminoglycoside ("neoglycoside") antibiotic closely related to sisomicin and structurally recalling gentamicin. Its molecular structure was designed to be resistant against aminoglycoside-modifying enzymes, which are often expressed in CREB isolates (77). For example, in non-NDM-expressing CREB, the MICs of plazomicin ranged between > 0.5 and 2 mg/L, compared to 0.25/ > 256 mg/L and 1/128 mg/L for gentamicin and amikacin, respectively (78).

Three-hundred multidrug resistant ESBL-producing and/or carbapenemase-producing Enterobacteriaceae isolates from Athens, Greece (a CREB endemic area), most of which were also resistant to previous generation aminoglycosides (e.g., MIC50/MIC90 to amikacin = 32/ > 32), were tested for sensitivity to plazomicin. This novel aminoglycoside retained activity against all tested isolates of K. pneumoniae, E. coli, and Enterobacter spp., with MIC50 and MIC90 of 1 and 2 μg/ml, respectively, irrespective of their multidrug-resistant phenotype (79). In strains of CREB resistant to gentamicin, tobramycin and amikacin, plazomicin exhibited an MIC range of 0.12-4 mg/L, with MIC50 and MIC90 values of 0.25 and 1 mg/L, Archivio Italiano di Urologia e Andrologia 2018; 90, 2

91

Perletti_Stesura Seveso 28/06/18 16:33 Pagina 92

G. Perletti, V. Magri, T. Cai, K. Stamatiou, A. Trinchieri, E. Montanari

respectively. Interestingly, in CPKP isolates, synergy was observed when plazomicin was combined with meropenem, colistin or fosfomycin, whereas the combination with tigecycline resulted in indifference (80).

The safety and efficacy of plazomicin vs. levofloxacin in treating UTIs was assessed in a phase II comparative study, which ended in 2012 (81). Microbiological eradication in the plazomicin group (15 mg/kg) was achieved in 93.1% of the patients whose baseline urinary pathogens had a plazomicin MIC of 4 mg/L. Microbiological eradication in the group receiving levofloxacin (750 mg) was achieved in 93.8% (15/16) of patients with levofloxacin-susceptible baseline urinary pathogens (MIC = 4 mg/L). The EPIC and CARE phase III trials, investigating the safety and efficacy of plazomicin in patients with complicated UTIs and other infections caused by gram-negative pathogens including CREB, have been concluded but not yet published in the form of journal articles.

Fosfomycin Only case reports are available showing the efficacy of fosfomycin -administered in monotherapy for uncomplicated UTIs or combined with colistin against urosepsisin infections caused by Enterobacteriaceae expressing KPC, OXA-48 and NDM carbapenemases (82, 83). Case reports include accounts of successful combination therapy including dual carbapenem plus oral fosfomycin in UTIs caused by NDM-expressing Enterobacteriaceae (57).

Such approach is preferable, as the rapid development of resistance during therapy is a major problem related to the usage of fosfomycin as single agent (84).

Intravenous formulations of fosfomycin allow administration of high doses of the drug (e.g., 4g q6h), if necessary (85). A small prospective case series including eleven critically ill ICU patients affected by CPKP bacteremia, UTI or pneumonia, was based on administration of intravenous fosfomycin (2-4g q6h) for about 14 days, combined with colistin (n = 6), gentamicin (n = 3) or piperacillin/tazobactam (n = 1), based on ascertained susceptibility. All-cause hospital mortality was 18.2%, and no infection relapse was observed in enrolled patients. Intravenous therapy with high-dose fosfomycin appeared to be well tolerated, without renal or liver function test abnormalities (86). Further large-scale studies are warranted to confirm these encouraging safety and efficacy results.

Oritavancin Oritavancin is a semi-synthetic lipoglycopeptide, characterized by a threefold mechanism of action: (i) inhibition of the transglycosylation pathway in the bacterial wall synthesis, (ii) inhibition of the transpeptidation step by binding to the peptide bridging cell wall segments and (iii) cell wall disruption.

A recent in vitro subset study in the frame of a prevalence analysis performed on over 140.000 bloodstream isolates of Enterococci from Europe and the USA demonstrated that oritavancin was active against vancomycin-resistant E. faecalis (MIC50/90, 0.25-0.5 mg/L), and showed MIC50, MIC90 and MIC100 values of 0.03, 0.12 and 0.25 mg/L against VanA-positive E. faecium, respectively (87).

92

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

Oritavancin is renally and fecally excreted as unmodified molecule and may represent an interesting agent for treating complicated UTIs, though such approach would be off-label, as this drug is approved for the moment only for Gram-positive skin and skin structure infections.

Fluoroquinolones Chen et al. have examined in detail how the pharmacokinetic-pharmacodynamic properties of fluoroquinolones could be exploited to design treatment strategies in areas with high rates of fluoroquinolone resistance (43).

Levofloxacin appears to be a better option compared to ciprofloxacin, since the excretion of the former is by 87% renal (ciprofloxacin: 50%), and since efflux pumps like AcrAB, MdfA and NorE are more active on the latter (88). Thus, as the bactericidal activity of these agents is concentration-dependent, the achievement of high peak urine concentrations as a result of high-dose treatment with levofloxacin may be the key for eradicating pathogens showing intermediate FQ resistance levels.

For example, a single 750 mg dose of levofloxacin achieves a mean urinary Cmax of 620 mg/L, with prolonged post-antibiotic effect, compared to 340 mg/L attained by a standard 500 mg dose (89). Chen et al. also suggested that in areas with resistance uropathogen rates > 20%, high-dose levofloxacin might be considered as an option for UTIs caused by E. coli isolates showing a MIC â&#x2030;¤ 32 mg/L, after taking into consideration the potential adverse effects of such therapy (43).

The aac (6')-I gene product (AAC) confers to Enterobacteriaceae resistance to aminoglycoside antibiotics through acetylation of specific -NH2 residues at the level of specific amino sugars. A mutated variant of AAC (aac (6')-Ib-cr) confers resistance to certain fluoroquinolones via acetylation of the (= NH) residue within the piperazine ring of drugs like ciprofloxacin or norfloxacin. This decreases by 4-fold the susceptibility of pathogens to such drugs (90) and increases by 16 times the fluoroquinolone mutant prevention concentration in E. coli (0.2 â&#x20AC;&#x201C;> 3.2 mg/L), thus facilitating the survival of target site mutants (91). Interestingly, FQs like levofloxacin have a methylated piperazine residue which is virtually protected from the action of AAC. Thus, if resistance rates caused by the AAC are present or suspected, levofloxacin, or other "protected" FQs like prulifloxacin or pefloxacin may be temptatively administered.

Glycylcyclines Together with colistin, tigecycline is often the only agent to which CPKP is residually susceptible. However, the use of this agent for treatment of urological infections is significantly associated with subsequent development of resistance, as shown by van Duin and coworkers (OR, 6.13; 95% CI, 1.15-48.65) (92).

CONCLUSIONS

In conclusion, in the next decades the world will be facing a major medical emergency generated by the rapid spread of pathogens carrying resistance determinants of unprecedented power. All medical specialties will be affected by such spread, including foremostly urology.

Perletti_Stesura Seveso 28/06/18 16:33 Pagina 93

Uropathogen resistance threats, trends and treatments

As far as urinary tract diseases are concerned, we believe that the old definition of complicated vs uncomplicated infections should be modified, as any UTI involving carbapenemase-expressing uropathogens, or MDR/XDR uropathogens, should be considered and managed as complicated conditions.

Urgent containment measures must be put into effect, with priority given to those areas of the world characterized by climatic conditions favoring the seasonal outburst of infection epidemics, but also by negligent clinical practice, unprofessional pharmaceutical dispensing, as well as by poor patient compliance and education. Rigorous antibiotic stewardship and restriction of novel and old last resort agents to the sole hospital setting will also contribute to the containment of “superbug” epidemics.

Regretfully, major pharmaceutical companies have abandoned research for novel antibacterial agents due to the little financial reward ensured by drugs which can cure diseases in a very short time and at the same time may become rapidly obsolete due to the emerging of pathogen resistance.

Nevertheless, public or private research mainly aimed at discovering new therapies against Gram-negative organisms is of vital importance. Only the future will tell us who will prevail in the struggle for survival between humans and bacteria, and ultimately in the war between the immense resources of human ingenuity and the immense adaptability of genomes and species.

ACKNOWLEDGEMENTS

We are thankful to medical student Louise Beckers (Ghent University School of Medicine) for assistance in literature search and retrieval, and in study data extraction.

REFERENCES

1. Nordmann P, Cuzon G, Naas T. The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect Dis. 2009; 9:228-36.

2. Nordmann P, Poirel L. The difficult-to-control spread of carbapenemase producers among Enterobacteriaceae worldwide. Clin Microbiol Infect. 2014; 20:821-30.

3. https://ecdc.europa.eu/sites/portal/files/documents/AMR-surveillance-Europe-2016.pdf.

9. Bushnell G, Mitrani-Gold F, Mundy LM. Emergence of New Delhi metallo-β-lactamase type 1-producing Enterobacteriaceae and non-enterobacteriaceae: global case detection and bacterial surveillance. Int J Infect Dis. 2013; 17:e325-33.

10. Cao VT, Arlet G, Ericsson BM, et al. Emergence of imipenem resistance in Klebsiella pneumoniae owing to combination of plasmid-mediated CMY-4 and permeability alteration. J Antimicrob Chemother. 2000; 46:895-900.

11. Stapleton PD, Shannon KP, French GL. Carbapenem resistance in Escherichia coli associated with plasmid-determined CMY-4 betalactamase production and loss of an outer membrane protein.

Antimicrob Agents Chemother. 1999; 43:1206-10.

12. Walther-Rasmussen J, Høiby N. OXA-type carbapenemases. J Antimicrob Chemother. 2006; 57:373-83.

13. Hiraga N, Muratani T, Naito S, et al. Genetic analysis of faropenem-resistant Enterococcus faecalis in urinary isolates. J Antibiot (Tokyo). 2008; 61:213-21.

14. Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011; 52:e103-20.

15. http://uroweb.org/guideline/urological-infections/#3.

16. Yoshida H, Bogaki M, Nakamura M, et al. Quinolone resistancedetermining region in the DNA gyrase gyrA gene of Escherichia coli.

Antimicrob Agents Chemother. 1990; 34:1271-25.

17. Korten V, Huang WM, Murray BE. Analysis by PCR and direct DNA sequencing of gyrA mutations associated with fluoroquinolone resistance in Enterococcus faecalis. Antimicrob Agents Chemother.

1994; 38:2091-4.

18. Tran JH, Jacoby GA, Hooper DC. Interaction of the plasmidencoded quinolone resistance protein Qnr with Escherichia coli DNA gyrase. Antimicrob Agents Chemother. 2005; 49:118-25.

19. Robicsek A, Strahilevitz J, Jacoby GA, et al. Fluoroquinolonemodifying enzyme: a new adaptation of a common aminoglycoside acetyltransferase. Nat Med. 2006; 12:83-8.

20. Yamane K, Wachino J, Suzuki S, et al. New plasmid-mediated fluoroquinolone efflux pump, QepA, found in an Escherichia coli clinical isolate. Antimicrob Agents Chemother. 2007; 51:3354-60.

21. Hansen LH, Johannesen E, Burmølle M, et al. Plasmid-encoded multidrug efflux pump conferring resistance to olaquindox in Escherichia coli. Antimicrob Agents Chemother. 2004; 48:3332-7.

4. Xu L, Sun X, Ma X. Systematic review and meta-analysis of mortality of patients infected with carbapenem-resistant Klebsiella pneumoniae. Ann Clin Microbiol Antimicrob. 2017; 16:18.

22. Ruiz E, Sáenz Y, Zarazaga M, et al. qnr, aac(6')-Ib-cr and qepA genes in Escherichia coli and Klebsiella spp.: genetic environments and plasmid and chromosomal location. J Antimicrob Chemother.

2012; 67:886-97.

5. Patel G, Bonomo RA. "Stormy waters ahead": global emergence of carbapenemases. Front Microbiol. 2013; 4:48.

23. Gao R, Hu Y, Li Z, et al. Dissemination and Mechanism for the MCR-1 Colistin Resistance. PLoS Pathog. 2016; 12:e1005957.

6. Logan LK, Weinstein RA. The Epidemiology of CarbapenemResistant Enterobacteriaceae: The Impact and Evolution of a Global Menace. J Infect Dis. 2017; 215:S28-S36.

24. Jeannot K, Bolard A, Plésiat P. Resistance to polymyxins in Gramnegative organisms. Int J Antimicrob Agents. 2017; 49:526-535.

7. Villegas MV, Lolans K, Correa A, et al. First identification of Pseudomonas aeruginosa isolates producing a KPC-type carbapenem-hydrolyzing beta-lactamase. Antimicrob Agents Chemother.

2007; 51:1553-5.

8. Hopkins KL, Findlay J, Meunier D, et al. Serratia marcescens producing SME carbapenemases: an emerging resistance problem in the UK? J Antimicrob Chemother. 2017; 72:1535-1537.

25. Woodford N. Biological counterstrike: antibiotic resistance mechanisms of Gram-positive cocci. Clin Microbiol Infect. 2005; 11Suppl 3:2-21.

26. Hollenbeck BL, Rice LB. Intrinsic and acquired resistance mechanisms in Enterococcus. Virulence. 2012; 3:421-33.

27. Lee CR, Lee JH, Park KS, et al. Global Dissemination of Carbapenemase-Producing Klebsiella pneumoniae: Epidemiology, Archivio Italiano di Urologia e Andrologia 2018; 90, 2

93

Perletti_Stesura Seveso 28/06/18 16:33 Pagina 94

G. Perletti, V. Magri, T. Cai, K. Stamatiou, A. Trinchieri, E. Montanari

Genetic Context, Treatment Options, and Detection Methods. Front Microbiol. 2016 Jun 13; 7:895.

28. Hoban DJ, Nicolle LE, Hawser S, et al. Antimicrobial susceptibility of global inpatient urinary tract isolates of Escherichia coli: results from the Study for Monitoring Antimicrobial Resistance Trends (SMART) program: 2009-2010. Diagn Microbiol Infect Dis. 2011; 70:507-11.

29. Biedenbach D, Bouchillon S, Hackel M, et al. Dissemination of NDM metallo-β-lactamase genes among clinical isolates of Enterobacteriaceae collected during the SMART global surveillance study from 2008 to 2012. Antimicrob Agents Chemother. 2015; 59:826-30.

30. Peirano G, Lascols C, Hackel M, et al. Molecular epidemiology of Enterobacteriaceae that produce VIMs and IMPs from the SMART surveillance program. Diagn Microbiol Infect Dis. 2014; 78:277-81.

31. Jean SS, Coombs G, Ling T, et al. Epidemiology and antimicrobial susceptibility profiles of pathogens causing urinary tract infections in the Asia-Pacific region: Results from the Study for Monitoring Antimicrobial Resistance Trends (SMART), 2010-2013.

Int J Antimicrob Agents. 2016; 47:328-34.

32. Jean SS, Hsueh PR; SMART Asia-Pacific Group. Distribution of ESBLs, AmpC β-lactamases and carbapenemases among Enterobacteriaceae isolates causing intra-abdominal and urinary tract infections in the Asia-Pacific region during 2008-14: results from the Study for Monitoring Antimicrobial Resistance Trends (SMART). J Antimicrob Chemother. 2017; 72:166-171.

33. Karlowsky JA, Hoban DJ, Hackel MA, et al. Resistance among Gram-negative ESKAPE pathogens isolated from hospitalized patients with intra-abdominal and urinary tract infections in Latin American countries: SMART 2013-2015. Braz J Infect Dis. 2017; 21:343-348.

34. Lob SH, Biedenbach DJ, Badal RE, et al. Antimicrobial resistance and resistance mechanisms of Enterobacteriaceae in ICU and non-ICU wards in Europe and North America: SMART 2011-2013.

J Glob Antimicrob Resist. 2015; 3:190-197.

35. Lob SH, Nicolle LE, Hoban DJ, et al. Susceptibility patterns and ESBL rates of Escherichia coli from urinary tract infections in Canada and the United States, SMART 2010-2014. Diagn Microbiol Infect Dis. 2016; 85:459-65.

36-https://ecdc.europa.eu/sites/portal/files/documents/AMR%202016_ Final-with-cover-for-web-2017.pdf 37. Giani T, Antonelli A, Caltagirone M, et al. Evolving beta-lactamase epidemiology in Enterobacteriaceae from Italian nationwide surveillance, October 2013: KPC-carbapenemase spreading among outpatients. Euro Surveill. 2017; 22.

38. https://ecdc.europa.eu/sites/portal/files/documents/AMR-country-visit-Italy.pdf 39. Kaase M, Schimanski S, Schiller R, et al. Multicentre investigation of carbapenemase-producing Escherichia coli and Klebsiella pneumoniae in German hospitals. Int J Med Microbiol. 2016; 306:415-20.

40. De Laveleye M, Huang TD, Bogaerts P, et al. Increasing incidence of carbapenemase-producing Escherichia coli and Klebsiella pneumoniae in Belgian hospitals. Eur J Clin Microbiol Infect Dis. 2017; 36:139-146.

41. Dortet L, Cuzon G, Ponties V, et al. Trends in carbapenemaseproducing Enterobacteriaceae, France, 2012 to 2014. Euro Surveill.

2017; 22.

94

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

42. Okesola AO, Aroundegbe TI. Antibiotic resistance pattern of uropathogenic Escherichia coli in South West Nigeria. Afr J Med Med Sci. 2011; 40:235-8.

43. Chen YH, Ko WC, Hsueh PR. The role of fluoroquinolones in the management of urinary tract infections in areas with high rates of fluoroquinolone-resistant uropathogens. Eur J Clin Microbiol Infect Dis. 2012; 31:1699-704.

44. Rodrigues WF, Miguel CB, Nogueira AP, et al. Antibiotic Resistance of Bacteria Involved in Urinary Infections in Brazil: A Cross-Sectional and Retrospective Study. Int J Environ Res Public Health. 2016; 13.

45. Nolan LK, Li G, Logue CM. Origin and Dissemination of Antimicrobial Resistance among Uropathogenic Escherichia coli.

Microbiol Spectr. 2015; 3.

46. Sanchez GV, Master RN, Karlowsky JA, et al. In vitro antimicrobial resistance of urinary Escherichia coli isolates among U.S. outpatients from 2000 to 2010. Antimicrob Agents Chemother.

2012; 56:2181-3.

47. Yanat B, Rodríguez-Martínez JM, Touati A. Plasmid-mediated quinolone resistance in Enterobacteriaceae: a systematic review with a focus on Mediterranean countries. Eur J Clin Microbiol Infect Dis. 2017; 36:421-435.

48. Stamatiou K, Pierris N. Mounting resistance of uropathogens to antimicrobial agents: A retrospective study in patients with chronic bacterial prostatitis relapse. Investig Clin Urol. 2017; 58:271-280.

49. Toner L, Papa N, Aliyu SH, et al. Vancomycin resistant enterococci in urine cultures: Antibiotic susceptibility trends over a decade at a tertiary hospital in the United Kingdom. Investig Clin Urol.

2016; 57:129-34.

50. Kiffer CR, Mendes C, Oplustil CP, et al. Antibiotic resistance and trend of urinary pathogens in general outpatients from a major urban city. Int Braz J Urol. 2007; 33:42-8.

51. Kahlmeter G, Poulsen HO. Antimicrobial susceptibility of Escherichia coli from community-acquired urinary tract infections in Europe: the ECO·SENS study revisited. Int J Antimicrob Agents.

2012; 39:45-51.

52. Kresken M, Körber-Irrgang B, Biedenbach DJ, et al.

Comparative in vitro activity of oral antimicrobial agents against Enterobacteriaceae from patients with community-acquired urinary tract infections in three European countries. Clin Microbiol Infect.

2016; 22:63.e1-63.e5.

53. Edlin RS, Shapiro DJ, Hersh AL, et al. Antibiotic resistance patterns of outpatient pediatric urinary tract infections. J Urol. 2013; 190:222-7.

54. Morrill, Thaden JT, Pogue JM, et al. Role of newer and reemerging older agents in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae. Virulence. 2017; 8:403-416.

55. Tumbarello M, Viale P, Viscoli C, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis. 2012; 55:943-50.

56. Souli M, Karaiskos I, Masgala A, et al. Double-carbapenem combination as salvage therapy for untreatable infections by KPC2-producing Klebsiella pneumoniae. Eur J Clin Microbiol Infect Dis. 2017; 36:1305-1315.

57. De Pascale G, Martucci G, Montini L, et al. Double carbapenem as a rescue strategy for the treatment of severe carbapenemaseproducing Klebsiella pneumoniae infections: a two-center, matched case-control study. Crit Care. 2017; 21:173.

Perletti_Stesura Seveso 28/06/18 16:33 Pagina 95

Uropathogen resistance threats, trends and treatments

58. Rosa R, Rudin SD, Rojas LJ, et al. "Double carbapenem" and oral fosfomycin for the treatment of complicated urinary tract infections caused by bla(NDM) -harboring Enterobacteriaceae in kidney transplantation. Transpl Infect Dis. 2018; 20.

59. Morrill HJ, Pogue JM, Kaye KS, et al. Treatment Options for Carbapenem-Resistant Enterobacteriaceae Infections. Open Forum Infect Dis. 2015; 2:ofv050.

60. Lahiri SD, Johnstone MR, Ross PL, et al. Avibactam and class C β-lactamases: mechanism of inhibition, conservation of the binding pocket, and implications for resistance. Antimicrob Agents Chemother. 2014; 58:5704-13.

61. de Jonge BL, Karlowsky JA, Kazmierczak KM, et al. In Vitro Susceptibility to Ceftazidime-Avibactam of CarbapenemNonsusceptible Enterobacteriaceae Isolates Collected during the INFORM Global Surveillance Study (2012 to 2014). Antimicrob Agents Chemother. 2016; 60:3163-9.

62. Karaiskos I, Giamarellou H. Multidrug-resistant and extensively drug-resistant Gram-negative pathogens: current and emerging therapeutic approaches. Expert Opin Pharmacother. 2014; 15:1351-70.

63. Stone GG, Bradford PA, Newell P, et al. In Vitro Activity of Ceftazidime-Avibactam against Isolates in a Phase 3 Open-Label Clinical Trial for Complicated Intra-Abdominal and Urinary Tract Infections Caused by Ceftazidime-Nonsusceptible Gram-Negative Pathogens. Antimicrob Agents Chemother. 2017; 61.

64. Jayol A, Nordmann P, Poirel L, et al. Ceftazidime/avibactam alone or in combination with aztreonam against colistin-resistant and carbapenemase-producing Klebsiella pneumoniae. J Antimicrob Chemother. 2018; 73:542-544.

65. Wagenlehner FM, Sobel JD, Newell P, et al. Ceftazidimeavibactam Versus Doripenem for the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis: RECAPTURE, a Phase 3 Randomized Trial Program. Clin Infect Dis. 2016; 63:754-762.

66. Carmeli Y, Armstrong J, Laud PJ, et al. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study. Lancet Infect Dis. 2016; 16:661-673.

67. Lob SH, Hackel MA, Kazmierczak KM, et al. In Vitro Activity of Imipenem-Relebactam against Gram-Negative ESKAPE Pathogens Isolated by Clinical Laboratories in the United States in 2015 (Results from the SMART Global Surveillance Program).

Antimicrob Agents Chemother. 2017; 61.

68. Lapuebla A, Abdallah M, Olafisoye O, et al. Activity of Imipenem with Relebactam against Gram-Negative Pathogens from NewYork City. Antimicrob Agents Chemother. 2015; 59:5029-31.

69. Sims M, Mariyanovski V, McLeroth P, et al. Prospective, randomized, double-blind, Phase 2 dose-ranging study comparing efficacy and safety of imipenem/cilastatin plus relebactam with imipenem/cilastatin alone in patients with complicated urinary tract infections. J Antimicrob Chemother. 2017; 72:2616-2626.

Resistant, KPC-Producing, Multidrug-Resistant, and Extensively Drug-Resistant Enterobacteriaceae. Antimicrob Agents Chemother.

2017; 61.

72. Walsh TJ, Bhowmick T, Darouiche R, et al. MeropenemVaborbactam vs. Piperacillin-Tazobactam in TANGO I (a Phase 3 Randomized, Double-blind Trial): Outcomes by Baseline MIC in Adults with Complicated Urinary Tract Infections or Acute Pyelonephritis. Open Forum Inf Dis. 2017; 4:suppl-1:S536.

73. http://www.themedicinescompany.com/investors/news/medicines-company-announces-tango-2-trial-meropenem-vaborbactamformerly-carbavance.

74. Tängdén T, Giske CG. Global dissemination of extensively drugresistant carbapenemase-producing Enterobacteriaceae: clinical perspectives on detection, treatment and infection control. J Intern Med. 2015; 277:501-12.

75. Tascini C, Tagliaferri E, Giani T, et al. Synergistic activity of colistin plus rifampin against colistin-resistant KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2013; 57:3990-3.

76. Luque S, Escaño C, Sorli L, et al. Urinary Concentrations of Colistimethate and Formed Colistin after Intravenous Administration in Patients with Multidrug-Resistant GramNegative Bacterial Infections. Antimicrob Agents Chemother.

2017; 61.

77. Zhanel GG, Lawson CD, Zelenitsky S, et al. Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. Expert Rev Anti Infect Ther. 2012; 10:459-73.

78. Livermore DM, Mushtaq S, Warner M, et al. Activity of aminoglycosides, including ACHN-490, against carbapenemresistant Enterobacteriaceae isolates. J Antimicrob Chemother.

2011; 66:48-53.

79. Galani I, Souli M, Daikos GL, et al. Activity of plazomicin (ACHN-490) against MDR clinical isolates of Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp. from Athens, Greece.

J Chemother. 2012; 24:191-4.

80. Rodríguez-Avial I, Pena I, Picazo JJ, et al. In vitro activity of the next-generation aminoglycoside plazomicin alone and in combination with colistin, meropenem, fosfomycin or tigecycline against carbapenemase-producing Enterobacteriaceae strains. Int J Antimicrob Agents. 2015; 46:616-21.

81. Connolly LE, Riddle V, Cebrik D, et al. A Multicenter, Randomized, Double-Blind, Phase 2 Study of the Efficacy and Safety of Plazomicin Compared with Levofloxacin in the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis.

Antimicrob Agents Chemother. 2018; 62.

82. Peirano G, Ahmed-Bentley J, Woodford N, et al. New Delhi metallo-beta-lactamase from traveler returning to Canada. Emerg Infect Dis. 2011; 17:242-4.

83. Navarro-San Francisco C, Mora-Rillo M, Romero-Gómez MP, et al. Bacteraemia due to OXA-48-carbapenemase-producing Enterobacteriaceae: a major clinical challenge. Clin Microbiol Infect. 2013; 19:E72-9.

70. Zhanel GG, Lawrence CK, Adam H, et al. ImipenemRelebactam and Meropenem-Vaborbactam: Two Novel Carbapenem-β-Lactamase Inhibitor Combinations. Drugs. 2018; 78:65-98.

84. Karageorgopoulos DE, Miriagou V, Tzouvelekis LS, et al.

Emergence of resistance to fosfomycin used as adjunct therapy in KPC Klebsiella pneumoniae bacteraemia: report of three cases.

J Antimicrob Chemother. 2012; 67:2777-9.

71. Castanheira M, Huband MD, Mendes RE, et al. MeropenemVaborbactam Tested against Contemporary Gram-Negative Isolates Collected Worldwide during 2014, Including Carbapenem-

85. Perez F, El Chakhtoura NG, Papp-Wallace KM, et al.

Treatment options for infections caused by carbapenem-resistant Enterobacteriaceae : can we apply "precision medicine" to Archivio Italiano di Urologia e Andrologia 2018; 90, 2

95

Perletti_Stesura Seveso 28/06/18 16:33 Pagina 96

G. Perletti, V. Magri, T. Cai, K. Stamatiou, A. Trinchieri, E. Montanari

antimicrobial chemotherapy? Expert Opin Pharmacother. 2016; 17:761-81.

86. Michalopoulos A, Virtzili S, Rafailidis P, et al. Intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant Klebsiella pneumoniae in critically ill patients: a prospective evaluation. Clin Microbiol Infect. 2010; 16:184-6.

87. Mendes RE, Castanheira M, Farrell DJ, et al. Longitudinal (2001-14) analysis of enterococci and VRE causing invasive infections in European and US hospitals, including a contemporary (2010-13) analysis of oritavancin in vitro potency. J Antimicrob Chemother. 2016; 71:3453-3458.

88. Yang S, Clayton SR, Zechiedrich EL. Relative contributions of the AcrAB, MdfA and NorE efflux pumps to quinolone resistance in Escherichia coli. J Antimicrob Chemother. 2003; 51:545-556.

89. Stein GE, Schooley SL, Nicolau DP. Urinary bactericidal activ-

Correspondence Gianpaolo Perletti, PhD (Corresponding Author) gianpaolo.perletti@uninsubria.it Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, UniversitĂ degli Studi dellâ&#x20AC;&#x2122;Insubria Via A. Da Giussano, 12 - 21052 Busto A., Italy Vittorio Magri, MD Urology Secondary Care Clinic, ASST-Nord, Milan, Italy Tommaso Cai, MD Department of Urology, Santa Chiara Regional Hospital, Trento, Italy Konstantinos Stamatiou, MD Department of Urology, Tzaneio General Hospital of Piraeus, Piraeus, Greece Alberto Trinchieri, MD Urology Unit, A. Manzoni Hospital, Lecco, Italy Emanuele Montanari, MD Department of Urology, University of Milan-Ca' Granda Foundation Ospedale Maggiore Policlinico, Milan, Italy

96

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

ity of single doses (250, 500, 750 and 1000 mg) of levofloxacin against fluoroquinolone-resistant strains of Escherichia coli. Int J Antimicrob Agents. 2008; 32:320-5.

90. Robicsek A, Strahilevitz J, Jacoby GA, et al. Fluoroquinolonemodifying enzyme: a new adaptation of a common aminoglycoside acetyltransferase. Nat Med. 2006;12:83-8.

91. Cattoir, V; Nordmann, P. Plasmid-Mediated Quinolone Resistance in Gram-Negative Bacterial Species: An Update. Curr Med Chem. 2009; 16:1028-1046.

92. van Duin D, Cober ED, Richter SS, et al. Tigecycline therapy for carbapenem-resistant Klebsiella pneumoniae (CRKP) bacteriuria leads to tigecycline resistance. Clin Microbiol Infect. 2014; 20:O1117-20.

93. Kim S, Thiessen PA, Bolton EE, et al. PubChem Substance and Compound databases. Nucleic Acids Res. 2016; 44:D1202-13.

Cai_Stesura Seveso 28/06/18 16:34 Pagina 97

DOI: 10.4081/aiua.2018.2.97

ORIGINAL PAPER

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 Tommaso Cai 1, Andrea Cocci 2, Daniele Tiscione 1, Marco Puglisi 1, Fabrizio Di Maida 2, Gianni Malossini 1, Paolo Verze 3, Alessandro Palmieri 3, Vincenzo Mirone 3, Truls E. Bjerklund Johansen 4 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; 4 Department of Urology, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

2 Department

Summary

Objective: To evaluate the efficacy of a phytotherapic combination of L-Methionine associated with Hibiscus sabdariffa and Boswellia serrata for treatment of acute episodes of uncomplicated urinary tract infections (UTI) in women affected by recurrent UTIs. Materials and methods: In this randomized phase III clinical trial, adult females with uncomplicated UTI were enrolled into one of the following treatment groups: Group A: phytotherapic combination 1 tablet in the morning and 1 tablet in the evening for 7 days; Group B: Short term antibiotic treatment according to international guidelines recommendations. At baseline, all patients were evaluated by a urologist and quality of life (QoL) questionnaires and mid-stream urine culture. Same clinical and laboratory investigations were repeated at each follow-up visit.

Results: Forty-six patients were enrolled in Group A and 47 in Group B. At the first follow-up (30 days), both groups showed a statistically significant improvement in quality of life scores as compared with baseline assessment [Group A: (QoL 94.3 VS 98.5 p < 0.001); Group B: (QoL 94.5 VS 98.7 p < 0.001)]. An improvement from baseline was also seen at the second followup evaluation after 3 months [Group A: (QoL 94.3 VS 99.1 p < 0.001); Group B: (QoL 94.5 VS 98.1 p < 0.001)]. At the second follow-up visit, a statistically significant difference in QoL was reported between the two groups (99.1 VS 98.1; p < 0.003) and a transition from UTI to asymptomatic bacteriuria (ABU) was observed 12 of 46 (26%) patients in Group A, while no patients in Group B demonstrated ABU (p = 0.007).

Conclusions: Here, we demonstrated that this phytotherapic combination is able, in comparison to antibiotic treatment, to improve patients quality of life, reducing symptoms in acute setting and preventing the recurrences. Interestingly, a significantly higher proportion of patients in the phytotherapy group had ABU after three months. Our findings are of great interest in an antibiotic stewardship perspective.

significant impact on patientsâ&#x20AC;&#x2122; quality of life and public health care costs (1). More than half of women report having had at least one UTI during their lifetime, and almost 11% of women suffer from a UTI every year (23). In particular, 20-30% of women experience another UTI within 6 months after their first episode (1).

The most common management of recurrent UTIs is a short course of oral antimicrobial therapy, with possible alteration of the normal microbial flora of the vagina and/or gastrointestinal tract. Moreover, frequent use of antibiotics for treatment and prevention of UTIs increases healthcare costs and the spread of multidrug-resistant microorganisms (4-7). Nowadays, there are no universally accepted recommendations on prophylactic antibiotic management to prevent recurrent UTI (3). Reduced antibiotic prescription would not only prevent resistance but will also lower public health care costs. In this scenario, the use of phytotherapy for symptom relief and decrease of symptomatic recurrences in UTI is an intriguing alternative (3). The aim of the present study was to compare the effectiveness of a combination of L-Metionina associated with Hibiscus sabdariffa and Boswellia serrata (Acidif plusÂŽ) and standard antibiotic treatment of acute episodes of uncomplicated UTI in women affected by recurrent UTI, focusing on QoL improvement and the capability to reduce antibiotic usage.

MATERIALS

AND METHODS

Study design This is a single Centre, randomized and controlled phase KEY WORDS: Urinary tract infection; L-Methionine; Hibiscus sabdariffa; III study. From January to June 2017, we enrolled all Boswellia serrata; Plant extracts; Antibiotic stewardship; Treatment. women affected by recurrent uncomplicated UTI seen in our referral centre. Written informed consent was obtained Submitted 19 March 2018; Accepted 25 March 2018 from all subjects before proceeding with the enrollment.

Baseline assessment comprised evaluation by urologist, INTRODUCTION completion of QoL questionnaires and a mid-stream urine Urinary tract infections (UTIs) represent one of the most culture. All patients in the antibiotic arm were treated common community-acquired infectious diseases with according to an empirical approach, in line with the No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

97

Cai_Stesura Seveso 28/06/18 16:34 Pagina 98

T. Cai, A. Cocci, D. Tiscione, M. Puglisi, F. Di Maida, G. Malossini, P. Verze, A. Palmieri, V. Mirone, Truls E. Bjerklund Johansen

European Association of Urology (EAU) guidelines recommendations (8). The results of mid-stream urine culture were used only for confirmation of the diagnosis and not for tailoring the treatment. All selected patients were, then, randomly allocated into one of the two following groups: • Group A: one-week therapy of Acidif Plus®, 1 tablet in the morning and 1 tablet in the evening for 7 days.

• Group B: Short term antibiotic therapy according to the trialist’s choice based on the EAU guidelines on urological infections (8).

After one week from the start of treatment, all patients were contacted by phone in order to ensure compliance to the treatment in both arms. The follow up schedule included urologic visit after one and three months with QoL questionnaires and mid-stream urine cultures.

The study schedule is shown in Figure 1.

underwent a short course of antibiotic therapy according to the antibiogram and guidelines recommendations.

