Archivio Italiano di Urologia e Andrologia - Vol. 91 - n. 3 - 2019 by Edizioni Scripta Manent

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Vol. 91; n. 3, September 2019

PRESIDENTI P RESIDENTI D DEL EL C CONGRESSO ONGRESSO F. S SEMINARA EMINARA G. G. M MESSINA ESSINA

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

14-15-16 1 4-15-16 N NOVEMBRE OVEMBRE 2 2019 019

Archivio Italiano di Urologia e Andrologia / Archives of Italian Urology and Andrology - Vol. 91; n. 3 September 2019

SIUT S I UT

PRESIDENTE P RESIDENTE NAZIONALE NAZIONALE SIUT SIUT C C.. F FRANZESE RANZESE

REVIEW 139

Nutraceutical treatment and prevention of benign prostatic hyperplasia and prostate cancer Arrigo F.G. Cicero, Olta Allkanjari, Gian Maria Busetto, Tommaso Cai, Gaetano Larganà, Vittorio Magri, Gianpaolo Perletti, Francesco Saverio Robustelli Della Cuna, Giorgio Ivan Russo, Kostantinos Stamatiou, Alberto Trinchieri, Annabella Vitalone

ORIGINAL PAPERS 153

Green tea catechins for chemoprevention of prostate cancer in patients with histologically-proven HG-PIN or ASAP. Concise review and meta-analysis Gianpaolo Perletti, Vittorio Magri, Anne Vral, Konstantinos Stamatiou, Alberto Trinchieri

157

Safety and efficacy of retroperitoneal sutureless zero ischemia laparoscopic partial nephrectomy for low nephrometry score masses Emanuele Corongiu, Pietro Grande, Angelo Di Santo, Giorgio Pagliarella, Stefano Squillacciotti, Emanuele Liberati, Alessandra Zampelli, Valerio Olivieri, Michele Innocenzi, Flavio Forte

163

Assesment of anogenital distance as a marker in diagnosis of prostate cancer

167

Role of sterile pyuria in association to elevated PSA values in the diagnosis of non-palpable prostate cancer?

̈ rkmez, Serkan Akan, Ayhan Verit Aytac Sahin, Musab Ali Kutluhan, Tuncay Toprak, Yasin Vural, Ahmet U

Selamettin Demir

171

The comparative analysis of the three dilatation techniques in percutaneous nephrolithotomy: Which one is safer? Aytac Sahin, Fatih Uruc

174

Transurethral endoscopic approach for large bladder diverticula: Evaluation of a large series Mauro Pacella, Nicolò Testino, Guglielmo Mantica, Matteo Valcalda, Rafaela Malinaric, Carlo Terrone

continued on page III

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

ASSOCIATE EDITORS Emanuele Montanari, Department of Urology, IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Italy – Gianpaolo Perletti, Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, Italy; Department of Human Structure and Repair, Ghent University, Ghent, Belgium

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

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

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

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

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

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

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

GUN EDITORIAL BOARD

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

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

SIA ASSISTANT EDITORS

HONORARY EDITOR

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

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

SIA EDITOR

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ll ruolo della SIEUN La SIEUN (Società Italiana di Diagnostica Integrata in Urologia, Andrologia, Nefrologia) riunisce diversi medici specialisti e non che si occupano di tutte quelle metodiche in cui gli ultrasuoni vengono utilizzati a scopo diagnostico ed interventistico in ambito uronefro-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 UroNefro-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 2019 sarà presente con relazioni, moderazioni e letture nei congressi delle più prestigiose Società scientifiche di Urologia, Andrologia ed Ecografia.

CONVEGNO NAZIONALE: NEPHROIMAGING 2019 Milano, 6 dicembre 2019 – Milan Marriott Hotel

Società Italiana di Diagnostica Integrata in Urologia, Andrologia, Nefrologia

XXII X XX XII Congresso Congrresso Nazionale Nazionale

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PRESIDENTE S.I.E.U.N. Andrea Andrea Benedett Benedetto o Galosi PRESIDENTI DEL C CONGRESSO ONGRESSO Lucio Lucio Dell’Atti Dell’Atti Gian M Marco arco Giuseppetti Andrea Andrea Ranghino Ranghino TOPICS T OPICS CORSO CORSO SIU-SIRM SIU-SIRM RM PROSTATA PROST TA T ATA BIOPSIA

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ORIGINAL PAPERS 177

Chronic prostatic infection: Microbiological findings in two Mediterranean populations Konstantinos Stamatiou, Vittorio Magri, Gianpaolo Perletti, Vaia Papadouli, Nectaria Recleiti, Vassiliki Mamali, Olympia Zarkotou

182

How much do people know about male sexual problems? A survey in a selected population sample Edoardo S. Pescatori, Anna Baldini, Fabio Parazzini, Nicola Ghidini, Giovanni L. Briganti

187

Effects of antioxidant treatment on seminal parameters in patients undergoing in vitro fertilization Laura Gambera, Anita Stendardi, Camilla Ghelardi, Benedetta Fineschi, Rosamaria Aini

CASE REPORTS 191

193

Priapism induced by use of tamsulosin: A case report and review of the literature Marcelo Marconi, Pablo Pavez, Ignacio San Francisco, Paulette Narvaez

196

A complicated case of recurrent Cowper’s gland abscess Pietro Pepe, Ludovica Pepe, Astrid Bonaccorsi, Paolo Panella, Michele Pennisi

198

Vena cava defect repair using a polytetrafluoroethylene graft after a radical nephrectomy and vena cava resection: A case report Volkan Izol, Mutlu Deger, Mustafa Zuhtu Tansug

202

Archivio Italiano di Urologia e Andrologia 2019, 91, 3

III

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Cicero_Stesura Seveso 01/10/19 12:56 Pagina 139

REVIEW

DOI: 10.4081/aiua.2019.3.139

Nutraceutical treatment and prevention of benign prostatic hyperplasia and prostate cancer Arrigo F.G. Cicero 1, Olta Allkanjari 2, Gian Maria Busetto 3, Tommaso Cai 4, Gaetano Larganà 5, Vittorio Magri 6, Gianpaolo Perletti 7, Francesco Saverio Robustelli Della Cuna 8, Giorgio Ivan Russo 5, Kostantinos Stamatiou 9, Alberto Trinchieri 10, Annabella Vitalone 2 1 Dip.

di Scienze Mediche e Chirurgiche, Alma Mater Studiorum Università di Bologna, Bologna, Italy; di Farmacologia e Fisiologia “V. Erspamer”, Sapienza, Università di Roma, Roma, Italy; 3 Department of Urology, Sapienza Università di Roma, Policlinico Umberto I, Roma, Italy; 4 Department of Urology, Santa Chiara Regional Hospital, Trento, Italy; 5 Urology Department, University of Catania, Catania, Italy; 6 Ambulatorio Territoriale di Urologia ed Ecografia Urologica, ASST Nord Milano, Milano, Italy; 7 Dipartimento di Biotecnologie e Scienze della Vita, Sezione di Scienze Mediche e Chirurgiche, Università degli Studi dell'Insubria, Varese, Italy, and Faculty of Medicine and Medical Sciences, Ghent University, Ghent Belgium; 8 Department of Drugs Sciences, University of Pavia, Pavia, Italy; 9 Urology Department, Tzaneion Hospital, Piraeus, Greece; 10 CDC Ambrosiana Milano, Italy. 2 Dipartimento

Summary

During the last years, pharmaceutical innovations in primary care are dramatically less frequent and will be even more rare in the next future. In this context, preclinical and clinical research oriented their interest toward natural compounds efficacy and safety, supporting the development of a new “nutraceutical” science. Medicinal plants, in the form of plant parts or extracts of them, are commonly used for the treatment of prostate diseases such as benign hypertrophy, prostatitis and chronic pelvic pain syndrome. The pharmacological properties searched for the treatment of prostatic diseases are anti-androgenic, anti-estrogenic, antiproliferative, antioxidant and anti-inflammatory. The most studied and used medicinal plants are Serenoa repens, Pygeum africanum and Urtica dioica. Other promising plants are Cucurbita pepo, Epilobium spp, Lycopersum esculentum, Secale cereale, Roystonea regia, Vaccinium macrocarpon. In parallel, epidemiological studies demonstrated that diet may play an important role on incidence and development of prostatic diseases. The Mediterranean diet is rich of elements with anti-oxidant properties that act as a protective factor for prostatic cancer. Similarly, low intake of animal protein, high intake of fruits and vegetable, lycopene and zinc are a protective factor for benign prostatic hyperplasia (BPH). Serenoa repens in the treatment of symptoms of BPH has been tested either alone or, more frequently, in combination with other medicinal plants, alpha-blockers and inhibitors of 5alpha reductase (5-ARI). Recent meta-analyses found the effectiveness of Serenoa repens similar or inferior of that of finasteride and tamsulosin but clearly higher than that of placebo in the treatment of mild and moderate low urinary tract symptoms (LUTS), nocturia and discomfort. Clinical trials showed potential synergistic effect of Serenoa repens with other medicinal plants and drugs. In addition to Serenoa repens, there are many other medicinal plants for which clinical evidence is still controversial. Urtica dioica, Pygeum africanum and Curcubita pepo can be considered as an adjunct to the common therapies and their use is supported by studies showing improvement of symptoms and flowmetric indices. Lycopene and selenium are