Outcome measures and statistical analysis The primary endpoint was the rate of responders defined as the demonstration of urinary pathogens < 103 CFU/mL in a mid-stream urine culture on the second and third follow up visit (after one and three months respectively from the beginning of the treatment) as well as improvement in symptoms scores. Data about the compliance to treatment, frequency of UTI recurrences or transition from symptomatic UTI to asymptomatic bacteriuria at subsequent follow up visits were also recorded. In order to obtain valid results for analysis, sample size calculation was based on the following assumptions. Difference between the groups, 3 ± 1 score

Figure 1.

The figure shows the study schedule. QoL: quality of life evaluation. Group A: one-week therapy of ACIDIF PLUS®, 1 tablet in the morning and 1 tablet in the evening for 7 days. Group B: Short term antibiotic therapy according to the trialist’s choice and EAU guidelines on urological infections.

Composition and characterization of the phytotherapeutic extracts used All patients who were randomized to the Acidif Plus® group received oral administration of 1 tablet of Acidif Plus® in the morning and 1 tablet in the evening, in line with the manufacturer’s instructions (Biohealth srl, Rivoli - TO), Italy (http://www.biohealth.it/it/prodotti/linea-acidif/25-acidif-plus).

Each dose contained a combination of 400 mg of LMethionine associated with 100 mg of Hibiscus sabdariffa and 100 mg of Boswellia serrata (L.) Roxb.

Inclusion and exclusion criteria Exclusion criteria comprised: evidence of overactive bladder; anatomical abnormalities or previous surgery of the urinary tract; complicated UTI; intake of antibiotics within 4 weeks before enrollment; pregnancy; indwelling urinary catheter or stent.

M icrobiological and clinical considerations Treatment failure in group A was defined as microbiological colonization of at least 105 colony-forming units per milliliter (CFUs/mL) of a single uropathogen in the midstream urine culture associated with the persistence of urinary tract symptoms. Transition from symptomatic UTI to asymptomatic bacteriuria was not considered as treatment failure, but was registered as an improvement in symptoms. In case of treatment failure in group A, patients

98

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

points in the QoL questionnaire; α error level, 0.05 twosided; statistical power, 80%; anticipated effect size, Cohen’s d = 0.5. The calculation yielded 2×41 individuals per group. Taking into account a drop-out rate of 10%, the final sample size was set to 90 patients in both groups. Statistical analysis was performed by using SPSS.

RESULTS

Ninety-three female patients with clinical evidence of uncomplicated UTI entered the study. Forty-six and fortyseven patients were enrolled in Group A (mean age 46.5 range: 23-62) and Group B (mean age 47.1 range: 22-63), respectively. Demographic and clinical characteristics of the study population are shown in Table 1.

The most commonly isolated bacterial strain at the time of enrollment was Escherichia Coli (E. coli) in 86.9% (40/46) of patients in Group A and in 82.9% (39/47) in Group B, respectively.

Treatment compliance and treatment related adverse effects After 7 days treatment compliance was complete in Group A (100%), while within Group B 14.9% (7/47) of patients discontinued the prescribed therapy because of drug-related adverse effects. No side effects occurred in the phytotherapy group.

Cai_Stesura Seveso 28/06/18 16:34 Pagina 99

Nutraceuticals and recurrent UTI

Table 1.

Demographic, clinical and microbiological characteristics of all enrolled and analysed women, at the baseline.

Group A: one-week therapy of Acidif Plus ®, 1 tablet in the morning and 1 tablet in the evening for 7 days.

Group B: Short term antibiotic therapy according to the trialist’s choice and EAU guidelines on urological infections.

Demographic and clinical characteristics of the study population at baseline Group A Group B P Enrolled patients 46 47 Age (mean) 46.5 47.1 Previous UTI per year (mean) 4.3 4.7 Number of sexual partners 1 44 (95.6) 43 (91.4) >1 Marital status Married 31 (67.3) 29 (61.7) Single 15 (32.7) 18 (38.3) Sexual encounters per week (mean) 2.1 2.0 Bacterial strains E. coli 40 (86.9) 39 (82.9) E. faecalis 2 (4.4) 2 (4.3) E. faecium 1 (2.2) 1 (2.2) Klebsiella spp.

3 (6.5) 5 (10.6)

First follow-up evaluation (30 days) At one month follow up visit, a statistically significant clinical improvement was reported in 95.7% (44/46) of patients in Group A (QoL 94.3 VS 98.5 p < 0.001) and 100% (47/47) in Group B (QoL 94.5 VS 98.7 p < 0.001), respectively. No statistically significant differences emerged when comparing QoL results in the two groups.

A sterile urine culture was reported in 80.4% (37/46) and in 95.7% (45/47) of patients in Group A and Group B, respectively. Notably, in the remaining 19.6% (9/46) of Table 2.

Outcome variables before and after treatment, in the two groups. Group A: one-week therapy of Acidif Plusn®, 1 tablet in the morning and 1 tablet in the evening for 7 days.

Group B: Short term antibiotic therapy according to the trialist’s choice and EAU guidelines on urological infections.

ABU: asymptomatic bacteriuria; UTI: symptomatic urinary tract infection; n.s.: not statistically significant.

Outcomes variable Clinical improvement Group A Group B p (between the groups) QoL (questionnaire) Group A Group B p (between the groups) Microbiological improvement Sterile urine Group A Group B p (between the groups) Transition to ABU from UTI Group A Group B p (between the groups)

Baseline

Follow-up 30 days

Follow-up 90 days

P

0/46 0/47

44/46 (95.5) 47/47 (100) n.s.

44/46 (95.5) 45/47 (95.7) n.s.

< 0.001 < 0.001

94.3 94.5

98.5 98.7 n.s.

99.1 98.1 < 0.003

< 0.001 < 0.001

0/46 0/47

37/46 (80.4) 45/47 (95.7) n.s.

34/46 (73.9) 44/47 (93.6) n.s.

n.s. n.s.

-

9/46 (19.6) 2/47 (4.3) n.s.

12/46 (26) 0/46 0.007

n.s. n.s.

patients within Group A a transition from symptomatic UTI to asymptomatic bacteriuria (ABU) was observed and also a change in microorganism (from E. coli to Enterococcus faecalis). On the contrary, only 4.3% (2/47) of patients among Group B showed a transition from UTI to ABU. No treatment failures were recorded in Group A. All findings at the first follow-up are shown in Table 2.

Second follow-up evaluation (90 days) At the 3 month follow up visit, 95.7% (44/46) of patients in Group A showed a clinically significant improvement (QoL 94.3 VS 99.1 p < 0.001), as well as 95.7% (45/47) patients in Group B (QoL 94.5 VS 98.1 p < 0.001). A statistically significant difference emerged in terms of QoL between the two groups (p < 0.003; 99.1 VS 98.1).

In Group A, 73.9% (34/46) of patients demonstrated a second sterile mid stream urine culture, while the remaining 26% (12/46) of patients showed a transition from symptomatic UTI to ABU and a change of microorganism (from E. coli to Enterococcus faecalis) (p = 0.007). Again, no treatment failures were recorded in Group A while 2 patients in Group B showed symptomatic UTI with microbiological demonstration of Escherichia coli. No patients in Group B showed transition from UTI to ABU. Table 2 shows all findings at the second follow-up visit.

DISCUSSION

Although antimicrobials remain the mainstay of treatment for UTI, the spread of multidrug resistant microorganisms among community-acquired isolates is worrying and calls for stronger surveillance and new preventive approaches. Today, inappropriate antibiotic use and antimicrobial resistance have become major issues worldwide. Unfortunately, there is no “gold standard” prophylactic regimen to prevent recurrent UTI. Actually, EAU guidelines present several non-antibiotic measures for preventing recurrent UTIs but only few are based on well-designed randomized clinical trials (8).

Furthermore, many women have signs of UTIs without evidence of bacterial presence, a clinical condition known as ABU. Although ABU is usually treated in women with recurrent UTIs there is no clear indication for this treatment. A significant body of recent evidence (6-7, 9) has demonstrated that antibiotic treatment of ABU is not only pointless, but could even be harmful. Particularly, in a randomized controlled study, Cai et al. showed that after a 12-month period of antimicrobial therapy of ABU in women affected by recurrent UTIs, the rate of symptomatic UTIs was higher in patients treated with antibiotics.

There was also a higher prevalence of multidrug-resistant E. coli after antibiotic treatment of ABU due to Enterococcus faecalis (9). These data suggest that ABU could play a protective role in preventing symptomatic recurrences, interfering with the settlement in the urinary tract of many enteric pathogens, such as E. coli. In this sense, a non-antibiotic approach should be preferred because it doesn’t modify the normal commensal bowel flora. As a result, research on non-antibiotic prophylaxis of recurrent UTIs has gradually grown during recent years. Particularly, the use of phytotherapy and neutraceuticals could represent a feasible alternative Archivio Italiano di Urologia e Andrologia 2018; 90, 2

99

Cai_Stesura Seveso 28/06/18 16:34 Pagina 100

T. Cai, A. Cocci, D. Tiscione, M. Puglisi, F. Di Maida, G. Malossini, P. Verze, A. Palmieri, V. Mirone, Truls E. Bjerklund Johansen

approach for reducing the use of antibiotics and decreasing the rate of symptomatic recurrences (3, 10-11). In this light, we wanted to evaluate an oral supplementation of L-Methionine combined with Hibiscus sabdariffa and Boswellia serrata (named Acudif plus®). L-Methionine is a sulfur donor which is necessary for the biosynthesis of cysteine, a sulfide aminoacid. A physiological pH is obtained by the action of L-Methionine which creates unfavorable conditions for bacterial colonization since a large number of Gram-negative bacteria are able to alkalize the urine by enzymatic degradation of urea.

Furthermore, dry extract of Hibiscus sabdariffa is a phytocomplex containing Sambubiosides, which seems to have an anti-inflammatory activity by lowering the levels of inflammatory mediators including iNOS, NO, IL-6, MCP1, and TNF-α induced by LPS (12). Moreover, several preliminary studies demonstrated that Hibiscus sabdariffa is able to prevent recurrent uncomplicated urinary tract infections due to its inhibitory activity against Escherichia coli and Candida albicans (13). Finally, Boswellia serrata also seems to inhibit some inflammation mediators, in particular 5-lipoxygenase, with a subsequent decrease in inflammatory response mediated by leukotrienes (14). In our knowledge, this is the first study evaluating the prophylactic effect of L-Methionine associated with Hibiscus sabdariffa and Boswellia serrata extracts in women suffering from recurrent uncomplicated UTIs. In a recent multicenter observational study Passaro et al. (15) had already assessed the effectiveness of Acidif Plus® in reducing the bacterial load and improving symptoms in pregnant women affected by symptomatic UTI. In our experience, Acid Plus® was well tolerated with optimal compliance and no side effects. As many as 95.7% (44/46) of patients demonstrated relevant clinical improvement with a statistically significant difference compared to women treated with standard antibiotic therapy 3 months after the beginning of treatment. Moreover, at first follow up visit almost 20% of patients within Group A showed a transition from symptomatic UTI to ABU with lasting results at 3 months.

Noteworthy, the fact that Acidif Plus® was able to establish an ABU is a tangible proof of absence of effect on the normal urine microbiota. Increased understanding of the action of phytotherapy and nutraceuticals will enable us to develop appropriate non-antibiotic treatment and prevention strategies for recurrent UTIs (16). Larger highquality studies are required to confirm the findings in our study.

REFERENCES

CONCLUSIONS

16. Cai T, Mazzoli S, Migno S, et al. Development and validation of a nomogram predicting recurrence risk in women with symptomatic urinary tract infection. Int J Urol. 2014; 21:929-34.

Urinary tract infections affect a large number of women and many suffer from recurrent UTIs. Actually, current antibiotic treatments select multi-drug resistant microorganism, both in the gut and in the bladder, and this practice is no longer sustainable. Use of phytotherapy and nutraceuticals is an intriguing approach to reduce the excessive prescription of antibiotics. In the present study we could demonstrate that Acidif Plus® was able to improve patients QoL, lower symptoms in the acute setting and prevent UTI recurrences in women with recurrent UTIs as compared to antibiotic treatment. Further prospective studies are needed to validate our results.

100

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

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, Barlow R, D'Arcy H, et al. Urinary tract infection: selfreported incidence and associated costs. Ann Epidemiol. 2000; 10:509-515.

3. 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; 89:1-6.

4. 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.

5. Gupta K, Scholes D, Stamm WE. Increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in women. JAMA 1999; 281:736-8.

6. 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.

7. Cai T, Koves B, Johansen TE. Asymptomatic bacteriuria, to screen or not to screen - and when to treat? Curr Opin Urol. 2017; 27:107-111.

8. European Association of Urology Guidelines on Urological Infections. http://uroweb.org/guideline/urological-infections/ 9. Cai T, Nesi G, Mazzoli S, et al. Asymptomatic bacteriuria treatment is associated with a higher prevalence of antibiotic resistant strains in women with urinary tract infections. Clin Infect Dis. 2015; 61:1655-61.

10. 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.

11. Ledda A, Belcaro G, Dugall M, et al. Highly standardized cranberry extract supplementation (Anthocran®) as prophylaxis in young healthy subjects with recurrent urinary tract infections. Eur Rev Med Pharmacol Sci. 2017; 21:389-393.

12. Sogo T, Terahara N, Hisanaga A, et al. Anti-inflammatory activity and molecular mechanism of delphinidin 3-sambubioside, a Hibiscus anthocyanin. Biofactors. 2015; 4:58-65.

13. UTirose™: a natural answer to urinary tract infections issues.

Brochure produit, RSO -002/1, certifié par Bureau Veritas.

14. Pandey RS, Singh BK, Tripathi YB. Extract of gum resins of Boswellia serrata L. inhibits lipopolysaccharide induced nitric oxide production in rat macrophages along with hypolipidemic property.

Indian J Exp Biol. 2005; 43:509-16.

15. Passaro M, Mainini G, Ambrosio F, et al. Effect of a food supplement containing L-Methionine on urinary tract infections in pregnancy: a prospective, multicenter observational study. J Altern Complement Med. 2017; 23:471-478.

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 - Fabrizio Di Maida, MD Department of Urology, University of Florence, Florence, Italy Paolo Verze, MD - Alessandro Palmieri, MD - Vincenzo Mirone, MD Department of Urology, University of Naples, Federico II, Naples (Italy) Truls E. Bjerklund JohanseN, MD Department of Urology, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo (Norway)

Del Popolo okkkkkkk_Stesura Seveso 28/06/18 16:34 Pagina 101

DOI: 10.4081/aiua.2018.2.101

ORIGINAL PAPER

Recurrent bacterial symptomatic cystitis: A pilot study on a new natural option for treatment Giulio Del Popolo, Federico Nelli Department of Neuro-Urology, Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy.

Summary

Objectives: The aim of our study was to explore the effectiveness of the combination of D-mannose, Salicin, and Lactobacillus acidophilus (La-14) in patients complaining recurrent symptomatic cystitis due to E. coli.

Materials and methods: From July 2013 to September 2014, 85 consecutive subjects (68 women and 17 men) affected by recurrent symptomatic cystitis were enrolled. Of those, 46 (33 women and 13 men) suffered from neurogenic bladder.

Overall 78 patients received an initial 5-days regimen consisting on a tid oral combination of 1000 mg of D-mannose plus 200 mg of dry willow extract (salicin) (attack phase), followed by bid 7-days with 700 mg of D-mannose plus 50 mg (1x109 CFU) of Lactobacillus acidophilus (La-14) (maintenance treatment). The maintenance treatment was repeated every 15 days for the next two months. Patients’ symptoms were evaluated through a 3-days bladder diary and a Visual Analogic Scale (VAS).

Results: After treatment VAS scores decreased from 8.07 ± 1.70 to 4.74 ± 2.07 (p = 0.001) in non-neurological patients (group A) and from 7.21 ± 1.90 to 3.74 ± 3.12 (p = 0.001) in the neurological patients (group B). A significant reduction of daily frequency was noted in both groups: from 14 ± 3 to 7 ± 3 (p = 0.001) in group A and from 15 ± 3 to 8 ± 3 (p = 0.001) in group B. A reduction of incontinence episodes in Group A patients was observed, as well as in 12/39 Group B. Improvements were maintained during follow- up.

Conclusion: This therapeutic approach combining D-Mannose with Salicin (acute treatment) and Lactobacillus acidophilus La-14 (maintaining treatment) seems to be effective in symptomatic bacterial UTIs. Further larger and randomized control trials (RCTs) are needed to confirm our results.

KEY WORDS: Bacterial cystitis; UTI; D-mannose; Neurogenic bladder dysfunction, Lactobacillus acidophilus La-14; Salicin.

Submitted 19 March 2018; Accepted 9 May 2018

INTRODUCTION

Urinary tract infections (UTIs) are among the most common infections in humans and affect both sexes and all age groups. Among them, cystitis is a clinical syndrome characterized by dysuria, urinary frequency and urgency, with or without suprapubic pain. The most common cause of cystitis is bacterial from common pathogens of the lower urinary tract. Bacterial cystitis is usually associated with bacteriuria and leukocyturia.

In Europe, Escherichia coli (E. coli) is the most common uropathogen, accounting for up to 86% of all UTIs (1);

other pathogens are Proteus and Klebsiella species, enterococci, Group B streptococci and Pseudomonas aeruginosa, but UTIs can be also due to the association of several pathogens with greater clinical impact and potential complications.

Women are more likely to be affected by UTI than men, with an estimated incidence of 1 42 in 3 among females versus only 1 in 20 among males (14). The higher incidence of UTIs among women can be attributed to the shorter urethral length, which provides an effective barrier against bacterial contamination.

UTIs can also be due to neurogenic bladder and it may result from decreased local immune defenses, impaired lower urinary tract function, bladder management (e.g. intermittent catheterism, indwelling catheter) and the coexisting condition of neurogenic bowel dysfunction.

In any case an excessive use of antibiotics may also increase the UTI risk by altering the normal microbiota and increasing bacterial resistance.

Treatment is generally multimodal and includes antibiotic and anti-inflammatory therapy together with dietary supplements and behavioral interventions.

Recommended preventive measures such as adequate water intake, rhythm in urinary voiding and non-antibiotic prophylaxis (e.g., cranberry, urine acidifiers, probiotics) are not yet supported by evidence (3, 4).

D-mannose has long been studied and has been shown to be effective and safe in treating and preventing UTIs also in neurological populations such as multiple sclerosis (2). Through its mechanism of action, it prevents bacterial colonization and invasion of the bladder by pathogens, and is effective in multiresistant UPEC (Uropathogenic E. coli) infections (5). In vitro studies have shown that D-mannose binds and blocks FimH adhesins positioned on the tip of type 1 bacterial fimbriae.

During bacterial colonization, FimH binds to the glycoprotein-containing carbohydrate receptors on the urinary epithelium. D-mannose acts as a competitive inhibitor of bacterial adhesion as it has a structure similar to the binding site of glycoproteic urothelial receptors; in sufficient concentrations in urine, D-mannose causes saturation of FimH adhesins and therefore prevents bacteria from binding to urothelial receptors.

In vitro studies show that the local application of D-mannose decreased the adherence of E. coli, Pseudomonas aeruginosa and Streptococcus zooepidemicus to urothelial endometrial cells in horses. Reduction of bacteriuria lev-

No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

101

Del Popolo okkkkkkk_Stesura Seveso 28/06/18 16:34 Pagina 102

G. Del Popolo, F. Nelli

els has also been confirmed by in vivo animal models of recurrent UTIs. A randomized, non-blind, placebo-controlled study to evaluate prophylaxis of recurrent urinary infections conducted on 308 women showed that Dmannose used for 6 months at a dose of 2 g per day was significantly more effective than placebo and as effective as nitrofurantoin 50 mg in preventing recurrence (6, 7).

Salicin (an alcoholic β-glucoside between glucose and salicylic alcohol), has anti-inflammatory properties (8).

Lactobacilli possess antimicrobial properties that regulate the urogenital microbiota. Lactobacillus acidophilus La-14 has shown excellent adherence to epithelial surfaces in vitro demonstrating inhibition of selected pathogens, including E. coli (9-12).

The recurrence of urogenital infections leads to a change in local flora from a predominance of lactobacilli to coliform uropathogens.

Therefore, the use of systemic probiotics containing Lactobacillus acidophilus that help to restore the microbiota has been proposed for the treatment and prophylaxis of bacterial urogenital infections (13).

The aim of the present clinical study was to evaluate the feasibility and efficacy of a new combined 2-phase approach in order to treat neurological and non-neurological patients affected by recurrent symptomatic bacterial cystitis mainly due to E. coli.

MATERIALS

AND METHODS

Between July 2013 and September 2014, consecutive subjects attending to our Neuro-Urology clinic with diagnosis of recurrent bacterial cystitis, were enrolled in our study.

Definition of symptomatic UTIs included the presence of at least 2 of the following symptoms: dysuria, new onset and/or worsening of urgency and/or urgency urinary incontinence, flank and/or suprapubic pain, worsening of muscle spasticity (in SCI and MS patients) and/or autonomic dysreflexia (in SCI patients) combined with a ≥ 105 CFU/mL at urine culture (in non-neurological) or ≥ 106 CFU/mL (in neurological population). Only adults between 18 and 80 years-old were included. Other inclusion criteria were: history of ≥ 3 acute episodes of recurrent symptomatic cystitis in the last year with at least two positive urine cultures for E. coli in the last 3 months before the screening, previous unsuccessful treatment with D-mannose and/or cranberry. Exclusion criteria was the presence of positive urine culture not due to E. coli at the screening, pregnancy, breastfeeding, haematuria, fever, any uro-genital abnormalities at ultrasound, history of any allergies to salicylates and/or D-mannose, any use of antiobiotics for any reasons within the last two weeks before the enrollment and overall during the study.

All patients received an initial 5-days regimen consisting on an oral combination of 1000 mg of D-mannose plus 200 mg of dry willow extract (salicin) three times daily (attack phase, morning-midday-evening always on a full stomach), followed by 7-days with 700 mg of D-mannose plus 50 mg (1x109 CFU) of Lactobacillus acidophilus (La-14) twice daily (maintenance treatment, morning and evening on a full stomach). This latest combination (D-mannose plus La-14) was repeated at the same dosage for 15-days at each month for two months.

102

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

Changes in patients’ symptoms and was monitored at baseline (T0), 2-weeks (T1), 12-weeks (end of treatment, T2) and at one month after the end of treatment (T3) by a 3-days bladder diary and the Visual Analogic Scale (VAS). The efficacy in preventing new recurrences was assessed by repeated urine cultures during follow-ups.

RESULTS

Eighty-five patients were included in our study with a mean age of 45,2 years (range, 22-78). Forty-six out of 85 were affected by neurogenic bladder (Group B) due to spinal cord injury or multiple sclerosis (33 females and 13 males) with a mean age of 37,4 years (range, 25-54).

Thirty-seven out of 46 neurological patients were managed by intermittent catheterization regimen. Seven patients in the Group B missed the T2 follow up, then were considered as drop out. None of the 39 non-neurological patients (group A) dropped out during the study.

Patients with neurogenic bladder (group B) reported a decrease of mean VAS scores from 7.21 ± 1.90 to 3.74 ± 3.12 starting from the first days of treatment until the end of the attack and maintenance phases (T1), and maintained the result at T2 and one month after the end of treatment (T3). Symptoms at baseline were pain, urgency/frequency, urinary incontinence (Table 1).

Again, a decrease of the mean VAS scores during followup was also found in group A. This result was maintained at T2 and T3. The improvements in clinical symptoms in both groups (e.g. dysuria, frequency, urgency) were already significant 2 weeks after (T1) the beginning of treatment and these results were confirmed after the maintenance therapy (T2) and 1 month after the end of treatment (T3) (Table 2).

In particular, group A showed a significant decrease from 14.0 ± 2.6 to 6.9 ± 1.3 (p = 0.001) in daily urinary frequency at T1, a reduction that was maintained both at T2 (6.5 ± 1.2) and one month after the end of treatment (T3) 6.2 ± 0.9.

In Group B, a significant reduction in daily urinary frequency from 15 ± 3 to 8 ± 3 (p = 0.001) was observed at T1, a reduction that was maintained both at T2 and one month after the end of treatment (T3).

Table 1.

Symptoms at baseline.

Pain > 3 on VAS scale Urgency/frequency ≥ 8 times/day Incontinence episodes

Group A Pts n° 33/39 39/39 -

Group B Pts n° 15/39 26/39 12/39

Table 2.

Mean VAS score pre and during treatment in both population.

VAS Score T0 VAS Score T1 VAS Score T2 VAS Score T3

Group A 8.07 (± 1.70) 4.74 (± 2.07) 4.45 (± 2.19) 4.24 (± 2.23)

Group B 7.21 (± 1.9) 3.74 (± 3.12) 3.51 (± 2.32) 3.40 (± 2.20)

Del Popolo okkkkkkk_Stesura Seveso 28/06/18 16:34 Pagina 103

Symptomatic cystitis a new natural treatment

In this Group B we observed also a reduction of the incontinence episodes at the 3-days bladder diary in 11 patients managed by intermittent catheterization ranging from 4.2+/- 0.60 (T0) to 2.8 +/- 1,33 (T2) (p > 0.001).

No significant side effect was reported during the treatment.

DISCUSSION

Urinary tract infections are still a major problem in clinical practice. Advances in antibiotic therapy have allowed clinicians to decrease the duration of treatment and drastically reduce the complications associated with UTIs but they have not reduced UTI frequency. On the other hand, an indefinite antibiotic prophylaxis would lead to selection of multiresistant microbial strains and exposure of the patients to serious infectious complications.

Various publications emphasize the importance of a moderate use of antibiotics. For this reason, research has focused on enhancing exogenous antibacterial defenses in the bladder.

An attack treatment with D-mannose and salicin, followed by maintenance and/or prophylaxis therapy with D-mannose and probiotics was found to be effective in the treatment of urological infections, including recurrent bacterial cystitis (predominantly due to E. coli) also in different populations (neurological vs non-neurological) D-mannose acts to promote the elimination of bacteria from the bladder and Lactobacillus acidophilus helps to rebalance the intestinal flora, thus reducing the presence of E. coli, which could reach the bladder via the urethra.

The administration of D-mannose in combination with salicin results in an additive anti- inflammatory activity of the two components in the treatment of inflammation and pain In addition, D-mannose and probiotics, administered in combination rather than separately, have demonstrated a surprising complementary activity resulting in a bacteria-repelling effect, which, unlike bactericidal or bacteriostatic effects, allows removal of the pathogenic bacteria/bacilli. Although statistics was limited due to the small number and heterogeneity of patients, the study shows that this combination may be effective in resolving sympoms of UTI. In addition, with the use of this proposed treatment we avoided to repeat antibiotics even in case of E. coli positivity during follow-up because of early solved acute symptoms at the first evaluation which was maintained also one month after the end of treatment. We are conscious that the main limit of this single-arm study was the lack of placebo-control. Again no comparisons with other possible treatment combinations or single use of any of these solutions was done, although we intentionally included patients who were already unsuccessfully treated with D-mannose and/or cranberry before study.

CONCLUSIONS

In our experience we found that the administration of an initial combination of D-mannose and salicin and a maintenance and/or prophylactic combination of Dmannose and probiotics, in particular Lactobacillus acidophilus, could be effective in the treatment and prophy-

laxis of recurrent cystitis with E. coli infection both in non-neurological and neurological patients.

The treatment effectiveness can be measured with the resolution of cystitis-related symptoms.

This combination treatment could be also promising as adjuvant therapy due to its bacteria-repelling, antiinflammatory and analgesic properties and rebalancing effects on the intestinal flora, leading to reduced antibiotic use and resistance.

These positive results, obtained with these treatment and schedule, should be validated by further larger and randomized studies.

REFERENCES

1. Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol 2015; 13:269-284.

2. Phé V, Pakzad M, Haslam C, et al. Open label feasibility study evaluating D-mannose combined with home- based monitoring of suspected urinary tract infections in patients with multiple sclerosis.

Neurourol Urodyn. 2017; 36:1770-1775.

3. Jepson RG, Williams G, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev. 2012; 10:CD001321 4. Juthani-Mehta M, Van Ness PH, Bianco L, et al. Effect of cranberry capsules on bacteriuria plus pyuria among older women in nursing homes. JAMA. 2016; 316:1879-1887.

5. Hickling DR, Nitti VW. Management of recurrent urinary tract infections in healthy adult women. Rev Urol. 2013; 15:41-48.

6. Kranjc˘ec B, Papeš D, Altarac S. D-mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. World J Urol. 2014; 32:79-84.

7. Altarac S, Papes D. Use of d-mannose in prophylaxis of recurrent urinary tract infections (UTIs) in women. BJUI. 2014; 9-10.

8. Khayyal MT, El-Ghazaly MA, Abdallah DM, et al. Mechanisms involved in the anti-inflammatory effect of a standardized willow bark extract. Arzneimittelforschung. 2005; 55:677-87.

9. Shim YH, Lee SJ, Lee JW. Antimicrobial activity of lactobacillus strains against uropathogens. Pediatr Int. 2016; 58:1009-1013.

10. Ibrahem KH, Hasan S. Studying the ability of lactobacillus bacteria inhibit the growth of uropathogens and their adhesion to uroepithelial cells. J College of Basic Education. 2009; 60:73-84.

11. Todorov SD, Furtado DN, Saad SM, et al. Bacteriocin production and resistance to drugs are advantageous features for Lactobacillus acidophilus La-14, a potential probiotic strain. New Microbiol. 2011; 34:357-70.

12. Lactobacillus acidophilus La-14. Technical Memorandum. Danisco.

13. Barrons R, Tassone D. Use of Lactobacillus probiotics for bacterial genitourinary infections in women: a review. Clin Ther. 2008; 30:453-6.

14. Foxman B, Barlow R, D'Arcy H, et al. Urinary tract infection: self-reported incidence and associated costs. Ann Epidemiol. 2000; 10:509-515.

Correspondence Giulio Del Popolo, MD - dpgiulio@gmail.com Federico Nelli, MD Department of Neuro-Urology, Azienda Ospedaliero-Universitaria Careggi L.go G. Alessandro Brambilla, 3 - Firenze, Italy Archivio Italiano di Urologia e Andrologia 2018; 90, 2

103

Yucel_Stesura Seveso 28/06/18 16:35 Pagina 104

DOI: 10.4081/aiua.2018.2.104

ORIGINAL PAPER

The sufficiency of 6 core sextant prostate biopsy in patients with prostate specific antigen (PSA) values over 20 ng/mL Cem Yücel, Salih Budak, Erdem Kısa, Orcun Celik, Zafer Kozacıoglu Tepecik Training and Research Hospital, Urology Clinic, Izmir, Turkey.

Summary

Objective: In this study, we aimed to investigate sufficiency of 6 core prostate biopsy in patients with PSA levels elevated above 20 ng/mL. Materials and methods: The medical record of the patients who received prostate biopsy at our institution between August 2011 to August 2016 who had serum total PSA values above 20 ng/mL, were reviewed retrospectively. In this study, we included 40 patients who received 6 core prostate biopsy and 40 patients who received 12 core prostate biopsy. A total number of 80 patients were enrolled in this study. Patients were divided into two groups, a 6 core biopsy group and a 12 core biopsy group. These groups are compared according to age, total PSA, prostate volume and final pathological diagnosis.

Results: Based on final pathological diagnosis, 2 patients (5%) had benign pathology and 38 patients (95%) had PCa in both group 1 and 2. The cancer detection rate in both groups was 95%. Although there were higher values of mean age, mean total PSA, and mean prostate volume in group 1, there was no statistically significantly difference at this variables in both groups.

Conclusion: Although taking 6 core biopsies is not recently recommended, we proved that 6 core biopsy is adequate for patients with PSA values above 20 ng/mL.

KEY WORDS: Prostate cancer; Biopsy; Detection rate; Core number.

Submitted 25 August 2017; Accepted 23 October 2017

INTRODUCTION

Prostate cancer (PCa) is the most common cancer in men worldwide (1). The diagnosis of PCa depends on sufficient tissue sampling of the prostate gland with prostate biopsy (2). The technique of prostate biopsy has evolved through the years with the advent of new technologies.

In 1989 Hodge et al. first described transrectal ultrasound (TRUS) guided sextant biopsy method (3). Since then, this method has become the worldwide most popular and PCa detection has significantly improved. Its limitations were soon discovered. Many investigator reported falsenegative rates of up to 20-25% for the sextant biopsy (4).

This naturally resulted in the development of refinements to the TRUS-guided sextant biopsy. Stamey et al. suggested directing the biopsy more laterally (5). Multiple biopsy schemes were subsequently proposed to enhance cancer detection by increasing the number and revising the

104

location of cores (6). Six core sextant biopsy is no longer considered adequate. Recently, 10 to 12 core biopsies are recommended and biopsies with > 12 cores are not being significantly more conclusive (7). Patients with prostate spesific antigen (PSA) levels > 20 ng/mL are classified as high risk group for diagnosis of PCa (8). This risk increases with age and these patients have higher possibility to have locally advanced or metastatic disease at the time of diagnosis. In the present study, we aimed to investigate sufficiency of 6 core sextant prostate biopsy in patients with PSA levels elevated above 20 ng/mL. We hypothesized that there is no significant difference in cancer detection rate between 6 core and 12 core prostate biopsies of men presenting PSA values of above 20 ng/mL.

MATERIALS

AND METHODS

The medical record of the patients who received prostate biopsy at our institution between August 2011 to August 2016 and had serum total PSA values above 20 ng/mL, were reviewed retrospectively. In the present study, we included 40 patients who received 6 core prostate biopsy and 40 patients who received 12 core prostate biopsy.

We excluded the patients who have chronic diseases (diabetes, hyperlipidemia, hypertension, cardiovascular disease), malignancy, psychiatric disorders, acute infections, a history of urinary tract surgery, a prior diagnosis of PCa and a history of irradiation. We also excluded patients with PSA < 20 ng/mL. After obtaining informed consent from patients, all biopsies were taken transrectally with ultrasonography guidance using a 25 cm 18 gauge, side-notch cutting (Tru-cut) needle.

The biopsy was applied with patient in lateral decubitus position with periprostatic nerve blockage. A total number of 80 patients were enrolled in this study. The clinic-biological features of patients were recorded. Patients were divided into two groups, a 6 core biopsy group (Group 1) and a 12 core biopsy group (Group 2). These groups were compared according to age, total PSA, prostate volume and final pathological diagnosis. We also identified the cancer detection rate and Gleason scores of these groups.

Statistical analysis The conformity of variables to normal distribution was assessed with the Shapiro Wilk test. Descriptive statistics No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

Yucel_Stesura Seveso 28/06/18 16:35 Pagina 105

Sextant prostate biopsy in high PSA

for variables with a normal distribution and categorical variables were shown as mean ± standard deviation (SD) and percentage (%), respectively. Student’s t-test and chisquare test were used for inter group analyses of continuous variables. More than two independent average compared with ANOVA test and Kruskal Wallis test.

The data analysis was performed using Statistical Package for the Social Science (SPSS Inc, Chicago, Illinois, USA) version 22.0 and a p value of < 0.05 was considered as significant.

RESULTS

A total of 80 patients participated in this study. The mean age of all patients was 72.2±8.4, the mean total PSA was 126.0 ± 101.3 ng/mL, the mean prostate volume was 50.4 ± 41.6 mL and overall cancer detection rate was 95.0%. Clinical and demographic characteristics of all study patients are listed in Table 1. Based on final pathological diagnosis, 2 patients (5%) had benign pathology and 38 patients (95%) had PCa in both group 1 and 2.

The cancer detection rate in both groups was 95%.

The Gleason score was found to be 6 in 3 (7.9%), 7 in 14 (36.8%) and ≥ 8 in 21 (55.3%) patients who were diagnosed as PCa in group 1 and from the other side 6 in 4 (10.5%), 7 in 11 (28.9%) and ≥ 8 in 23 (60.5%) patients who were diagnosed as PCa in group 2. The differances in Gleason scores was not determined to be statistically significant (p= 0.783). Although there was higher values of mean age, mean total PSA, and mean prostate volume in group 1, there was no statistically significantly difference at this variables in group 1 and 2 (Table 2).

The cancer detection rates of both groups were similar (p = > 0.999).

DISCUSSION

PCa is still a major health problem among males all over the world. Despite efforts made to identify new serum and biologic markers of disease and refinement of imaging modalities, TRUS guided biopsy is still most important diagnostic tool. Important improvements in the prostate biopsy have evolved though the past century.

Modern technique of prostate biopsy first began with the Table 1.

Clinical and biological characteristics of all patients (n = 80).

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

Mean (SD) 72.2 (± 8.4) 126.0 (± 101.3) 50.4 (± 41.6) 4 (5.0) 76 (95.0) 7 (9.2) 25 (32.9) 44 (57.9)

PSA: prostate-specific antigen, BPH: benign prostatic hyperplasia; PCa: prostate cancer; SD: standard deviation.

Table 2.

Comparison of clinical characteristics of 2 groups.

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

Group 1 74.1 ± 6.8 139.4 ± 123.0 54.4 ± 52.5

Group 2 70.3 ± 8.9 112.6 ± 72.7 46.4 ± 26.9

P value 0.072 0.265 0.358

2 (5.0) 38 (95.0)

2 (5.0) 38 (95.0)

> 0.999 > 0.999

3 (7.9) 14 (36.8) 21 (55.3)

4 (10.5) 11 (28.9) 23 (60.5)

0.689 0.602 0.783

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

study of Hodge et al. Their method involved taking biopsies from apex, middle and base of each prostate gland para-sagitally. In addition to these six anatomic sites they suggested to take biopsy from hypoechoic regions (3).

Since then, this method has become the worldwide most popular and PCa detection has significantly improved. In 1995, Stamey et al. modified the sextant method and directed the biopsy more laterally to peripheral zone where most PCa are located. They achieved 20-25% more cancer detection rate than Hodges method (5).

Then many researchers investigated the acceptable number of core biopsies for diagnosis. They make an effort to improve the negative predictive value of prostate biopsy.

Guichard et al. found the cancer detection rates of 6, 12, 18 and 21 core prostate biopsies were 31.7%, 38.7%, 41.5% and 42.5% respectively (9). Similarly to this study, Ceylan et al. reported cancer detection rates of 8, 10, 12, 16, and 20 core prostate biopsies as 18.3%, 14.8%, 24%, 22.1%, and 30.3% respectively (10).

The logic of these studies is based on increasing the possibility of detecting PCa by increasing the sample. Six core biopsy is no longer considered adequate. In present study, we found there is no significant difference in cancer detection rate between 6 core and 12 core prostate biopsies of men presenting PSA values of above 20 ng/mL. According to current literature, 6 cores biopsy is not recommended but may be sufficient especially in patients with high PSA (over 20 ng/mL).

Prostate cancer risk was summarized using the D'Amico classification and PSA level is one of three variables on which the risk classification is based (11). According to D'Amico scheme, patients with a PSA over 20 ng/mL are classified as high risk and these patients have higher possibility to have locally advanced or metastatic disease at the time of diagnosis. Stephenson et al. reported that the 15 years prostate cancer specific mortality was 22% in patients with PSA of 20.1-50 ng/mL and 4-11% in those with PSA < 20 ng/mL and suggested that a PSA > 20 ng/mL may indeed be considered a high-risk factor (12).

Heyns et al. reported that a PSA level > 50 ng/mL was associated with a 96% positive predictive value for prostate cancer (13). Gerstenbluth et al. reviewed the records of 1,250 patients undergoing TRUS guided prostate biopsy and identified 187 men (15%) presenting with PSA greater than 20 ng/mL. Of these 187 men, 157 Archivio Italiano di Urologia e Andrologia 2018; 90, 2

105

Yucel_Stesura Seveso 28/06/18 16:35 Pagina 106

C. Yücel, S. Budak, E. Kısa, O. Celik, Z. Kozacıoglu

(84.0%) were diagnosed with prostate cancer on initial biopsy and 12 patients had repeat biopsy and 6 of these eventually diagnosed PCa. Overall, 163 of the 187 men (87.2%) were diagnosed with prostate cancer by biopsy.

They suggested that carefully selected elderly patients with severe comorbidities may not require biopsy before androgen ablative therapy since PSA is highly accurate in diagnosing prostate cancer at levels greater than 50 ng/mL (14). Anai et al. recommended that highly select symptomatic men with extremely high serum PSA could be started on immediate androgen ablative therapy even without a tissue diagnosis of prostate cancer (15). In the present study, we found 95% cancer detection rate and detected that 90.8% of all patients had high risk PCa according to their final pathological diagnosis.

The morbidity of prostate biopsy is minimal, reported at < 1% (4). Early complications of prostate biopsies include hematospermia (37%), hematuria more than 1 day (14.5%), rectal bleeding more than 2 days (2.2%) and urinary retention that required observation or intervention (1.8%). Delayed complications of prostate biopsies are urinary tract obstruction (10.9%), fever (2.9%), sepsis (0.1%) (16). Naughton et al. reported similar complication results in a prospective evaluation of 6 and 12 core biopsies (17). Contrary to this study, Feliciano et al. reported that the increased number of biopsy cores contributed to increased morbidity associated with prostate biopsy (18). We thought that there is not necessary to increase the core number of prostate biopsy if it have not additional contribution to cancer detection.

Our study has limitations. First limitation of our study is its retrospective nature. Not assessing the complications of biopsies was the second limitation of our study. The other limitation of this study is small sample size and this limitation could affect the interpretation of results. A larger series of patients will provide a more accurate picture.

CONCLUSIONS

Although taking 6 core biopsies is not recently recommended, we proved that 6 core biopsy is adequate for patients with PSA values above 20 ng/mL. Our results may provide additional information for importance of 6 core biopsy and we believe that a large-scale, multicenter, prospective study will provide a more accurate picture for the clinical significance of 6 core sextant prostate biopsies of men presenting PSA values of above 20 ng/mL. As a result, 6 core may be sufficient if prostate biopsy can not be tolerated especially in patients with high PSA.

REFERENCES

1. Ismail MT, Gomella LG. Transrectal prostate biopsy. Urol Clin North Am. 2013; 40:457-72.

2. Abd TT, Goodman M, Hall J, et al. Comparison of 12-core versus 8-core prostate biopsy: multivariate analysis of large series of US veterans. Urology. 2011; 77:541-7.

3. Hodge KK, McNeal JE, Terris MK, Stamey TA. Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J Urol. 1989; 142:71-4.

4. Mariappan P, Chong WL, Sundram M, Mohamed SR. Increasing

106

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

prostate biopsy cores based on volume vs the sextant biopsy: a prospective randomized controlled clinical study on cancer detection rates and morbidity. BJU Int. 2004; 94:307-10.

5. Stamey TA. Making the most of six systematic sextant biopsies.

Urology. 1995; 45:2-12.

6. Silletti JP, Gordon GJ, Bueno R, et al. Prostate biopsy: past, present, and future. Urology. 2007; 69:413-6.

7. Kim JW, Lee HY, Hong SJ, Chung BH. Can a 12 core prostate biopsy increase the detection rate of prostate cancer versus 6 core?: a prospective randomized study in Korea. Yonsei Med J. 2004; 45:671-5.

8. Ang M, Rajcic B, Foreman D, et al. Men presenting with prostate specific antigen (PSA) values of over 100 ng/mL. BJU Int. 2016; 117:68-75.

9. Guichard G, Larre S, Gallina A. Extended 21-sample needle biopsy protocol for diagnosis of prostate cancer in 1,000 consecutive patients. Eur Urol. 2007; 52:430-5.

10. Ceylan C, Doluoglu OG, Aglamis E, Baytok O. Comparison of 8, 10, 12, 16, 20 cores prostate biopsies in determination of prostate cancer and importance of prostate volume. Can Urol Assoc J. 2014; 8:81-5.

11. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998; 280:969-74.

12. Stephenson AJ, Kattan MW, Eastham JA, et al. Prostate cancerspecific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era. J Clin Oncol. 2009; 27:4300-5.

13. Heyns CF, Naude AM, Ahmed G, et al. Serum prostate-specific antigen as surrogate for the histological diagnosis of prostate cancer.

S Afr Med J. 2001; 91:685-9.

14. Gerstenbluth RE, Seftel AD, Hampel N, et al. The accuracy of the increased prostate specific antigen level (greater than or equal to 20 ng./ml.) in predicting prostate cancer: is biopsy always required?

J Urol. 2002; 168:1990-3.

15. Anai S, West CS, Chang M, Nakamura K, et al. Outcomes of men who present with elevated serum PSA (> 20 ng/mL) to an innercity hospital. J Natl Med Assoc. 2007; 99:895.

16. Moyer VA. U.S. Preventive Services Task Force Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012; 157:120-34.

17. Naughton CK, Ornstein DK, Smith DS, Catalona WJ. Pain and morbidity of transrectal ultrasound guided biopsy: a prospective randomized trial of 6 versus 12 cores. J Urol. 2000; 163:168-71.

18. Feliciano J, Teper E, Ferrandino M, et al. The incidence of fluoroquinolone resistant infections after prostate biopsy are fluoroquinolones still effective prophylaxis? J Urol. 2008; 179:952-7.

Correspondence Cem Yücel, MD meclecuy@hotmail.com Salih Budak, MD (Corresponding Author) salihbudak1977@gmail.com Erdem Kısa, MD drerdemkisa@hotmail.com Orcun Celik, MD orcuncelik82@hotmail.com Zafer Kozacıoglu, MD Associate. Prof. zaferkozacioglu@gmail.com Tepecik Training and Research Hospital, Urology Clinic, Izmir, Turkey 206/26 sok. no:16 D:24 yıldız mah. Buca/Izmir, Türkiye

Fabiani_Stesura Seveso 28/06/18 16:36 Pagina 107

DOI: 10.4081/aiua.2018.2.107

ORIGINAL PAPER

Effect on prostatic specific antigen by a short time treatment with a Curcuma extract: A real life experience and implications for prostate biopsy Andrea Fabiani 1, Carolina Morosetti 2, Alessandra Filosa 3, Emanuele Principi 4, Luca Lepri 1, Valentina Maurelli 1, Fabrizio Fioretti 1, Lucilla Servi 1 1 Unit

of Urology, Surgical Department, Macerata Hospital, Area Vasta 3, ASUR Marche, Italy; Pathology, Jesi (AN), Italy; 3 Section of Pathological Anatomy, Department of Clinical Pathology, Macerata Hospital, Area Vasta 3, ASUR Marche, Italy; 4 Resident, Urologic Clinic, Politechnic University of Marche Region, Ancona, Italy.

2 Clinical

Summary

Introduction and objectives: PSA elevation is associated with prostate cancer and it is used in screening programs for its diagnosis. It is one of the most common indications for referral to an urologist. There’s no consensus about what to do in PSA elevation management.

Antibiotics, nutraceuticals or anti-inflammatories are commonly prescribed in daily practice. Our objective was to verify the effect on the PSA value of a short 30-day trial of a curcuma extract, than to discuss the implications in terms of reducing the number of prostate biopsies performed.

Patients and methods: We enrolled 50 consecutive patients admitted at our attention for a first PSA over the level of 4 ng/ml or for a suspected PSA rising defined as PSA velocity (PSAv) > 0.75 ng/ml/years. They received treatment with curcuma extract, 2 tablets per day for 30 day. All patients received a second PSA measurement and TRUS within 6 days from the end of the therapy. In case of PSA reduction below 4 ng/ml, patients were reassured and invited to repeat a PSA control over the time. When PSA level were persistently high over 4 ng/ml or in case of any rising, patients underwent a transrectal ultrasound guided 12-core prostatic biopsy (TRUSbx).

Results: Mean age of the patients was 64.56 ± 8.88 (range, 4281 years). Prostate volume was 48.34 ± 15,77 ml (range, 18-80 ml). At visit 1, PSA value was in mean 6,84 ± 3.79 ng/ml (range 2.93-21ng/ml). Consequently, mean PSA density value was 0.16 ± 0.16 (range 0.05-1.11). PSA free and PSA total ratio at baseline was 16.85 ± 3.9% (range 8-26%). At visit 2, the prostate volume did not change. Total PSA was 4.65 ± 2,67 ng/ml (range 1-16.82 ng/ml). PSA free and PSA total ratio (PSAF/T) after treatment was 19.68 ± 5.35 % (range 7.8-29%).

The differences of total PSA and PSAF/T between visit 1 and visit 2 were < 0.0001 and p < 0.0036, respectively. We performed 26 TRUSbx. Prostate cancer was diagnosed in 6 cases, PIN HG in 2 cases and non neoplastic findings in the remnants 18 patients.

Conclusions: Use of the Curcuma extract is able to lower the PSA value after a 30-day intake period. We are not able to state that the reduction of PSA after intake of this Curcuma extract may exclude a prostate cancer. We need further studies to evaluate that.

KEY WORDS: Prostatic specific antigen; Curcuma; Prostate biopsy; Prostate cancer; Nutraceuticals.

Submitted 31 December 2017; Accepted 12 March 2018

INTRODUCTION

Prostatic specific antigen (PSA) may be raised as a result of prostate cancer, benign prostatic hyperplasia, prostatic infection or inflammation (1). A raised PSA, over a value considered as normal (i.e. 4 ng/ml), usually prompts an ultrasound guided prostate biopsy (TRUSbx) even in absence of an abnormal digital rectal examination (DRE).

TRUSbx is a procedure performed in an ambulatory setting but it is characterized by a morbidity and a patient’s discomfort (2). The scientific literature does not define with certainty what should be the attitude to be taken by the urologist when he is managing a PSA elevation, without symptoms and without anomalous findings to the DRE. Although the prescription of antibiotics or nutraceuticals or anti-inflammatories is widespread in daily practice, the guidelines recommend repeating PSA over time, but this does not protect against performing biopsies with negative results for neoplasia.

Our objective was to verify the effect on the PSA value of a short 30-day trial of a Curcuma extract and if this effect could have an implication in terms of reducing the number of prostate biopsies.

PATIENTS

AND METHODS

Patients and study design This was a prospective mono-institutional real-life study of 50 patients who were admitted at our attention for a first PSA raised over the level of 4 ng/ml or for a suspected PSA rising defined as PSA velocity (PSAv) > 0.75 ng/ml/years. The exclusions criteria were any previous surgical prostatic treatment, any prior prostate biopsy, any therapy with 5-alpha-reductase inhibitors (5ARI); (finasteride or dutasteride), any abnormalities detected at DRE, any alterations in transrectal ultrasound prostate study (TRUS), any low urinary tract symptoms (LUTS) suggesting for urinary tract infection (UTI) or recognized physiologic or iatrogenic cause of PSA rising.

Patients enrolled received treatment with PROSTAFLOG®, 2 tablets per day for 30 day. They received a second PSA

No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

107

Fabiani_Stesura Seveso 28/06/18 16:36 Pagina 108

A. Fabiani, C. Morosetti, A. Filosa, E. Principi, L. Lepri, V. Maurelli, F. Fioretti, L. Servi

measurement and TRUS within 6 days from the end of the therapy. In case of PSA reduction below 4 ng/ml, patients were reassured and invited to repeat a PSA control over the time. When PSA level were persistently high over 4 ng/ml or in case of any rising, patients underwent a transrectal ultrasound guided 12-core prostatic biopsy (TRUSbx).

Technical aspect and measurements At first line visit, patients in each group underwent a clinical evaluation with a DRE and TRUS (end fire BK Medical probe, 8808). Prostate volume (ml) was measured according to the prostatic ellipsoid formula, multiplying the largest anteroposterior, transverse and cephalocaudal prostate diameters by 0.524. PSA density (PSAD) (ng/ml/g) was defined as PSA (ng/ml) at the enrolling visit time divided by prostate volume (ml).

TRUS guided prostate biopsy was performed by a single experienced urologist and consisted in 12 cores of tissue targeting the peripheral zone at the apex, mid gland and the base on each side of the gland, whit an end fire needle access route. Prostatic cores were evaluated by a single dedicated genitourinary pathologist.

Herbal product PROSTAFLOG® (Naturmed srl) is a food supplement based on plant extracts of Curcuma, Boswellia, Nettle and Maritime Pine, which promote the physiological functions of the prostate. Component quantitative are, per dose (2 tablets): Curcumin 500 mg, Boswellia 300 mg, Nettle 240 mg (Betasitosterol intake 1 mg), Maritime Pine 200 mg (Betasitosterol intake 150 mg), Soy’s Lecitine 70 mg.

Statistical analyses The statistical analysis was performed with Med Calc ver. 9.0.2.1 demo mode.

For quantitative parameters were determined: mean, standard deviation, median. For all quantitative parameters, the normality or less of the distribution was preliminarily verified with D'AgostinoPearson test. If the normality was accepted, the data analysis was performed with parametric tests.

Otherwise with non-parametric tests.

RESULTS

As showed in Table 1, mean age of the patients was 64.56 ± 8.88 (range, 42-81 years). Prostate volume was 48.34 ± 15.77 ml (range, 18-80 ml). At visit 1, PSA value was in mean 6.84 ± 3.79 ng/ml (range, 2.93-21 ng/ml).

Consequently, mean PSA density value was 0.16 ± 0.16 (range 0.05-1.11).

PSA free and PSA total ratio at baseline was 16.85 ± 3.9% (range,

108

8-26%). At visit 2, the prostate volume did not change.

Total PSA was 4.65 ± 2.67 ng/ml (range, 1-16.82 ng/ml).

PSA free and PSA total ratio (PSAF/T) after treatment was 19.68 ± 5.35% (range, 7.8-29%).

The differences of total PSA and PSAF/T between visit 1 and visit 2 were calculated. Given the non-normal distribution of data, the analysis was performed with Wilcoxon tests for paired data.

The value of p was < 0.0001 for total PSA. For PSAF/T, p < 0.0036. The differences, therefore, between “before and after” were statistically significant. The power of the test was equal to 0.979 (used software G*Power 3.0.10).

Total PSA reduction was observed in 41 cases (82%).

Of 50 patients, 26 (52%) underwent TRUSbx because of persistent total PSA elevation (9/50, 18%) or PSA reduction but not under the cut off value of 4 ng/ml (17/50, 34%). Hystopathologic results showed prostatic adenocarcinoma in 6 cases (6/26, 23%), in 10 (10/26, 38.5%) acute and chronic flogosis, in 8 (8/26, 30.8%) atrophic findings. Monofocal PIN HG was detected in 7.69% (2/26). Gleason score was 3+3 in 67% (4/6), 4+4 in 17% (1/6). In case of positivity for prostatic cancer, PSA was Table 1.

Patients characteristics at visit 1 and visit 2.

Age (mean, years) PSA (mean, ng/ml) PSA F/T (mean, %) Prostate volume (mean, ml) PSA D

Visit 1 64.56 6.84 16.8 48.34 0.16

Visit 2 4.65 19.68 -

P (< 0.005) < 0.0001 < 0.0036 -

Table 2.

Patient’s characteristics according to the PSA value after trial *.

Mean age (years) Mean PSA variation (ng/ml) Mean prostatic volume (ml) Number positive biopsies Number negative biopsies

Patients with PSA lowered under 4 ng/ml (n. 24) 63.4 2.91 46.62 -

Patients withwith PSA lowered still over 4 ng/ml (n. 17) 65.29 2.71 53.17 1 16

Patientswith PSA augmentation (n. 9) 66.2 0.70 43.7 5 4

* Not statistically significant differences were found.

Table 3.

Patient’s characteristics according to the prostatic biopsies results.

Number of patients Mean PSA (ng/ml) Mean PSA D Mean PSA F/T (%) Mean PSA variation (ng/ml)

Biopsy positive for cancer Biopsy negative for cancer Biopsy not performed 6 20 24 6.48 6.19 2.89 0.14 0.17 0.16 13.8 20.35 20.75 0.664* 2.43** 2.91

* Mean value calculated on 5 cases with PSA progression; in one case, PSA total has been lowered by trial (0.5 ng/ml) ** All variation were negative.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

Fabiani_Stesura Seveso 28/06/18 16:36 Pagina 109

Effect on prostatic specific antigen by a short time treatment with a Curcuma extract: A real life experience and implications for prostate biopsy

in elevation in 5 cases out of 6. Only in one positive case, despite the total PSA reduction of 0.5 ng/ml (from 9 ng/ml to 8,5 ng/ml), we have diagnosed an adenocarcinoma. This could mean that in 16 case of 17 (94%) who underwent TRUSbx for PSA not sufficiently reduced, TRUSbx could not be performed based on the finding of PSA reduction after the trial with curcuma extract.

The mean of reduction was 2,94 ng/ml (range 0.26-16.2 ng/ml). The 44.5% (4/9) of patients in whom PSA increased despite the extract intake had a neoplastic biopsy outcome, but in 2/9 biopsy findings was a PIN hg. Thus, the 67% of these (6/9) with a PSA elevation after the trial, had a non benign biopsy result.

In Table 2 and Table 3 we reported mean PSA values according to results after trial and biopsies findings (negative or positive for neoplasm). All subjects included in the evaluation tolerated treatments with Curcuma extract. No major complications were registered in case of ultrasound guided prostate biopsy.

DISCUSSION

A raised PSA is one of the most common indications for referral to an urologist. However, before a PSA test is undertaken, it is important that a frank and honest discussion should be had with the patient about the pros and cons of this blood test (3). In effect, PSA measurement has marked a new era in the diagnosis of prostate cancer (4). This antigen, produced almost exclusively by the epithelial cells of the prostate, is not a cancer specific but an organ-specific marker (5). Therefore, its serum levels may increase in non malignant conditions such as benign prostate hypertrophy, prostatic infection or inflammation, and prostate cancer (1). The histological architecture of the prostate is disturbed in both prostate cancer and prostatitis, causing greater PSA leakage from the lumen of the prostatic glands into the circulation, increasing PSA levels (6). Because elevated serum PSA is associated with prostate cancer and is used in screening programs for prostate cancer, patients with benign causes for elevation of serum PSA present a challenge, especially when clinical evaluation and DRE are unremarkable. Twenty-five percent of men with PSA levels from 4 to 10 ng/ml have a biopsy-proven prostate cancer, but 75% undergo unnecessary prostate biopsies, potentially leading to anxiety, discomfort and significant additional health care cost (7). In men with an increasing PSA without clinical evidence of infection, a common rational is to treat a subclinical prostate infection, in order to reduce the PSA value, avoiding unnecessary prostate biopsies (8). Several years ago, already, Scardino criticized the unjustified use of antibiotics in a group of patients with a PSA elevation and no symptoms due to an UTI. He emphasized the various inherent disadvantages associated with this approach, such as costs, toxicity, and the promotion of resistant bacterial species development that would have exposed the biopsied patient to more resistant and aggressive sepsis (9). Also in 2014, Fandella et al., showed no advantages due to an empiric antibiotic therapy (full dose fluoroquinolone for 20 days) to reduce PSA values and avoid unnecessary biopsy in patients with PSA levels between 4-10 ng/mL

and no signs or symptoms of infections. They concluded that empiric use doesnâ&#x20AC;&#x2122;t seem to be of clinical benefit in absence of a clinical or laboratory evidence of infection and it might paradoxically be harmful. In their opinion, the repetition of a PSA test before scheduling a biopsy remains the only acceptable approach (10). However, over the years, we have witnessed the presentation of various therapeutic approaches aimed at the intervention on the increase of PSA before resorting to a biopsy. Even the current increased recourse to multiparametric Magnetic Resonance Imaging (mpMRI) presents some aspects of accuracy and costs that make it impracticable in a first level of investigation (11-12). Bozzini et al. recently reported their multicentric observational experience with beclomethasone dipropionate (BDP) rectal suppositories in case of nonbacterial prostatitis. The eightyfour percent of the patients enrolled underwent a 20-day course of therapy with BDP suppositories and Serenoa Repens (Saw palmetto, dose of 320 mg per day).

Results showed an effect on symptoms related to prostatitis, but not on PSA levels. Authors declared that, as expected, PSA levels remained stable since it is not a specific parameter for lower urinary tract inflammation (13).

But, we know from the literature that inflammation of the prostate is an histological finding in almost every set of prostate biopsies, even when there are no signs of clinical prostatitis. As observed in our study population, this subclinical inflammation can cause PSA elevation.

Furthermore, not the extent of inflammation is of importance, but the disruption of epithelial integrity caused by the inflammatory infiltrate. When confronted with a patient with an elevated PSA level whose prostate biopsies reveal no malignancy but only inflammation, this concept can help in determining the need for quick repeat biopsies (14). Instead, a PSA assessment is more and more frequently prescribed also by general practitioners before being sent to the specialist. Hence, the increasing interest in and use of complementary and alternative therapies (CAM), especially nutraceuticals (15).

In Italy, 50% of the medications used for benign prostatic hyperplasia are phytotherapies, and in Germany and other European countries, phytotherapies are first-line treatment for mild to-moderate benign prostatic hyperplasia (BPH)/LUTS (16). The best-studied CAM therapies for prostate disease include dietary modification, the aforementioned Serenoa repens (Saw palmetto), Pygeum africanum, phytosterols, rye pollen extract and others, and vitamins and minerals, such as vitamin E and selenium (17-20). These products may be utilized alone or in association with antibiotics (21, 22) or anti-inflammatory drugs (23) exploiting in particular the rational of Serenoaâ&#x20AC;&#x2122;s anti-inflammatory action (24). Nevertheless, many of the studies are small, short, not randomized, and/or not placebo controlled and they are not focused on the effects on the PSA. We have focused our study on curcuma for the growing attention that literature is addressing to this substance, given its proven effects on PSA (25-26) and the interest of research on the possible use in the treatment of symptomatic prostatitis (27).

In particular, we wanted to evaluate the possibility of obtaining an effect on PSA in just a few weeks so as to reduce the patient's stress and reassure him about the Archivio Italiano di Urologia e Andrologia 2018; 90, 2

109

Fabiani_Stesura Seveso 28/06/18 16:36 Pagina 110

A. Fabiani, C. Morosetti, A. Filosa, E. Principi, L. Lepri, V. Maurelli, F. Fioretti, L. Servi

need to deal with a diagnosis of cancer (28). The results obtained allowed us to verify how curcuma extract is able to lower PSA. Among the biopsies performed, we observed that the positive ones show a PSA increasing or however a less marked reduction compared to patients with negative biopsy. As regards the analysis of the data, taking into account the number of biopsies carried out in patients treated with curcuma extract, it can of course be said that the treatment with this curcuma extract has greatly reduced the number of biopsies to be performed, with 26 biopsies performed respect the 50 that would have been made on the basis of the value of the initial PSA, with a reduction of biopsy performed of 48%.

We are certainly not able to state that the reduction of PSA after intake of curcuma extract, in case of PSA > 4 ng/ml and negative DRE, can be used as “ex adiuvantibus criterion” for not perform unnecessary biopsy. However, considering the verified statistical power of the results obtained in our cohort, it is undeniable that this curcuma extract is able to lower the value of PSA. In particular, when PSA raise after trial, biopsy results are not benign in 67% of cases. We recognize that our study suffer from several limitations. First. The lack of a control group. In order to define the role of curcuma extract in reducing unnecessary biopsy, we should make a comparison with a placebo control group. Second, to confirm our preliminary real life experience, concerning the rapid and significant reduction of PSA, this curcuma extract must be employed in a more sized patient’s sample. Third. Not all 50 patients enrolled were biopsied.

It should be recognized that the execution of the biopsy with a reduced PSA, after rising, would have been outside the current indications (2).

CONCLUSIONS

PSA rising is one of the most common indications for urological evaluation. Because elevated serum PSA is associated with prostate cancer and is used in screening programs, patients with benign causes for elevation of serum PSA present a challenge, especially when clinical evaluation and DRE are unremarkable. Use of curcuma extract is able to lower the value of PSA. We are not able to state that the reduction of PSA after trial may exclude a prostate cancer. We need further studies to evaluate that. It is desirable that the use of nutraceutical products in the treatment of prostatic pathology is correctly evaluated in appropriate studies so that, in particular, the use of curcuma does not remain a non-evidence-based practice.

AUTHORS’

CONTRIBUTIONS

3. Kirby RS. Raised Prostate-Specific Antigen. In Gontero P, et al.

(Eds.) Problem Based Urology. chapter 24, Springer-Verlag London 2013; pp 185-189.

4. Stamey TA, Yang N, Hay AR, et al. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med. 1987; 317:909-916.

5. Mottet N, Bastian PJ, Bellmunt J, et al. Guidelines on prostate cancer. In: European association of urology guidelines. European Association of Urology 2014; p. 16 6. Ornstein DK, Smith DS, Rao GS, et al. Biological variation of total, free and percent free serum prostate specific antigen levels in screening volunteers. J Urol. 1997; 157:2179-2182.

7. Catalona WJ, Smith DS, Ratliff TL, et al. measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med. 1991; 324:1156-1161.

8. Lorente JA, Arango O, Bielsa O, et al. Effect of antibiotic treatment on serum PSA and percent free PSA levels in patients with biochemical criteria for prostate biopsy and previous lower urinary tract infections. Int J Biol Markers. 2002; 17:84-89.

9. Scardino PT. The responsible use of antibiotics for an elevated PSA level. Nat Clin Pract Urol. 2007; 4:1.

10. Fandella A, Benvenuto S, Guidoni E, et al. Empiric antibiotics therapy for mildly elevated prostate specific antigen: Helpful to avoid unnecessary biopsies? Arch Ital Urol Androl. 2014; 86:202204.

11. Ahmed HU, Bosaily AES, Brown LC, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet 2017; 389:815-822.

12. Faria R, Soares MO, Spackman E, et al. Optimising the diagnosis of prostate cancer in the era of multiparametric magnetic resonance imaging: a cost effectiveness analysis based on the prostate MR imaging study (PROMIS). Eur Urol. 2018; 73:23-30.

13. Bozzini G, Provenzano M, Buffi N, et al. An observational study of the use of beclomethasone dipropionate suppositories in the treatment of lower urinary tract inflammation in men. BMC Urology; 2016; 16:25-32.

14. Schatteman PH, Hoekx L, Wyndaele JJ, et al. Inflammation in prostate biopsies of men without prostatic malignancy or clinical prostatitis: correlation with total serum PSA and PSA density. Eur Urol. 2000; 37:404-412.

15. Curtis NJ, Shoskes D, Roehrborn GC, et al. Nutraceuticals in prostate disease: The Urologist role. Reviews in Urology. 2010; 10:192-206.

16. Dreikorn K. Complementary and alternative medicine in urology. BJU Int. 2005; 96:1177-84.

All Authors participated in the design and conduct of the study. All Authors reviewed and approved the final version of the manuscript.

17. Morgia G, Cimino S, Favilla V, et al. Effects of serenoa repens, selenium and lycopene (Profluss) on chronic inflammation associated with benign prostatic hyperplasia: results of “FLOG” (Flogosis and Profluss in prostatic and Genital Disease), a multicentre Italian study. Int Braz J Urol. 2013; 39:214-221.

REFERENCES

18. Suardi N, Gandaglia G, Nini A, et al. Effects of Difaprost on voiding dysfunction, hystology and inflammation markers in patients with benign prostatic hyperplasia who are candidates for surgical treatment. Minerva Urol Nefrol. 2014; 66:119-125.

1. Tchetgen MB, Oesterling JE. The effect of prostatitis, urinary retention, ejaculation and ambulation on the serum prostate-specific antigen concentration. Urol Clin North Am. 1997; 24:283-291.

110

2. Fandella A, Scattoni V, Galosi A. Italian Prostate Biopsies Group: 2016 Updated Guidelines Insights. Anticancer Res 2017; 37:413424.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

Fabiani_Stesura Seveso 28/06/18 16:36 Pagina 111

Effect on prostatic specific antigen by a short time treatment with a Curcuma extract: A real life experience and implications for prostate biopsy

19. Tiscione D, Gallelli L, Tamanini I, et al. Daidzein plus isolase associated with zinc improves clinical symptoms and quality of life in patients with LUTS due to benign prostatic hyperplasia: Results from a phase I-II study. Arch Ital Urol Androl. 2017; 89:12-16.

20. Pirola GM, Puliatti S, Bocchialini T, et al. Efficacy of pollen extract in association with group B vitamins for pain relief in chronic prostatitis/chronic pelvic pain syndrome: A survey of urologists' knowledge about its clinical application. Arch Ital Urol Androl.

2017; 89:22-25.

21. Magri V, Trinchieri A, Montanari E, et al. Reduction of PSA values by combination pharmacological therapy in patients with chronic prostatitis: implications for prostate cancer detection. Arch Ital Urol Androl. 2007; 79:84-92.

22. Cai T, Tiscione D, Gallelli L, et al. Serenoa repens associated with selenium and lycopene extract and bromelain and methylsulfonylmethane extract are able to improve the efficacy of levofloxacin in chronic bacterial prostatitis patients. Arch Ital Urol Androl.

2016; 88:177-182.

23. Gallo L. The Effect of a Pure Anti-inflammatory Therapy on

Reducing Prostate-specific Antigen Levels in Patients Diagnosed With a Histologic Prostatitis. Urology. 2016; 94:198-203.

24. Saidi S, Stavridis S, Stankov O, et al. Effects of Serenoa repens Alcohol Extract on Benign Prostate Hyperplasia. Pril (Makedon Akad Nauk Umet Odd Med Nauki. 2017; 38:123-129.

25. Gupta SC, Patchva S, Aggarwal BB. Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J. 2013; 15:195218.

26. Ide H, Tokiwa S, Sakamaki K, et al. Combined inhibitory effects of soy isoflavones and curcumin on the production of prostate-specific antigen. Prostate. 2010; 70:1127-1133.

27. Morgia G, Russo IG, Urzì D, et al. A phase II, randomized, single blinded, placebo-controlled clinical trial on the efficacy of Curcumina and Calendula suppositories for the treatment of patients with chronic prostatitis/chronic pelvic pain syndrome type III. Arch Ital Urol Androl. 2017; 89:110-113.

28. Evans R, Edwards AGK, Elwyn G. ‘It’s a maybe test’: men’s experiences of prostate specific antigen testing in primary care. Brit J Gen Pract. 2007; 57:303-310.

Correspondence Andrea Fabiani, MD (Corresponding Author) andreadoc1@libero.it Luca Lepri, MD lucalepri3@libero.it Valentina Maurelli, MD valentinamaurelli@hotmail.it Fabrizio Fioretti, MD, PhD fa.fioretti@libero.it Lucilla Servi, MD lucilla.servi@sanita.marche.it Surgery Department, Urology Unit, Macerata Hospital, ASUR Marche Area Vasta 3, Macerata, Italy Carolina Morosetti, MD carolina.morosetti@gmail.com Clinical Pathology, Jesi, Italy Alessandra Filosa, MD PhD alessandrafilosa@yahoo.it Section of Pathological Anatomy, Department of Clinical Pathology Macerata Hospital, ASUR Marche Area Vasta 3, Macerata, Italy Emanuele Principi, MD principie@gmail.com Resident, Urologic Clinic, Politechnic University of Marche Region, Ancona, Italy

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

111

Kisa_Stesura Seveso 28/06/18 16:37 Pagina 112

ORIGINAL PAPER

DOI: 10.4081/aiua.2018.2.112

The effect of the American Society of Anesthesiology classification scores on complications associated with percutaneous nephrolithotomy Erdem Kisa 1, Cem Yücel 1, Salih Budak 2, Murat Ucar 1, Mehmet Zeynel Keskin 1, Ozgur Cakmak 1, Gokhan Koc 1, Zafer Kozacioglu 1 1 Tepecik 2 Sakarya

Training and Research Hospital, Turkey; Training and Research Hospital, Turkey.

Summary

Objectives: We aimed to evaluate the effect of American Society of Anesthesiology (ASA) classification scoring and age on complications and surgical outcomes during and after percutaneous nephrolithotomy (PCNL) operation.