natural products with antioxidant and anti-inflammatory action. The combination of lycopene and selenium with Serenoa repens was able to reduce inflammation in histological prostate sections and to further improve symptom scores and urinary flow in patients with BPH on tamsulosin treatment. Similar effects could be obtained with the use of other carotenoids, such as astaxanthin, and/or zinc. Efficacy on symptoms of patients with BPH of some polyphenols such as quercitin, equol and curcumin have been demonstrated by clinical studies. Pollen extract is a mixture of natural components able to inhibit several cytokines and prostaglandin and leukotriene synthesis resulting in a potent anti-inflammatory effect. Pollen extracts significantly improve symptoms, pain, and quality of life in patients affected by chronic pelvic pain syndrome and chronic prostatitis. Beta-sitosterol is a sterol able to improve urinary symptoms and flow measures, but not to reduce the size of the prostate gland. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide-signaling molecule with anti-inflammatory and neuroprotective effects that can have an interesting role in the management of chronic pelvic pain syndrome and chronic urological pain. Finally, several plant-based products have been subjected to preclinical, in vitro and in vivo, investigations for their potential pharmacological activity against prostate cancer. Some epidemiological studies or clinical trials evaluated the effects of beverages, extracts or food preparations on the risk of prostate cancer. Some plant species deserved more intense investigation, such as Camelia sinensis (green or black tea), Solanum lycopersicum (common tomato), Punica granatum (pomegranate), Glycine max (common soy) and Linum usitatissimum (linen).

KEY WORDS: Medicinal plant; Prostate; Benign prostatic hyperplasia; Prostate cancer; Antiproliferative effect; 5α-reductase; Serenoa repens; Pygeum africanum; Urtica dioica; Cucurbita pepo; Lycopene; Selenium; Polyphenols; Pollen extract; Beta-sitosterol; Palmitoylethanolamide. Submitted 1 July 2019; Accepted 25 July 2019

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 3

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INTRODUCTION

TO NUTRACEUTICAL PRESCRIPTION

(Arrigo F.G. Cicero) During the last years, the pharmaceutical innovation in primary care are dramatically less frequent and will be even more rare in the next future. In this context, preclinical and clinical research oriented their interest toward natural compounds efficacy and safety, supporting the development of a new nutraceutical science. The term “nutraceutical” has been created by Stephen De Felice in 1989 from the union of the words “nutrition” and “pharmaceutical”, to include dietary components or (more generically) botanical bioactive compounds with positive effects on well-being and health preservation, but also for the cure of some common health disorders (1). The most part of nutraceuticals has been identified in vegetables (2) such as β-glucans, tocotrienols, plant sterols/stanols, polifenols (anthocyanins, proanthocyanidins, flavonols, stilbens, catechins, epicatechins, cumarins, ellagic acid, isoflavons, lignans, etc.) whose biological activities are numerous and often well-documented. Much less numerous are the nutraceuticals of animal origin, even if some of them, as the omega 3 polyunsaturated fatty acids are among the most used nutraceuticals around the world (4). There are a large number of medical areas where nutraceuticals are currently used, among them urology and andrology. To warrant the consumer safety and to help the citizens to correctly choose the most adequate nutraceuticals, current laws state that the marketed products should be safe and adequately labelled. Then, the European Commission promoted specific rules on the nutritional and healthy properties of dietary supplements that can be disclaimed on nutraceutical boxes (Health Claims) (December 20th, 2006) (5, 6). The European Commission approved health claims are based on the opinions of an external agency, the European Food Safety Authority (EFSA), that periodically should organize meeting of expert panels selected to evaluate and re-evaluate health claims based on the available preclinical and clinical scientific data (7, 8). Currently, the use of dietary supplements and functional foods for the health maintenance and disease prevention is in continuous increase and the number of available products in the market is growng even more intensively. So, how to navigate (as prescribers, sellers or consumers) among 20-30 products containing similar bioactives, in different combinations, that suggest similar effects but with costs often really different? For some of them we have (almost) complete preclinical and clinical pharmaco-toxicological dossiers, till the availability of metaanalysis of randomized clinical trials. However, in the most part of cases, what is known about single bioactives is transferred to the combined marketed products without any kind of test on the final formulation. The main reasons of this are resumed in Table 1. In fact, the companies need to market new (at least apparently) “unique” products in a context where the registration and copyright are easily copied and scarcely protected. The cost of the high quality bioactives and the need to create original products often push the industries to add more and more low-dosed components in a single

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Table 1. Factors limiting the application of available scientific data to the combinations of nutraceutical products available in the market.

• • • • • •

No legal need to prove efficacy No legal possibility to declare efficacy (lack of approved health claim) Incomplete pharmaco-toxicological dossiers Cost of high quality bioactives and/or of pharmaceutical technologies used to make them bioavailable (for instance Coenzyme Q10, Resveratrol, Lycopene) Industry need to differentiate their product from the other ones Need to produce absolutely safe products (often limiting the dosage under the efficacy level)

pill/tablet to make the product more complex (“original”) trying to make up eventual synergies, almost never demonstrated. Of course, the use of low-dosed bioactives is a warranty of product safety and tolerability and to avoid the comparison to pharmacological drugs of natural origin, however it reduces the probability to observe a clinical effect. Thus, how to recognize a serious product? As regards monocomponent products, it is relatively easy. The proposed nutraceuticals should have an adequate bibliography support that should include (at least): – The description of the mechanism of action, eventually associated with notes on pharmacokinetic (for instance, resveratrol has an oral bioavailability near to zero, being the supplementation of the raw form of the molecule very doubtful); – A therapeutic indication supported by randomized, double-blind, placebo-controlled clinical trials carried out on subjects similar to the ones we need to treat in regard to age, ethnicity, and disease profile; – Quality (bioactive titration) and dosage similar to the one shown to be efficacious and safe in clinical trial. As regards nutraceuticals in combination, the requirement are similar if the single components are all supported by scientific evidence of efficacy and safety, and if they are included in the same pill/tablet at the tested doses. If a kind of synergy of components is suggested, this has to be clearly demonstrated with specific trials or, alternatively, it should be never mentioned. Of course, the risk of interaction between the components of a combined nutraceutical should also been considered (9). When the informative brochure of the product is complete and correct, this will help the prescriber to adequately select the more adequate product in the market, being also more protected from a legal point of view (10). We have to remember that the final responsibility of the prescriber remains in the knowledge to of the effective dosages of the bioactives (based on the results of adequately designed clinical trials or their meta-analysis), of possible pharmacological interaction and adverse events, and of the adequate length of treatment (in particular, avoiding short cyclic treatment for chronic diseases).

PRECLINICAL

STUDIES ON MEDICINAL PLANTS, USED IN THE TREATMENT OF PROSTATIC DISEASES

(Annabella Vitalone, Olta Allkanjari) Phytotherapy could be useful in the treatment and pre-

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Nutraceutical treatment and prevention of benign prostatic hyperplasia and prostate cancer

vention of mild to moderate prostatic diseases. The etiology of prostatitis, benign prostatic hyperplasia and hypertrophy (BPH) can be complex and the intervention is often multi-targeted. The pharmacological properties useful for the treatment of the urinary tract diseases are anti-androgenic, antiestrogenic, anti-proliferative, antioxidant and antiinflammatory. The most studied and used medicinal plants are: Serenoa repens, Pygeum africanum and Urtica dioica. Phytosterols and fatty acids are the pharmacologically active phytochemicals usually found in these plants; however, they are more used as a phytocomplex (total extract of the plant) than as isolated compounds. In preclinical research, Serenoa is responsible of numerous mechanisms of action, including: inhibition of the dihydrotestosterone binding (DHT) to its receptors present in the cytosol of prostatic cells, of 5α-reductase (both isoforms), of cyclooxygenase (COX) and of 5-lipoxygenase (LOX); it induces apoptosis of prostatic epithelial cells and it presents antiestrogenic activity, spasmolytic effect due to blockage of calcium channels and β-adrenergic antagonism (11). Similar mechanisms have been found for Pygeum and nettle, probably due to the presence of β-sitosterol and consisting in the inhibition of 5α-reductase, of prostatic cell proliferation, blockage of the cell cycle in the G2 phase and induction of apoptosis in prostate cancer cells (12, 13). Furthermore, atranorin and atraric acid, present in Pygeum, inhibit the androgen receptor nuclear translocation, endogenous PSA expression, and fibroblast proliferation in human prostate cells. Lignans, lectins and polysaccharides contained in nettle extract, seem to exert anti-proliferative and anti-inflammatory activity, and to inhibit the binding of sex hormones to the sex hormone binding globulin. Other promising plants are Cucurbita pepo, Epilobium spp (14), Lycopersum esculentum, Secale cereale, Roystonea regia, Vaccinium macrocarpon. They have anti-inflammatory and anti-androgenic properties. In particular, the tomato fruit extract (containing lycopene, polyphenols, etc.) down-regulates 5α-reductase and inhibits COX. The inhibitory properties against 5α-reductase appear also for Roystonea regia, probably exerted by the fatty acids. Furthermore, in vitro, antiproliferative, antimicrobial, antioxidant and radical scavenger properties seem encouraging for epilobio, tomato, pollen extracts of Secale cereale and Roystonea regia (15). Vaccinium macrocarpon inhibits aromatase and is helpful in the urinary tract infection, because it acidifies the urine and inhibits bacterial adherence to uroepithelial cells (16). The mechanism of action of the plants listed above has to be confirmed in in vivo models. Other specific plants and/or substances have still limited scientific evidence.