Material and methods: The records of 263 patients, above the age of 18 years, that underwent PCNL surgery between October 2014 and May 2017 were evaluated retrospectively.

The patients were divided into three groups based on their ASA risk scores (ASA 1, 2, 3) and into two groups based on their age (younger and older than 65 years). Postoperative complications were assessed according to the ASA groups and age and according to the Clavien classification system.

Results: The number of patients in the ASA 1, 2, and 3 groups were 97 (36.8%), 131 (49.8%) and 35 (13.3%), respectively.

Four patients in ASA4 were not included in the study. There was no significant difference in ASA 1, 2, 3 groups in terms of changes in Hgb values, mean duration of operation, and mean hospital stay. When ASA1 was compared to ASA3 and ASA2 was compared to ASA3, there was no significant difference in the incidence of all complication rates.

There were 159 (60.4%) patients in the young group and 104 (39.5%) patients in the elderly group. Postoperative PCNL complications of these 2 groups were compared according to Clavien classification system and no significant difference was found in incidence of complications.

Conclusions: We believe that PCNL operation can be performed effectively and safely in both ASA3 patients and patients above the age of 65 years.

(PCNL) is a standard operation in following cases: staghorn stones larger than 20 mm, stones resistant to shock wave lithotripsy (SWL), cystine stones, patients with anatomically anomalous upper urinary system, patients with anatomical defects (scoliosis, kyphosis or spasticity), lower pole stones larger than 15 mm and stones in transplant kidneys (2, 3). The reliability, efficacy and complication rates of the PCNL operation in elderly patients have been evaluated in many studies, just like the impact of the American Society of Anesthesiologist (ASA) classification scores (4-10).

The prevalence of systemic diseases increases with aging.

The ASA classification is a system in which patients are evaluated according to the risk of anesthesia prior to surgery. This system can be used to choose the type of anesthesia, to determine the monitoring method, and to assess the tolerance of patients to various surgical manipulations such as surgical position. Staying in prone position during PCNL can lead to some difficulties; such as those in controlling the airway, maintaining the vascular access and ventilation of patients with lung diseases in particular (11, 12).

In this study, we aimed to compare the effect of ASA risk classification scores on complications during and after PCNL surgery.

KEY WORDS: American Society of Anesthesiologists’ scoring system; MATERIALS AND METHODS We retrospectively reviewed the records of 263 patients Clavien classification system; Percutaneous nephrolithotomy; over the age of 18 years who underwent PCNL surgery in Surgical complications; Geriatric. our clinic between October 2014 and May 2017. Patients Submitted 25 March 2018; Accepted 29 April 2018 were divided into three groups: ASA1, ASA2 and ASA3.

Patients with an ASA score of 4 were excluded from the study. Patients were also divided into two groups accordINTRODUCTION ing to their age: elderly (65 years and over) and young Nephrolithiasis is one of the most common diseases, (18-65). Local ethics committee approved our study. An affecting nearly one in thirteen women and one in seven expert anesthesiologist evaluated all the patients preopermen (1). Certain factors such as location and composiatively. The risk of surgery was determined according to tion of the stone, patients’ anatomy and comorbidities the ASA classification score (Table 1). play an important role in the choice of treatment in uriDemographic, surgical and perioperative anesthetic data nary system stone disease. Stone size is the most imporand postoperative outcomes were obtained from patient tant factor in choosing the surgical modality for the records (Table 2 and 3). Patients with sterile urine culremoval of the stone. Percutaneous nephrolithotomy ture were taken into operation. Patients with urinary

112

No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

Kisa_Stesura Seveso 28/06/18 16:37 Pagina 113

The effect of the American Society of Anesthesiology classification scores on complications associated with percutaneous nephrolithotomy

complex, while partial or complete staghorn stones and stones located in both renal pelvis and a single calyx were classified as complex stones.

ASA-I A completely healthy patient All PCNL operations were performed in prone ASA-II A patient with mild systemic disease position and under general anesthesia and fluoASA-III A patient with severe systemic disease that is not incapacitating roscopy. A single dose of appropriate intravenous ASA-IV A patient with incapacitating disease that is a constant threat to life antibiotic was used as antimicrobial prophylaxis.

A ureteral catheter fixed to the Foley catheter was ASA-V A moribund patient who is not expected to live for 24 h with or without surgery placed. Tract dilation up to 30-French was achieved with Amplatz dilators and a 30-French Table 2. plastic Amplatz sheath was introduced. A 26The patients’ demographic data and stone locations.

French rigid nephroscope and ultrasonic lithotripter were used in all cases. A 24-French ASA 1 ASA 2 ASA3 nephrostomy tube was used for drainage when Patients, n (%) 97 (36.9%) 131 (49.8%) 35 (13.3%) necessary. The complications of the patients in Mean age ± standard deviation 44.4 ± 14.8 44 (18-75) 59.7 ± 11.6 ASA risk groups were classified according to the median (min-max) 65 (29-87) 65.8 ± 8.8 66 (50-93) modified Clavien scoring system (Table 4). Same Mean stone burden (mm2) 443.9 ± 364.3 500.2 ± 438.8 434.6 ± 311.7 criteria were used to compare the patients in the ± standard deviation 322 375 399 age groups (Table 5). All patients underwent nonmedian (min-max) (60-2275) (112-2772) (126-1880) contrast CT at first month postoperatively and Complex stone, n (%) 54 (55.6%) 61 (46.5%) 20 (57.1%) overall stone-free rate was evaluated.

Noncomplex stone, n (%) 43 (44.3%) 70 (53.4%) 15 (42.8%) Since the numerical variables in the groups did not Stone location show normal distribution, the median (minimumSuperior n=8 n=8 n=0 maximum) was used as the descriptive statistic.

Middle n = 13 n = 13 n=2 Moreover, the number (%) was used as a descripInferior n = 45 n = 72 n = 21 tive statistic for the categorical variables. A nonPelvis n = 31 n = 38 n = 12 parametric Kruskal-Wallis test was used to deterAverage access number 1.2 (117/97) 1.1 (152/131) 1.2 (42/35) mine whether there is a difference in numerical variables among the groups. The two proportions Z Test or the Fisher exact test were used to assess tract infections were treated according to the antibithe difference between the prevalence percentages of catogram. All patients were assessed by direct urinary sysegorical variables within the groups, depending on the tem RX-graphy and unenhanced computerized tomograassumptions. For all tests, the probability of Type I error phy (CT) preoperatively. The locations of the renal stones was set to α = 0.05. The R Project 3.2.5 package program were identified as upper, middle or lower calyx, and was used for all statistical analyses. pelvis. The stone size was calculated by multiplying the widest width and height of the stone. In patients with multiple stones in their urinary system, stone sizes were RESULTS calculated separately and added. Isolated stones in the The mean age of the groups, the stone dimensions, the upper, middle or lower calyces were classified as nonratio of complex to non-complex stones, the distribution of stone location, and the average number of accesses are shown in Table 3.

Table 2.

Study results by groups.

The changes in hemoglobin (Hgb) levels before and after the operaASA 1 ASA 2 ASA3 P tion, the mean duration of opera1Hgb preop-postop 1.70 (-0.80-8.70) 1.50 (-0.40-5.50) 1.50 (-0.30-6.10) 0.474 tion, and the mean hospital stay Median (min-max) of the groups are shown in Table 1Mean operative time (min) 93.0 ± 34.2 92.5 ± 37.3 100.5 ± 37.5 0.389 3. There was no statistically signifMean ± standard deviation 90 (40-230) 85 (45-210) 90 (55-225) icant difference between the Median (min-max) groups in terms of Hgb change, 1Mean hospitalization (days) 2.8 ± 1.3 3 ± 1.7 3.0 ± 1.9 0.674 mean duration of operation and Mean ± standard deviation 2 (2-8) 2 (2-10) 2 (2-10) mean hospital stay (p = 0.474, Median (min-max) 0.389 and 0.674, respectively).

2Postop 1-month stone free (%) 69 (71.1) 89 (67.9) 25 (71.4) 0.974ac, 0.687bc The overall stone free rates in Complications patients in the ASA 3 group were 3Grade1 n (%) 5 (5.1%) 5 (3.8) 1 (2.8) 0.999ac, 0.999bc compared with those in ASA 2 3Grade2 n (%) 8 (8.1%) 16 (12.1%) 5 (14.2%) 0.356ac, 0.752bc and ASA 1 groups (Table 3).

3Grade3 n (%) 3 (3.0%) 6 (4.5%) 2 (5.7%) 0.608ac, 0.676bc The overall stone-free rates of the 3Grade4 n (%) 0 2 (1.5%) 1 (2.8%) 0.265ac, 0.511bc 2Overall complication rates groups were 71.1% for ASA1, 16.4% 22.1% 25.7% 0.266ac, 0.664bc 67.9% for ASA2, and 71.4% for 1 Kruskal-Wallis Test; 2 Two Proportion Z Test (Bonferroni Correction was made); 3 Fisher Exact Test (Bonferroni Correction was made).

ASA3. The separate comparison Table 1.

ASA scoring system.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

113

Kisa_Stesura Seveso 28/06/18 16:37 Pagina 114

E. Kisa, C. YĂźcel, S. Budak, M. Ucar, M. Zeynel Keskin, O. Cakmak, G. Koc, Z. Kozacioglu

Table 4.

Modified Clavien classification according to ASA groups.

Clavien complication rates ASA 1 n (%) GRADE 1 Fever (over 38.5°C, requiring antipyretic treatment) 5 (5.1) GRADE 2 Blood transfusion 6 (6.1) Urinary tract infection requiring additional antibiotics (instead of prophylactics) 2 (2.0) GRADE 3a Double-J stent placement for urine leakage > 24 h (local anesthesia) 1 (1.0) Pleural effusion 0 Pneumothorax 0 GRADE 3b Double-J stent placement for urine leakage > 24 h (ureter stone, general anesthesia) 1 (1.0) AV fistula Perirenal hematoma needing intervention 1 (1.0) Perioperative bleeding requiring termination of the operation 0 0 GRADE 4a Pulmonary Emboli (requiring intensive care unit) 0 Neighboring organ injury 0 Nephrectomy 0 Urosepsis 0 GRADE 5 Death 0

ASA 2 n (%)

ASA3 n (%)

5 (3.8)

1 (2.8)

13 (9.9)

4 (11.4)

3 (2.2)

1 (2.8)

3 (2.2) 1 (0.7) 1 (0.7)

1 (2.8) 0 0

1 (%0.7) 0 0 0

1 (2.8)

1 (0.7) 0 0 1 (0.7)

0 0 0 1 (2.8)

0

0

65> young n = 159 n (%)

P

0 0 0

Table 5.

Modified Clavien scoring according to the age groups.

Clavien complication

65 < elderly n = 104 n (%)

GRADE 1 Fever 5 (4.8) GRADE 2 Blood transfusion 12 (7.5) Urinary tract infection requiring additional antibiotics (instead of prophylactics) 2 (1.2) Total 14 GRADE 3a Double-J stent placement for urine leakage > 24 h (local anesthesia) 1 (0.6) Pleural effusion 0 Pneumothorax 2 (1.2) GRADE 3b Double-J stent placement for urine leakage > 24 h (ureter stone, general anesthesia) 0 AV fistula 0 Perirenal hematoma needing intervention 0 Perioperative bleeding requiring termination of the operation 4 Total 0 GRADE 4a Pulmonary Emboli (requiring intensive care unit) 1 (0.6) Neighboring organ injury 0 Nephrectomy 0 Urosepsis 1 (0.6) GRADE 5 Death 0 1 Two

114

Proportion Z Test; 2 Fisher Exact Test

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

0.6891 6 (3.8) 0.3231 11 (10.5) 4 (3.8) 15 0.9992 1 (0.6) 4 (3.8) 0 1 (0.9) 1 (0.9) 1 (0.9) 0 7

DISCUSSION

0 0 0 0 0

between ASA3 and ASA1, ASA3 and ASA2 groups at 1-month follow-up did not reveal any statistically significant difference in terms of stone-free percentage (p = 0.974 and 0.687, respectively).

The complications in patients in the ASA 3 group were compared with those in ASA 2 and ASA 1 groups (Table 3). There was no significant difference between ASA1 and ASA3 groups in terms of the separate incidence of grade 1, grade 2, grade 3, and grade 4 complications (p = 0.999, 0.356, 0.608, 0.265, respectively). The comparison of ASA2 and ASA3 groups also did not show any significant difference in terms of the separate incidence of grade 1, grade 2, grade 3, and grade 4 complications (p = 0.999, 0.752, 0.676, and 0.511 respectively). When ASA1 and ASA3, ASA2 and ASA3 groups were compared separately, there was no significant difference in terms of percentage of overall complication rates (Bonferroni correction, p = 0.266 and 0.664, respectively).

There were 104 patients (39.5%) in the elderly group and 159 patients (60.4%) in the young group.

The post-PCNL surgery complications of these two groups were compared according to modified Clavien classification system (Table 5). There was no significant difference in the incidence of Grade 1, Grade 2, Grade 3 complications between the age groups (> = 65 and < 65) (p = 0.689, 0.323, and 0.999, respectively).

Patients' comorbidities were divided according to the groups.

The mean number of comorbidities in ASA1 was 0.06 (6/97), in ASA2 was 1.2 (158/131), and in ASA3 was 2.1 (75/35). The most commonly observed comorbidity was hypertension (100/263, 38%).

The PCNL surgery is the standard treatment option for large kidney stones. Many studies have shown that PCNL can be successful in high-risk patients (ASA3 and ASA4) (8-10). An increase in the rate of systemic disease is expected in patients with advanced age.

In a study by Kuzgunbay et al. the

Kisa_Stesura Seveso 28/06/18 16:37 Pagina 115

The effect of the American Society of Anesthesiology classification scores on complications associated with percutaneous nephrolithotomy

patients who underwent PCNL surgery were divided into two groups based on their age: elderly (65 years and older) and the control group (18-36 years). The comparison of comorbidity prevalence showed that while 73% of patients in the elderly group had at least one comorbidity, there were no comorbidities in control patients (13). In a study by Nouralizadeh et al. the number of co-morbidities in high-risk patients was 2, while this ratio was 5.4 in a study by Patel et al. (8-10). In our study, we observed that the average number of co-morbidities increased from 0.06 to 2.1 when going from ASA1 to ASA3. This increased rate increases the number of medications used by patients, which in turn is an important factor to consider before, during and after the operation by both surgeons and the anesthesiologists, especially in ASA3 patients.

In the literature, the proportion of the elderly individuals among patients undergoing PCNL surgery ranges 10 to 12% (14). However, in a study by Anagnostou et al., where they set the lower age limit to 70 years, 17% of the patients undergoing PCNL surgery were in that group (4). In our study, the ratio of elderly patients was 39%.

We believe that our ratio is high because the age limit in our study was 65, our hospital is an institution that receives many referrals, and because the patients who need intensive care after operation were also treated in our hospital.

Bleeding and septic complications of PCNL may become more significant in elderly patients with impaired cardiopulmonary and renal function (15). For this reason, the risks associated with anesthesia may be more prevalent in older patients compared to younger patients.

The anesthesiologists and surgeons are always concerned about invasive treatments such as PCNL when it comes to older patients with renal stones. Therefore, when evaluating treatment alternatives in these patients, general health of the patient should be considered along with the size and location of the stone (16). Careful pre-operative examinations can provide comprehensive safety for surgical procedures in elderly patients (4).

Higher prevalence of complex stones in elderly and highrisk patients can be explained by patientsâ&#x20AC;&#x2122; and surgeonsâ&#x20AC;&#x2122; initial reluctance to do surgery in favor of more conservative treatments and as a result stones get bigger and develop a staghorn formation (10). Sahin et al. reported that stone sizes are larger in elderly patients compared to younger patients (1077.92 mm2 versus 920.85 mm2) (5).

Similarly, in our study, the median stone size and percentage of complex stone structures were higher in ASA3 patient group.

Although PCNL surgery has been shown to be safe and effective in all age groups, minor and life-threatening complications can occur during and after surgery (7, 17, 18).

PCNL related fever (0-32.1%), hemorrhage requiring transfusion (0-20%), embolization (0-1.5%), urinoma (01%), sepsis (0.3-1.1%), thoracic complications (0-1.6%), organ injury (0-1.7%), and death (0-0.3%) can be observed at varying rates (19). In 2007, Tefekli et al. developed a modified Clavien classification system for PCNL surgeries in order to better evaluate and inform patients about possible complications. This system also classifies complications seen during and after the operation by grading them (20).

Patel et al. found that the overall risk of complications was higher in the high-risk group compared to the lowrisk group (21.2% vs. 18.5%). The majority of complications in the high-risk group consisted of grade 2 complications (12.1%), while grade 1 complications made up 9.1%. However, there was no significant difference between the complication rates of high-risk group and the low risk group (8). Similarly, the most common complication in our study was grade 2. When ASA1 was compared with ASA3 and ASA2 was compared with ASA3 there was no significant difference in terms of percentage of overall complication rates. Moreover, the comparison of age groups (older and younger than 65 years) also did not show any significant difference in terms of percentage of overall complications.

The studies on bleeding complications during and after PCNL operation in high-risk and elderly patients are controversial. Resorlu et al. have shown that the probability of bleeding increases when comorbidity increases (21).

Similarly, Nouralizadeh et al. found that the rate of blood transfusion was higher in in high-risk group compared to the low-risk (ASA1, 2) groups, but Hgb replacement was similar in all groups (10). However, Patel et al. assessed the patientsâ&#x20AC;&#x2122; complications based on the modified Clavien system, and found no difference in terms of bleeding and transfusion requirements between high and low risk groups (8). In the study by Stoller et al. the patients were divided into groups: over and below the age of 65 years.

Although both groups had similar preoperative Hgb levels, post-operative blood transfusion rates were higher in elderly group compared to the younger group (26% to 13.7%) (6). In our study, we did not find any differences in Hgb exchange and blood transfusion requirements in both ASA risk groups and in patients younger and older than 65 years. At the same time, there was no difference in terms of Hgb exchange and blood transfusion requirements.

Comorbidities and older age have been shown to affect stone-free rates. Karami et al. reported not seeing any significant difference in stone-free rates between patients younger and older than 65 years (7). Resorlu et al. reported that the increase in the Charlson comorbidity score had significantly reduced the stone-free rates (21).

In the study by Patel et al. the total stone-free rate was 61% in the high-risk group and 92% in the low-risk group, and this difference was significant (8). In our study, according to the results of the CT scans on 1month postoperative follow-up there was no significant difference in terms of complete stone-free percentage when we compared ASA1 with ASA3 and ASA2 with ASA3 groups (p = 0.974 and 0.687, respectively).

The first limitation of this study is that it was performed retrospectively. Our second limitation is that although the diameter of the access sheath is gradually reduced in PCNL surgeries, we have used 30F sheath in our study.

However, since the blood transfusion rates in our study were compatible with the current literature, we decided not to change the sheet diameter.

CONCLUSIONS

With increase in the life expectancy and aging of the world population improving quality of life has become Archivio Italiano di Urologia e Andrologia 2018; 90, 2

115

Kisa_Stesura Seveso 28/06/18 16:37 Pagina 116

E. Kisa, C. Yücel, S. Budak, M. Ucar, M. Zeynel Keskin, O. Cakmak, G. Koc, Z. Kozacioglu

very imperative. Aging is associated with increased prevalence of comorbidity and other concomitant risks.

We found that although the number of comorbidities and the risk of anesthesia are higher in ASA3 risk group compared with patients in the ASA1 and ASA2 risk groups, there was no significant difference in terms of complete stone-free rates, complication rates, and hospitalization times following a PCNL surgery. Therefore, we believe that PCNL surgery can be performed safely and effectively in both high-risk patients with comorbidities as well as elderly patients.

REFERENCES

1. Stamatelou KK, Francis ME, Jones CA, et al. Time trends in reported prevalence of kidney stones in the United States: 1976 1994. Kidney Int, 2003; 63:1817.

2. Morris DS, Taub DA, Wei JT, et al. Regionalization of percutaneous nephrolithotomy: evidence for the increasing burden of care on tertiary centers. J Urol. 2006; 176:242-246.

3. Srirangam SJ, Darling R, Stopford M, et al. Contemporary practice of percutaneous nephrolithotomy: a review of practice in a single region of the UK. Ann R Coll Surg Engl. 2008; 90:40-44.

4. Anagnostou T, Thompson T, Ng CF, et al. Safety and outcome of percutaneous nephrolithotomy in the elderly: retrospective comparison to a younger patient group.J Endourol. 2008; 22:2139-45.

5. Sahin A, Atsu N, Erdem E, et al. Percutaneous nephrolithotomy in patients aged 60 years or older. J Endourol. 2001; 15:489-491.

6. Stoller ML, Bolton D, St Lezin M, et al. Percutaneous nephrolithotomy in the elderly. Urology. 1994; 44:651-654.

11. Ozturk E, Yilmazlar T. Factors affecting the mortality risk in elderly patients undergoing surgery. ANZ J Surg. 2007; 77:156-159.

12. Froehner M, Koch R, Litz R, et al. Comparison of the American Society of Anesthesiologists physical status classification with the Charlson score as predictors of survival after radical prostatectomy.

Urology. 2003; 62:698-701.

13. Kuzgunbay B, Turunc T, Yaycioglu O, et al. Percutaneous nephrolithotomy for staghorn kidney stones in elderly patients. Int Urol Nephrol 2011; 43:639-643.

14. Gentle DL, Stoller ML, Bruce JE, et al. Geriatric urolithiasis. J Urol. 1997; 158:2221-2224.

15. Tonner PH, Kampen J, Scholz J. Pathophysiological changes in the elderly. Best Pract Res Clin Anaesthesiol. 2003; 17:163-177.

16. Akman T, Binbay M, Ugurlu M, et al. Outcomes of retrograde intrarenal surgery compared with percutaneous nephrolithotomy in elderly patients with moderate-size kidney stones: a matched-pair analysis J Endourol. 2012; 26:625-9.

17. De la Rosette J, Assimos D, Desai M, et al. CROES PCNL Study Group: The Clinical Research Office of the Endourological Society Percutaneous Nephrolithotomy Global Study: indications, complications, and outcomes in 5,803 patients. J Endourol. 2011; 25:11-17.

18. Kumar R, Anand A, Saxena V, et al. Safety and efficacy of PCNL for management of staghorn calculi in pediatric patients. J Pediatr Urol. 2011; 7:248-251.

7. Karami H, Mazloomfard MM, Golshan A, et al. Does age affect outcomes of percutaneous nephrolithotomy? Urol J. 2010; 7:17-21.

19. Seitz C, Desai M, Häcker A, et al. Incidence, prevention, and management of complications following percutaneous nephrolitholapaxy. Eur Urol. 2012; 61:146.

8. Patel SR, Haleblian GE, Pareek G. Percutaneous nephrolithotomy can be safely performed in the high-risk patient. Urology. 2010; 75:51-55.

20. Tefekli A, Karadag M, Tepeler K, et al. Classification of percutaneous nephrolithotomy complications using the modified Clavien grading system: looking for a standard. Eur Urol. 2008; 53:184.

9. Toksoz S, Dirim A, Kizilkan Y, et al. The effect of American Society of Anesthesiology scores on percutaneous nephrolithotomy outcomes. Urol Int. 2012; 89:301-6.

21. Resorlu B, Diri A, Atmaca AF, et al. Can we avoid percutaneous nephrolithotomy in high-risk elderly patients using the Charlson Comorbidity Index? Urology. 2012; 79:1042-1047.

Correspondence Erdem Kisa, MD drerdemkisa@hotmail.com Cem Yücel, MD Murat Ucar, MD drmuratucar@hotmail.com Mehmet Zeynel Keskin. MD zeynel_akd@hotmail.com Ozgur Cakmak, MD drozgurcakmak577@yahoo.com Gokhan Koc, MD gokfekoc@gmail.com Zafer Kozacioglu, MD zaferkozacioglu@gmail.com Tepecik Training and Research Hospital, Urology Department, Izmir, Turkey Salih Budak, MD salihbudak1977@gmail.com Sakarya Training and Research Hospital, Turkey

116

10. Nouralizadeh A1, Lashay A, Ziaee SA, et al. Percutaneous nephrolithotomy in high-risk patients: a single-center experience with more than 350 cases Urol Int. 2013; 90:394-8.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

Celik_Stesura Seveso 28/06/18 16:54 Pagina 117

DOI: 10.4081/aiua.2018.2.117

ORIGINAL PAPER

Tadalafil versus alpha blockers (alfuzosin, doxazosin, tamsulosin and silodosin) as medical expulsive therapy for < 10 mm distal and proximal ureteral stones Serdar Celik 1, Firat Akdeniz 1, Muge Afsar Yildirim 2, Ozan Bozkurt 3, Merve Gursoy Bulut 2, Mehmet Levent Hacihasanoglu 1, Omer Demir 3 1 Gaziemir

Nevvar Salih Isgoren Hospital, Department of Urology, Izmir, Turkey; Nevvar Salih Isgoren Hospital, Department of Radiology, Izmir, Turkey; 3 Dokuz Eylul University, School of Medicine, Department of Urology, Izmir, Turkey.

2 Gaziemir

Objectives: To evaluate the effect of tadalafil compared with four alpha blockers (alfuzosin, doxazosin, tamsulosin and silodosin) as medical expulsive treatment for ureteral stones in male adults.

Materials and methods: Male adults who were admitted to urology clinic with flank pain and diagnosed with non complicated < 10 mm ureteral stone on non-contrast computed tomography (NCCT) between June 2014-September 2015 were retrospectively evaluated. A total of 273 patients with ureteral stone were divided into five groups. Alfuzosin 10 mg/daily, doxazosin 8 mg/daily, tamsulosin 0.4 mg/daily, silodosin 8 mg/daily and tadalafil 5 mg/daily for 6 weeks were prescribed respectively.

Stone localization, diameter, volume and Hounsfield units were noted as NCCT findings. The patients were divided into the two groups based on their stone localization as distal and mid-proximal stones. These two groups were evaluated separately.

Expulsion rate were noted at the end of 6 weeks. NCCT and treatment findings were compared between five drug groups in distal and mid-proximal stones separately.

Results: Age was higher in tadalafil group in distal stones (p = 0.032). Expulsion rate was found 78.1% for alfuzosin, 75.7% for doxazosin, 76.5% for tamsulosin, 88.6% for silodosin and 90% for tadalafil in distal (p = 0.44) and 21.7%, 30%, 30%, 30% and 54.5% in mid-proximal stones (p = 0.034) respectively.

Conclusions: Expulsion rate was higher in silodosin and tadalafil for distal ureteral stones but the difference didnâ&#x20AC;&#x2122;t meet statistical significance. However the expulsion rate was significantly higher in tadalafil than in the other groups for mid-proximal ureteral stones. The result of this study showed that tadalafil may increases ureteric stone expulsion.

Summary

KEY WORDS: Alpha blockers; Medical expulsive theraphy; tadalafil; Ureteral stone.

Submitted 17 March 2018; Accepted 4 April 2018

INTRODUCTION

Urinary tract stone disease is most prevalent between the ages of 20 and 40 years and 3 times more common in men than women (1). Twenty percent of all urinary tract stones are found in the ureter and many of these stones should be treated with efficacious treatment modalities such as extracorporeal shock wave lithotripsy (SWL) and endoscopic laser

or pneumatic lithotripsy with ureterorenoscopy (URS) (2, 3).

But these treatments include some risks such as complications of treatment, failure and high cost. Therefore, some predictors were determined on non-contrast computed tomography (NCCT) of stone diameter, stone volume, Hounsfield units (HU) and Hounsfield density (HD) to reduce these risks (4). For ureteral stones, although the watchful waiting approach has been reported to be associated with spontaneous stone expulsion for about 50% of ureteral stones, some complications may occur such as urinary tract infections, hydronephrosis and colic events (3). Medical expulsive therapy (MET), another method for stone expulsion, has become routine in the treatment of obstructive ureteral calculi in recent years. The use of various drugs as MET, which affect the ureter via different mechanisms, can reduce symptoms and facilitate stone expulsion. Alpha and beta adrenergic receptors were found in the ureter (5). Alpha-1 and particularly subtype alpha-1D are the most commonly observed adrenergic receptor subtypes in the ureteral smooth muscle cells (6). Alpha blockade has been proven to decrease peristaltic activity, contraction and intraureteral pressure and to improve spontaneous stone passage and decrease both the time to stone passage and analgesic requirements (7, 8). According to European Association of Urology Guidelines, alpha-blockers are recommended for MET because they should ensure well controlled pain, no clinical evidence of sepsis, and adequate renal functional reserve (9). A phosphodiesterase-5 (PDE-5) inhibitor (tadalafil), which acts on the NO/cGMP signaling pathway of smooth muscles, causes ureteral relaxation (10). A recent study reported that tadalafil showed a high ureteral stone expulsion rate and significant pain control (11).

Alpha blockers and tadalafil in MET have a proven role to promote stone passage and reduce the need for minimally invasive surgery for distal ureteral stones. However, these findings were not investigated for proximal ureteral stones.

In related studies only two of three drugs were compared for MET with distal ureteral stones. Therefore we wanted to evaluate the possible effect of tadalafil compared with alpha blockers, which are alfuzosin, doxazosin, tamsulosin and silodosin, for MET in uncomplicated distal and proximal ureteral stones in male adults.

No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

117

Celik_Stesura Seveso 28/06/18 16:54 Pagina 118

S. Celika, F. Akdeniza, M. Afsar Yildirimb, O. Bozkurtc, M. Gursoy Bulutb, M. Levent Hacihasanoglua, O. Demirc

MATERIAL

AND METHODS

After approval obtained from the Local Ethics Committee, we retrospectively reviewed the records of > 18 year old male patients with uncomplicated ureteral stones of < 10 mm diameter on NCCT images between June 2014 and September 2015. After the informed consent, only male patients were included in the study to standardize patients and to eliminate the differences in expulsion time depending on anatomical differences between female and male patients. There is also an indication problem for tamsulosin, silodosin and tadalafil treatment for female patients in our country. Therefore only male patients were selected for the study. Patients who had not previously received any alpha blocker or tadalafil treatment were treated with alpha blockers or PDE-5 inhibitor for 6 weeks. Patients who had only ureteral stone and were treated with one of four alphablockers (alfuzosin 10 mg/daily (Xatral, Sanofi Aventis), doxazosin 8 mg/daily (Cardura, Pfizer), tamsulosin 0.4 mg/daily (Tamprost, Zentiva), silodosin 8 mg/daily (Urorec, Recordati)) as MET were included in the study. Patients who had concomitant erectile dysfunction and did not accept the use of alpha blockers were treated with tadalafil 5 mg/daily (Cialis, Lilly and Lifta, Abdi Ibrahim) for possible effect of ureteral stones expulsion and erectile dysfunction treatment. Patients who were diagnosed with nephrolithiasis, > 10 mm ureteral stones, bilateral ureteral stones, ureteral stones requiring drainage or obstructive, grade 3 hydronephrosis, multiple ureteral stones and any anatomical abnormalities on NCCT examination were excluded from the study. Patients with urinary tract infection, fever and elevated creatinine level were also excluded.

All patients who had unsuccessful MET underwent shock wave lithotripsy (SWL) or ureterorenoscopic (URS) treatment.

Demographic data of included patients (age, height, weight and body mass index (BMI)) were noted. Before MET, NCCT images using 2 mm sections with the liver's dome as cranial border and pubis joint as caudal border at 100 mA 120 kV (Alexion TSX-034A, Toshiba®, Japan) were taken. The localization of stone, the stone diameter, the stone volume, grade of hydronephrosis, the distance of stone from ureterovesical junction (for distal stones) as described by Yuceturk CN et al. (12), the distance of stone from ureteropelvic junction (for proximal stones), Hounsfield units (HU) and Hounsfield density (HD) of the stone measured by NCCT were noted. All measurements were calculated by one radiologist. Largest stone diameters were measured on longitudinal, transverse, and axial images and mean stone diameter was calculated as the average of these three values. HU and stone volume were calculated with computed tomography viewer program.

HD was calculated as the HU divided by mean stone diameter (13). All patients were divided into five drug groups as alfuzosin, doxazosin, tamsulosin, silodosin and tadalafil groups. Drug groups were subdivided into two groups according to the stone localization on NCCT images as distal and mid-proximal ureteral stones and were evaluated separately. For stone localization, the anatomical limit of ureteral parts was defined as the level of the iliac artery crossing the ureter. Below this area was defined as distal, while above this area was defined as mid-proximal. Time interval follow-up of MET was 6 weeks. Patients were instructed to take diclofenac 50 mg tablets orally during

118

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

episodes of pain, and filter their urine to detect stone expulsion. Expulsion time was noted when the stone was observed in the filtered urine. Suspicious expulsions or unsuccessful expulsion of stone were confirmed with NCCT at the end of the 6th week. Treatment findings (expulsion success rate and expulsion time) were noted at the end of MET. Demographic data of patients, NCCT findings and treatment findings were compared between drug groups for distal and mid-proximal ureteral stones separately. The primary endpoint expected from the study is the expulsion rate for alpha-blockers and tadalafil groups. The secondary endpoint is expulsion times for the groups. Finally an important endpoint is the tadalafil expulsion success for mid-proximal ureteral stones.

Statistical analysis Demographic data of patients were analyzed and compared for all groups. The parameters measured on NCCT (the stone diameter, grade of hydronephrosis, the stone volume, the distance of stone from ureterovesical junction, the distance of stone from ureteropelvic junction, HU and HD) were compared between all 5 groups.

The Pearson χ2 test and Kruskal-Wallis test were applied between the groups for nonparametric statistical analysis using commercially available software (Statistical Package for the Social Sciences, Version 20.0; SPSS, Chicago, III).

The alpha level of statistical significance was set at .05.

RESULTS

Male adults who were admitted to the urology clinic with flank pain and diagnosed with uncomplicated ureteral Table 1.

Demographic data, tomography findings and expulsion findings of the study population.

Variables Age, year; mean ± SD (range) Height, cm; mean ± SD (range) Weight, kg; mean ± SD (range) BMI, kg/m2; mean ± SD (range) Percentage of stone localization Distal Mid-Proximal Mean stone diameter, mm; mean ± SD (range) Stone volume, mm3; mean ± SD (range) The distance of distal ureteral stone from ureterovesical junction, mm; mean ± SD (range) The distance of mid-proximal ureteral stone from ureteropelvic junction, mm; mean ± SD (range) HU; mean ± SD (range) HD, HU/mm; mean ± SD (range) Percentage of hydronephrosis grade None Grade 1 Grade 2 Grade 3 Percentage of expulsion success rate Expulsion time, day; mean ± SD (range)

All patients (n = 273) 41 ± 11.3 (20.3-80) 1.74 ± 6 (161-190) 82.7 ± 13.7 (56-125) 27.2 ± 4.1 (18.3-39.9) 61.5 38.5 4.9 ± 1.7 (1-10) 80.3 ± 83.5 (0.5-502) 9.7 ± 4.3 (1-22) 84.9 ± 37.7 (29-152) 571.2 ± 307.8 (89-1384) 114.5 ± 40 (41.4-280.5) 16.9 53.1 30 0 63 11.3 ± 9.5 (2-39)

Abbreviations: BMI, Body Mass Index; HU, Hounsfield Units; HD, Hounsfield Density.

Celik_Stesura Seveso 28/06/18 16:54 Pagina 119

Tadalafil as medical expulsive therapy

stone on NCCT between June 2014 and September 2015 were retrospectively evaluated.

A total of 273 male adults were included in the study.

Mean age was 41 ± 11.3 (20.3-80) years and mean BMI was 27.2 ± 4.1 (18.3-39.9) kg/m2 for the whole group.

Mean age, height, weight, BMI, stone localization, mean stone diameter, stone volume, the distance of stone from ureterovesical junction, the distance of stone from ureteropelvic junction, HU, HD, grade of hydronephrosis, stone expulsion rate and expulsion time are given in Table 1 for all patients.