NUTRITIONAL EPIDEMIOLOGICAL STUDIES AND PROSTATE DISEASES (Giorgio Ivan Russo, Gaetano Larganà) Prostatic diseases, like prostatic cancer (PCa) and benign prostatic hyperplasia (BPH), are influenced by different factors, like age, hormone profile and genetics. Several epidemiologic studies demonstrated how diet may play

an important role in prostatic diseases incidence and development. Knowledge of the different kind of effects of foods on prostate could help us to understand how better prevent and treat these diseases, exploiting synergic effects of specific drugs. PCa represented the most common incident cancer in men in developed countries in 2013 (17). Western diet, characterized by high intake of energy, red and processed meats and fat but low intake of fibres has been associated to an increased risk to develop an advanced PCa (18, 19). Instead, Mediterranean diet (MeDi), that is characterized by use of olive oil and high intake of fibres, fish, fruits, vegetables, legumes and cereals in association with moderate to low intake of dairy products and moderate intake of wine, is a diet rich of components with anti-oxidant proprieties that could protect from PCa (20). In fact, countries following MeDi, particularly Southern European countries, have a lower incidence and mortality from PCa, compared to other European countries (21, 22). A 2015 review included several papers evaluating the effect of single components of MeDi on incidence and development of PCa: olive oil, an unsaturated fat, was not associated with the risk of advanced PCa, that was increased for saturated fat (23-26); in a 2010 metanalysis (27) there was an association between fish consumption and a significant reduction of PCa-specific mortality; higher intake of legumes and cereals has been associated with a decreased risk of several cancer (28) , included PCa (29, 30); there was a positive association between dairy product consumption and PCa (31); a 2010 review showed how a moderate daily intake of alcohol, 3 drinks per day, does not appear to influence PCa risk (32); lastly Russo et al. showed how consumption of food rich of phenolic acids, like fruits, vegetable, coffee, tea and cacao were associated to a reduced risk of PCa development (33). BPH is one of the most common medical conditions in older men (34). A study evaluating more than 3500 patients showed that total protein intake (particularly animal protein) is positively associated with the risk of BPH, while in men who consumed at least 4 servings per day of fruits and vegetable, there was a lower risk of BPH (35-38). Lycopene, contained in tomatoes, seems to help to reduce lower urinary tract symptoms (LUTS) and to inhibits BPH progression, as well as epigallocatechin-3gallate, contained in green tea (39, 40). The human prostate gland contains higher level of zinc than other tissues and Kristal et al. (38) showed that zinc could have a protective role for BPH, although excessive consumption may significantly increase the risk of advanced PCa (41-43). Like fot PCa, high alcohol intake may be associated with BPH (44). In conclusion, epidemiologic studies demonstrated that diet habits could help to prevent PCa and BPH incidence and their development and could be used in a multimodal therapy to prevent and treat these diseases. Particularly, MeDi, a diet rich of elements with anti-oxidant properties related to use of olive oil, high intake of fibres, fish, fruits, vegetables, legumes and cereals, moderate to low intake of dairy products and moderate intake of wine, is a protective factor for PCa. Similarly, Archivio Italiano di Urologia e Andrologia 2019; 91, 3

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low intake of animal protein, high intake of fruits and vegetable, lycopene and zinc are a protective factor for BPH. Instead, high intake of saturated fats and animal meat, and excessive alcohol consumption could be a risk for both PCa and BPH development.

CLINICAL USE OF SERENOA REPENS IN BPH TREATMENT (Kostantinos Stamatiou)

A variety of phytotherapeutic agents are used in traditional and alternative medicine to treat lower urinary tract symptoms. The most commonly used preparations originate from the species Saw palmetto. Their extract Serenoa repens (SR) exhibits marked anti-inflammatory, anti-androgenic and anti-proliferative effects. For this reason, it has been the subject of clinical and experimental research on the treatment of symptoms of benign prostatic hyperplasia. A non-systematic search was performed in electronic libraries for clinical trials, experimental studies and systematic reviews on the topic. Main outcomes of the abovementioned studies are displayed in Table 2. SR in the treatment of symptoms of BPH has been tested either alone or, more frequently, in combination or in comparison with other phytotherapeutics, alpha-blockers and inhibitors of 5-α reductase (5-ARI). With regard to studies using SR extract as monotherapy for men with BPH an confirmed lower urinary tract symptoms (LUTS), Lopatkin et al. and Giulianelli et al. showed significant improvement in symptom scores (IPSS ans IIEF-5) and uroflowmetry at 6-month follow up (45, 46). Accordingly, Sinescu et al. (47) demonstrated a significant improvement of mild or moderate LUTS, quality of life (QoL), urinary flow, residual urinary volume and erectile function and Gerber et al. demonstrated improvement in urinary symptoms compared with placebo (but no measurable effect on urinary flow) (48). On the contrary, the large trial of CAMUS Study Group found no differences between improvements of urinary symptoms between SR extract and placebo group at 72-week follow-up (49) in accordance to other placebo-controlled trials (50, 51). Recently, Ye et al. (52) in a double blind, placebo-controlled study found significant improvements in the urinary flow, IPSS, male sexual function (MSF-4 and IIEF scores) in the SR extract group. In none of these studies significant side effects of SR were observed. Higher doses of SR cannot influence neither the impact on LUTS nor the quality of sexual performance (53, 54). Efficacy of SR was compared to other treatments. Alcaraz et al. (55) found equivalent efficacy with respect to alpha-blockers and 5-ARI in LUTS improvement; Pytel et al. (56, 57) confirmed similar results as measured by IPSS, QoL, index of sexual function (MSF-4), size of the prostate, urodynamic parameters (but no change of plasma sexual hormones). A prospective multicentre doubleblind randomized study comparing tamsulosin (0.4 mg/24h) with SR (320 mg/24h) found no differences in IPSS, urinary flow and PSA at 12-month follow up (58). SR was used in combination with other treatment. The addition of dietary supplements or other phytotherapeutic agents improved the effect of SR (59, 60). The combination of SR with alpha-blockers agents (tamsulosin,

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silodosin) was more effective than monotherapy according to some Authors (61, 62) although others were not able to demonstrate no extra benefits by combination therapy (63-68). Recent meta-analyses found the effectiveness of SR similar or inferior of that of finasteride and tamsulosin but clearly higher than that of placebo in the treatment of mild and moderate LUTS, nocturia and discomfort (69-71). The ability of SR to reduce prostatic size is controversial, although the association with other natural compounds (such as lycopene, other carotenoids and selenium) could enhance the activity of SR alone by augmenting pro-apoptotic effects and suppressing growth factors expression in hyperplastic prostates (72). The evaluation of the results of BPH treatment with SR is made difficult by the variability of the composition of products of different brands in relation the concentration of free fatty acids and the method of extract preparation. Table 2. Design of studies of Serenoa repens for BPH treatment. Placebo SR 5ARI Alpha- Pinus + SR+LY+ Alpha- Alphablockers Crocus +SE blocker blocker +SR SR+LY+ SR SE Dedhia (50) + + Bent (51) + + Ye (52) + ++ Barry (53) + + Alcaraz (55) + + + Debruyne (58) + + Cai (59) + ++ Morgia (60) + ++ Morgia (61) + + ++ Ryu (63) + ++ Boeri (62) + + ++ Argirovic (64) + + + Bertaccini (67) + + Gerber (48) + ++ Helfand (49) + + Glemain (65) + + + Hizli & Uygur (66) + + +

CLINICAL USE OF OTHER MEDICINAL PLANTS FOR BPH TREATMENT: URTICA DIOICA, PYGEUM AFRICANUM E CUCURBITA PEPO (Gian Maria Busetto)

Alongside the traditional 5α-reductase and β-blockers, medical therapy for LUTS secondary to BPH, is based on nutraceuticals and compounds. In addition to Serenoa repens, which has been extensively studied, there are many other substances for which scientific evidence is often controversial. Urtica dioica has the capability to decrease testosterone conversion to dyhdrotestosterone (DHT), interact with sex hormone-binding globulin (SHBG) and block the conversion of androgens to estrogens. Other studies report even an antiproliferative action on prostate cancer cells. Pygeum africanum is rich in phytosterols and antioxidants. An inhibitory effect on prostate growth factors, on androgenic hormones and an effect on the contractility of

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Table 3. Symptoms, IPSS and flowmetric indices after treatment with Urtica dioica, Pygeum africanum and Cucurbita pepo. Author, year

Study design

Safarinejad 2005 (73) Urtica dioica Double-blind placebo-controlled randomized Patients with LUTS secondary to BPH

Patients & Controls n° and response rate 305 (287 evaluable) Urtica dioica 315 (271 evaluable) placebo

Comparator

Outcomes measured

Placebo

Urtica dioica vs placebo - Improved LUTS 81% vs 16% (p < 0.001) - IPSS 19.8 to 11.8 vs 19.2 to 17.7 (p = 0.002) - Peak flow rates +8.2 mL/s vs +3.4 mL/s (p < 0.05) - PVR 73 to 36 ml vs no change (p < 0.05) - PSA and testosterone unchanged in both groups - Prostate volume by TRUS 40.1 to 36.3 cc vs no change (p < 0.001) - No side effects

Pavone 2010 (74)

Serenoa repens 320 mg + Urtica dioica 120 mg + Pinus pinaster 5 mg for 30-365 days in LUTS associated to BPH (46%) or CP/CPPS (43%) or other conditions (11%)

320 patients (80 evaluable)

Symptom score significant benefit in 85% No change of prostate volume and Qmax

Lopatkin 2005 (75)

160 mg sabal fruit extract (Serenoa) + 120 mg urtica root extract 2 capsule/day RCT 24 weeks

129 (127 evaluable) 128 (126 evaluable)

Placebo

Treated vs placebo IPSS -6 points vs -4 points (p = 0.003) - excellent tolerability

Lopatkin 2007 (76)

160 mg sabal fruit extract (Serenoa) + 120 mg urtica root extract 2 x 1 capsule/day open-label extension of RCT for 96 weeks

219 subjects

I-PSS -53% (p < 0.001) Peak and average urinary flow +19% (p < 0.001) PVR -44% (p = 0.03) adverse events 1/1,181

Changping 2016 (77)

Metanalysis of 5 papers LUTS associated with BPH

1128 patients

Placebo

Standardized mean difference (SMD) IPSS 10.47 (95% CI 18.12 to -2.82, p = 0.007) Peak urinary flow rate (Qmax) 4.37 (95%CI = 1.55 to 7.19, p = 0.002) Prostate volume 3.63 (95%CI = -4.67 to -2.57, p＜0.00001) PSA 0.08 (95%CI = -0.23 to 0.07, p = 0.31)

Barlet 1990 (78)

Pygeum africanum extract (50 mg) or placebo (1 capsule BID) double-blind 60 days 8 centres (Germany, France, Austria)

263 patients

Placebo

micturition improvement 66% vs 31% p < 0.001 gastrointestinal side effects in 5 patients

Barth 1981 (79)

Pygeum africanum

215 patients

Improvement Nocturia, Qmax, PVR

Wilt & Ishani 1998 (80) Pygeum africanum Metanalysis of 18 RCTs Treatment of BPH

1562 patients mean study duration was 64 days (range, 30 to 122 days)

Placebo

Effect size of combined outcome of urologic symptoms and flow measures (-0.8 SD [95% CI -1.4 to -0.3) (n = 6 studies) improvement symptoms (RR = 2.1, 95% CI = 1.4 to 3.1) nocturia - 19%, residual urine volume - 24%, peak urine flow + 23% mild adverse effects

Hong 2009 (81)

Pumpkin seed oil 320 mg day randomized, double-blind, placebo-controlled trial 12 months BPH patients

47 patients

Placebo Saw palmetto oil Pumpkin+Saw Palmetto

IPSS & QoL reduced after Pumpkin, Saw Palmetto, Pumpkin+Saw palmetto PSA reduced after Pumpkin+Saw palmetto Qmax increased after Pumpkin and Saw Palmetto Prostate volume no change

Friederich 2000 (82)

Pumpkin seed extract multicentric clinical trial BPH (stage I to II according to Alken) 12 weeks

2245

IPSS decreased by 41.4% life quality improved by 46. 1% no side effects in 96%

Vahlensieck 2015 (83) Pumpkin seed 5 gr BID or Pumpkin seed extract 500 mg BID Randomized partially blinded placebo-controlled parallel-group trial 12 months patients with LUTS suggestive of BPH

1431

Placebo

Responders (IPSS decrease > = 5 points) pumpkin seed vs placebp 58.5% vs 47.3% no difference between pumpkin seed extract and placebo

Damiano 2016 (84)

6 clinical studies

IPSS and uroflowmetry improvement in 6 studies QoL improvement in 4 studies

Narrative review

the detrusor musculature of the bladder have been hypothesized. Some authors have also reported an improvement in the parameters of the semen, in particular on sperm motility. Curcubita pepo mainly contain fatty acids, specific sterols, tocopherol, carotenoids, vitamins and micronutrients. It is mainly the high ∆-7-sterol content that has the therapeutic effect and that has been shown to reduce prostate volume in the main animal models.

These treatments can be considered as an adjunct to the common therapies and their effect is supported by improving symptoms, IPSS and flowmetric indices (Table 3) (73-84). Their action on the volume of the prostate gland and on inflammation is more controversial. The literature is lacking data and double-blind placebo-controlled studies able to improve levels of evidence. It is therefore necessary to continue studying these substances, commissioning adequate trials with Archivio Italiano di Urologia e Andrologia 2019; 91, 3

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high statistical power, strict inclusion and exclusion criteria and with adequate case studies.

CAROTENOIDS

AND MINERAL SUPPLEMENTS

(Vittorio Magri) Lycopene and selenium are two natural products with antioxidant and anti-inflammatory action. Lycopenes are carotenoids, natural pigments widely distributed in the environment that are synthesized both by plants and bacteria, but not by the animals that must take them with the diet. Lycopene accumulates in the prostate and is secreted in the seminal fluid. Dietary supplementation of rats resulted in accumulation of lycopene in all prostatic lobes, but preferentially in the lateral lobes. Lycopene concentrations are gradually increased and interfered with local prostate androgenic signaling, IGF-1 expression, and inflammatory mediators (85, 86). Selenium has an essential role in some enzymatic activities such as glutathione-peroxidases (87, 88) that can reduce hydrogen peroxide, and lipid and phospholipid hydroperoxides, counteracting free radical damage and oxygen-reactive species (ROS). Furthermore, selenium is important for maintaining an efficient immune response (89, 90). Studies in vitro and on animal models, have shown that Serenoa repens-Selenium-Lycopene (SeR-SeLy) administered in combination, are synergistic and amplify their action both on the inflammatory and proliferative component (91-93). Some clinical studies have confirmed the efficacy of the SR-Se-Ly association in patients with BPH. In the FLOG study the administration of SR-Se-Ly in patients who had to undergo prostatic rebiopsy due to suspected prostate cancer showed a significant reduction in inflammation and the number of lymphocytes and macrophages in histological sections (94). In the PROCOMB study (61), patients treated with SR-SeLy + tamsulosin had a greater reduction in the IPSS score, an increase in Qmax and a reduction in the post-voiding urinary volume, compared to those treated with tamsulosin alone. A randomized double-blind study of patients with BPH treated with an herbal mixture that also contains lycopene showed a significant reduction in the total IPSS score, pollakiuria and nocturia in treated patients (95). Similar effects to those obtained with lycopene and selenium could be obtained with the use of other carotenoids and/or zinc. Astaxanthin, at low concentration, was able to inhibit in vitro 5α-reductase by 98% and to decrease growth of cultured prostate cancer cell lines (96). The accumulation of zinc in prostate tissue depends, more than on dietary intake, on the activity of specific transporters (ZnT4 and ZIP4) that can be modulated by natural products as diadzein and genistein (97, 98). In patients with symptomatic BPH a combination of zinc, daidzein and Isolase (a mixture of enzymes that increases the bioavailability of plant polyphenols) improved at 6-month follow up IPSS score, peak urinary flow rate and quality of life (99). The close correlation between prostatic inflammation and LUTS associated to BPH, as demonstrated by MTOPS and REDUCE clinical studies (100, 101), suggests a new systematic approach to the medical therapy of symptomatic BPH based on the association of a drug with anti-inflammatory activity to alpha-blockers and/or 5ARI drugs. Considering the side effects of non-steroidal anti-inflamma-

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tory drugs (NSAID), the use of natural substances with a low risk of complications is attractive. Further studies are needed to evaluate the short and long-term efficacy of this approach to validate its use in the daily clinical practice for treatment of benign prostate diseases.