Considering the stone localization there were 168

patients with distal and 105 patients with mid-proximal ureteral stones. In drug groups; 55 patients were treated with alfuzosin, 57 with doxazosin, 54 with tamsulosin, 55 with silodosin and 52 with tadalafil. In the drug groups 32, 37, 34, 35 and 30 patients had distal, and 23, 20, 20, 20 and 22 patients had mid-proximal ureteral stones, respectively. There was no significant difference in the demographic data (height, weight and BMI) of the five groups for distal and mid-proximal ureteral stones (p > .05) (Table 2 and 3).

Age was higher in the tadalafil group than the other groups for distal ureteral stones (p = .032) (Table 2).

Table 2.

Comparison of computed tomography findings and expulsion rate and time between alfuzosin, doxazosin, tamsulosin, silodosin and tadalafil groups of MET in distal ureteral stones.

Distal ureteral stones (n = 168) Variables a Age, year; median ± SD Height, cm; median ± SD Weight, kg; median ± SD BMI, kg/m2; median ± SD Stone diameter, mm; median ± SD Stone volume, mm3; median ± SD The distance of stone from ureterovesical junction, mm; median ± SD Hounsfield units, HU; median ± SD Hounsfield density, HU/mm; median ± SD Percentage of hydronephrosis grade 2 Percentage of expulsion rate Expulsion time, day; median ± SD

Alfuzosin (n = 32)

Doxazosin (n = 37)

Tamsulosin (n = 34)

Silodosin (n = 35)

tadalafil (n = 30)

P value

41.7 ± 13.3

38.2 ± 12.8

43.9 ± 11.5

39.2 ± 11

46.3 ± 9.9

.026

172.9 ± 5.7 82 ± 14 27.4 ± 3.9 4.9 ± 1.4 75.1 ± 73.1

175.1 ± 4.8 82.6 ± 11 26.9 ± 3.4 4 ± 1.7 48.6 ± 56.5

175.2 ± 7.4 82.1 ± 12.6 26.6 ± 2.8 4.5 ± 1.8 68.9 ± 94.4

176.3 ± 5.2 82.3 ± 10.9 27.2 ± 3.7 4.5 ± 1.7 66.3 ± 69.7

178 ± 1.7 85.7 ± 12.2 27.1 ± 4.3 4.7 ± 1.8 75.1 ± 84.5

.322 .663 .542 .227 .220

9.5 ± 4.2 9.6 ± 4.9 9.1 ± 3.8 9.5 ±3. 6 10.9 ± 5.1 527.2 ± 270.6 442.5 ± 269.3 461.3 ± 291.6 491.8 ± 287.5 494.2 ± 268.4 103.5 ± 35.9 111.1 ± 36.1 99.8 ± 34.2 104.8 ± 34.7 105.2 ± 35.9 18.7 21.6 129.4 37.1 33.3 78.1 75.7 76.5 88.6 90 11.7 ± 5.7 11.6 ± 7.2 9.5 ± 7.6 10.9 ± 10.1 5.7 ± 3.4

.66 .471 .689 .404 .44 .019

BMI, Body Mass Index; HU, Hounsfield Units. variables were compared by Kruskal-Wallis test.

a Continuous

Table 3.

Comparison of computed tomography findings and expulsion rate and time between alfuzosin, doxazosin, tamsulosin, silodosin and tadalafil groups of MET in mid-proximal ureteral stones.

Mid-proximal ureteral stones (n = 105) Variables a Age, year; median ± SD Height, cm; median ± SD Weight, kg; median ± SD BMI, kg/m2; median ± SD Stone Diameter, mm; median ± SD Stone Volume, mm3; median ± SD The distance of stone from ureteropelvic junction, mm; median ± SD Hounsfield units, HU; median ± SD Hounsfield density, HU/mm; median ± SD Percentage of hydronephrosis grade 2 Percentage of expulsion rate Expulsion time, day; median ± SD

Alfuzosin (n = 23)

Doxazosin (n = 20)

Tamsulosin (n = 20)

Silodosin (n = 20)

Tadalafil (n = 22)

P value

40.8 ± 10.7 172 ± 4.9 89.6 ± 16.4 30.3 ± 5.7 5.3 ± 1.8 101.8 ± 102.2

39.6 ± 8.7 175.3 ± 4.6 91.7 ± 19.7 29.8 ± 5.8 5.2 ± 1.2 79.4 ± 52.7

39.1 ± 10.4 172.5 ± 6.6 77.7 ± 13 26.2 ± 4.4 5.3 ± 1.6 100.4 ± 115.3

37.8 ± 13.1 173.2 ± 5.6 83.6 ± 15.7 27.8 ± 4.9 6 ± 1.2 123.5 ± 61.2

41.2 ± 8.3 172.7 ± 5.7 79.2 ± 8.3 26.6 ± 2.3 5.7 ± 1.6 119 ± 100.9

.765 .525 .177 .147 .251 .207

90.7 ± 36.3 775 ± 259.6 145.7 ± 38.3 30 30 10.7 ± 12.4

81.2 ± 40.6 721.7 ± 344 116.6 ± 42.2 40 30 8.3 ± 6

90.8 ± 40.8 838.7 ± 327.2 143.9 ± 35 40.1 54.5 18.3 ± 14.7

.889 .125 .062 .185 .034 .191

84.4 ± 37.1 77.6 ±35.2 672.6 ± 294.2 606.7 ± 241.9 127.5 ± 48.7 116.4 ± 36.9 26.1 30 21.7 30 26 ± 5.6 18 ± 20.8

BMI, Body Mass Index; HU, Hounsfield Units. variables were compared by Kruskal-Wallis test.

a Continuous

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

119

Celik_Stesura Seveso 28/06/18 16:54 Pagina 120

S. Celika, F. Akdeniza, M. Afsar Yildirimb, O. Bozkurtc, M. Gursoy Bulutb, M. Levent Hacihasanoglua, O. Demirc

NCCT findings of the drug groups are given in Table 2 and 3. There was no significant difference in stone diameter, stone volume, the distance of stone from ureterovesical junction, the distance of stone from ureteropelvic junction, HU, HD and grade of hydronephrosis between the five groups with distal and mid-proximal ureteral stones (p > .05). Expulsion rate was 78.1% for alfuzosin, 75.7% for doxazosin, 76.5% for tamsulosin 88.6% for silodosin and 90% for tadalafil for distal ureteral stones and 21.7%, 30%, 30%, 30% and 54.5% for mid-proximal ureteral stones, respectively.

Median expulsion time was 11.7 days for alfuzosin, 11.6 days for doxazosin, 9.5 days for tamsulosin, 10.9 days for silodosin and 5.7 days for tadalafil for distal and 26, 18, 10.7, 8.3 and 18.3 days for mid-proximal ureteral stones, respectively. Expulsion rates for silodosin and tadalafil groups with distal ureteral stones were higher than the other three groups, but this result was not statistically significant (p = .44).

Expulsion time for the tadalafil group was significantly lower than the other drug groups with distal ureteral stones (p = .019) (Table 2). Expulsion rate of the tadalafil group was significantly higher than the other groups with mid-proximal ureteral stones (p = .034). However, there was no statistically significant difference between the groups in terms of expulsion time for mid-proximal ureteral stones (Table 3).

DISCUSSION

In brief, the expulsion rate was higher in silodosin and tadalafil groups compared to the other groups for distal ureteral stones, but did not reach statistical significance between the groups (expulsion rate was 78.1%, 75.7%, 76.5%, 88.6%, and 90% for alfuzosin, doxazosin, tamsulosin, silodosin and tadalafil, respectively).

However, the expulsion rate was significantly higher in the tadalafil group compared to the other groups for mid-proximal ureteral stones (21.7%, 30%, 30%, 30% and 54.5%, respectively). Also, age was higher in the tadalafil group than in the other groups for distal ureteral stones.

In European Association of Urology (EAU) guidelines, MET, SWL and URS are recommended in the treatment of ureteral stones (9). In recent studies, some possible and accurate predictors were determined that affect the success of SWL and URS (4, 14). These predictors were stone diameter, stone volume, HU, and HD of ureteral stones and grade of hydronephrosis on NCCT. Therefore, in our study these factors were equivalent in the drug groups to reduce the effect on MET. According to previous studies, the expulsion rate of distal ureteral stones during watchful waiting is 25-54% with mean expulsion time > 10 days. To increase the expulsion rate and decrease the analgesic requirements, medical therapy is recommended for distal ureteral stones (15-18). In an AUA/EAU panel, two medical therapies, which are calcium channel blocker and alphareceptor antagonists, were optionally recommended for distal ureteral stones.

The meta-analysis of six studies of alpha blockers (280 patients) yielded an expulsion rate of 81% (19).

120

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

There are several studies that show no significant difference between expulsion rates of alpha-blockers for distal ureteral stones. Alfuzosin expulsion rates were reported as 85.6% in a randomized controlled prospective study (20). In a recent randomized, placebo-controlled trial comparing placebo, tamsulosin and nifedipine as MET for distal, middle and proximal ureteral stones, there was no significant difference between the groups (21).

In a recent meta-analysis, there was no statistically significant difference in stone expulsion rate and time between alfuzosin and tamsulosin (22). In a study evaluating alfuzosin and doxazosin as MET for distal ureteral stones, expulsion rates and time were reported as 52.9% and 7.38 ± 5.55 days with alfuzosin, 62% and 7.85 ± 5.11 days with doxazosin, respectively (23).

In a prospective randomized study comparing silodosin with tamsulosin, the efficacy of silodosin (high selective antagonist of alpha-1A receptor) was shown to be superior to tamsulosin (alpha-1D and alpha-1A receptors selective antagonist) (24, 25). Tadalafil, which is a smooth muscle relaxant, has recently been approved by the US Food and Drug Administration (FDA) for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia and erectile dysfunction (10). Gratzke et al. demonstrated the role of the PDE-5 inhibitors of vardanafil, sildenafil and tadalafil in relaxation of ureteral muscles (26-29).

In a recent study Kumar et al. detected significantly higher expulsion rate and lower expulsion time in a silodosin group compared to tamsulosin and tadalafil groups for distal ureteral stones (11).

In another recent study which compared the expulsion rate and expulsion time of tamsulosin with the combination of tadalafil and tamsulosin, higher expulsion rate and lower expulsion time were detected in the tamsulosin plus tadalafil group (83.6% and 14.9 ± 4.4 days) compared with the tamsulosin group (65.5% and 16.7 ± 4.8 days) (30).

In this study, we divided ureteral stones into two groups according to their localization as distal and midproximal. For distal ureteral stones, the stone expulsion rates with silodosin and tadalafil were higher than alfuzosin, doxazosin and tamsulosin, but the difference did not reach statistical significance. However, expulsion time in the tadalafil group was lower than in alpha blocker groups (alfuzosin, doxazosin, tamsulosin and silodosin) for distal ureteral stones. We found a higher expulsion rate in the tadalafil group compared to alphablockers (alfuzosin, doxazosin, tamsulosin and silodosin) for mid-proximal ureteral stones and that was statistically significant. However, expulsion time was not found to be statistically significant between the groups. Alpha-blockers and PDE-5 inhibitors have separate mechanisms that increase the stone expulsion compared to watchful waiting. Successful combination of tamsulosin and tadalafil used by Jayant et al. opened up the potential use of a combination of silodosin with tadalafil (11, 30).

The limitations of this study are that it is retrospective, non-randomized and has a limited number of patients in drug groups for ureteral stones. Due to the retrospective nature of the study, three major parameters, which were

Celik_Stesura Seveso 28/06/18 16:54 Pagina 121

Tadalafil as medical expulsive therapy

quantity of additional analgesic usage, frequency of acute renal colic and emergency visits of patients, could not be evaluated. Also, age was higher and expulsion time was lower in the tadalafil group than in the other groups for distal ureteral stones. The explanation of this result may be that stone expulsion was a rapid condition of the tadalafil usage or that elderly patients could expel stones more easily due to possibly more compliant ureters.

Another limitation is that concomitant erectile dysfunction was only present in the tadalafil group. However, additional drug usage or concomitant diseases were not significantly different between the groups.

Finally the important result of the study and the difference from the other studies is that 5 mg daily tadalafil usage is associated with high stone expulsion success in patients diagnosed with mid-proximal ureteral stones.

CONCLUSIONS

The result of this study indicates that tadalafil showed a significantly lower stone expulsion time compared with alpha-blockers for distal ureteral stones.

The most important finding is the higher expulsion rate with tadalafil for mid-proximal ureteral stones compared with alpha-blockers.

Therefore this situation opens up the potential use of a combination of tadalafil and silodosin for distal and midproximal ureteral stones and this combination of tadalafil in MET may reduce the need for SWL therapy and minimally invasive procedures. However, there is a need for large prospective randomized studies to clarify these findings.

REFERENCES

9. Türk C, Knoll T, Petrik A, et al. Guidelines on Urolithiasis European Association of Urology Updated March 2015.

10. Oelke M, Giuliano F, Mirone V, et al. Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial. Eur Urol. 2012; 61:917.

11. Kumar S, Jayant K, Agrawal MM, et al. Role of tamsulosin, tadalafil, and silodosin as the medical expulsive therapy in lower ureteric stone: a randomized trial (a pilot study). Urology. 2015; 85:59.

12. Yuceturk CN, Dadali M, Bagbanci MS, et al. Efficacy of Silodosin Dose in Medical Expulsive Therapy for Distal Ureteral Stones: A Retrospective Study. Urol J. 2017; 14:2944.

13. Nakada SY, Hoff DG, Attai S, et al. Determination of stone composition by noncontrast spiral computed tomography in the clinical setting. Urology. 2000; 55:816.

14. Ito H, Kawahara T, Terao H, et al. Predictive value of attenuation coefficients measured as Hounsfield units on noncontrast computed tomography during flexible ureteroscopy with holmium laser lithotripsy: a single-center experience. J Endourol. 2012; 26:1125.

15. Bensalah K, Pearle M, Lotan Y. Cost effectiveness of medical expulsive therapy using alpha-blockers for the treatment of distal ureteral stones. Eur Urol. 2008; 53:411.

16. Wolf JS Jr. Treatment selection and outcomes: ureteral calculi.

Urol Clin N Am. 2007; 34:421.

17. Wang CJ, Tsai PC, Chang CH. Efficacy of silodosin in expulsive therapy for distal ureteral stones: a randomized double-blinded controlled trial. Urol J. 2016; 13:2666.

18. Celik S, Akdeniz F, Afsar Yildirim M, et al. Computed tomography findings predicting the success of silodosin for medical expulsive therapy of ureteral Stones. Kaohsiung J Med Sci. 2017; 33:290.

1. Manglaviti G, Tresoldi S, Guerrer CS, et al. In vivo evaluation of the chemical composition of urinary stones using dual-energy CT. AJR Am J Roentgenol. 2011; 197:76.

19. Preminger GM, Tiselius HG, Assimos DG, et al. Management of ureteral calculi: EAU/AUA Nephrolithiasis Panel. J Urol. 2007; 178:2418.

2. Ahmed AF, Al-Sayed AY. Tamsulosin versus Alfuzosin in the Treatment of Patients with Distal Ureteral Stones: Prospective, Randomized, Comparative Study. Korean J Urol. 2010; 51:193.

20. Sameer, Lal S, Charak KS, Chakravarti S, Kohli S, Ahmad S. Efficacy of nifedipine and alfuzosin in the management of distal ureteric stones: A randomized, controlled study. Indian J Urol.

2014; 30:387.

3. Dellabella M, Milanese G, Muzzonigro G. Randomized trial of the efficacy of tamsulosin, nifedipine and phloroglucinol in medicalexpulsive therapy for distal ureteral calculi. J Urol. 2005; 174:167.

4. Celik S, Bozkurt O, Kaya FG, et al. Evaluation of computed tomography findings for success prediction after extracorporeal shock wave lithotripsy for urinary tract stone disease. Int Urol Nephrol. 2015; 47:69.

5. Malin JM Jr, Deane RF, Boyarsky S. Characterisation of adrenergic receptors in human ureter. Br J Urol. 1970; 42:171.

6. Küpeli B, Irkilata L, Gürocak S, et al. Does tamsulosin enhance lower ureteral stone clearance with or without shock wavelithotripsy? Urology. 2004; 64:1111.

7. Yilmaz E, Batislam E, Basar MM, et al. The comparison and efficacy of 3 different alpha1-adrenergic blockers for distal ureteral stones. J Urol. 2005; 173:2010.

8. Watts HF, Tekwani KL, Chan CW, et al. The effect of alphablockade in emergency department patients with ureterolithiasis. J Emerg Med. 2010; 38:368.

21. Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015; 386:341.

22. Liu C, Zeng G, Kang R, et al. Efficacy and safety of alfuzosin as medical expulsive therapy for ureteral stones: a systematic review and meta-analysis. PLoS One. 2015; 10:e0134589.

23. Gurbuz MC, Polat H, Canat L, et al. Efficacy of three different alpha 1-adrenergic blockers and hyoscine N-butylbromide for distal ureteral stones. Int Braz J Urol. 2011; 37:195.

24. Dell'Atti L. Silodosin versus tamsulosin as medical expulsive therapy for distal ureteral stones: a prospective randomized study.

Urologia. 2015; 82:54.

25. Wang CJ, Huang SW, Chang CH. Efficacy of an alpha1 blocker in expulsive therapy of lower ureteral stones. J Endourol. 2008; 22:41.

26. Gratzke C, Uckert S, Reich O, et al. PDE5 inhibitors. A new option in the treatment of ureteral colic? Urologe A. 2007; 46:1219.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

121

Celik_Stesura Seveso 28/06/18 16:54 Pagina 122

S. Celika, F. Akdeniza, M. Afsar Yildirimb, O. Bozkurtc, M. Gursoy Bulutb, M. Levent Hacihasanoglua, O. Demirc

27. Gratzke C, Uckert S, Kedia G, et al. In vitro effects of PDE5 inhibitors sildenafil, vardenafil and tadalafil on isolated human ureteral smooth muscle: a basic research approach. Urol Res. 2007; 35:49.

29. KĂźhn R, Uckert S, Stief CG, et al. Relaxation of human ureteral smooth muscle in vitro by modulation of cyclic nucleotidedependent pathways. Urol Res. 2000; 28:110.

28. Taher A, Schul-Knappe P, Meyer M, et al. Characterization of cyclic nucleotide phosphodiesterase isoenzymes in the human ureter and their functional role in vitro. World J Urol. 1994; 12:286.

30. Jayant K, Agrawal R, Agrawal S. Tamsulosin versus tamsulosin plus tadalafil as medical expulsive therapy for lower ureteric stones: a randomized controlled trial. Int J Urol. 2014; 21:1012.

Correspondence Serdar Ă&#x2021;elik, MD, FEBU, sPhD (Corresponding Author) serdarcelik84@hotmail.com Firat Akdeniz, MD, FEBU dr.frt@mynet.com Mehmet Levent Hacihasanoglu, MD lhhasan@mynet.com Gaziemir Nevvar Salih Isgoren Hospital, Department of Urology, Izmir, Turkey Muge Afsar Yildirim, MD mugeavsar@yahoo.com Merve Gursoy Bulut, MD gursoymerve@yahoo.com Gaziemir Nevvar Salih Isgoren Hospital, Department of Radiology, Izmir, Turkey Ozan Bozkurt, Associate Professor drozanbozkurt@gmail.com Omer Demir, MD, Professor omer.demir@deu.edu.tr Dokuz Eylul University, School of Medicine, Department of Urology, Izmir, Turkey

122

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

Arena_Stesura Seveso 28/06/18 16:54 Pagina 123

DOI: 10.4081/aiua.2018.2.123

ORIGINAL PAPER

Utility of uroflowmetry during the follow-up of children affected by balanitis xerotica obliterans (BXO) Salvatore Arena, Tiziana Russo, Pietro Impellizzeri, Saveria Parisi, Patrizia Perrone, Carmelo Romeo Department of Human Pathology in Adult and Developmental Age â&#x20AC;&#x153;Gaetano Barresiâ&#x20AC;?, Unit of Paediatric Surgery, University of Messina, Italy.

Summary

Introduction: To evaluate the outcome of circumcised patients with balanitis xerotica obliterans (BXO) using uroflowmetry (UF).

Methods: Between 2011 and 2013, 180 children underwent a circumcision for phimosis. The foreskin was examined on microscopy. Patients with an histological diagnosis of BXO were included in the study. Patients with BXO underwent UF two weeks after surgery and treatment with clobetasol propionate ointment. Patients were re-evaluated at 6, 12, 18 and 24 months postoperatively clinically and using UF. Results: 75 of 180 circumcised patients (41.6%) were included.

At two weeks, Thirtytwo of 75 patients (42.7%) displayed a pathological UF. At six months, 15 patients (20%) had pathological UF and a new cycle of clobetasol was prescribed. At one year, 10 patients (13.3%) displayed patholgocial UF and underwent progressive urethral dilatation or meatoplasty. At 18 months, 71 patients (94.7%) displayed regular UF, 3 underwent a meatoplasty and one a staged urethroplasty for a severe urethral stenosis. At two years, UF was normal in 74 out of 75 (98.7%).

Conclusions: We recommend to send for hystological examination all foreskins excised after circumcision. We believe that a clinical and uroflowmetric follow-up of pediatric patients with BXO is mandatory for a prompt identification of post-voiding dysfunction.

KEY WORDS: Phimosis; Balanitis xerotica obliterans; Uroflowmetry.

Submitted 3 April 2018; Accepted 29 April 2018

INTRODUCTION

Lichen sclerosus et atrophicus of the foreskin called also balanitis xerotica obliterans (BXO) is one of main causes of acquired phimosis (1, 2), firstly reported in pediatric age

by Catterall in 1962 (2).

It is a chronic inflammatory disease of unclear etiology, which can affect the foreskin, frenulum, glans, meatus and urethra (1-3). It is believed that the real incidence of BXO is underestimated in the general population and BXO is considered uncommon in children (4). Significant obstructive complications secondary to phimosis complicated by BXO are described (5-7), among them urethral meatal stenosis is the most frequent one. As regards, recent studies report that 7-19% of boys circumcised for BXO require a subsequent meatal procedure (5, 8-12) and a meatoplasty is required in up to 36% of cases (5). Rarely, BXO affects

the urethra causing stenosis and, even if it is related to squamosus cell carcinoma in adulthood, no cases of malignant lesion are reported in pediatric age (5, 7, 9).

Uroflowmetry (UF) has been traditionally used in the follow-up of patients with voiding dysfunction including children, because it is a simple, non invasive and unexpensive diagnostic tool (13, 14). Despite the welldescribed complications of BXO in term of obstructive uropathy, UF is not routinely used during post follow-up in patients undergoing circumcision with a histological diagnosis of BXO. Aim of the study is to assess the short and long-term outcome of circumcised patients with BXO using UF, in order to identify early obstructive features related to this disease.

MATERIALS

AND METHODS

Between January 2011 to December 2013, 180 children underwent a circumcision for clinical diagnosis of secondary phimosis at our Department. The foreskin was examined on light microscopy by a pathologist. Patients with an histological diagnosis of BXO were included in the study. BXO was defined as an epithelial-stromal lesion characterized by squamous atrophy or hyperplasia, band like infiltration, hyalinization of the papillary dermis, hyperkeratosis, pigment incontinence and/or dermal edema. We excluded from the study patients with pre-operative treatment with corticoid ointment or cream and without histologically proven BXO. A chart review was performed, collecting data relating to demographics, clinical presentation, histopathological findings, steroid therapy and follow-up.

Patients with BXO underwent UF two weeks after surgery and clobetasol propionate 0.05% ointment was applied once daily, at night, for 4 weeks, then on alternate nights for 4 weeks, and then twice weekly for a further 4 weeks, according to Pugliese JM et al. (15).

UF was carried out in a quiet and private room, with a comfortable environment to prevent any performance failure. An hour before the test, the children drank fluids for a total equal to the expected bladder capacity (age x 30 ml + 30 ml). The test was performed when the children felt the normal sensation of fullness in the bladder or in the presence of urinary urgency. Volume of 50 mL or more and between 50% and 100% if the expected

No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

123

Arena_Stesura Seveso 28/06/18 16:54 Pagina 124

S. Arena, T. Russo, P. Impellizzeri, S. Parisi, P, Perrone, C. Romeo

bladder capacity were considered as relevant for interpretation. At least, two tests are usually done since high variability in UF tests could lead to a misleading diagnosis (16). Voided volume, Qmax (peak flow rate with a duration of at least two seconds) and uroflow curves were considered for interpretation of results.

Patients were re-evaluated at 6, 12, 18 and 24 months postoperatively clinically and using UF. The Qmax was plotted on body surface related flow rate nomograms that correlate the voided volume of urine to the Qmax.

The upper 95% tolerance limits for the 5th, 10th, 15th, 20th and 25th percentiles of normal population were used for comparison. To interpret uroflow data we used flow rate nomograms proposed by Tonguri (17). The flow pattern was classified as bell ring, plateau or intermittent (18, 19).

and a two stage buccal mucosal graft was started. At two years, Qmax was normal (14.8 ± 2.2 ml/sec) with a bell ring UF pattern in 74 out of 75 (98.7%) patients while it was not assessable in patient underwent first stage of buccal mucosal graft procedure.

Table 1 summarizes the results.

DISCUSSION

Reviewing the literature, the incidence of BXO in patients with phimosis ranges from 5 to 50%, with the peak of incidence at 7-8 years age (1).This difference in the studies could be due to various factors, including the different indications for circumcision and the assessment made by different specialists such as pediatricians, dermatologists, urologists and pediatrics surgeons (1-3).

Usually, the diagnosis of BXO is initially clinical, displayRESULTS ing un-retractable foreskin, white xerotic appearance of 75 out of 180 patients (41.6%) with an histological diagglans and foreskin, dysuria and voiding disturbances. nosis of BXO were included in the study. The mean age at However, the final diagnosis needs to be confirmed by diagnosis was 9.2 ± 2.1 years, ranging from 5 to 15 years. histological examination (20). Furthermore, clinical At two weeks, UF showed a mean Qmax 10.1 ± 3.3 ml/sec; diagnosis seems to underestimate the real incidence of 32 out of 75 patients (42.7%) displayed a significant low histological BXO. As regards, Bochove reported that the Qmax (6.7 ± 1.4 ml/sec) and a plateau flow pattern. At six 50% of patients with BXO would not have been diagmonths after surgery, all patients repeated UF, showing a nosed if it was not carried out histological examination, mean Qmax 11.9 ml/sec ± 3.3 ml/sec. Fifteen (20%) of and this data is also confirmed from studies in the adult these patients had a significant low Qmax and a plateau population (10) curve, with a mean Qmax of 5.9 ± 0.7 ml/sec, while 60 On a systematic histological study of foreskin of pediatric (80%) patients had a normal Qmax of with a mean of 13.4 patients underwent a circumcision for phimosis, it has ± 1.5 ml/sec with bell ring flow pattern. We prescribed a been documented that 45.1% of congenital phimosis and new cycle of clobetasol topic treatment for 12 weeks in 62.3% of acquired phimosis had histological features of patients with obstructive pattern at UF. BXO (9). Kiss et al. (21) reported that 40% of children At one year after surgery, overall mean Qmax in 75 UF was with phimosis treated by circumcision had a BXO, with 13.0 ± 2.5 ml/sec and 10 out of 75 patients (13.3%) disa higher incidence in patients aged between 9 and 11 played a significant low Qmax and a pleateau flow patyears, and a secondary phimosis was found in 90-93% of tern; 65 out of 75 patients showed normal Qmax (13.9 ± the boys with BXO (21-22). Moreover, BXO was found 1.2 ml/sec) with a bell ring UF pattern. The 10 patients in 52.6% of patients with phimosis under the age of five with pathological UF (7.3 ± 0.6 ml/sec) underwent proyears (23). Recently, the incidence of the disease seems to gressive urethral dilatation (5 patients) and diagnostic be increased, with a peak between 9 and 11 years (5). It cystoscopy (5 patients). In the latter, cistoscopy was negis unclear the reason of this increment, but an increased ative for urethral pathology and a meatoplasty was perincidence could be linked to the fact that more foreskin formed. At 18 months, 71 out of 75 patients (94.7%) samples have been sent for histopathological examinadisplayed regular Qmax according to age and bell ring tion, due to surgeons awareness about this disease and flow pattern (mean 14.5 ± 1.0 ml/sec). Differently, 4 the foreskin examination, that is performed with more patients, that previously had undergone progressive uresuspicious (5). Furthermore, it has been reported an thral dilatation, showed low Qmax and a plateau flow alarming increase of incidence of unrecognized diagnosis pattern (mean 7.3 ± 0.9 ml/sec). A cistoscopy was then of BXO that is placed only when it is responsible of comperformed that was negative for urethral obstruction in 3 plications (4). We agree with some Authors' suggestion patients. The latter underwent a meatoplasty. to performing routinely histological analysis of the foreDifferently, a severe urethral stenosis occurred in a patient skin after circumcision, to avoid potential complications related to BXO. In our experience, an histological diagnosis of BXO was done in 41.6% of children undergone circumcision for secTable 1. ondary phimosis, with an average age of 9.2 Qmax values in patients with histological BXO. ± 2.1 years. Data of our study confirmed Normal UF Patological UF Overall those of literature.

2 weeks 12.6 ± 1.6 ml/sec (43) 6.7 ± 1.4 ml/sec (32) 10.1 ± 3.3 ml/sec Circumcision appears as the definitive treat6 months 13.4 ± 1.5 ml/sec (60) 5.9 ± 0.7 ml/sec (15) 11.9 ± 3.3 ml/sec ment in 96% of cases in several studies (8, 22-25) and the treatment with topical 12 months 13.9 ± 1.2 ml/sec (65) 7.3 ± 0.6 ml/sec (10) 13.0 ± 2.5 ml/sec steroids following circumcision appears 18 months 14.5 ± 1.0 ml/sec (71) 7.3 ± 0.9 ml/sec (4) 14,1 ± 1.9 ml/sec decisive for avoiding complications, the 24 months 14.8 ± 2.2 ml/sec (74) N/A 14.8 ± 2.2 ml/sec most common of which are stenosis of the

124

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

Arena_Stesura Seveso 28/06/18 16:54 Pagina 125

Uroflowmetry in children affected by BXO

meatus or urethra (15, 25, 26, 28). As regards, Kulkarni described 215 adult patients who underwent surgery for hystologically proven BXO involving the foreskin and the anterior urethra (20), Christman et al. described six cases of obstructive urinary complication secondary to BXO in children (7). Corbett et al. described meatus as abnormal o affected in 23% patients with BXO at time of circumcision (29). In our experience, 8 patients underwent a successful meatoplasty (in 3 after failed cycles of progressive urethral dilatation), one patient healed after progressive urethral dilatation and another required a two stage urethral reconstruction for severe urethral stricture.

While rare, the morbidity that can result from progression of this disease can be significant, leading to obstructive disease with impaired bladder and renal function (7, 30).

The diagnosis of BXO can be straightforward with earlier diagnosis and we consider as mandatory the surveillance of patients with BXO following circumcision and to perform UF during follow-up for monitoring changes in urinary flow, evaluating response to topical therapy and deciding whether to switch to second-level exams and/or therapeutic management.

The UF test has gained wide acceptance, as the initial screening tool to evaluate voiding function in children because it is considered as a reliable test for the diagnosis and for the follow-up of post-voiding abnormality. As regards, it is traditionally used to evaluate the functional results following hypospadias repair to identify asymptomatic obstruction early, being considered the most accurate, physiologic and non invasive method of assessing bladder outflow obstruction (31).

In fact, it is well know that in the urethral strictures, Qmax is diminished and the flow pattern loses is normal bell shape and becomes flattened (31). UF allowed us to identify 32 patients with voiding dysfunction out of 75 patients with a histological diagnosis of BXO (44%) and to successfully and promptly treat them with medical or mini-invasive management in 31 cases (97%), recording just one serious urethral lesion, requiring a major surgery.

CONCLUSIONS

We recommend that all foreskins excised after circumcision have to be sent for hystological examination for and earlier identification of BXO. We believe that a follow-up of pediatric patients with BXO is mandatory for a prompt identification of post-voiding dysfunction and that the non-invasive, well-accepted and reliable nature of the UF makes it a first tool for the diagnosis and evaluation of BXO related meatal and urethral complications.

REFERENCES

1. Jasaitiene D, Valiukeviciene S, Vaitkiene D, et al. Lichen sclerosus et atrophicus in pediatric and adult male patients with congenital and acquired phimosis. Medicina (Kaunas) 2008; 44:460-6.

2. Russo T, Currò M, Barbera A, et al. Expression of transglutami-

nase in foreskin of children with balanitis xerotica obliterans. Int J Mol Sci. 2016;17. pii: E1551.

3. Currò M, Russo T, Ferlazzo N, et al. Anti-inflammatory and tissue regenerative effects of topical treatment with ozonated olive oil/vitamin E acetate in balanitis xerotica obliterans. Molecules.

2018; 23. pii: E645.

4. Catterall RD, Oates JK. Treatment of balanitis xerotica obliterans with hydrocortisone injections. Br J Vener Dis. 1962; 38:75-7.

5. Celis S, Reed F, Murphy F, et al. Balanitis xerotica obliterans in children and adolescents: a literature review and clinical series. J Pediatr Urol. 2014; 10:34-9.

6. Gargollo PC, Kozakewich HP, Bauer SB, et al. Balanitis xerotica obliterans in boys. J Urol. 2005; 174:1409-12 7. Christman MS, Chen JT, Holmes NM. Obstructive complications of lichen sclerosus. J Pediatr Urol. 2009; 5:165-9.

8. Becker K. Lichen Sclerosus in boys. Dtsch Arztzebl Int. 2011; 108:53.

9. Clouston D, Hall A, Lawrentschuk N. Penile lichen sclerosus (balanitis xerotica obliterans). BJU Int. 2011; 108:14-9.

10. Bochove-Overgaauw DM, Gelders W, De Vylder AM. Routine biopsies in pediatric circumcision: (non) sense? J Pediatr Urol. 2009; 5:178-80.

11. Holbrook C, Tsang T. Management of boys with abnormal appearance of meatus at circumcision for balanitis xerotica obliterans. Ann R Coll Surg Engl. 2011; 93:482-4.

12. Wilkinson DJ, Lansdale N, Everitt LH, et al. Foreskin preputioplasty and intralesional triamcinolone: a valid alternative to circumcision for balanitis xerotica obliterans. J Pediatr Surg. 2012; 47:756-9.

13. Alyami F, Farhat W, Figueroa VH, et al. Utility and cost-effectiveness of uroflowmetry in a busy pediatric urology practice. Can Urol Assoc J. 2014; 8:E615-8 14. Anwar A, Kurokawa Y, Takahashi M, et al. Functional evaluation of one-stage urethroplasty with parameatal foreskin flaps repair of hypospadias using uroflowmetry. Int J Urol. 2003; 10:297-301.

15. Pugliese JM, Morey AF, Peterson AC. Lichen sclerosus: review of the literature and current recommendations for management. J Urol.

2007; 178:2268-76.

16. Chang SJ, Yang SS. Variability, related factors and normal reference value of post-void residual urine in healthy kindergarteners. J Urol. 2009; 182:1933-8.

17. Toguri AG, Uchida T, Bee DE. Pediatric uroflow rate nomograms. J Urol. 1982; 127:727-31.

18. Siroky MB. Interpretation of urinary flow rates. Urol Clin North Am. 1990; 17:537-42.

19. Austin PF, Bauer SB, Bower W, et al. The standardization of terminology of lower urinary tract function in children and adolescents: Update report from the standardization committee of the International Children's Continence Society. Neurourol Urodyn.

2016; 35:471-81.

20. Kulkarni S, Barbagli G, Kirpekar D, et al. Lichen sclerosus of the male genitalia and urethra: surgical options and results in a multicenter international experience with 215 patients. Eur Urol. 2009; 55:945-54.