POLYPHENOLS

(Alberto Trinchieri) Polyphenols are a large class of organic chemicals (> 8000) characterized by the presence of large multiples of phenols structural units. They can be differentiated according to the chemical structure of the polyphenol skeleton. Flavonoids, lignins, phenolic acids, stilbenes and other polyphenols belong to this class (Table 4). Polyphenols can act on prostatic hyperplasia with different mechanisms: inhibition of 5α-reductase; decreased expression of growth factors (IGF-I and IGF-II); anti-inflammatory action (reduction of interleukin levels IL 1-β, IL 6, IL-I6 and tumor necrosis factor TNF-α, inhibition of COX-2 and 5-lipogenase, increased synthesis of nitric oxide and expression of nitric oxide synthase ); induction of apoptotic activity (increased expression of pro-apoptotic caspase-3 protein, up-regulation of peroxisomal proliferation receptors PPAR α and γ, increased expression of G protein estrogen receptor 1 coupled GPER); increased antioxidant activity (superoxide dismutase, glutathione peroxidase). Experimental evidences based on in vitro studies on homogenates of hyperplastic prostate cells or prostatic cell lines demonstrated prevalent inhibitory effect of 5αreductase type 2 of isoflavones (phytoestrogens), while flavonols and flavones show inhibitory effect of 5α-reductase type 1 but also anti-inflammatory ant antioxidant effects and induction of apoptosis (102, 103). Phenolic acids and lignins also have a combined action on 5αreductase and induction of apoptosis (104). In experimental models of BPH in rats, the efficacy of cocoa extract, soy-derived isoflavones, quercitin, a mixture of baicalin and catechin (flavocoxid), equol, anthocyanins derived from black soy, flavonoids extracted from Garcinia kola (kolaviron), epigallocatechin-3-gallate, secoisolariciresinol and curcumin was demonstrated (105-115). Clinical studies in patients with BPH have demonstrated the efficacy of quercitin, a flavonol contained in various foods such as onions, citrus fruits, cranberry, spices, tea and red wine (116), of equol (a metabolite of daidzein which is a soy isoflavon) (117), a flaxseed extract containing the lignin secoiso-lariciresinol diglucoside (SDG) (118) and of curcumin, a derivative of the spice Curcuma longa (119). Conversely, resveratrol has not been shown to be effective in reducing prostate volume and levels of testosterone, didrotestosterone (DHT) and PSA (120). Different types of polyphenols are contained in medicinal plants that have been used in the treatment of IPB, such as epliobium (121) and extract from the bark of French maritime pine (122).

POLLEN EXTRACT, BETA-SITOSTEROL AND PALMITOYLETHANOLAMIDE (PEA) (Tommaso Cai)

Pollen extract is a mixture of natural components, such as amino acids, carbohydrates, lipids, vitamins, phytos-

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Table 4. Classification, sources, biological and clinical activity of polyphenols used for BPH treatment. Classification FLAVONOIDS Flavonols

Name Source In vitro 5-AR C6–C3–C6 general structural backbone with two C6 units of phenolic nature Quercitin onions 5-AR type 1 inhibition citrus (?) cranberry Decreased DHT spices by androgen-indetea pendent effect red wine SHBG Mirecitin Fisetin

red wine strawberry apples grapes

In vitro other effects

Animal models

Clinical studes

Decreased prostate volume

IPSS decreased Qmax increased

5-AR type 1 inhibition 5-AR type 1 inhibition

Antinflammatory (decrease cytochines, suppressed TNF-alfa and MCP-1 expression by NF-kappa B inhibition) Antioxidant Proapoptotic (TGF increase) -

Antioxidant

Decreased prostate volume

Antinflammatory (decreased IL-Iβ, IL-I6, and TNFα) Antioxidant Decreased IGF-I e IGF-II Proapoptotic PPAR-α e PPAR-γ up-regulation

Decreased prostate volume

Antinflammatory (inhibition cicloxigenase 2 and 5-lipooxigenase Decrease growth factors

Decreased prostate volume by a mixture of baicalin and catechin (flavocoxid),

Proapoptotic

Decreased prostate volume

Flavanons

GB1 e GB2 Garcinia kola kolaflavonone binaringenina (Kolaviron)

Flavan-3-ols

Epigallocatechin-gallate

Green tea

Flavones

Baicalin

Scutellaria baicalensis and Scutellaria lateriflora

5-AR type 1 inhibition

Kaempferol

Apples broccoli, onions, tomatoes

5-AR type 1 inhibition

Anthocyanidins

Antocianin

Black soy

Isoflavones (phytoestrogens)

Daidzein Genistein

Soy Soy Fava beans Soy Peanuts Soy

Biocanin A Equol STILBENS

LIGNANS

FENOLIC ACIDS

No No

5-AR type 2 inhibition 5-AR type 2 inhibition

Decreased prostate volume by soy-derived isoflavones

5-AR type 2 inhibition 5-AR type 2 inhibition

Decreased prostate volume

Hydroxylated derivatives of stilbene with C6–C2–C6 structure Resveratrol Grapes Red wine

Two units of a phenylpropene derivative Secoisolarici-resinol Flaxseed diglucoside Enterolactone Sesame Flaxseed

No decrease prostate volume No effect on testosterone and DHT

5-AR type 2 inhibition

Proapoptotic Increased GPER expression

Phenolic ring and an organic carboxylic acid function (C6-C1 skeleton) Caffeic Acid Phenethyl Propoli 5-AR type 2 inhibition Ester (CAPE)

OTHER POLYFENOLS Curcumin

Curcuma lunga (spice)

terols and minerals (123). The compound of the pollen extract is able to inhibit several cytokines, such as prostaglandin and leukotriene synthesis and this effect is comparable to that of diclofenac and indomethacin and approximately 10 times higher than that of aspirin (124). The pharmacological effects are due to the inhibiting activity of carvacrol, a pollen extract component, on the NF-KB (Nuclerar Factor Kappa Light Chain Enhancer of Activated B Cells). The inhibition of NF-KB reduce the

IPSS decrease DHT Decrease

Decreased prostate volume No No

Decreased growth factors (VEGF, TGF-ß1, and IGF1).

Decreased prostate volume

IPSS decrease

levels of prostaglandin E2 and increase the production of beta-endorphins with inflammation decrease and pain relief (125). Moreover, several authors demonstrated that pollen extract has a possible pro-apoptotic effect on the prostate via the androgen metabolism. In particular, it protects acinar prostate epithelial cells and inhibits stromal proliferation in association with enhanced apoptosis. Finally, several in vitro studies demonstrated that pollen extract is able to inhibit the prostate cancer cell growth Archivio Italiano di Urologia e Andrologia 2019; 91, 3

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Table 5. Pre-clinical and clinical trials about the use of pollen-extract. Outcomes measured

Study design

Buck AC, 1989 (132)

Prospective trial (phase II)

Patients & controls n° and response rate 15 (86.6)

Cai T, 2013 (133)

Prospective trial (phase II)

20 (90.0)

Cai T, 2014 (134)

Randomized controlled trial

41 (75.6) 46 (41.3)

Ibuprofen

Pollen extract significantly improved quality of life of patients when compared with those treated with ibuprofen (treatment difference in the NIH-CPSI pain domain, -2.14 ± 0.51, p < 0.001; QoL scores, p = 0.002)

Elist J, 2006 (135)

Randomized controlled trial

30 (73.3) 28 (64.2)

Placebo

Pollen extract is superior to placebo in providing symptomatic relief in men with chronic nonbacterial prostatitis/chronic pelvic pain syndrome

Iwamura H, 2015 (136)

Randomized placebo-controlled trial

50 (78.1) 50 (88.2)

Eviprostat (phyto-therapeutic agent)

Pollen extract significantly reduced the symptoms of category III CP/CPPS without any adverse events, in terms of NIH-CPSI, IPSS, and QoL

Jodai A, 1988 (137)

Prospective trial (phase II)

32 (75.0)

Pollen extract significantly reduced the symptoms in 75.0% of all treated patients

Monden K, 2002 (138)

Prospective trial (phase II)

24 (91.6)

Pollen extract significantly reduced the symptoms of chronic prostatitis group

Rugendorff EW, 1993 (139)

Prospective trial (phase II)

90 (62.2)

Pollen extract significantly reduced the symptoms of category III CP/CPPS without any adverse events, in terms of urinary symptoms and QoL

Suzuki T, 1992 (140)

Prospective trial (phase II)

25 (96.0)

Pollen extract significantly reduced the symptoms of prostatitis patients without any adverse events

Wagenlehner FM, 2009 (141) Randomized controlled trial

70 (70.6) 69 (49.3)

and this effect is even more pronounced in the hormoneindependent models, suggesting that there might be a place for the pollen extract in the control of abnormal growth in hormone-insensitive cells (126-130). On the clinical point of view, pollen extracts significantly improve symptoms, pain, and quality of life in patients affected by chronic pelvic pain syndrome and chronic prostatitis. These evidences have been done by a recent systematic review and meta-analysis (131) of 4 RCTs, that demonstrated that the use of flower pollen extracts in the management of CP/CPPS patients is associated with a high rate of clinical response without any significant adverse events. The Table 5 of all pre-clinical and clinical trials about the use of pollen-extract. No side effects are reported in all clinical trials (132-141). Beta-sitosterol is a sterol commonly present in the almost all plants, such as rice bran, wheat germ, peanuts, corn oils, soybeans, saw palmetto, rye grass pollen and pygeum. Its activity is due to the fact that cannot be converted to testosterone and inhibits aromatase and 5αreductase (142). Due to these pharmacological properties, beta-sitosterol is able to improve urinary symptoms and flow measures, as demonstrated by a Cochrane Review (143). On the other hand, beta-sitosterol is not able to reduce the size of the prostate gland. In general, no adverse effects are reported during therapy, even if

146

Comparator

Author, year

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Pollen extract effective in the treatment of chronic prostatitis and prostatodynia Pollen extract significantly improved total symptoms, pain, and QoL in patients with non-inflammatory CP/CPPS without severe side effects

Placebo

Pollen extract significantly improved total symptoms, pain, and QoL in patients with inflammatory CP/CPPS without severe side-effects

gastrointestinal side effects are the most common. However, we need consider that this compound can enhance the cholesterol-lowering effects of antihyperlipidemic medications. Palmitoylethanolamide (PEA), an endogenous fatty acid amide-signaling molecule has well-known anti-inflammatory and neuroprotective effects. The clinical antiinflammatory effect is due to the downregulation of mediator release from mast cells, monocytes and macrophages. In particular, in recent experience, PEA seems to have interesting activities in regulation of neurogenic and neuropathic pain. It has been demonstrated that PEA is able to act on TRPV1 channels, by indirect activity and desensitization. Several authors showed an interesting role in the management of chronic pelvic pain syndrome and chronic urological pain (144-146).

MEDICINAL

PLANTS FOR PREVENTION AND TREATMENT OF PROSTATIC CARCINOMA

(Gianpaolo Perletti) Medicinal plants and herbal products, in the form of plant parts or extracts of them, are commonly used for the treatment of prostate diseases such as benign hypertrophy, prostatitis and chronic pelvic pain syndrome. Over the past 20 years, dozens of plant-based products

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have been subjected to preclinical in vitro and in vivo investigations for their potential pharmacological activity against prostate cancer (PCa). Less numerous but worthy of special attention are epidemiological studies or clinical trials in which plant species, administered in the form of beverages, extracts or food preparations, have been studied for their effect on prostate cancer. Here follows an example of plant species which have been subjected to deeper investigation. Camelia sinensis (CS), in the form of unfermented (green) or fermented (black) tea, is rich in polyphenols, the most representative and investigated being epigallocatechin-3gallate (EGCG; green tea contains about 10-fold ECGC compared to black tea). A number of epidemiological and clinical studies have attempted to investigate the preventive effect of CS intake on prostate cancer. Such studies have been pooled in at least 6 meta-analyses, among which the work of Fei et al. (147), including 29 data series, appears to be the most comprehensive. We deemed interesting to integrate such meta-analysis with the more recent studies of Lassed et al. (280 patients, risk ratio = 0.51; 95% CI: 0.14-1.82) and Sen et al., (142, 196 men, of which 7036 PCa cases; risk ratio: 1.06; 95% CI: 0.98-1.14) (148, 149). Our metanalysis (Figure 1) (150) shows that, in contrast to the significant

data of Fei and coworkers (147), (risk ratio = 0.84; 95% CI: 0.71-0.98), the addition of the Lassed and Sen (148, 149) trials results in a non-significant pooled risk ratio (0.89; 95% CI: 0.77-1.02). The publication bias for this pooled analysis is not significant (Egger's test: p = 0.542; Begg&Mazumdar's test: p = 0.311), but the analysis shows substantial heterogeneity (I2 = 0.69). More focused analyses, investigating the effect of high doses of green tea catechins, tested in the frame of randomized-controlled studies, resulted in a significant protective effect against PCa. Thus, whereas studies about consumption of CS infusions in the general population have given contradictory results â&#x20AC;&#x201C; probably also due to uncertain dosage, length of therapy, herb quality, patient compliance, etc. â&#x20AC;&#x201C;, rigorous, controlled clinical trials seem to provide encouraging evidence about the antitumor activity of CS catechins. Solanum lycopersicum, the common tomato, contains high quantities of lycopene, a carotenoid antioxydant hydrocarbon (C40H56) devoid of vitamin-A activity. Lycopene, investigated in the frame of meta-analyses of epidemiological studies, doesn't seem to show a significant PCa preventive activity (151, 152). However, single studies suggest that lycopene shows indeed protective activity (153), and can as well lower PSA levels in prostate cancer Figure 1. Forest plot. Risk-ratio for the association between the consumption of various preparations of tea (beverage, concentrates, etc.) and prostate cancer, assessed by pooling 23 epidemiological studies (31 data series). The values at the right of the no-effect unit (n = 1) show an increased relative risk for prostate cancer, whereas data plotted on the left show a protective effect of tea intake against prostate cancer. Arch Ital Urol Androl, this issue. Random effect model, MantelHaenszel statistics, MetaEssentials software.

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patients (154). Punica granatum, pomegranate (PG), contains a number of active polyphenol compounds (e.g., elagitannins) and fatty acids (punicic acid). Promising preclinical results have not been translated so far into sound clinical evidence. Whereas in earlier clinical studies PG seemed to significantly prolong the PSA doubling time in patients with localized PCa (155), recent placebo-controlled trials failed to show increased PSA doubling times by PG preparations, compared to placebo (156, 157). Glycine max, the common soy, and Linum usitatissimum, known as flax or lineseed, contain isoflavones (e.g., genistein) and lignans which are known to act as phytoestrogens. These compounds, which have been hypothesized to be active against PCa growth, have been tested in the frame of clinical trials in PCa patients. It is not clear whether soy extracts show any effect on PCa and PSA, as clinical data produced so far didn't show univocal therapeutic effects (158, 159). Similarly, single clinical trials and meta-analyses suggest that flax lignans do not seem to have a significant therapeutic activity (160). However, a metanalysis of observational studies by He and coworkers has evidenced a significant association between high serum levels of the lignan metabolite enterolactone and a reduced odds of prostate cancer (OR = 0.76, 95% CI: 0.60-0.97) (He et al.). In conclusion, Camelia Sinensis catechins, Solanum lycopersicum lycopene and the flax lignan metabolite enterolactone have shown some chemopreventive or therapeutic activity against PCa. The major limitation of the clinical studies and meta-analyses produced so far is the great variability of key elements such as (i) compound quality (poor standardization), (ii) patient compliance (virtually unknown in observational studies), (iii) active drug dosages (extremely diverse according to dietary customs worldwide), and (iv) preparation modalities. Randomized controlled trials versus placebo or versus compounds of established efficacy are still scant. To draw any final conclusion concerning the efficacy of medicinal plants and fruits for preventing or treating PCa, additional well-designed, adequately powered clinical trials are urgently needed.

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Gaetano Larganà, MD Giorgio Ivan Russo, MD giorgioivan1987@gmail.com Urology Section, University of Catania, Catania (Italy) Vittorio Magri, MD vittorio.magri@virgilio.it Ambulatorio Territoriale di Urologia ed Ecografia Urologica ASST Nord Milano, Milano (Italy) Gianpaolo Perletti, PhD gianpaolo.perletti@uninsubria.it Dipertimento di Biotecnologie e Scienze della Vita, Sezione di Scienze Mediche e Chirurgiche, Università degli Studi dell'Insubria, Busto Arsizio (VA), (Italy)

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Alberto Trinchieri, MD (Corresponding Author) alberto.trinchieri@gmail.com CDC Ambrosiana Milano

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DOI: 10.4081/aiua.2019.3.153

ORIGINAL PAPER

Green tea catechins for chemoprevention of prostate cancer in patients with histologically-proven HG-PIN or ASAP. Concise review and meta-analysis Gianpaolo Perletti 1, 2, Vittorio Magri 3, Anne Vral 2, Konstantinos Stamatiou 4, Alberto Trinchieri 5 1 Department

of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, Italy; of Human Structure and Repair, Faculty of Medicine and Medical Sciences, Ghent University, Ghent, Belgium; 3 ASST Nord Milano, Milan, Italy; 4 Department of Urology, Tzaneio Hospital, Piraeus, Greece; 5 Urology Unit, Manzoni Hospital, Lecco, Italy. 2 Department

Summary

A focused, single outcome meta-analysis on the protective role of extracts of green tea catechins against prostate cancer. Randomized, placebo-controlled studies enrolling patients with a histologically confirmed diagnosis of high-grade Prostate Intraepithelial Neoplasia or Atypical Small Acinar proliferation but no prostate cancer were included. Meta-analysis for binary data was performed using Mantel-Haenszel statistics, using a random-effects model. Heterogeneity was investigated by calculating the I2. Four studies matched the inclusion criteria for the review. The pooled population was 223 patients; 114 and 109 patients were randomized to catechin and placebo groups, respectively. Nine cases of prstate cancer occurred in the catechin arm (7.9%), and 24 cases were reported in the placebo arm (22%). Pooled analysis resulted in a significant reduction of cancer risk in favor of the catechin arm (risk-ratio = 0.41; 95% CI: 0.190.86; I2 = 0). In conclusion, our data suggest that the intake of concentrated green tea catechin preparations may confer a significant protective effect to carriers of early neoplastic lesions in the prostate. The quality of the evidence is moderate, and additional, largescale studies are warranted to substantiate these preliminary findings.