21. Edmonds EV, Hunt S, Hawkins D, et al. Clinical parameters in male genital lichen sclerosus: a case series of 329 patients. J Eur Acad Dermatol Venereol. 2012; 26:730-7.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

125

Arena_Stesura Seveso 28/06/18 16:54 Pagina 126

S. Arena, T. Russo, P. Impellizzeri, S. Parisi, P, Perrone, C. Romeo

22. Kiss A, Király L, Kutasy B, et al. High incidence of balanitis xerotica obliterans in boys with phimosis: prospective 10-year study.

Pediatr Dermatol. 2005; 22:305-8.

23. Meuli M, Briner J, Hanimann B, et al. Lichen sclerosus et atrophicus causing phimosis in boys: a prospective study with 5-year followup after complete circumcision. J Urol. 1994; 152:987-9.

28. Kizer WS, Prarie T, Morey AF. Balanitis xerotica obliterans: epidemiologic distribution in an equal access health care system. South Med J. 2003; 96:9-11.

24. Jayakumar S, Antao B, Bevington O, et al. Balanitis xerotica obliterans in children and its incidence under the age of 5 years. J Pediatr Urol. 2012; 8:272-5.

29. Homer L, Buchanan KJ, Nasr B, et al. Meatal stenosis in boys following circumcision for lichen sclerosus (balanitis xerotica obliterans). J Urol. 2014; 192:1784-8.

25. Mattioli G, Repetto P, Carlini C, et al. Lichen sclerosus et atrophicus in children with phimosis and hypospadias. Pediatr Surg Int. 2002; 18:273-5.

30. Sandler G, Patrick E, Cass D. Long standing balanitis xerotica obliterans resulting in renal impairment in a child. Pediatr Surg Int. 2008; 24:961-4.

26. Depasquale I, Park AJ, Bracka A. The treatment of balanitis xerotica obliterans. BJU Int. 2000; 86:459-65.

31. González R, Ludwikowski BM. Importance of urinary flow studies after hypospadias repair: a systematic review. Int J Urol. 2011; 18:757-61.

27. Liatsikos EN, Perimenis P, Dandinis K, et al. Lichen sclerosus et

Correspondence Salvatore Arena, MD (Corresponding Author) salarena@unime.it; tel +390902213014 Tiziana Russo, MD Pietro Impellizzeri, MD Saveria Parisi, MD Patrizia Perrone, MD Carmelo Romeo, MD Department of human pathology in adult and developmental age “Gaetano Barresi”, University of Messina, Unit of Paediatric Surgery AUO “Gaetano Martino”, viale Gazzi, 98124 Messina, Italy

126

atrophicus. Findings after complete circumcision. Scand J Urol Nephrol. 1997; 31:453-6.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

Ferrara_Stesura Seveso 28/06/18 16:38 Pagina 127

DOI: 10.4081/aiua.2018.2.127

ORIGINAL PAPER

Desmopressin 120 mcg, 180 mcg, 240 mcg: The right treatment for the right patient Pietro Ferrara 1, 2, Ester Del Vescovo 2, Francesca Ianniello 1, Giulia Franceschini 2, Luciana Romaniello 3, Alberto Verrotti 4 1 Institute

of Pediatrics, Catholic University Medical School, Rome, Italy; Bio-Medico University, Rome, Italy; 3 San Carlo Hospital, Potenza, Italy; 4 Department of Pediatrics, University of L’Aquila, L’Aquila, Italy.

2 Campus

Summary

Background: The first-line drug therapy for patients with nocturnal enuresis (NE) associated with nocturnal polyuria and normal bladder function is desmopressin (dDAVP).

Objective: To evaluate if increasing dose of oral desmopressin lyophilisate (MELT) can improve response rates to dDAVP and is useful in enuretic children.

Materials and methods: We enrolled a total of 260 children all diagnosed with NE. Enuretic children were treated with increasing MELT at a dose of 120, 180 and 240 mcg a day.

Results. We included in our study a total of 237 children, 164 males (69.2%) and 73 females (30.8%) aged between 5 and 18 years (mean age 10.32 ± 2.52 years). Of the 237 patients enrolled in the study and treated with MELT 120 mcg, a full response was achieved in 135 (56.9%). A partial response was achieved in 21 (8.9%) patients, therefore the dose was increased up to 180 mcg, with further improving symptoms (14.3%) or full response (9.5%), and up to 240 mcg, without usefulness.

Conclusions: MELT at the dose of 120 mcg resulted efficacy and safety; the increased dose up to 180 mcg resulted poorly efficacy; finally, the further increase up to 240 mcg did not improve the symptoms with the increased risk of side effects.

KEY WORDS: Desmopressin; Nocturnal enuresis.

Submitted 14 February 2018; Accepted 16 March 2018

INTRODUCTION

Nocturnal enuresis (NE) is a very common pediatric disorder. According to recent International Children’s Continence Society (ICCS), NE is defined as intermittent incontinence occurs exclusively during sleeping periods. NE should not be used to refer to daytime incontinence (1).

In children without any other lower urinary tract symptoms and without a history of bladder dysfunction is defined as mono-symptomatic NE (MNE).

NE is a multifactorial disorder. It has 3 main pathophysiological determinants that are nocturnal polyuria, detrusor overactivity and failure to awaken in response to bladder sensations. When organic disease is not suspected and children suffer from MNE that causes a significant problem, it should be treated (2).

The first-line drug therapy for patients with MNE associ-

ated with nocturnal polyuria and normal bladder function is desmopressin (dDAVP) for a period of 3 months following by withdrawal. dDAVP is associated with a response rate of about 40-60%, however its effect may not be maintained on discontinuing treatment, and symptoms have been found to recur in about 50-80% after stopping treatment (3).

The different formulations of dDAVP are an intranasal solution, an oral tablet formulation and the recent oral sublingual lyophilisate (MELT). The aim of this study is to evaluate if increasing dose of MELT (120, 180, 240 mcg/day) can improve response rates to dDAVP in enuretic children.

MATERIALS

AND METHODS

We enrolled a total of 260 children all diagnosed with NE, between April 2014 and April 2017, at the Paediatric Service of Campus Bio-Medico Hospital in Rome.

Inclusion criteria were: age > 5 years and a diagnosis of primary MNE (PMNE) without NE treatment in the last 3 months. Exclusion criteria were the presence of secondary NE, any provided story of urinary infection, nephrogenic diabetes or congenital genitourinary anomalies. The children and their families were asked to participate in the study. This study was conducted in accordance with the regulatory standards of Good Clinical Practice and the Declaration of Helsinki.

We carefully evaluated each patients with medical history and physical examination, including monitoring blood pressure, possible sign of spinal dysraphism or polythelia, neurological reflexes and genital examination.

During the period of treatment, all patients and their parents were asked to keep a NE calendar depicting the wet and the dry nights and in addition, we educated both child and parents with dietary advices (4).

During the follow-up, families were called to verify their adherence and responses to the therapy and dietary recommendations.

Enuretic children were initially treated for a period of 3 weeks with MELT (Minirin®) at a dose of 120 mcg a day and after this observation period, the responders or full responders continued treatment up to three months, the

No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

127

Ferrara_Stesura Seveso 28/06/18 16:38 Pagina 128

P. Ferrara, E. Del Vescovo, F. Ianniello, G. Franceschini, L. Romaniello, A. Verrotti

partial responders increased MELT at a dose of 180 mcg and non responders were excluded. Patients who had increased the dose to 180 were observed for 3 weeks and even in this observation period, the responders or full responders continued treatment up to three months, the partial responders increased MELT at a dose of 240 mcg and non responders were excluded. Finally patients treated with MELT 240 mcg were observed for 3 weeks and even in this observation period, the responders or full responders continued treatment up to three months and non responders were excluded.

According to the ICCS classification for initial success, the children were classified as non-responders if there was no or less than 50% decrease in wet nights compared to baseline; partial responders if there was 50% or more, but less than 90% decrease in wet nights compared to baseline; responders if there was a 90% or more decrease in wet nights compared to baseline; full responders if there was a 100% decrease or less than 1 symptom occurrence monthly.

RESULTS

We enrolled 260 children with PNE. Of these, 23 were excluded for the following reasons: 15 had undergone therapy with MELT, 5 were lost to the follow up, 3 because of a further period of observation. We included in our study a total of 237 children, 164 males (69.2%) and 73 females (30.8%) aged between 5 and 18 years (mean age 10.32 Âą 2.52 years).

Of the 237 patients enrolled in the study and treated with MELT 120 mcg, a full response was achieved in 135 (56.9%), a partial response was achieved in 21 (8.9%) and 81 (34.2%) had no response in terms of a decreased number of wet nights, reflecting values in the literature.

When the 21 partial responders increased MELT at a dose of 180 mcg, 16/21 (76.2%) had no further improvement and a mild improved response was achieved in 3/21 (14.3%); in these patients in which MELT dosage was increased to 240 mcg/day, a response or full response was achieved only in 2/21 (9.5%).

They were evaluated again after 3 weeks of pharmacological therapy combined with dietary advices. Of the 3 patients that increased the dosage to 240 mcg/day, no one had response in terms of a decreased number of wet nights.

DISCUSSION

In our study we would like to highlight the importance of appropriate dDAVP administration and to clarify best practice in the use of this medication.

Reported response rates vary, only 41% of patients achieved â&#x2030;Ľ 50% reduction in wet nights in the study by Lottman et al. (5), but 77% achieved > 90% reduction in the study by Onol et al. (6). It depends on the type of patients selected, suboptimal adherence rates, administration methods and doses and formulations used (7).

Several studies have demonstrated decreased secretion of ADH and a reduced response to antidiuretic hormone in children affected. Moreover, NE may be present with several comorbidities such as sleep disorders, psychological

128

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

problems, parasomnias, left-handedness, polythelia, language disorders and testicular pathology (8-10).

Various formulations of dDAVP are available (tablets, nasal spray) and many studies also showed that the dosage for MELT is more predictable due to the significantly smaller variance, however there is only limited information on the response to dDAVP in children relative to the dose required to produce an antidiuretic effect for the entire night. In a previous dose-ranging study, dDAVP tablets of up to 600 mcg at bedtime did not appear to reach a maximum effect (11, 12).

In our study only a small percentage of patients who had increased the dose of MELT to 180 mcg have further improved symptoms (14.3%) or was full responders (9.5%). No patient treated with 240 mcg had usefulness.

It can suggests the importance of selecting the right treatment for the right patients.

Patients must be properly evaluated and diagnosed, and therapy must be used appropriately for the treatment to be successful. Data show that proper patient screening can predict treatment response, as well as failure rates.

A recent study, in fact, suggests that also the use of bladder diaries is highly recommended wherever possible (13).

Therefore, it is essential that the treating physician recognize that dDAVP will not work for all patients, and increasing dosage is not helpful if we do not use some tools to predict response. It is important that the most appropriate treatment strategy is selected as quickly as possible in order to minimize distress and difficulty for the patient and family.

MELT at the dose of 120 mcg resulted efficacy and safety; the increased dose up to 180 mcg resulted poorly efficacy; finally, the further increase up to 240 mcg did not improve the symptoms with the increased risk of side effects.

REFERENCES

1. Austin PF, Bauer SB, Bower W, et al. The standardization of terminology of lower urinary tract function in children and adolescents: update report from the standardization Committee of the International Children's Continence Society. J Urol. 2014; 191:1863-5.

2. Harari MD. Nocturnal enuresis. J Paediatr Child Health. 2013; 49:264-71.

3. Ferrara P, Romano V, Cortina I, et al. Oral desmopressin lyphilisate (MELT) for monosymptomatic enuresis: Structured versus abrupt withdrawal. J Ped Urol. 2014; 10:52-5.

4. Ferrara P, Del Volgo V, Romano V, et al. Combined dietary recommendations, desmopressin, and behavioral interventions may be effective first-line treatment in resolution of enuresis. Urol J. 2015; 12:2228-32.

5. Lottmann H, Baydala L, Eggert P, et al. Long-term desmopressin response in primary nocturnal en- uresis: open-label, multinational study. Int J Clin Pract. 2009;63:35-45.

6. Onol FF, Guzel R, Tahra A, et al. Comparison of long-term efficacy of desmopressin lyophilisate and enuretic alarm for monosymptomatic enure- sis and assessment of predictive factors for success: a randomized prospective trial. J Urol. 2015; 193:655-61.

7. Ferrara P, Marrone G, Emmanuele V, et al. Homotoxicological remedies versus desmopressin versus placebo in the treatment of

Ferrara_Stesura Seveso 28/06/18 16:38 Pagina 129

Desmopressin 120 mcg, 180 mcg, 240 mcg: The right treatment for the right patient

enuresis: a randomised, double-blind, controlled trial. Pediatr Nephrol. 2008; 23:269-74.

8. Ferrara P, De Angelis MC, Caporale O, et al. Possible impact of comorbid conditions on the persistence of nocturnal enuresis: results of a long-term follow-up study. Urol J. 2014; 11:1777-82.

9. Ferrara P, Ianniello F, Romani L, et al. Five years of experience in nocturnal enuresis and urinary incontinence in children: where we are and where we are going. Urol Int. 2014; 92:223-9.

10. Garcovich S, Gatto A, Ferrara P, Garcovich A. Vulvar pyoderma gangrenosum in a child. Ped Derm. 2009; 26:629-31.

11. Wolfish NM, Barkin J, Gorodzinsky F, Schwarz R. The Canadian Enuresis Study and Evaluation – short- and long-term safety and efficacy of an oral desmopressin preparation. Scand J Urol Nephrol.

2003; 37:22-7.

12. Schulman SL, Stokes A, Salzman PM. The efficacy and safety of oral desmopressin in children with primary nocturnal enuresis. J Urol. 2001; 166:2427-31.

13. Vande Walle J, Rittig S, Bauer S, et al. Practical consensus guidelines for the management of enuresis. Eur J Pediatr. 2012; 171:971-83.

Correspondence Pietro Ferrara, MD pietro.ferrara@unicatt.it - p.ferrara@unicampus.it Francesca Ianniello, MD Institute of Pediatrics, Catholic University Medical School Largo F. Vito 8, 00168. Rome, Italy Ester Del Vescovo, MD Giulia Franceschini, MD Campus Bio-Medico University, Rome, Italy Luciana Romaniello, MD San Carlo Hospital, Potenza, Italy Alberto Verrotti, MD Department of Pediatrics, University of L’Aquila, L’Aquila, Italy Archivio Italiano di Urologia e Andrologia 2018; 90, 2

129

Maglia_Stesura Seveso 28/06/18 16:38 Pagina 130

DOI: 10.4081/aiua.2018.2.130

ORIGINAL PAPER

Clinical comparison between conventional and microdissection testicular sperm extraction for non-obstructive azoospermia: Understanding which treatment works for which patient Elia Maglia, Luca Boeri, Matteo Fontana, Andrea Gallioli, Elisa De Lorenzis, Franco Palmisano, Stefano Paolo Zanetti, Gianluca Sampogna, Liliana Restelli, Edgardo Somigliana, Mariapia Serrago, Franco Gadda, Emanuele Montanari IRCCS Fondazione Caâ&#x20AC;&#x2122; Granda, Ospedale Maggiore Policlinico, Department of Urology, Milan, Italy.

Summary

Objectives: The superiority of microdissection testicular sperm extraction (mTESE) over conventional TESE (cTESE) for men with non-obstructive azoospermia (NOA) is debated. We aimed to compare the sperm retrieval rate (SRR) of mTESE to cTESE and to identify candidates who would most benefit from mTESE in a cohort of Caucasian-European men with primary coupleâ&#x20AC;&#x2122;s infertility.

Material and methods: Data from 49 mTESE and 96 cTESE patients were analysed. We collected demographic and clinical data, serum levels of LH, FSH and total testosterone. Patients with abnormal karyotyping were excluded from analysis.

Age was categorized according to the median value of 35 years.

FSH values were dichotomized according to multiples of the normal range (N) (N and 1.5 N: 1-18 mIU/mL, and > 18 mIU/mL). Testicular histology was recorded for each patient.

Descriptive statistics and logistic regression analyses tested the impact of potential predictors on positive SRR in both groups.

Results: No differences were found between groups in terms of clinical and hormonal parameters with the exception of FSH values that were higher in mTESE patients (p = 0.004).

SRR were comparable between mTESE and cTESE (49.0% vs.

41.7%, p = 0.40). SRRs were significantly higher after mTESE in patients with Sertoli cell-only syndrome (SCOS) (p = 0.038), in those older than 35 years (p = 0.03) and with FSH > 1.5N (p < 0.001), as compared to men submitted to cTESE. Multivariable logistic regression analysis showed that mTESE was independent predictor of positive SR in patients older than 35 years (p = 0.002) and with FSH > 1.5N (p = 0.018).

Moreover, increased FSH levels (p = 0.03) and both SCOS (p = 0.01) and MA histology (p = 0.04) were independent predictors of SRR failure.

Conclusions: Microdissection and cTESE showed comparable success rates in our cohort of patients with NOA. mTESE seems beneficial for patients older than 35 years, with high FSH values, or when SCOS can be predicted. Given the high costs associated with the mTESE approach, the identification of candidates most likely to benefit from this procedure is a major clinical need.

KEY WORDS: Testicular sperm extraction; Non-obstructive azoospermia; Infertility; Risk factors.

Submitted 17 February 2018; Accepted 10 April 2018

130

INTRODUCTION

In contrast to obstructive azoospermia in which there is an obstruction in the ductal system, non-obstructive azoospermia (NOA) refers to the absence of spermatozoa in semen analysis due to minimal or no production of fully developed spermatozoa in the testicles.

Approximately 1% of all men and 10% of infertile men are affected by testicular failure as a result of NOA (1).

Testicular spermatozoa can be retrieved in some NOA men even despite the absence of ejaculated spermatozoa in their semen, from isolated foci of active spermatogenesis. The chance of fatherhood for the NOA patient has changed dramatically in recent years following the introduction of surgical sperm retrieval techniques, in particular conventional TESE (cTESE) and microdissection TESE (mTESE). Until recently, cTESE represented the first-line option to retrieve spermatozoa in NOA subjects for intracytoplasmic sperm injection (ICSI) (2). However, since its introduction in 1999, mTESE has continuously been found to be associated with better sperm retrieval rates (SRRs) and fewer complications compared to cTESE (3).

Direct vision with the operating microscope in mTESE is of great advantage as larger, whitish tubules, presumably containing more germ cells with active spermatogenesis, can be identified. Indeed, as reported by various authors, the rate of positive SRR differs significantly between the two techniques, ranging from about 63% to 42% in mTESE and from 16% to 45% in cTESE (4-6). Moreover, cTESE can be undermined by potential surgical complications, which are virtually absent in the mTESE series (7, 8). This should not be ignored given that a significant number of azoospermic patients are typically affected by secondary disturbances, such hypogonadism, for which mTESE may allow for better preservation of the testicular tissue. On the contrary, other authors have failed to find a significant superiority of mTESE over cTESE in terms of SRRs (9, 10). Moreover, the overall positive SRR, lower costs and high reproducibility of cTESE represent unique characteristics that should be taken into account when counseling NOA infertile couples (10).

Microdissection TESE, indeed, is a technically challengNo conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

Maglia_Stesura Seveso 28/06/18 16:39 Pagina 131

Personalized treatment for infertile men

ing and expensive procedure that requires dedicated equipment and specifically trained surgeons.

Considering the different characteristic of each surgical technique and the high heterogeneity in the current literature regarding which technique is superior, we believe it to be of paramount importance to define which patients could benefit most from a complex surgery such as microdissectional TESE. The aim of the present study is to compare SRR by mTESE with that obtained by conventional TESE in NOA patients and to identify the patients who could most benefit from a microsurgical approach by finding the best predictors of positive sperm retrieval in our cohort.

MATERIALS

AND METHODS

The analyses of this cross-sectional study were based on a sample of 145 consecutive white-European men assessed at a single academic centre for primary couple’s infertility (non-interracial infertile couples only) between January 2012 and April 2017. The initial cohort included 149 patients, however 4 (2.68%) men were excluded from the final analysis for missing values. According to the World Health Organisation (WHO) criteria, infertility was defined as not conceiving a pregnancy after at least 12 months of unprotected intercourse regardless of whether or not a pregnancy ultimately occurred (11). Primary infertility is defined as when a couple has never been able to conceive (11). Infertile patients were enrolled if they were between 18 and 55 years of age and had only male factor infertility (MFI); MFI was defined after a comprehensive gynecological evaluation of the female partner. All patients were diagnosed with NOA on the basis of a complete history, physical examination, endocrine profile, and chromosomal analysis before being scheduled for TESE with sperm freezing.

All patients underwent chromosomal analysis and those with abnormal karyotyping were excluded from the study cohort. Patients underwent at least two consecutive semen analyses, both showing absence of spermatozoa in the ejaculate after centrifugation. Semen samples were collected by masturbation and analysed within 2 h according to the WHO criteria.

Patients were assessed with a thorough medical history including age and comorbidities. Age was categorized according to the median value of 35 yrs. Comorbidities were scored with the Charlson Comorbidity Index (CCI) (12). We used the International Classification of Diseases, 9th revision. For the specific purpose of the analysis, CCI was categorized as 0 or ≥ 1. All individuals were sexually active, reporting to have intercourse at least four times per month.

Body mass index (BMI) defined as weight in kilograms by height in square meters, was calculated. BMI was considered using the cut offs proposed by the National Institutes of Health (NIH): normal weight (18.5-24.9), overweight (25.0-29.9), and class ≥ 1 obesity (≥ 30.0). Lifestyle factors potentially related with any impairment of semen quality were carefully assessed. Colour-Doppler ultrasound was used to detect spermatic vein reflux and to classify the grade of varicocele in infertile patients. As a main entry criterion for the study, only patients with complete data collection were included; therefore, patients with incomplete

medical history were excluded. Venous blood samples were drawn from each infertile patient between 7 AM and 11 AM after an overnight fast. Follicle-stimulating hormone (FSH), luteinising hormone (LH) and prolactin (PRL) were measured using a heterogeneous competitive magnetic separation assay (Bayer Immuno 1 System, Bayer Corp., Tarrytown, NY, USA). Total testosterone (tT) levels were measured via a direct chemiluminescence immunoassay (ADVIA Centaur; Siemens Medical Solutions Diagnostics, Deerfield, IL, USA). Hypogonadism was defined as tT less than 3 ng/ml (13). The same laboratory analyzed all parameters for all patients. FSH values were categorized into two groups according to multiples of the normal range (N) (N and 1.5N: 1-18 mIU/mL, and > 18 mIU/mL).

Patients included in the study were scheduled for conventional cTESE or mTESE based on the availability of the surgical waiting list. Informed consent was obtained after a thorough explanation of results in the literature and the invasiveness of the surgical technique. Testicular histology was recorded based on the predominant histological pattern, such as hypospermatogenesis (HS), maturation arrest (MA) and Sertoli cell-only syndrome (SCOS). The same pathologist reviewed all the tissue samples.

Conventional TESE was performed, under general or local anesthesia, unilaterally on the larger testis; when testes volume was equal, the right testis was used.

Through a small horizontal incision in the right-median part of the scrotal, the skin, dartos muscle, and tunica vaginalis were opened to expose the tunica albuginea.

The tunica albuginea was incised for about 5 mm at the middle of the testis. Multiple testicular specimens were excised and dispersed between two glass slides, and the embryologist observed the samples under the optic microscope. If no sperm were seen in the initial sample, subsequent samples were taken from other locations, in the upper and lower pole of the testis, and subsequently from the contralateral testis (in only 12% of the cases).

Microdissection TESE was performed under general anesthesia according to the procedure reported previously (3). An attempt was made to identify individual seminiferous tubules that were larger, more opaque and whiter than other tubules in the testicular parenchyma, which were considered to likely contain spermatozoa. If all tubules were seen to have an identical morphological appearance, at least three samples (upper, middle, and lower) were obtained. If no sperm were obtained from the initial sample, the same procedure was performed in the contralateral testis (in 20% of the cases). At the same time of testicular intervention in both procedures, a small tissue specimen was placed in Bouin’s solution and sent for histopathological examination.

Data collection was carried out following the principles outlined in the Declaration of Helsinki; after approval of the IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico Ethical Committee, all patients signed an informed consent agreeing to supply their own anonymous data for this and future studies.

Data are presented as means (SD; ranges). The statistical significance of differences in means and proportions was tested with the one-way analysis of variance (ANOVA) and Pearson chi-square test, respectively. A 95% confidence interval was estimated for the association of categorical Archivio Italiano di Urologia e Andrologia 2018; 90, 2

131

Maglia_Stesura Seveso 28/06/18 16:39 Pagina 132

E. Maglia, L. Boeri, M. Fontana, A. Gallioli, E. De Lorenzis, F. Palmisano, S.P. Zanetti, G. Sampogna, L. Restelli, E. Somigliana, M. Serrago, F. Gadda, E. Montanari

parameters. Exploratory analyses were initially applied to all variables; variables were retained for analysis when deemed clinically significant to the results. Descriptive statistics tested the association between clinical and hormonal variables and the sperm retrieval rate according to the surgical technique. Logistic regression univariable analysis (UVA) and multivariable analysis (MVA) tested the associaTable 1.

Characteristics and descriptive statistics of patients (No. = 145).

No. of patients [No. (%)] Age (years) Mean (SD) Range Categorized age [No. (%)] 50-60 61-70 71-80 ≥ 81 BMI (kg/m2) Mean (SD) Range Categorized BMI [No. (%)] 18.5-24.9 25-29.9 ≥ 30 CCI [No. (%)] CCI 0 CCI ≥ 1 Current Smokers [No. (%)] Varicocele [No. (%)] Cryptorchidism [No. (%)] Positive SRR [No. (%)] Histologic reports [No. (%)] Hypospermatogenesis Maturation arrest Sertoli cell-only syndrome Postop. complications [No. (%)]

Overall 145 (100)

cTESE 96 (66.2)

tions between clinical and laboratory predictors and sperm retrieval failure. Moreover, logistic regression analyses tested the association between clinical predictors (e.g age, FSH, testicular histology and surgical technique) and positive sperm retrieval in patients older than the median value of 35 years and in those with FSH > 1.5N (18 mUI/mL). Statistical tests were performed using SPSS v. 19 (IBM Corp., Armonk, NY, USA).

All tests were two sided, with a significance level set at 0.05.

mTESE 49 (33.8)

P value (F)*

RESULTS

0.55 (0.34) 35.4 (5.4) 21-54

35.6 (5.4) 21-54

34.9 (5.5) 23-48

3 (2.1) 73 (50.3) 67 (46.2) 2 (1.4)

2 (2.6) 48 (50.0) 44 (44.9) 2 (2.6)

1 (2.9) 25 (50.0) 23 (47.1) 0 (0.0)

26.8 (3.4) 19.0-34.9

26.2 (3.1) 19.0-31.1

29.0 (3.7) 24.1-34.9

39 (26.8) 83 (57.2) 23 (15.8)

32 (33.3) 55 (57.1) 9 (9.5)

7 (14.3) 28 (57.1) 14 (28.6)

110 (75.8) 35 (24.1) 35 (24.1) 52 (35.8) 27 (18.6) 64 (44.1)

75 (77.8) 21 (22.2) 21 (22.2) 35 (36.5) 22 (23.2) 40 (41.7)

35 (72.7) 14 (27.3) 14 (27.3) 17 (34.6) 5 (9.1) 24 (49.0)

49 (33.7) 32 (22.0) 64 (44.1) 3 (2.0)

28 (28.9) 23 (23.7) 45 (47.4) 2 (2.1)

21 (42.6) 9 (19.1) 19 (38.3) 1 (2.0)

0.82 (χ2, 0.9)

0.07 (4.09)

BMI = body mass index; CCI = Charlson Comorbidity Index; SRR = Sperm retrieval rate; *P value according to chi-square test or analysis of variance (ANOVA), as indicated.

0.36 (χ2, 2.00)

0.74 (χ2, 0.11) 0.72 (χ2, 0.13) 0.86 (χ2, 0.31) 0.15 (χ2, 2.1) 0.40 (χ2, 0.70) 0.30 (χ2, 2.39)

0.43 (χ2, 1.04)

Table 2.

Hormonal characteristics of patients (No. = 145).

FSH (mUI/mL) Mean (SD) Range LH (mUI/mL) Mean (SD) Range tT (ng/mL) Mean (SD) Range tT < 3 ng/mL [No. (%)] PRL (ng/mL) Mean (SD) Range

Overall

cTESE

mTESE

14.8 (11.8) 1.71-59

12.8 (11.1) 1.71-52.3

20.9 (12.1) 1.81-59

5.7 (4.3) 1.91-18.5

5.3 (4.1) 1.91-18.5

7.2 (4.9) 2.55-17.7

5.0 (4.1) 1.17-24.1 34 (23.4)

5.4 (4.5) 1.17-24.1 18 (19.2)

3.6 (1.7) 2.16-7.58 16 (33.3)

26.3 (9.2) 4.6-68.1

30.1 (10.6) 4.6-68.1

11.7 (6.44) 5.0-26

P value (F)* 0.04 (8.89)

0.15 (2.12)

0.12 (2.36)

0.25 (χ2, 1.33) 0.54 (0.36)

tT = Total Testosterone; FSH = Follicle-stimulating hormone; LH = Luteinising hormone; PRL = prolactin. *P value according to chi-square test or analysis of variance (ANOVA), as indicated.

132

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

Table 1 lists the characteristics and the descriptive statistics of the entire cohort of individuals. Overall, 96 (66.2%) and 49 (33.8%) infertile patients were submitted to cTESE and mTESE, respectively. The two groups did not differ in terms of age, BMI and CCI. There were no differences in terms of lifestyle factors, history of cryptorchidism, presence of varicocele and postoperative complications between groups. Histologic reports showed hypospermatogenesis, maturation arrest and Sertoli cell-only syndrome in 49 (33.7%), 32 (22%) and 64 (44.1%) patients, respectively, with no difference according to the surgical technique. The success rate of sperm retrieval in patients with NOA was comparable between mTESE and cTESE (49.0% vs. 41.7%, p = 0.40).

Table 2 depicts the hormonal characteristics of infertile patients according to the surgical technique. No differences were found between groups in terms of hormonal parameters with the exception of FSH values that were higher in mTESE patients (20.9 vs. 12.8 mUI/ml; p = 0.004).

Table 3 shows the influence of clinical parameters (age, FSH values and histological reports) on the success rate of sperm retrieval between groups. Sperm retrieval rate was positive in 22/61 (36.1%) patients with FSH ≥ 1.5N (18 mIU/mL) (18/30 with mTESE, 4/31 with cTESE) and in 42/84 (50.0%) patients with FSH < 1.5N (6/19 with mTESE, 36/65 with cTESE). mTESE resulted in a higher SRR for those with FSH ≥ 1.5N (p = 0.001). Age had a significant impact on sperm retrieval rate in the two groups. In patients younger than 35 years, SRR was positive in 48.9% and 41.6% of men submitted to cTESE and mTESE, respectively. However, for those older than 35 years, mTESE resulted in a significantly higher SRR (56.0% vs.

35.0%, p = 0.03). The influence of histological diagnosis on the success rate of

Maglia_Stesura Seveso 28/06/18 16:39 Pagina 133

Personalized treatment for infertile men

Table 3.

Sperm retrieval rate according to the class of FSH values, age and histologic reports.

FSH (mUI/mL) < 18 > 18 Age (years) < 35 > 35 Histologic reports Hypospermatogenesis Maturation arrest Sertoli cell-only syndrome

cTESE

mTESE

P value (F)*

36/65 (55.3%) 4/31 (12.9%)

6/19 (31.5%) 18/30 (60.0%)

0.66 (0.18) 0.001 (7.0)

23/47 (48.9%) 17/49 (35.0%)

10/24 (41.6%) 14/25 (56.0%)

0.67 (0.18) 0.03 (4.27)

18/28 (64.2%) 8/23 (34.7%) 14/45 (31.1%)

12/21 (55.0%) 3/9 (33.3%) 9/19 (50.0%)

0.77 (0.01) 0.76 (0.09) 0.03 (4.29)

*P value according to chi-square test analysis.

Table 4.

Logistic regression models predicting positive sperm retrieval (OR; p value [95%CI]) in patients with age > 35 years and FSH > 18 mUI/mL.

cTESE vs. mTESE Age FSH Histologic report Hypospermatogenesis Sertoli cell-only syndrome Maturation arrest

Positive sperm retrieval Age > 35 years FSH > 18 mUI/mL UVA model MVA model UVA model MVA model 13.40; 0.04 7.22; 0.002 12.66; 0.001 9.52; 0.018 (1.41-21.17) (2.01-15.82) (2.49-24.22) (1.96-19.26) 0.23; 0.76 0.11; 0.18 (0.11-1.15) (0.06-1.89) 0.97; 0.10 0.18; 0.90 (0.88-1.02) (0.05-1.17) Ref. 0.21; 0.12 (0.02-1.52) 0.34; 0.19 (0.06-1.74)

Ref. 0.12; 0.24 (0.03-4.31) 0.11; 0.21 (0.05-3.40)

Ref. 0.20; 0.11 (0.03-1.43) 0.23; 0.11 (0.04-1.35)

UVA = Univariate model; MVA = Multivariate model.

Table 5.

Logistic regression models predicting negative sperm retrieval (OR; p value [95% CI]) in the whole cohort (n = 145).

Ref. 0.31; 0.78 (0.21-1.63) 0.34; 0.78 (0.20 -1.45)

association between mTESE and positive sperm retrieval in older men and in those with higher FSH levels we conducted a logistic regression analysis assessing the relationship between clinical predictors (e.g age, FSH, testicular histology and surgical technique) and positive sperm retrieval in the two groups (Table 4). In patients older than the median value of 35 years mTESE was univariably associated with positive SR (p = 0.04) and emerged as the only independent predictor of positive SR (OR 7.22; p = 0.002) after adjusting for FSH values and testicular histology. Similarly, in men with FSH > 18 mUI/mL, mTESE was associated with positive SRR (p = 0.001) at UVA and showed independent predictor status for positive SR (OR 9.52; p = 0.018) at MVA, after adjusting for age and testicular histology.

Table 5 details UVA and MVA logistic regression models testing the associations between predictors and sperm retrieval failure. UVA showed that higher FSH (p = 0.008), a histological report of SCOS (p = 0.014) and MA (p = 0.04) were associated with negative SRR. Conversely, age, LH and testosterone values were not. Similarly, logistic MVA revealed that FSH levels (OR 1.3, p = 0.03), histological reports of SCOS (OR 2.17, p = 0.01) and MA (OR 1.87, p = 0.04) achieved independent predictor status for sperm retrieval failure.

DISCUSSION

This study was conducted to evaluate potential differences in terms of SRRs between mTESE and cTESE in our Sperm retrieval failure cohort of NOA men, and to determine UVA model MVA model OR (95% CI) P value OR (95% CI) P value which patients could most benefit from each procedure. We found that mTESE Age 1.04 (0.95- 1.13) 0.38 1.13 (0.83-1.55) 0.41 yields overall greater, albeit not signifiFSH 1.11 (1.02-1.16) 0.008 1.31 (1.01-1.68) 0.03 cantly, rates of sperm retrieval than LH 0.76 (0.91-1.21) 0.46 0.65 (0.89-1.26) 0.07 cTESE. Secondly, we noted that mTESE Testosterone 0.96 (0.92-1.22) 0.40 0.98 (0.79-1.21) 0.87 lead to a higher SRR than cTESE in Histologic report older patients (> 35 years), in patients Hypospermatogenesis Ref. Ref. with elevated FSH (i.e > 18 mUI/ml) Sertoli cell-only syndrome 4.21 (1.31-3.32) 0.014 2.17 (1.01-8.87) 0.01 and in those with a histological diagnoMaturation arrest 3.20 (1.16-1.32) 0.04 1.87 (1.02-7.52) 0.04 sis of SCOS. mTESE emerged as indeUVA = Univariate model; MVA = Multivariate model. pendent predictor of positive SR in patients older than 35 years and in those with FSH >18 mUI/mL. sperm retrieval was also considered. We obtained spermaMoreover, the most reliable predictors of negative sperm tozoa via cTESE in 64.2% and via mTESE in 55.0% of retrieval were elevated FSH and both SCOS and MA hismen with a histological diagnosis of hypospermatogenesis. tology.