KEY WORDS: Green tea; Prostate cancer; Prostate; Polyphenols; Catechins; Epigallocatechin-3-gallate. Submitted 8 July 2019; Accepted 22 July 2019

INTRODUCTION

In vitro, in vivo and epidemiological studies suggest that the high polyphenol content of green tea may confer to this beverage a protective effect against prostate cancer (PCa) (1-5). From year 2006, randomized clinical trials have been performed, focusing on the role of green tea catechins (mainly epigallocatechin-3-gallate) on the prevention or retardation of the onset of prostate cancer. In 2017, a meta-analysis by Cui et al., based on two randomized, double-blind, placebo-controlled phase II trials, resulted in a slightly significant protective effect of concentrated green tea catechin preparations, in patients with histologically proven suspicious lesions (high-grade

prostatic intraepithelial neoplasia [HG-PIN], atypical smallacinar proliferation [ASAP]) (6). In the same year, Guo et al. performed a similar meta-analysis by adding a third updated study to the pooled trials. Also in this case, catechins showed a significant protective effect against prostate cancer (5). The aim of this review and metaanalysis was to search for additional phase II studies published in the literature, and, if possible, to attempt meta-analysis of the global data published so far.

MATERIALS

AND METHODS

A search of the PubMed/Medline and Embase databases of publications in English, indexed up to June 7th, 2019 was performed, using the following terms: prostate, prostate cancer, *carcinoma, green tea, tea, catechin*, *gallate, ECGC. The single outcome for this review was the incidence/prevalence of prostate cancer in included patients. Inclusion criteria (i) patients with histologically-proven HG-PIN and/or ASAP of any age, included in randomized, placebo-controlled clinical trials; (ii) the active treatment arm received a concentrated preparation of green tea catechins; (iii) placebo-controlled studies. Exclusion criteria (i) non-randomized trials; (ii) a diagnosis of prostate cancer; (iii) any combination therapy (catechins combined with other drugs or supplements, with surgical procedures, with radiotherapy, etc.). Risk of bias analysis was performed by two investigators using the Cochrane risk of bias tool (7). The MetaEssentials software was used for publication bias analysis (8). Meta-analysis for binary data was performed using Mantel-Haenszel statistics with the Cochrane Review Manager 5.3 software. We planned to use a random-effects model, and to attempt confirmatory analysis with a fixed-effects model in case of low heterogeneity. Heterogeneity was investigated by calculating the I2.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 3

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G. Perletti, V. Magri, A. Vral, K. Stamatiou, A. Trinchieri

Figure 1. Pooled analysis of four randomized, placebo-controlled studies investigating the protective effect of green tea catechins on the incidence of prostate cancer. The number of subjects allocated to treatment arms, the number of cases of PCa, the risk-ratios, the 95% confidence intervals, the Z value for the overall effect, the significance of the pooled comparisons, and heterogeneity data (Chi2, I2), are presented. Data to the left of the vertical no-effect line of the forest plot represent decreased risk for prostate cancer. The diamond represents the overall effect size extending to the limits of the 95% confidence interval of the pooled risk-ratio. The risk of bias analysis for each included study, with explanatory footnotes, is also shown.

RESULTS

Literature database search retrieved 3230 deduplicated records. Title and abstract were screened by two investigators, who selected 7 records for further full-text reading, with no disagreements. Three articles were agreed to be excluded for the following reasons: (i) catechins not administered as single-agents, but combined with other supplements (9), (ii) a feasibility study, without cancer incidence as an outcome (10), (iii) a study performed before prostatectomy in men diagnosed with PCa (11).

Four articles were finally selected for risk of bias assessment and meta-analysis (12-15). Two and three of these studies were included in the metaanalyses of Cui et al. (6) and Guo et al. (5), respectively. Thus, the present meta-analysis updates their results by addition of two or one extra trial(s), respectively. Figure 1 shows the forest plot for the present metaanalysis. The total population is 223 patients; 114 and 109 patients were randomized to catechin and placebo groups, respectively. Nine cases of PCa occurred in the catechin arm (7.9%), and 24 cases were reported in the placebo arm (22%). Although 3 out of 4 studies showed non-significant risk-ratios (12, 13, 15), pooled analysis resulted in a significant reduction of PCa risk in favor of the catechin arm (RR = 0.41; 95% CI: 0.19-0.86; p = 0.02), thus confirming and supporting the significant data shown by Cui et al. (RR = 0.39; 95% CI: 0.16-0.97) and by Guo et al. (RR = 0.38; 95% CI: 0.16-0.86) (5, 6). Calculation of the odds ratio for the same studies also resulted in a significant associa-

Figure 2. Funnel plot for publication bias analysis. We found no evidence of publication bias; the combined effect size (CES, green) and the adjusted estimate of the combined effect size (red) are identical, as no imputation of missing studies was made by the "trim-and-fill" method. In this plot the effect size is expressed as the natural logarithm of the odds ratio.

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Green tea catechins and prostate cancer

Table 1. Green tea catechins for the prevention of prostate cancer. Patient or population: men with HG-PIN and/or ASAP Intervention: green tea catechin preparations Comparison: placebo Outcomes Illustrative comparative risks* Assumed risk Corresponding risk (95% CI) Placebo Catechins Prostate cancer occurrence

220 per 1000

90 per 1000 (42 to 189)

Relative effect (95% CI)

No of Participants (studies)

Quality of the evidence (GRADE)

Comments

Risk-ratio: 0.41 (0.19 to 0.86)

223 (5 studies)

⊕⊕⊕⊖ Moderate

⊖High risk of attrition bias in two studies and small number of participants; ⊕Low heterogeneity; ⊕Low probability of publication bias

*The assumed risk is based on the occurrence of cases of prostate cancer in the placebo population. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; OR: odds ratio GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

tion between catechin consumption and a lesser prevalence of PCa (OR = 0.34; 95% CI: 0.15-0.80; p = 0.01). Since the present meta-analysis was devoid of heterogeneity (I2 = 0), we re-calculated the risk-ratio using a fixed-effect model. The significance of the pooled data was confirmed (RR = 0.36; 95% CI: 0.17-0.74; p = 0.006; I2 = 0). The publication bias was found to be non-significant by both Egger's and Begg-Mazumdar's tests (p = 0.36 and p = 0.17, respectively), and the "trim-and-fill" method applied to funnel plot analysis did not impute missing studies (Figure 2). The Cochrane risk of bias tool allowed to assign a high risk of attrition bias to the studies by Kumar et al. and Micali et al. (Figure 1, red symbols); this was due to incomplete outcome data owing to 28% and 27% patient dropout rates, respectively. The remaining items of the Cochrane tool show low or unclear risk of bias (Figure 1, green or yellow symbols respectively). The overall quality of the evidence is "moderate", as shown in the summary of findings table for the present meta-analysis (GRADE criteria, Table 1).

CONCLUSIONS

In conclusion, our updated meta-analysis suggests that the intake of concentrated green tea catechin preparations may confer a significant protective effect to carriers of early neoplastic lesions in the prostate (HG-PIN, ASAP). Strengths The meta-analysis was devoid of heterogeneity and publication bias; the general quality of the evidence is moderate, according to GRADE criteria. Limitations: the considerable percentage of dropouts in two studies suggests the presence of attrition bias.

Caveat It is known that lesions like HG-PIN may co-exist with frank carcinoma lesions, which may remain undetected in standard bioptic assessments due to their small size or to the low number of cores. This may be a confounder and a source of detection bias in the studies included in this analysis.

ACKNOWLEDGEMENTS We thank Louise Beckers (Ghent University, Belgium) for assistance in database search and data extraction.