In case of MA, we retrieved sperm in 34.7% of patients via This study was prompted by existing controversies in the cTESE and in 33.3% via mTESE. For those with SCOS, scientific literature regarding the role of mTESE and mTESE produced a significantly higher SRR (50.0% vs. cTESE as treatment options for azoospermic men. In 31.1% with cTESE, p = 0.03). In order to strengthen the fact, determining which of the two procedures is more Archivio Italiano di Urologia e Andrologia 2018; 90, 2

133

Maglia_Stesura Seveso 28/06/18 16:39 Pagina 134

E. Maglia, L. Boeri, M. Fontana, A. Gallioli, E. De Lorenzis, F. Palmisano, S.P. Zanetti, G. Sampogna, L. Restelli, E. Somigliana, M. Serrago, F. Gadda, E. Montanari

likely to produce a better outcome remains challenging since, to date, a general consensus is still lacking among the different authors.

In terms of SRR, the current literature reports quite unanimously a superiority of mTESE over conventional TESE (46, 9, 14). For instance, Okada et al. (4) reported a SRR of 16.7% for the cTESE group and 44.6% for mTESE. More recently Ghalayini et al. (6) found that sperm retrieval was successful in 56.9% patients undergoing mTESE in comparison with only 38.2% of cTESE patients. The present study showed a slight, but not statistically significant, superiority of mTESE over cTESE in terms of SRR (49.0% vs 41.7%). Other authors have also shown a superiority of mTESE over cTESE in terms of overall SRR but without a statistically significant difference between groups (15).

Previous studies found conventional TESE to be associated with significantly higher complication rates than mTESE (4, 7). Acute and chronic ultrasonographic abnormalities such as haematoma, loss of testicular tissue, inflammatory changes and permanent devascularisation may be found after cTESE (7). Moreover, cTESE may be associated with higher rates of wound infection and iatrogenic hypogonadism that mTESE (4). We did not find any differences between groups in terms of postoperative complications, probably due to the low rate of adverse events in our cohort (3 patients, 2 with heamtomas and 1 with wound infections).

Conventional TESE could still offer some advantages over mTESE. Firstly, microsurgical training generally represents a lengthy, expensive and demanding process that likely cannot be sustained in every institution. In fact, Ishikawa et al. (15) showed a steeper learning curve for mTESE compared with cTESE, highlighting a positive correlation between surgical outcomes and turnover of mTESE operations. Secondly, mTESE requires dedicated and expensive equipment (especially an operating microscope) as well as longer operative times. It is therefore difficult to find a compromise that guarantees the best quality at the lowest cost. One way to deal with this issue could be tailor patient treatment based on robust predictive factors for positive SRR. To date, many promising candidates for predictors have been proposed, but a general consensus is still lacking.

Testicular volume is amongst the frequently proposed predictors. However, Colpi et al. (14) and Ghalayini et al.

(6) found contrasting results, with the former showing no correlation and the latter a positive correlation between higher testicular volume and SRRs. Another factor, advanced age, is generally associated with poorer sperm parameters and reproductive outcomes (16). However, recent studies have shown that age may not adversely affect sperm retrieval in men undergoing TESE (10, 17). Of clinical importance, we found significantly higher SRRs with mTESE in patients older than the median value of 35 years when compared to aged-match patients undergoing cTESE. Moreover, mTESE was an independent predictor of positive SR in men older than 35 years after adjusting for FSH values and testicular histology. This finding could provide an easy to obtain and reliable predictor for identifying the best candidates to submit to mTESE, especially if they belong to poor prognosis groups.

134

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

Serum hormonal values represent another potentially useful predictor of SRRs. Colpi et al. (14) and Ghalayini et al. (6) reported a higher failure in sperm retrieval among patients with increased FSH levels. Conversely, Ramasamy et al. (18) observed comparable or better results in men with high FSH in terms of microsurgical retrieval. Our study strongly supports the negative association between SRR and FSH levels as we found FSH to be an independent predictor of SR failure in the overall cohort of patients and, more importantly, we showed that SRR was significantly higher in mTESE patients with high FSH when compared with cTESE patients with comparable hormonal values. To strengthen this finding we performed a multivariable analysis to predict positive SRR in men with higher FSH values and we found that mTESE was independent predictor of positive SR after adjusting for age and testicular histology.

Testicular histological pattern is one of the most promising parameters for providing both the clinician and patient with a reliable and robust predictive tool for SR outcomes. Unfortunately, and differently from the other aforementioned factors, it can be provided only through an invasive surgical procedure and is, therefore, mainly evaluated intraoperatively or retrospectively.

Our data showed that SCOS patients had significantly higher SRRs from mTESE compared to cTESE. Moreover, SCOS and MA were independent predictors of SR failure.

Our outcomes are consistent with previous studies showing the superiority of mTESE over cTESE in SR outcomes for SCOS men (4, 6).

Similarly, the significant association between both SCOS and MA and sperm retrieval failure has been previously reported (6, 19). It can be concluded that progressively worse histological patterns are associated with lower retrieval results. We can therefore speculate that improvements in SRR in poor prognosis patients (those with older age, high FSH values and SCOS) could be achieved performing mTESE instead of cTESE. Our study presents some limitations. First, it is not a randomized controlled study; our patients were assigned to one of the two groups on the basis of the operating theatre waiting list. Second, we didnâ&#x20AC;&#x2122;t consider some variables such as inhibin B, Johnsen score and testicular volume, which have been shown to have a relevant albeit controversial predictive value. Finally, we were unable evaluate the pregnancy rate associated with ICSI procedures following sperm retrievals. Clinical pregnancy followed by the delivery of a healthy child is the main goal of all the procedures described, but it requires extensive follow up.

Nevertheless, our findings offer some positive implications that could be useful to clinicians not only to offer realistic counselling to couples undergoing ARTs treatments but also to tailor the best treatment to the patient who could most benefit from it. For example, we showed that mTESE was associated with a better SRR than cTESE in older patients. This finding is important in light of the fact that advanced age is associated with decreasing testosterone levels and mTESE guarantees better preservation of the testicular tissue. Thus, with mTESE representing a reduced risk of hypogonadism, the higher sperm retrieval rate would make mTESE doubly beneficial for the patient. Secondly, we confirmed the high predictive value of histology, espe-

Maglia_Stesura Seveso 28/06/18 16:39 Pagina 135

Personalized treatment for infertile men

cially for cases of poor prognosis (SCOS and MA), with mTESE yielding the best results for SCOS patients. A preoperative histological diagnosis is however difficult to obtain unless the patient has already undergone a sperm retrieval procedure. A proposed alternative could be a stepwise approach, such as that described by Franco et al. (20), which gradually increases surgical complexity only when necessary. It is undeniable, however, that patients with poor prognosis, as defined by histology, would greatly benefit from moving directly to a microsurgical approach and avoiding procedures that are extremely unlikely to produce positive results.

CONCLUSIONS

In conclusion, microdissection and conventional TESE showed comparable success rates for sperm retrieval in our cohort of patients with NOA. mTESE seems to be beneficial for patients older than 35 years, in patients with high FSH values, or when SCOS can be predicted.

Given the high costs associated with the mTESE approach, the identification of candidates most likely to benefit from this procedure is a major clinical need.

REFERENCES

1. Su LM, Palermo GD, Goldstein M, et al. Testicular sperm extraction with intracytoplasmic sperm injection for nonobstructive azoospermia: testicular histology can predict success of sperm retrieval. J Urol. 1999; 161:112-116.

2. Kahraman S, Ozgur S, Alatas C, et al. High implantation and pregnancy rates with testicular sperm extraction and intracytoplasmic sperm injection in obstructive and non-obstructive azoospermia.

Hum Reprod. 1996; 11:673-676.

3. Schlegel PN. Testicular sperm extraction: microdissection improves sperm yield with minimal tissue excision. Hum Reprod.

1999; 14:131-5.

4. Okada H, Dobashi M, Yamazaki T, et al. Conventional versus microdissection testicular sperm extraction for nonobstructive azoospermia. J Urol. 2002; 168:1063-7.

5. Ramasamy R, Yagan N, Schlegel PN. Structural and functional changes to the testis after conventional versus microdissection testicular sperm extraction. Urology 2005; 65:1190-4.

6. Ghalayini IF, Al-Ghazo MA, Hani OB, et al. Clinical Comparison of Conventional Testicular Sperm Extraction and Microdissection Techniques for Non-Obstructive Azoospermia. J Clin Med Res. 2011; 3:124- 131.

7. Schlegel PN, Su LM. Physiological consequences of testicular sperm extraction. Hum Reprod 1997; 12:1688-92.

8. Silber SJ. Microsurgical TESE and the distribution of spermatogenesis in non-obstructive azoospermia. Hum Reprod. 2000; 15:2278-84.

9. Tsujimura A, Matsumiya K, Miyagawa Y, et al. Conventional multiple or microdissection testicular sperm extraction: a comparative study. Hum Reprod. 2002; 17:2924-9.

10. Saccà A, Pastore AL, Roscigno M, et al. Conventional testicular sperm extraction (TESE) and non-obstructive azoospermia: is there still a chance in the era of microdissection TESE? Results from a single non-academic community hospital. Andrology. 2016; 4:425-9.

11. World Health Organization web chapter on couple’s infertility. http://www.who.int/reproductivehealth/topics/infertility/definitions (Accessed September 3rd, 2015).

12. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987; 40:373-83.

13. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone Therapy in men with androgen deficieny syndromes: an American Society clinical practice guidelines. J Clin Endocrinol Metab. 2010; 95:2536-59.

14. Colpi GM, Colpi EM, Piediferro G, et al. Microsurgical TESE versus conventional TESE for ICSI in non-obstructive azoospermia: a randomized controlled study. Reprod Biomed Online. 2009; 18:315-9.

15. Ishikawa T, Nose R, Yamaguchi K, et al. Learning curves of microdissection testicular sperm extraction for nonobstructive azoospermia. Fertil Steril. 2010; 94:1008-11.

16. Grunewald S, Glander HJ, Paasch U, Kratzsch J. Age-dependent inhibin B concentration in relation to FSH and semen sample qualities: a study in 2 448 men. Reproduction 2013; 145:237-244.

17. Ramasamy R, Trivedi NN, Reifsnyder JE, et al. Age does not adversely affect sperm retrieval in men undergoing microdissection testicular sperm extraction. Fertil Steril. 2014; 101: 653-5.

18. Ramasamy R, Lin K, Gosden LV, et al. High serum FSH levels in men with nonobstructive azoo spermia does not affect success of microdissection testicular sperm extraction. Fertil Steril. 2009; 92:590-3.

19. Caroppo E, Colpi EM, Gazzano G, et al. Testicular histology may predict the successful sperm retrieval in patients with nonobstructive azoospermia undergoing conventional TESE: a diagnostic accuracy study. J Assist Reprod Genet. 2017; 34:149-154.

20. Franco G, Scarselli F, Casciani V, et al. A novel stepwise microTESE approach in non obstructive azoospermia. BMC Urol. 2016; 16, 20.

Correspondence Elia Maglia, MD Elia.maglia@studenti.unimi.it Luca Boeri, MD (Corresponding Author) Dr.lucaboeri@gmail.com Matteo Fontana, MD Teo.fontana@me.com Andrea Gallioli, MD Andrea.gallioli@gmail.com Elisa De Lorenzis, MD Elisa.delorenzis@gmail.com Franco Palmisano, MD Franco.palmisano@hotmail.it Stefano Paolo Zanetti, MD Stefano.p.zanetti@gmail.com Gianluca Sampogna, MD Gianluca.sampogna@unimi.it Mariapia Serrago, MD Mariapia.serrago@policlinico.mi.it Franco Gadda, MD Franco.gadda@policlinico.mi.it Emanuele Montanari, MD IEmanuele.montanari@unimi.it RCCS Fondazione Ca’ Granda, Ospedale Maggiore Policlinico, Department of Urology via della Commenda 15, 20122 Milano, Italy Liliana Restelli, MD Liliana.restelli@policlinico.mi.it Edgardo Somigliana, MD Edgardo.somigliana@policlinico.mi.it IRCCS Fondazione Ca’ Granda, Ospedale Maggiore Policlinico, U.O.S.D Procreazione Medicalmente Assistita via Festa del Perdono 12, 20122 Milano, Italy

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

135

Yucel2_Stesura Seveso 28/06/18 16:40 Pagina 136

DOI: 10.4081/aiua.2018.2.136

ORIGINAL PAPER

Predictive factors of successful salvage microdissection testicular sperm extraction (mTESE) after failed mTESE in patients with non-obstructive azoospermia: Long-term experience at a single institute Cem YĂźcel, Salih Budak, Mehmet Zeynel Keskin, Erdem Kisa, Zafer Kozacioglu Department of Urology, Tepecik Training and Research Hospital, Izmir, Turkey.

Summary

Objective: To observe the clinical practice of salvage microdissection testicular sperm extraction (mTESE) in patients with non-obstructive azoospermia (NOA) and to determine the factors that may predict the presence of spermatozoa in preoperative salvage mTESE. Methods: We retrospectively reviewed the medical records of 445 patients with the diagnosis of NOA, who had undergone the mTESE operation consecutively in our institution between the dates of March 2008 and June 2017. The study included a total of 49 patients with failure to detect spermatozoa in the first mTESE and who had then undergone salvage mTESE. In order to investigate the factors that predict the result of salvage mTESE, the patients were classified into two groups according to the outcome of salvage mTESE, as those with and without spermatozoa retrieval. Patients in these two groups were compared with regard to age, body mass index, history of varicocele, history of cryptorchidism, duration of infertility, outcomes of genetic analysis, results of hormone profiles and the testicular histopathology results of the first mTESE. Results: The sperm retrieval rate following salvage mTESE was observed to be 42.8%. Statistically a significant difference was determined between the mean follicle stimulating hormone (FSH) values of the groups (p = 0.013). No significant difference was observed between the groups with regard to the remaining parameters.

Conclusion: It was observed that among the factors that predict the success of sperm retrieval in salvage mTESE in patients with NOA and previous unsuccessful sperm retrieval in mTESE operation, only the pre-operative FSH level was observed to significantly correlate with the success in salvage mTESE.

The current treatment of NOA is sperm retrieval from the testes via testicular sperm extraction (TESE) and using these sperms in intracytoplasmic sperm injection (ICSI) to obtain a healthy pregnancy (2). Currently, TESE operations are performed in the guidance of a microscope (mTESE). Although it was initially reported that retrieval rate following a first TESE attempt in a well-defined NOA population was around 50%, recovery rates reported subsequently in literature were inconsistent (3).

Unsuccessful sperm retrieval from the first TESE operation results in negative emotional and financial effects.

Salvage TESE offers a further chance of pregnancy for whom the first TESE has been unsuccessful. There is no clinical finding or test that precisely predicts the outcome of TESE preoperatively. Knowing the clinical characteristics that help predicting the outcomes of salvage TESE would be facilitative for the preoperative counseling and clinical management of patients undergoing salvage TESE. Currently, there are not many studies that have published the clinical application of salvage TESE in the literature.

The aim of this study was to observe the clinical practice of salvage mTESE in patients with NOA and to determine the factors that may predict the presence of spermatozoa in preoperative salvage mTESE, and help physicians determine the best candidates for this procedure.

KEY WORDS: Azoospermia; Salvage; Testicular sperm extraction; Spermatozoa.

MATERIALS

Submitted 11 January 2018; Accepted 20 February 2108

INTRODUCTION

Azoospermia is described as the absence of spermatozoa in the ejaculate and is observed in 1% of all men and 1015% of those with the complaint of infertility (1).

Azoospermia is examined in two groups according to its etiology as obstructive and non-obstructive azoospermia. Non-obstructive azoospermia (NOA) is accepted as the absence of spermatozoa in the ejaculate due to minimally developed or unproduced cells in the testicles.

136

AND METHODS

Patients and study design We retrospectively reviewed the medical records of 445 patients with the diagnosis of NOA, who had undergone the mTESE operation in our institution between the dates of March 2008 and June 2017. The diagnosis of NOA was confirmed by clinical findings, medical history, physical examination, serum hormone levels, genetic analysis and as suggested by the WHO guideline, 2 semen analysis. Semen analyses were obtained by masturbation after 3-4 days of sexual abstinence.

The levels of serum total testosterone, follicular stimulating hormone (FSH), luteinizing hormone (LH), estradiol, prolactin of the patients and the genetic analyses No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

Yucel2_Stesura Seveso 28/06/18 16:40 Pagina 137

Predictive factors of successful salvage mTESE after failed mTESE

(karyotype analysis and Y chromosome micro-deletion analysis) results were evaluated. For the hormone profile, blood was drawn from the antecubital vein of the patients after at least 8 hours of fasting. The micro-particle enzyme immuno-assay method (Roche/Hitachi, Cobas e601, Indianapolis, IN, USA) was used to determine all the hormone levels. For the chromosome analysis, the peripheral venous blood samples of the patients were subjected to 72 hours of phytohemagglutinin-induced cell culture.

The study included a total of 49 patients with NOA, who had previously mTESE and no sperm retrieval could be available. All patients included in the study had undergone TESE operations according to the mTESE procedure both in the previous attempt and in the second attempt. In order to ascertain wound healing following the first operation, salvage TESE was planned for a minimum of 3 months afterwards. No hormone therapy was administered to the patients in the time between the first TESE and salvage TESE. Those with a Y chromosome micro-deletion analysis revealing AZFa or AZFb, history of malignancy, those who were morbidly obese, those who had obstruction-related azoospermia, those who had undergone mTESE prior to the second ICSI attempt despite sperm retrieval being possible in the first TESE, and undergone multiple mTESEs, and those whose first TESE operation was conventional, were excluded from the study. The patients were classified into two groups as those with or without sperm retrieval in order to investigate the factors that predict the outcome of salvage mTESE. Patients in these two groups were compared with regard to age, body mass index (BMI), history of varicocele, history of cryptorchidism, duration of infertility, results of genetic analysis, results of hormone profiles and testicular histopathology results of the first mTESE. TESE technique On the day that the TESE operation was planned, additional sperm samples were obtained and it was confirmed that there were no sperms present. Informed consent was obtained from all of the patients before TESE. All of the patients underwent spinal anesthesia for TESE. A midline scrotal incision was made and the scrotal content was pushed out from the side with the larger testis.

The tunica vaginalis was opened and the tunica albuginea that surrounds the testicle was visualized. After this stage, the operation was handled under operating microscope. As described by Schlegel, an avascular area was selected from the antimesenteric area to the tunica albuginea and a 3 cm incision was made with a thin scalpel (4). Small samples were obtained from opaque, large, white tubules in the testicular parenchyma. Each sample was placed in a Petri dish filled with human tubal fluid.

All samples were immediately evaluated by an embryologist using a 200 x magnification microscope in order to investigate the presence of spermatozoa. The operation was terminated when suitable spermatozoa were found for ICSI. If spermatozoa were not detected in the first samples, additional samples were obtained from the same testicle. In cases where the spermatozoa were not found in the samples sent from the larger testis, the sam-

ples were also obtained from the contra-lateral testis. The biopsy specimen was sent to the pathology laboratory intraoperatively in order to determine the testicular histopathology.

Histopathological analysis In order to define the testicular histopathology, all testicular biopsy samples were fixed within Bouin's solution, and embedded into paraffin blocks following the tissue processing steps. 4 µm-thick sections were obtained, stained using hematoxylin and eosin dye, and evaluated under a microscope with 400 x magnification by the same pathologist who was experienced in this field for more than 10 years. Germinal epithelia of at least 100 seminiferous tubules were evaluated for each biopsy sample.

In the presence of germinal epithelium, the spermatogenetic situation was assessed using the Johnsen's score (JS).

According to JS, the tissue maturation and spermatogenetic situation of the germinal epithelia of each sample were scored between 1 and 10. In this scoring system, tubular necrosis was scored as 1, Sertoli cell only was scored as 2, spermatogonia only was scored as 3, arrest at primary spermatocyte was scored as 4 or 5, arrest at the early spermatid stage was scored as 6 or 7, arrest at the late spermatid stage was scored as 8 or 9, and full spermatogenesis was scored as 10 (5). The mean JS was calculated for each sample. Testicular biopsy specimens were classified according to the histopathological criteria as follows: normal spermatogenesis (NS) (mean JS; 10), hypospermatogenesis (HS) (mean JS; 8-9), late maturation arrest (LMA) (mean JS; 6-7), early maturation arrest (EMA) (mean JS; 3-4-5), Sertoli cell only (SCO) (mean JS; 2) and hyalinization of tubules (HT) (mean JS; 1).

Statistical analysis The conformity of the variables to the normal distribution was assessed with the Shapiro Wilk test. The categorical variables were described using frequencies with percentages, and the numerical variables were described using the mean and standard deviation values.

The Student’s t-test and the chi-square test were used for the intergroup analyses of the continuous variables.

The chi-square test or the Fisher’s exact chi-square was used to for the categorical variables. More than two independent averages were compared with the ANOVA test and the Kruskal Wallis test. We performed the univariate and the multivariate analysis to identify the factors associated with and predictive of positive sperm retrieval during a salvage mTESE. Multiple logistic regression analysis was performed using a model including age, FSH and LH levels, and JS. The data analysis was carried out using the Statistical Package for the Social Science (SPSS Inc, Chicago, Illinois, USA) version 22.0 and a p value of < 0.05 was considered significant.

RESULTS

In 21 of the 49 participants (42.8%), sperm retrieval was possible via salvage mTESE. A statistically significant difference was observed between the groups with and without sperm retrieval, with regard to FSH levels (20.4 ± 9.7 vs. 31.2 ± 10.4, respectively; p = 0.013) (Table 1).

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

137

Yucel2_Stesura Seveso 28/06/18 16:40 Pagina 138

C. Yücel, S. Budak, M. Zeynel Keskin, E. Kisa, Z. Kozacioglu

observed in a patient prior to salvage mTESE, and no sperm could be obtained in this patient in salvage mTESE. Grade 1-2 varciocele was Variables Overall Spermatozoa No Spermatozoa P value detected in the physical examination of (n=49) were retrievied were retrievied 4 patients in the sperm retrieval group (n = 21) (n = 28) and 5 patients in the no sperm retrieval Age (years) 35.7 ± 5.1 35.4 ± 5.9 36.0 ± 4.9 0.817 group. No serious complication was Duration of infertility (years) 6.82 ± 3.67 6.58 ± 3.94 7.01 ± 3.63 0.844 observed during mTESE or within the BMI 22.8 ± 1.2 23.7 ± 1.3 22.1 ± 1.2 0.902 post-operative 3 weeks. The mean JS of T (ng/dL) 401.1 ± 186.5 406.3 ± 279.0 397.3 ± 135.8 0.694 the 49 participants was found to be 5.4 E2 (pg/mL) 31.3 ± 12.4 30.0 ± 9.9 32.4 ± 13.3 0.729 ± 1.1. The JS among the sperm retrieval FSH (mIU/mL) 26.5 ± 10.2 20.4 ± 9.7 31.2 ± 10.4 0.013 group and the no sperm retrieval group LH (mIU/mL) 11.3 ± 7.1 8.7 ± 5.4 13.4 ± 9.1 0.161 were 4.2 ± 1.0 and 6.4 ± 1.1, respecPRL (ng/mL) 10.3 ± 3.8 10.5 ± 4.0 10.2 ± 3.9 0.834 tively. The sperm retrieval rates in Mean JS 5.4 ± 1.1 4.2 ± 1.0 6.4 ± 1.1 0.246 patients with HT, SCO, MA and HS histopathologies were 25% (2/8), 36% Histopathology (n/%) HT 8 (16.3) 2 (9.5) 6 (21.4) 0.621 (4/11), 38% (8/21) and 60% (3/5), SCO 11 (22.4) 4 (19.0) 7 (25) respectively. The sperm retrieval rate EMA 11 (22.4) 3 (14.2) 8 (28.5) among patients with NS histopathology LMA 10 (20.4) 5 (23.8) 5 (17.8) in the first mTESE was 100% (4/4). No HS 5 (10.2) 3 (14.2) 2 (7.1) statistically significant difference was NS 4 (8.1) 4 (19.0) 0 (0) observed between two groups with T, testosterone; E2, estradiol; FSH, follicle-stimulating hormone; LH, luteinizing hormone; PRL, prolactin; regard to testicular histopathology and HT, hyalinization of tubules; SCO, Sertoli cell only; EMA, early maturation arrest; LMA, late maturation arrest; mean JS (p = 0.621; p = 0.246, respecHS, hypospermatogenesis; NS, normal spermatogenesis; tively). The multiple logistic regression analysis was performed by constructing Table 2. a model including age, FSH and LH levels, and JS. This Logistic regression analysis model for successful sperm model has been presented in Table 2. It was observed that retrieval in salvage mTESE. FSH was a significant and independent predictive factor for positive sperm retrieval in salvage mTESE (p = 0.032).

Variables OR 95% CI p value

Table 1.

Comparison between the successful and unsuccessful sperm retrieval in salvage mTESE.

Age FSH LH JS

0.992 0.963 0.786 0.763

0.938-1.136 0.944-0.982 0.857-1.089 0.865-0.979

0.657 0.032 0.356 0.812

DISCUSSION

JS, Johnsen's score; FSH, follicle-stimulating hormone; LH, luteinizing hormone; OR, odds ratio; CI, confidence interval.

No significant difference was observed for the remaining hormone parameters, age, BMI, and duration of infertility. The clinical and laboratory findings of the patients have been presented in Table 1. No history of cryptorchidism was observed in any of the patients included in the study. Non-mosaic Klinefelter’s syndrome was

In this study, the factors predicting the success of positive sperm retrieval in salvage mTESE in patients with NOA and previous unsuccessful retrieval in mTESE were investigated, and a statistical correlation was observed only between the preoperative FSH level and the success in salvage mTESE. Herein, we have summarized our experience of salvage mTESE in patients with NOA in our single unit within an 9-year interval. There are only five studies investigating the factors predicting the success of salvage mTESE in patients with NOA and previous unsuccessful mTESE in the literature. In these studies, the sperm retrieval rates were reported to be between 30% and 46%.

Table 3.

Summary of the studies investigating the factors predicting the success of salvage TESE in patients diagnosed with NOA, who had previously undergone unsuccessful TESE. Variables Okuba et al. (2002) Tsujimara et al. (2006) Ramasamy and Schlegel (2007) Kalsi et al. (2015) Xu et al. (2016) This study

Initial TESE procedure Conventional Conventional Conventional Conventional Conventional Microscopic

Salvage TESE procedure Microscopic Microscopic Microscopic Microscopic Microscopic Microscopic

N 13 46 20 58 52 49

SRR in the study 30.7% 45.7% 45% 46.55% 38.5% 42.8%

SRR in the HT group 25% 25%

SRR in the SCO group 39.1% 34.3% 40% 5.5% 36%

SRR in the MA group 41.7% 61.55% 36.36% 25% 38%

SRR in the HS group 100% 93.3% 75% 83.3% 60%

HT, hyalinization of tubules; SCO, Sertoli cell only; EMA, early maturation arrest; LMA, late maturation arrest; HS, hypospermatogenesis; NS, normal spermatogenesis; SRR, sperm retrieval rate; TESE, testicular sperm extraction; N, number of patients included in the study.

138

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

SRR in the NS group 100%

Yucel2_Stesura Seveso 28/06/18 16:40 Pagina 139

Predictive factors of successful salvage mTESE after failed mTESE

Among those, the widest study included 58 patients.

The outcomes of these studies have been summarized in Table 3 (6-10). In all of these studies, the first unsuccessful TESE was performed via the conventional procedure, whereas salvage TESE was performed with the guidance of a microscope. Therefore, our study is the first to investigate the factors affecting the success of salvage mTESE in patients with NOA and previous unsuccessful TESE performed using the microscopic procedure.

Although empirical medical treatments may be given in patients with NOA prior to mTESE in order to increase the success rates, the efficacies of these treatments have not been confirmed via randomized controlled studies (11). Some authors claim that the possibility to retrieve sperm in salvage TESE may be increased via hormone therapies using clomiphene or human chorionic gonadotropin (HCG) following unsuccessful TESE (12).

However, due to the low level of evidence and lack of recommendations for these therapies in the guidelines, no hormone therapy was performed in the time between the first unsuccessful and salvage mTESEs. There are conflicting data about the effect of FSH level on the success of mTESE in the literature. There are studies demonstrating no effect of FSH on the success of mTESE, whereas there are others demonstrating the contrary (13). FSH acts by binding to its receptors on the Sertoli cells, which are important for spermatogenesis in the testis. Therefore, it tends to decrease in patients with impaired spermatogenesis. Although high FSH levels were related to global impairment of spermatogenesis, there may be normal foci of spermatogenesis in the testicles of these patients (14). Xu et al. and Kalsi et al. have reported no significant difference between the FSH levels of the patients with or without sperm retrieval in salvage TESE (9, 10). On the contrary, in our study, the FSH levels in patients with no sperm retrieval in salvage TESE was observed to be higher.

TESE is an invasive procedure that may lead to complications such as hematoma, infection, fibrosis and even permanent devascularisation. Diagnostic testicular biopsy has complications similar to the mTESE operation.

Furthermore, sperm retrieval in subsequent mTESE cannot be assured by retrieved sperm in diagnostic testicular biopsy in patients with NOA. Diagnostic testicular biopsy has not been recommended in clinical practice due to the additional cost, repetitive surgical procedures and the invasive nature of the procedure that increase the risk of complications (15). Thus, the diagnostic testicular biopsy procedure is not being performed in our clinics prior to TESE. Testicular biopsy samples have been obtained during the initial TESE surgery.

Additionally, one of the strong aspects of our study was that the testicular histopathology was evaluated by the same and experienced pathologist.Tsujimara et al., Ramasay et al., and Kalsi et al. have evaluated testicular histopathology by classifying into SCO, MA and HS subgroups in order to assess its predictive value for the outcome of salvage TESE (7-9). In addition to these three studies, Xu et al. have evaluated HT testicular histopathology as an individual subgroup (10).

In contrast to these studies, the NS testicular histopathology subgroup was individually evaluated in our study, and

patients with MA were divided into the LMA and EMA groups. This classification was made using the JS in our study and therefore, testicular histopathology is believed to be subgrouped more accurately. Tsujimara et al., Ramasay et al. and Kalsi et al. compared testicular histopathologies, and determined the sperm retrieval rates of 39.1%, 34.3% and 40%, respectively, in patients with SCO histopathology prior to salvage TESE (7-9). In our study, the sperm retrieval rate was 36% in patients with SCO histopathology. In the study of Xu et al., sperm retrieval was possible in 25% of the patients with HT histopathology in salvage TESE (10). Similiarly, in our study, the sperm retrieval rate among patients with HT histopathology was 25%. These results demonstrate that the possibility of sperm retrieval continues in salvage mTESE even after a previous unsuccessful TESE. In our study, the sperm retrieval rate in salvage mTESE in patients with NS histopathology was 100% and it was 60% in patients with HS histopathology.

Compared to the other studies in the literature, the sperm retrieval rate among patients in the HS subgroup of our study was lower. The reason for this difference may be the different subgrouping in our study to that in the literature.

It was also concluded that the testicular histopathology was not a predictive factor for the success of salvage TESE. The sample size in our study and those in other studies in the literature were small, it is believed that accurate results may be accessed via meta-analyses performed in the future.

Our study has some limitations. First, it was a retrospective study. The effects of cryptorchidism and Klinefelterâ&#x20AC;&#x2122;s syndrome could not be evaluated in salvage TESE, since there was no history of cryptorchidism and only one patient had a history of Klinefelterâ&#x20AC;&#x2122;s syndrome in our study. Although short-term complications following salvage TESE were evaluated, no long-term evaluation was carried out, which is the second limitation of our study.

Not all sperms retrieved in TESE can be used in the ICSI procedure. Reproductive analysis of the patients following ICSI was not included in our study, which may be considered as another limitation; however, the outcomes of ICSI are affected by many factors including those of the women as well, and since the priority of our study was the factors affecting the success in salvage mTESE, the ICSI results were not included in the study.

CONCLUSIONS

Our study suggests that salvage mTESE is a safe alternative treatment method in patients with NOA and previous unsuccessful TESE, since the sperm retrieval rate was relatively higher. Evaluation of the preoperative FSH levels may be useful in determining the best candidates for this patient group. Further multi-center, prospective studies with larger sample sizes should be conducted in order to better understand the subject.

ACKNOWLEDGEMENTS

We would like to thank to Mustafa Karabicak, Ertan Can, Ozgur Cakmak for their contribution to the statistical analysis and Can Kose, Ulku Kucuk, Gokhan Koc for their contribution to the acquisition of data.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

139

Yucel2_Stesura Seveso 28/06/18 16:40 Pagina 140

C. Yücel, S. Budak, M. Zeynel Keskin, E. Kisa, Z. Kozacioglu

REFERENCES

1. Keskin MZ, Budak S, Aksoy EE, et al. Investigation of the effect of body mass index (BMI) on semen parameters and male reproductive system hormones. Arch Ital Urol Androl. 2017; 89:219-21.

2. Yucel C, Keskin MZ, Cakmak O, et al. Predictive value of preoperative inflammation-based prognostic scores (neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and monocyte-toeosinophil ratio) in testicular sperm extraction: a pilot study.

Andrology. 2017; 5:1100-4.

3. Vloeberghs V, Verheyen G, Haentjens P, et al. How successful is TESE-ICSI in couples with non-obstructive azoospermia? Hum Reprod. 2015; 30:1790-1796.

4. Schlegel PN. Testicular sperm extraction: microdissection improves sperm yield with minimal tissue excision. Hum Reprod.

1999; 14:131-5.

5. Ustuner M, Yılmaz H, Yavuz U, et al. Varicocele repair improves testicular histology in men with nonobstructive azoospermia.

Biomed Res Int. 2015; 709452.

6. Okada H, Dobashi M, Yamazaki T, et al. Conventional versus microdissection testicular sperm extraction for nonobstructive azoospermia. J Urol. 2002; 168:1063-7.

7. Tsujimura A, Miyagawa Y, Takao T, et al. Salvage microdissection testicular sperm extraction after failed conventional testicular sperm extraction in patients with nonobstructive azoospermia.

J Urol. 2006; 175:1446-9.

8. Ramasamy R, Schlegel PN. Microdissection testicular sperm

Correspondence Cem Yücel, MD (Corresponding Author) meclecuy@hotmail.com Salih Budak, MD salihbudak1977@gmail.com Mehmet Zeynel Keskin, MD zeynel_akd@hotmail.com Erdem Kisa, MD drerdemkisa@hotmail.com Zafer Kozacıoglu, MD Associate Prof. zaferkozacioglu@gmail.com Tepecik Training and Research Hospital Yenisehir Mah, Gaziler Cad. No:468, Konak/Izmir, Turkey

140

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

extraction: effect of prior biopsy on success of sperm retrieval.

J Urol. 2007; 177:1447-9.

9. Kalsi JS, Shah P, Thum Y, et al. Salvage micro-dissection testicular sperm extraction; outcome in men with non-obstructive azoospermia with previous failed sperm retrievals. BJU Int. 2015; 116:460-5.

10. Xu T, Peng L, Lin X, et al. Predictors for successful sperm retrieval of salvage microdissection testicular sperm extraction (TESE) following failed TESE in nonobstructive azoospermia patients. Andrologia. 2017; 49: e12642.

11. Patel DP, Chandrapal JC, Hotaling JM. Hormone-based treatments in subfertile males. Curr Urol Rep. 2016; 17:1-8.

12. Hussein A, Ozgok Y, Ross L, et al. Optimization of spermatogenesis-regulating hormones in patients with non-obstructive azoospermia and its impact on sperm retrieval: a multicentre study.

BJU Int. 2013; 111:110-4.

13. Ramasamy R, Lin K, Gosden LV, et al. High serum FSH levels in men with nonobstructive azoospermia does not affect success of microdissection testicular sperm extraction. Fertil Steril. 2009; 92:590-3.

14. Hung AJ, King P, Schlegel PN. Uniform testicular maturation arrest: a unique subset of men with nonobstructive azoospermia.

J Urol. 2007; 178: 608-12.

15. Haimov-Kochman R, Lossos F, Prus D, et al. The value of repeat testicular sperm retrieval in azoospermic men. Fertil Steril. 2009; 91:1401-3.

Caria_Stesura Seveso 28/06/18 16:41 Pagina 141

DOI: 10.4081/aiua.2018.2.141

CASE REPORT

Skin flap squamous cell carcinoma developed after urethroplasty Danilo Abate, Giuseppe Giusti, Nicola Caria, Giuseppe De Vita, Marco Lucci Chiarissi, Antonello De Lisa Clinica Urologica, Università degli Studi di Cagliari, Ospedale SS. Trinità, Cagliari, Italy.

Summary

Objectives: To describe our experience in diagnosis and treatment of urethral carcinoma following urethroplasty with a Orandi penile skin flap.

Material and methods: Our patient underwent to Orandi penile skin flap urethroplasty then developed a urethral epidermoid carcinoma on the flap approximately 15 years later.

We treated this case with a partial penectomy surgery and perineostomy. Surgery was followed by chemotherapy with cisplatin and 5-fluorouracil. The progression of the disease led to a salvage surgery of total penectomy and asportation of testicles and scrotum.

Results: Despite the success of the surgery, the disease progressed and three months after the last surgical operation the patient died.

Conclusions: Urethral carcinoma on skin flap is a rare complication of the urethroplasty surgery but with severe consequences, so we recommend to undertake a long-term urological follow up in patients undergone such kind of surgery.

KEY WORDS: Skin flap; Squamous cell carcinoma; Urethroplasty.

Submitted 13 April 2018; Accepted 29 April 2018

INTRODUCTION

According to the American Association of Urology (AUA) guidelines, male urethral stenosis can be treated with urethral dilatation, endoscopic urethrotomy, and surgical urethroplasty.

Urethroplasty should be performed in patients that presented a post-dilatation relapse or a recurrence after an endoscopic urethrotomy for stenoses less than 2 cm in length. Urethroplasty is also the preferred treatment for patients with long (≥ 2 cm) bulbar urethral strictures, given the low success rate of direct visual internal urethrotomy (DVIU) or dilation. The surgical reconstruction of the urethral strictures can be carried out using oral mucosal grafts, penile fascia-cutaneous flaps or a combination of these techniques. In literature are reported isolated cases of urethral carcinoma following urethroplasty (1, 2). We report our experience in order to increase the scientific evidence.

CASE

DESCRIPTION

The patient was a 69 years old male who had in the previous year's several endoscopic surgeries for multiple

recurrences of urethral stenosis. So in July 2001 an Orandi flap urethroplasty with penile skin was performed.

Subsequently in July 2016 the patient presented multiple scrotal and penile urinary fistulae accompanied by urosepsis. Then an abdominal-pelvic MRI identified a multi-segmented abscess of the left inguinal scrotal region and a solid neoplasm involving the urethra and corpora cavernosa in their proximal part. The micturition cystography pointed out also a severe stenosis of the penile urethra, confirmed by an endoscopic exam.

So, a partial penectomy and distal ureterectomy were therefore performed with a perineal urethrostomy.

The operation was accomplished by a median incision of the penile shaft, from the external urethral meatus down to the perineum. The presence of hard tissue, sometimes ulcerated and with the presence of purulent material, which incorporated the urethra up to the bulbar section, made the correct distinction of the surgical planes difficult. In order to better guide the surgical choice, a tissue sample was taken and sent for extemporaneous histological examination which disclosed for "epidermoid carcinoma, affected by moderate interstitial leukocyte exudation, with granulomatous aspects similar to a foreign body".

Given the histological report, it was decided to proceed with total urethrectomy and the forging of a perineal urethral meatus.

In September 2016, the patient undertook an oncological assessment and subsequent cycle of systemic chemotherapy with Cisplatin and 5-FU, which was completed in January 2017. Unfortunately, no significant therapeutic response to systemic therapy was observed.

Due to the progression of the disease, the patient began to accuse diffuse pain in the hypogastric and inguinal regions. The MRI restaging demonstrated a neoplastic extension of the disease into the corpora cavernosa up to the bulbs and neighboring regions.

In March 2017 the patient underwent new surgery.

We proceeded with a median longitudinal incision at the level of the pubic symphysis and extended caudally down to the perineal urethral meatus, also invaded by neoplastic tissue. The proximal cavernous bodies appeared rigid and hard, deeply affected by the neoplasia. Even the tissues nearest to the corpora cavernosa bulbs appeared to be affected by the neoplasm.

For this reason we proceeded to a detachment of the

No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

141

Caria_Stesura Seveso 28/06/18 16:41 Pagina 142

D. Abate, G. Giusti, N. Caria, G. De Vita, M. Lucci Chiarissi, A. De Lisa

neoplastic plate from the periosteum of the pubis and its excision up to the bulbar section of the urethral stump and so on to a total penectomy, en-block removal of external genitalia and scrotal sac. Given the extent of the

tumor and its degree of infiltration, it was not possible to guarantee oncological radicalness. The intervention was completed by accomplishing a definitive suprapubic urinary derivation. The definitive histological report showed a "moderately differentiated spinocellular carcinoma with horn pearl formaFigure 1. tions of the periurethral tissue and the corHistology reports: "moderately differentiated spinocellular carcinoma with pora cavernosa, focally extended to the teshorn pearl formations of the periurethral tissue and the corpora cavernosa” ticular albuginea without infiltrating the H&E stain. 100x. pulp. The neoplastic involvement includes the tissues of the scrotum up to the dermis".

The rapid progression of the disease and the state of clinical impairment of the patient did not allow to consider treatments with an adjuvant intent.

The patient died in June 2017.

CONCLUSIONS

Although extremely rare, the malignant transformation of the skin flaps used during urethroplasty is possible. Such carcinoma if not early recognized can have harmful consequences as documented. It is therefore important to undertake a long urological follow-up in patients subjected to this kind of urethral surgery.

REFERENCES

1. Williams G, Ashken MH. Urethral carcinoma following urethroplasty. J R Soc Med. 1980; 73:370-1.

2. Sawczuk I, Acosta R, Grant D, et al. Post urethroplasty squamous cell carcinoma. N Y State J Med. 1986; 86:261-3.

Correspondence Danilo Abate, MD Giuseppe Giusti, MD (Corresponding Author) giuseppegiusti.med@gmail.com Nicola Caria, MD (Corresponding Author) nicolacaria1@gmail.com Giuseppe De Vita, MD Marco Lucci Chiarissi, MD Antonello De Lisa, MD Clinica Urologica, Università degli Studi di Cagliari, Ospedale SS. Trinità Via Is Mirrionis, Cagliari, Italy

142

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

Dell'Atti_Stesura Seveso 28/06/18 16:42 Pagina 143

DOI: 10.4081/aiua.2018.2.143

CASE REPORT

Rupture of the cavernous body diagnosed by contrast-enhanced ultrasound: Presentation of a clinical case Lucio Dell’Atti 1, Simone Scarcella 1, Giulio Argalia 2, Lorenzo Montesi 1, Gian Marco Giuseppetti 2, Andrea Benedetto Galosi 1 1 Department 2 Department

of Urology, Polytechnic University of Marche Region, University Hospital “Ospedali Riuniti”, Ancona, Italy; of Radiology, Polytechnic University of Marche Region, University Hospital “Ospedali Riuniti”, Ancona, Italy.

Summary

Penile trauma represents a urological emergency characterized by the breaking of the albuginea tunic. A fast diagnosis and early surgical repair are the best treatments to avoid post-operative sequelae such as curvatures or deformities of the penis. An ultrasound evaluation may not be able to identify the injury in the tunica albuginea due to the edematous swelling of the penis and clots within the tear deteriorate the image contrast and can hide the injury.

We here report a case study of successful management via surgical treatment for rupture of the cavernous body diagnosed by contrast-enhanced ultrasound in a young patient with penile trauma.

KEY WORDS: Penile fracture; Trauma; Ultrasound; Contrast enhanced ultrasonography.

Submitted 2 April 2018; Accepted 29 April 2018

INTRODUCTION

The fracture of the penis represents an urological emergency characterized by the breaking of the tunica albuginea and cavernous body (CB), frequently resulting in direct trauma, vigorous sexual intercourse, falls, forceful manipulation and masturbation (1). The diagnosis is usually delayed because of the patient’s embarrassment.

A fast diagnosis and early surgical repair are the best treatments to avoid post-operative sequelae such as curvatures or deformities of the penis (2). We here report a case study of successful management via surgical treatment for rupture of the CB diagnosed by contrast-enhanced ultrasound (CEUS) in a patient with penile trauma.

CASE

REPORT

A 25-years-old male patient presented to our Emergency Department for severe penile pain and suspicion of penile fracture after trauma during an act of masturbation.

On presentation, the penis showed swelling, ecchymosis without deformity and urethrorrhagia. An ultrasonographic evaluation (US), 7-12 MHz multi-frequency linear probe, was performed first on a transversal plane, from the glans to the base of the penile shaft, and then completed with a longitudinal scan. US examination of

the penis reported a hypo-anechoic mass on the right CB, highly suspicious for hematoma but without certain interruption of the tunica albuginea (Figure 1A, 1B).

Due to difficulty detecting the cause of acute hematoma, a CEUS study was performed through insertion of a 19 Gauge butterfly needle in the corpora cavernosa. CEUS examination showed a tunica albuginea’s defect in the right CB with a concomitant area characterized by absence of contrast enhancement, described as compatible with hematoma (Figure 1C). An emergency explorative surgery was immediately performed. After circumcision and degloving of the penile shaft we evacuated the hematoma and individuated a tear (maximum diameter 8 mm) in the right CB tunica albuginea. A running suture with absorbable 2-0 polydioxanone, was used for tear repair. No postoperative complications occurred and after 3 days the patient was discharged.

DISCUSSION

The use of US in traumas is now accepted in clinical practice as initial diagnostic evaluation of blunt abdominal trauma. However, up to date, ultrasonographic study of parenchymal lesions is characterized by the presence of frequent false negatives (3). Penile traumas generally occur in the proximal or mid shaft of the erect penis, and concomitant lesions to the urethra occur in approximately 10-20% of patients (1, 2). Penile fractures are urologic emergencies and require as soon as possible surgical repair. The diagnosis of penile fracture is usually established based on its characteristic history and physical findings (1).

However, in all cases an ultrasonographic evaluation should be performed to define the localization of the lesion (2, 3). It is important considering that subcutaneous hematoma confined to the Buck’s fascia, in absence of a tunica albuginea laceration, requires medical conservative treatment. Only if a tunica albuginea tear is suspected or confirmed by US is mandatory to perform surgery within 24 from the traumatic event in order to reduce hospitalization, perioperative penile deviation and erectile dysfunction risk (2). The echo structure of the corpora cavernosa are homogeneous and

No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

143

Dell'Atti_Stesura Seveso 28/06/18 16:42 Pagina 144

L. Dell’Atti, S. Scarcella, G. Argalia, L. Montesi, G.M. Giuseppetti, A.B. Galosi

Figure 1.

(A): Longitudinal and (B): transverse ultrasound image show an injury of the dorsal subtunical venous plexus in the absence of complete tunica disruption (white arrow).

(C): Late phase transverse CEUS dual mode showing the avascular area representing hematoma and the tear of the right cavernous body as an interruption of the thin echogenic line of the tunica albuginea (white arrow).

CEUS can improve tissue delineation and a better evaluation of the tunica albuginea integrity.

MRI, however, it is expensive and rarely used in the evaluation of acute penile trauma (1, 4).

CEUS, using micro-bubbles contrast agents and complementary harmonic pulse sequences can implements the diagnostic performance of the Bmode, distinguish the parenchymal perfusion and defects. Moreover, it improves patient tolerance, reduces radiation exposure and can be also safely performed in patients with renal impairment (4, 5). Guidelines and Recommendations on Clinical Practice of CEUS represent current indications for administration of ultrasound contrast enhancement agents in different urogenital pathologies, including penile conditions (6).

Conservative management of penile trauma lead to increased rate of complications, such as penile curvature or erectile dysfunction, compared to immediate surgical intervention. CEUS is noninvasive, widely viable and may help in the process of exact localization of the tear site in the tunica albuginea, especially in complex and atypical cases.

REFERENCES

1. Nomura JT, Sierzenski PR. Ultrasound diagnosis of penile fracture. J Emerg Med. 2010; 38:362-365.

2. Dell'Atti L. The role of ultrasonography in the diagnosis and management of penile trauma. J Ultrasound. 2016; 19:161-166.

3. Topsøe JF, Dencker D. Investigation of Penile Conditions

by Ultrasound and Contrast-Enhanced Ultrasound Presentation of Three Clinical Cases. Ultrasound Int Open. 2015; 1:E78-79.

4. Cokkinos DD, Antypa E, Kalogeropoulos I, et al.

Contrast-enhanced ultrasound performed under urgent conditions. Indications, review of the technique, clinical examples and limitations. Insights Imaging. 2013; 4:185-198.

identified as two hypoechoic circular structures surrounded by a thin hyperechoic line representing the tunica albuginea (4). In case of edematous swelling and massive clots formation close to the tunica defect, an only US in B-mode could be misleading (2). For a better characterization Magnetic Resonance Imaging (MRI) or Correspondence Lucio Dell’Atti, MD, PhD dellatti@hotmail.com Simone Scarcella, MD Lorenzo Montesi, MD Andrea Benedetto Galosi, MD Department of Urology, Polytechnic University of Marche Region, University Hospital “Ospedali Riuniti” via Conca 71, 60126 Ancona, Italy Giulio Argalia, MD Gian Marco Giuseppetti, MD Department of Radiology, Polytechnic University of Marche Region, University Hospital “Ospedali Riuniti”, Ancona, Italy

144

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

5. Catalano O, Aiani L, Barozzi L, et al. CEUS in abdominal trauma: multi-center study. Abdom Imaging. 2009; 34:225-234.

6. Tranquart F, Mercier L, Frinking P, et al. Perfusion quantification in contrast-enhanced ultrasound (CEUS)--ready for research projects and routine clinical use. Ultraschall Med. 2012; (33 Suppl1):S31-8.

Caria2_Stesura Seveso 28/06/18 16:43 Pagina 145

DOI: 10.4081/aiua.2018.2.145

CASE REPORT

Surgical approach to adrenal ganglioneuroma: Case report and literature review Danilo Abate, Giuseppe Giusti, Nicola Caria, Marco Lucci Chiarissi, Antonello De Lisa Clinica Urologica, UniversitĂ degli Studi di Cagliari, Ospedale SS. TrinitĂ , Cagliari, Italy.

Summary

Objective: Ganglioneuroma (GN) is a benign tumor with a slow growth that can originate from any paravertebral sympathetic plexus. It is usually asymptomatic or with nonspecific symptoms. TC and RM scan are helpful to study GN. It is usually represented by an ovalshaped retroperitoneal mass or, in case of adrenal impairment, by low radiologic contrast media attenuation. Surgical treatment is mandatory. Literature shows how the laparoscopic approach is the most used, especially in lesions that are 6 cm or smaller. Our purpose is to describe our experience on an incidental adrenal GN of about 5 cm treated by the laparoscopic transperitoneal approach.

Materials and methods: A 33-year-old male had ultrasound occasional finding of an about 4 cm adrenal mass. TC and RM scan identified a retroperitoneal mass (max diameter 48 mm).

The lesion was removed with a transperitoneal laparoscopic approach.

Results: No intraoperative or postoperative complications occurred. The patient was discharged 3 days after surgery.

Conclusions: Up to the present laparoscopic surgery is the best approach for GN treatment.

KEY WORDS: Adrenal ganglioneuroma.

Submitted 17 April 2018; Accepted 29 April 2018

INTRODUCTION

Ganglioneuroma (GN) is a benign tumor with a slow growth that can originate from any paravertebral sympathetic plexus but can occasionally develop in the adrenal medulla. It is usually asymptomatic or with nonspecific symptoms related to mass effect causing diaphragmatic compression, upper urinary tract or gastrointestinal upset and, rarely, spinal cord compression or bone erosions. Sometimes GN produces catecholamines or other hormones so patients can have hypertension, diarrhea or flushing.

TC and RM scan are helpful to study GNs. They are usually represented by an oval-shaped retroperitoneal mass or, in case of adrenal impairment, by low radiologic contrast media attenuation. RM study is characterized by signal hypointensity during T-1 weighted scans and a non uniform hyperintensity in T-2 weighted scans (1).

From the histopathologic point of view, GN presents mature Schwann cells, ganglion cells and nerve fiber (2).

Surgical treatment is mandatory. Literature shows how

the laparoscopic approach is the most used, especially in less than 6 cm lesions.

The majority of authors consider transperitoneal approach as best solution because it guarantees a good retroperitoneal access and maximum adrenal and big vessels exposition (3). According to this technique, with a patient in right lateral posture, Zofragos et al. have completed right adrenalectomy in a 33-year-old female with a 13 cm GN, whereas Abraham et al. have performed the same surgery in a 33-year-old female with a 17 cm GN. Low intraoperative blood loss and no postoperative complications occurred in both studies.

The open approach should be preferred when the tumor is close to big vessels or other organs.

CASE

DESCRIPTION

A 33-year-old male was hospitalized in March 2016 for urinary calculi. During ultrasound abdominal study, we occasionally found a 40 mm left adrenal mass.

In November 2016 he underwent TC abdomen scan with radiological contrast media. The lesion was an ovalshaped gross and homogeneous mass of about 46 mm.

Its radiological aspect was compatible with low adipose tissue adenoma (median density was 45 HU).

On 3 January 2017 he underwent an abdomen RM without radiological contrast media and the left adrenal lesion (48 x 30 mm) was featured by low hyperintensity in T-2 weighted scans and signal hypointensity during T1 weighted ones. In the beginning, the mass was described as low lipidic adenoma. Plasmatic values of cortisol, aldosterone, renin, and TSH were in range and plasmatic ACTH was not suppressed. Aldosterone/renin ratio was 4,86 pg/ml. Daily urinary metanephrine and normetanephrine were normal. We performed laparoscopic transperitoneal adrenalectomy. The patient was placed in right lateral posture. Pneumoperitoneum was induced with open Hasson technique. An optical port was placed at the umbilicus, the other 2 trocars were placed respectively in left iliac fossa and in the left pararectal region. The left paracolic gutter was incised and renal loggia was exposed. Then, the anterior membrane of Gerota fascia was incised and renal vascular hilum isolated. An accurate craniocaudal dissection was performer till the adrenal gland exposition. Adrenal ves-

No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

145

Caria2_Stesura Seveso 28/06/18 16:43 Pagina 146

D. Abate, G. Giusti, N. Caria, M. Lucci Chiarissi, A. De Lisa

sels were isolated and adrenal vein was cut between 3 Hem-o-Lok clips just at the confluence with the renal vein. The adrenal artery was cut by a vessel sealing device. Then, adrenalectomy was completed and adrenal gland was extracted into 10 mm Endo-bag. No drainage was placed. A urinary catheter was placed and then removed after 24 hours.

Routine blood samplings were taken. The difference between pre-surgery and 6 hours later hemoglobin values was 0.8 g/dl.

The patient was discharged 3 days after surgery.

Histopathological analysis showed an adrenal ganglioneuroma with isolated mature ganglion cells, packaged in 3-4 elements with no cellular atypia.

Immunohistochemistry was positive for S100 and NSE (Figure 1).

Figure 1.

Histology showed "adrenal ganglioneuroma with isolated mature ganglion cells, packaged in 3-4 elements with no cellular atypia”. Section 1 highlights in H&E stain 100x aggregates of ganglion cells, section II low positivity on Ki67 immunohistochemistry, section III & IV strong positivity on NSE and S100 respectively.

CONCLUSIONS Our case report and a literature review confirm feasibility, efficacy, and safety of surgical management of this disease. A laparoscopic approach can reduce invasivity, blood loss, and hospital stay.

REFERENCES

1. Ichikawa T, Ohtomo K, Araki T, et al. Ganglioneuroma: computed tomography and magnetic resonance features. Brit J Radiol.

1996; 69:114-121.

Correspondence Danilo Abate, MD Giuseppe Giusti, MD (Corresponding Author) giuseppegiusti.med@gmail.com Nicola Caria, MD (Corresponding Author) nicolacaria1@gmail.com Marco Lucci Chiarissi, MD Antonello De Lisa, MD Clinica Urologica, Università degli Studi di Cagliari, Ospedale SS. Trinità Via Is Mirrionis, Cagliari, Italy

146

Archivio Italiano di Urologia e Andrologia 2018; 90, 2

2. Chang CY, Hsieh YL, Hung GY, et al. Ganglioneuroma presenting as an asymptomatic huge posterior mediastinal and retroperitoneal tumor. J Chin Med Assoc. 2003; 66:370-374.

3. Zografos GN, Kothonidis K, Ageli C, et al. Laparoscopic resection of large adrenal ganglioneuroma. J Soc Laparoendoscopic Surg, 2007; 11:487-492.

Istruz_Stesura Seveso 28/06/18 17:14 Pagina 1

INSTRUCTIONS OPEN ACCESS

Open access publishing does have its costs. Information regarding authors’ payment are not made available to editors and reviewers ensuring that they cannot be influenced in their selection of papers for publication by payment conditions or limitations.

The Article Processing Charge for publication in this journal is EUR 200,00 (plus VAT, if applicable).

Our fees cover the costs of peer review, copyediting, publication, different format of publication (HTML, PDF), inclusion in many Open Access databases.

All bank charges shall be borne by the payer.

Please note that our fees do not include taxes (VAT): - Private or public ITALIAN customers (individuals, universities, hospitals, other organizations) must ALWAYS add VAT (IVA) at standard rate (4%); - European Union PRIVATE customers must add the standard rate of their own country VAT tax; - European Union private/public ORGANIZATIONS (universities, hospitals, others with regular VAT number) should not add any taxes at standard rate, provided that they indicate their VAT number; - Outside the European Union, individuals and organizations should not add any taxes at standard rate.

Important: Authors are NOT required to pay at the moment of submission. If the paper is accepted, the Managing Editor of Open Access Edition will guide the Authors through the payment procedure. No article will be published before waiver or payment.

According to the United Nations list of Least Developed Countries (LCDs) available from: http://www.un.org/en/development/desa/policy/cdp/ldc2/ldc_countries.shtml Authors coming from those countries are entitled to ask for a discount.

A “Formal Request for discount” has to be forwarded to the Managing Editor of Open Access Edition, after receiving the acceptance letter. The Editorial Committee will then evaluate the merits of each individual case.

Any other informal request (such as comments at the moment of submission, or made in the covering letter of the revised version) will not be taken into consideration.

FAST-TRACK PEER REVIEW

We offer fast-track peer review and publication of controlled trials that we judge of importance to practice or research. If you wish to discuss your proposed submission, please write (scriman@tin.it) or call our editorial office in Milan (+39 02 70608060). With the payment of a supplementary fee of 488 Euros (VAT included), the review, editorial decision, and author notification on this manuscript is guaranteed to take place within 4 weeks.

TRANSLATION

Manuscripts in Italian language can be published after translation (a supplementary fee for printed page will be charged to the Authors).

METHODS OF PAYMENT Authors can pay their fees by: PayPal PayPal is the most recommended and secure payment system. It enables you to pay getting your payment receipt immediately and without sharing your financial information.

Other methods of payment are: Bank transfer BANK NAME: Banca Popolare di Sondrio, Branch #1, Strada Nuova 75, I-27100 Pavia, Italy ACCOUNT HOLDER: PAGEPress Srl BIC/SWIFT: POSOIT22 IBAN: IT85Y0569611301000005086X83 Credit Card The credit card form to be filled and returned either via e-mail or via fax is available for download here. http://www.pagepress.org/journals/public/credit_card.pdf Check sent by surface mail Checks must be made payable to PAGEPress Srl and must be sent to our full postal address: PAGEPress Publications, via A. Cavagna Sangiuliani 5, 27100 Pavia, Italy.

Note: In any method of payment you choose, kindly specify: 1. journal name; 2. paper ID number; 3. first author.

Important: All papers published in Archivio Italiano di Urologia e Andrologia (AIUA) are peer reviewed. At present, Edizioni Scripta Manent Edizioni let everyone to read and download papers from its website. However, Edizioni Scripta Manent will retain copyright and will be granted publishing and distribution rights.

AUTHORS’ RESPONSIBILITIES

Manuscripts are accepted with the understanding that they have not been published or submitted for publication in any other journal.

Authors must submit the results of clinical and experimental studies conducted according to the Helsinki Declaration on clinical research and to the Ethical Code on animal research set forth by WHO (WHO Chronicle 1985; 39:51).

The Authors must obtain permission to reproduce figures, tables and text from previously published material. Written permission must be obtained from the original copyright holder (generally the Publisher).

MANUSCRIPT PRESENTATION

Authors must submit their manuscripts (MAC and WINDOWS Microsoft Word are accepted) after registration and login to the link: http://www.aiua.it. Surface or e-mail submission are not accepted.

Manuscripts must be written in English language in accordance with the “Uniform Requirements for Manuscripts submitted to biomedical journals” defined by The International Committee of Medical Journal Editors (http://www.ICMJE.org). Manuscripts in Italian language can be published after translation (expenses will be charged to the Authors).

Manuscripts should be typed double spaced with wide margins.

They must be subdivided into the following sections:

TO

AUTHORS TITLE PAGE

It must contain: a) title; b) a short (no more than 40 characters) running head title; c) first, middle and last name of each Author without abbreviations; d) University or Hospital, and Department of each Author; e) last name, address and e-mail of all the Authors; f) corresponding Author; g) phone and/or fax number to facilitate communication; h) acknowledgement of financial support; i) list of abbreviations.

SUMMARY

The Authors must submit a long English summary (300 words, 2000 characters).

Subheadings are needed as follows: Objective(s), Material and method(s), Result(s), Conclusion(s). After the summary, three to ten key words must appear, taken from the standard Index Medicus terminology.

TEXT

For original articles concerning experimental or clinical studies, the following standard scheme must be followed: Summary - Key Words - Introduction - Material and Methods - Results - Discussion - Conclusions - References - Tables - Legends - Figures. Case Report should be divided into: Summary - Introduction (optional) - Case report(s) - Conclusions - References (Discussion and Supplementary Figures, Tables and References can be submitted for publication in Supplementary Materials).

SIZE OF MANUSCRIPTS

Literature reviews, Editorials and Original articles concerning experimental or clinical studies should not exceed 3500 words with 3-5 figures or tables, and no more than 30 references.

Case reports, Notes on surgical technique, and Letters to the editors should not exceed 1000 words (summary included) with only one table or figure, and no more than three references. No more than five authors are permitted.

As an accompaniment to Case reports manuscripts for the print version of Archivio Italiano di Urologia e Andrologia (AIUA), authors may submit supplementary materials for posting on www.aiua.it.

The material is subject to the same editorial standards and peer-review procedures as the print publication.

REFERENCES

References must be sorted in order of quotation and numbered with arabic digits between parentheses. Only the references quoted in the text can be listed. Journal titles must be abbreviated as in the Index Medicus. Only studies published on easily retrieved sources can be quoted. Unpublished studies cannot be quoted, however articles “in press” can be listed with the proper indication of the journal title, year and possibly volume. References must be listed as follows:

JOURNAL ARTICLES

All Authors if there are six or fewer, otherwise the first three, followed by “et al.”.

Complete names for Work Groups or Committees. Complete title in the original language. Title of the journal following Index Medicus rules. Year of publication; Volume number: First page.

Example: Starzl T, Iwatsuki S, Shaw BW, et al. Left hepatic trisegmentectomy Surg Gynecol Obstet. 1982; 155:21.

BOOKS

Authors - Complete title in the original language. Edition number (if later than the first).

City of publication: Publisher, Year of publication.

Example: Bergel DIA. Cardiovascular dynamics. 2nd ed. London: Academic Press Inc., 1974.

BOOK CHAPTERS

Authors of the chapters - Complete chapter title. In: Book Editor, complete Book Title, Edition number. City of publication: Publisher, Publication year: first page of chapter in the book.

Example: Sagawa K. The use of central theory and system analysis. In: Bergel DH (Ed), Cardiovascular dynamics. 2nd ed. London: Academic Press Inc., 1964; 115.

TABLES

Tables must be aimed to make comprehension of the written text easier. They must be numbered in Arabic digits and referred to in the text by progressive numbers. Every table must be accompanied by a brief title. The meaning of any abbreviations must be explained at the bottom of the table itself. (If sent by surface mail tables must be clearly printed with every table typed on a separate sheet).

FIGURES

(Graphics, algorithms, photographs, drawings). Figures must be numbered and quoted in the text by number. The meaning of all symbols, abbreviations or letters must be indicated. Histology photograph legends must include the enlargement ratio and the staining method. Legends must be collected in one or more separate pages. Please follow these instructions when preparing files: • Do not include any illustrations as part of your text file.

• Do not prepare any figures in Word as they are not workable.

• Line illustrations must be submitted at 600 DPI. • Halftones and color photos should be submitted at a minimum of 300 DPI. • Power Point files cannot be uploaded.

• If at all possible please avoid transmitting electronic files in JPEG format. If this is unavoidable please be sure to save the JPEG at the highest quality available and at the correct resolution for the type of artwork it is.

• PDF files for individual figures may be uploaded.

MANUSCRIPT REVIEW Only manuscript written according to the above mentioned

rules will be considered. All submitted manuscripts are evaluated by the Editorial Board and/or by two referees designated by the Editors. The Authors are informed in a time as short as possible on whether the paper has been accepted, rejected or if a revision is deemed necessary. The Editors reserve the right to make editorial and literary corrections with the goal of making the article clearer or more concise, without altering its contents.

Submission of a manuscript implies acceptation of all above rules.

PROOFS Authors are responsible for ensuring that all manuscripts are accurately typed before final submission. Galley proofs will be sent to the first Author. Proofs should be returned within seven days from receipt.

Istruz_Stesura Seveso 28/06/18 17:15 Pagina 2

GENERAL INFORMATION

BUSINESS INFORMATION

AIMS

SUBSCRIPTION

AND

SCOPE

“Archivio Italiano di Urologia e Andrologia” publishes

DETAILS Annual subscription rate (4 issues) is Euro 52 for Italy and US $130 for all other Countries.

Price for single issue: Euro 13 for Italy US $32,5 for all other Countries.

Issues will be sent by surface mail; single issues can also be sent by air mail at an extra charge of US $12.

papers dealing with the urological, nephrological and andrological sciences.

Original articles on both clinical and research fields, reviews, editorials, case reports, abstracts from papers published elsewhere, book rewiews, congress proceedings can be published.

Papers submitted for publication and all other editorial correspondence should be addressed to:

Subscription orders should be sent to:

Edizioni Scripta Manent s.n.c.

Edizioni Scripta Manent s.n.c.

COPYRIGHT

Claim for missing issues should be made within 3 months from publication for domestic addresses, otherwise they cannot be honoured free of charge.

Via Melchiorre Gioia 41/A - 20124 Milano, Italy Tel. +39 0270608060 e-mail: scriman@tin.it www.edizioniscriptamanent.eu Papers are accepted for publication with the understanding that no substantial part has been, or will be published elsewhere. By submitting a manuscript, the authors agree that the copyright is transferred to the publisher if and when the article is accepted for publication. The copyright covers the exclusive rights to reproduce and distribute the article, including reprints, photographic reproduction and translation. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior written permission of the Publisher.

Direttore Responsabile: Pietro Cazzola Pubbliche Relazioni e Marketing: Donatella Tedeschi Comunicazione e Media: Ruben Cazzola Grafica e Impaginazione: Stefania Cacciaglia Affari Legali: Avv. Loredana Talia (MI) Stampa: Lalitotipo, Settimo Milanese (MI)

Via Melchiorre Gioia 41/A - 20124 Milano, Italy Tel. +39 0270608060 e-mail: scriman@tin.it

Changes of address should be notified Edizioni Scripta Manent s.n.c. at least 6-8 weeks in advance, including both old and new addresses. The handling of personal data concerning subscribers is managed by our electronic data base. It is in accordance with the law 675/96 regarding the tutorship of personal data.

The use of data, for which we guarantee full confidentiality, is to keep our readers up to date with new initiatives, offers and publications concerning Edizioni Scripta Manent s.n.c. Data will not be released or disseminated to others and the subscriber will be able to request, at any time, variation or cancellation of data.

ADVERTISING

For details on media opportunities within this journal please contact Mrs. Donatella Tedeschi, MD at +39 0270608060

Ai sensi della legge 675/96 è possibile in qualsiasi momento opporsi all’invio della rivista comunicando per iscritto la propria decisione a: Edizioni Scripta Manent s.n.c. - Via Melchiorre Gioia, 41/A - 20124 Milano

Istruz_Stesura Seveso 28/06/18 17:15 Pagina 3

Congresso Nazionale Urop ALBEROBELLO (BA) 6 - 8 GIUGNO 2019 Presidente del Congresso

Presidente UrOP

Giuseppe Ludovico

Angelo Porreca

CHI PUĂ&#x2019; FARNE PARTE Possono far parte dell'Associazione

QUOTA SOCIALE

ISCRIZIONE

strutture assistenziali urologiche private o a gestione privata.

della rivista "Archivio Italiano di

INFORMAZIONI

gli Urologi non facenti parte dell'ospedalitĂ a gestione privata e gli specializzandi.

segreteria dell'Associazione all'indirizzo: segreteria@urop.it

Istruz_Stesura Seveso 28/06/18 17:16 Pagina 4

Istruz_Stesura Seveso 28/06/18 17:16 Pagina 5

PR ES E NT A L A N U O V A R I VI ST A O RG AN O U F F IC IA L E DI

Multidisciplinare, dedicata all’adolescenza ed ai suoi più importanti temi; Diretta al grande pubblico degli adulti; Sfogliabile e consultabile gratuitamente O ONLINE NLINE su qualunque device: computer, tablet, smartphone…

PERCHÈ ADÒ È ONLINE? Rappresenta la rivoluzione del concetto di rivista, di aggiornamento, di letteratura; Fornisce un accesso facilitato ed immediato ad articoli, argomenti ed approfondimenti; Accelera la diffffusione di idee ed esperienze, migliora l'interazione culturale tra lettori ed autori; # # # # # Sostiene in tempo reale l’evoluzione del pensiero; Realizza l’espansione oltre misura della conoscenza, ne permette condivisione e diffffusione. # # # # # # # # # # # # # NEL EL PRIMO PRIMO# NUMERO NUM # ER O # # # social network# ,# # # # # # # # # sicurezza nel web, ambi#ente, # # # # 2 2 # # # # # alternanza scuola lavoro… # # # # A RT I CO L I DI : # # # # # Maurizio T # ucci, Pre#sidente d#i La#borato# rio Adolesc# enza, # # Fulvio Scap#arro, P# sicologo# e psicoter#apeuta, # # # # # # # Riccardo Re # nzi, #già Direttore di Corriere Salute (le pagine della salute del Corrie#re della# S# era), Professionisti e#sp#erti di ado# lesce#nz#a, # # # # # # Adolescenti, Redazione junior di "Scripta Restantt””, voce del Liceo s#cientifi#co Einste# in# di Mil#ano. # # # # # # # # # # # # # # # # # # Per leggere Adò e scaricarla gratuitamente # EERR CCONTATTI P ONT#ATT#I ED ED INFO I NF O collegarsi al seguente link: magazineado@gmail.com magazineado@gmail.com # https://issuu.com/edizioniscriptamanent/ T#el. 02 02 70608060 7 06 0 8 0 60 # Tel. # # # # # # # # docs/ado__1_18# # # # # # # ## # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # #

#

#

Istruz_Stesura Seveso 28/06/18 17:16 Pagina 6