REFERENCES 1. Hastak K, Agarwal MK, Mukhtar H, Agarwal ML. Ablation of either p21 or Bax prevents p53-dependent apoptosis induced by green tea polyphenol epigallocatechin-3-gallate. FASEB J. 2005; 19:789-91. 2. Siddiqui IA, Malik A, Adhami VM, et al. Green tea polyphenol EGCG sensitizes human prostate carcinoma LNCaP cells to TRAILmediated apoptosis and synergistically inhibits biomarkers associated with angiogenesis and metastasis. Oncogene. 2008; 27:2055-63. 3. Siddiqui IA, Shukla Y, Adhami VM, et al. Suppression of NFkappaB and its regulated gene products by oral administration of green tea polyphenols in an autochthonous mouse prostate cancer model. Pharm Res. 2008; 25:2135-42. 4. Zheng J, Yang B, Huang T, et al. Green tea and black tea consumption and prostate cancer risk: an exploratory meta-analysis of observational studies. Nutr Cancer. 2011; 63:663-72. 5. Guo Y, Zhi F, Chen P, et al. Green tea and the risk of prostate cancer: A systematic review and meta-analysis. Medicine (Baltimore). 2017; 96:e6426. 6. Cui K, Li X, Du Y, et al. Chemoprevention of prostate cancer in men with high-grade prostatic intraepithelial neoplasia (HGPIN): a systematic review and adjusted indirect treatment comparison. Oncotarget. 2017; 8:36674-36684. Archivio Italiano di Urologia e Andrologia 2019; 91, 3

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G. Perletti, V. Magri, A. Vral, K. Stamatiou, A. Trinchieri

7. Higgins JP, Altman DG, GĂ¸tzsche PC, et al. Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011; 343:d5928. 8. Suurmond R, van Rhee H, Hak T. Introduction, comparison, and validation of Meta-Essentials: A free and simple tool for metaanalysis. Res Synth Methods. 2017; 8:537-553. 9. Gontero P, Marra G, Soria F, et al. A randomized double-blind placebo controlled phase I-II study on clinical and molecular effects of dietary supplements in men with precancerous prostatic lesions. Chemoprevention or "chemopromotion"? Prostate. 2015; 75:1177-86. 10. Lane JA, Er V, Avery KNL, et al. A Phase II Randomized Placebo-controlled Trial of Green Tea Catechins and Lycopene in Men at Increased Risk of Prostate Cancer. Cancer Prev Res (Phila). 2018; 11:687-696. 11. Nguyen MM, Ahmann FR, Nagle RB, et al. Randomized, double-blind, placebo-controlled trial of polyphenon E in prostate can-

Correspondence Gianpaolo Perletti gianpaolo.perletti@uninsubria.it Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, Italy Department of Human Structure and Repair, Faculty of Medicine and Medical Sciences, Ghent University, Ghent, Belgium Vittorio Magri vittorio.magri@virgilio.it ASST Nord Milano, Milan, Italy Anne Vral Department of Human Structure and Repair, Faculty of Medicine and Medical Sciences, Ghent University, Ghent, Belgium Konstantinos Stamatiou stamatiouk@gmail.com Department of Urology, Tzaneio Hospital, Piraeus, Greece Alberto Trinchieri alberto.trinchieri@gmail.com Urology Unit, Manzoni Hospital, Lecco, Italy

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cer patients before prostatectomy: evaluation of potential chemopreventive activities. Cancer Prev Res (Phila). 2012; 5:290-8. 12. Kumar NB, Pow-Sang J, Egan KM, et al. Randomized, PlaceboControlled Trial of Green Tea Catechins for Prostate Cancer Prevention. Cancer Prev Res (Phila). 2015; 8:879-87. 13. Brausi M, Rizzi F, Bettuzzi S. Chemoprevention of human prostate cancer by green tea catechins: two years later. A follow-up update. Eur Urol. 2008; 54:472-3. 14. Bettuzzi S, Brausi M, Rizzi F, et al. Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. Cancer Res. 2006; 66:1234-40. 15. Micali S, Territo A, Pirola GM, et al. Effect of green tea catechins in patients with high-grade prostatic intraepithelial neoplasia: Results of a short-term double-blind placebo controlled phase II clinical trial. Arch Ital Urol Androl. 2017; 89:197-202.

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ORIGINAL PAPER

DOI: 10.4081/aiua.2019.3.157

Safety and efficacy of retroperitoneal sutureless zero ischemia laparoscopic partial nephrectomy for low nephrometry score masses Emanuele Corongiu 1, Pietro Grande 2, Angelo Di Santo 1, Giorgio Pagliarella 1, Stefano Squillacciotti 1, Emanuele Liberati 1, Alessandra Zampelli 1, Valerio Olivieri 3, Michele Innocenzi 4, Flavio Forte 1 1 Department

of Urology, M.G. Vannini Hospital, Rome, Italy; Université, Assistance Publique-Hôpitaux de Paris, Pitié Salpétière, Urology Department, Paris, France; 3 Department of Urology, Ivrea Hospital, ASL TO 4, Ivrea, Italy; 4 Department of Urology, Bambin Gesù Hospital, Rome, Italy. 2 Sorbonne

Summary

Objectives: To evaluate oncological feasibility and oncological and functional results of retroperitoneal sutureless zero ischemia laparoscopic partial nephrectomy (LPN). Patients and methods: Patients with posterior renal masses with low nephrometry score (RENAL ≤ 7) treated who underwent retroperitoneal sutureless zero ischemia.in a single center from January 2016 to November 2017. Clinical, surgical and pathological data were prospectively collected. Complications were reported according to the modified Clavien classification. Results: Retroperitoneal sutureless zero ischemia laparoscopic partial nephrectomy was performed on 15 patients. The indication for nephron-sparing surgery was elective in 11 (73%) patients and imperative in 4 (27%). Median RENAL score was 5 (IQR: 5-7), median tumor diameter 25 mm (IQR: 20-35). In 11 cases, the tumor was located polar (85%), and in 2 cases hilar (15%). There were no intraoperative complications. No cases were converted to radical nephrectomy, and in no case parenchyma suture was necessary. Median operative time was 90 min (IQR:40-150), in no case clamping of the renal artery was necessary, median hospital stay was 4 days, median estimated blood loss (EBL) was 310 (180-500) ml. Pathological analysis showed renal cell carcinoma in 11 patients (85%), 9 (60%) staged T1a and 2 (13%) T1b. In 4 (27%) an oncocytoma was found. There were no positive surgical margins. One patient developed a major postoperative complication (postoperative renal bleeding requiring super-selective embolization). Trifecta rate was 93%. Conclusions: Sutureless retroperitoneal zero ischemia LPN for the treatment of low-complexity posterior renal masses showed to be safe and feasible. Longer follow-up and higher numbers of patients are, however, warranted to draw definitive conclusions on functional outcomes.

KEY WORDS: Laparoscopy; Kidney cancer; Oncological surgery; Partial nephrectomy; Nephron sparing surgery. Submitted 12 July 2019; Accepted 21 July 2019

INTRODUCTION

Renal cell carcinoma represents 2-3% of all cancers, with the highest incidence in Western countries. Despite this, its mortality is slightly decreasing due to earlier detection and improved surgical and non-surgical treatments

made available in the last decades (1). Radical nephrectomy (RN) has represented the gold standard approach for years, lately different nephron sparing (NS) approaches (enucleo-resection, wedge resection, pure enucleation etc.) have been proposed to minimize impact on renal function granting optimal oncologic control. Multiple retrospective series have demonstrated a comparable cancer specific survival (CSS) for NS vs. RN for patients with organ-confined RCC of limited size (pT1) (2 4) making this approach the new gold standard for T1 masses. Both EAU and AUA guidelines recognize PN as a valuable option to be performed whenever feasible irrespective of the surgical approach (open or minimally invasive) (1, 5). Both transperitoneal and retroperitoneal approaches have shown to provide similar results in terms of oncologic and surgical safety, with the retroperitoneal one being fitter for posterior located masses (6-8). Nevertheless, improvements need to be performed to implement post-operative renal function preservation. Both ischemia time and parenchyma loss have been demonstrated to contribute to post-operative renal damage (9, 10). Along with complete tumor extirpation without complications, the primary goal for an ideal PN is the maximal preservation of renal function (RF) (11). Indeed, as suggested by extensive evidence, an impaired postoperative RF increases the risk of cardiovascular disease, use of specialized health care and death (12). With this regard, quantity and quality of preserved renal parenchyma are the most important determinants of functional recovery after surgery, with type and duration of ischemia possibly playing a secondary role (10). Considering this, efforts should be done in both reducing (or eliminating, whenever feasible) ischemia time and reducing the amount of healthy parenchyma removed during tumor resection or destroyed with the haemostatic suture. Objective of this study is to describe retroperitoneoscopic sutureless zero ischemia partial nephrectomy technique assessing its feasibility and safety, as well as shortterm oncologic and functional outcomes.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 3

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E. Corongiu, P. Grande, A. Di Santo, G. Pagliarella, S. Squillacciotti, E. Liberati, A. Zampelli, V. Olivieri, M. Innocenzi, F. Forte

PATIENTS

AND METHODS

Study population From January 2016 to November 2017, 40 consecutive patients with localized renal masses were treated by a single experienced surgeon (FF) in a single institution, with zero ischemia tumor enucleation PN. Every patient gave written informed consent to be included in our prospectively maintained institutional database, where clinicopathological data as well as follow-up and complication data of every patient were recorded. Approval for the study was granted by the hospital ethics committee and the study conformed to the provisions of the Declaration of Helsinki. Comorbidity status was assessed using Charson Comorbidity Index (CCI) (13) and the American Association of Anesthesiologists (ASA) scores (14). Clinical procedure and patient monitoring Fifteen patients with low nephrometry score (RENAL ≤ 7) renal masses, located on the posterior surface, were treated using retroperitoneal sutureless zero ischemia approach. Pre-operative exclusion criteria for sutureless technique was tumor close contact with collecting system at preoperative CT scan. The remaining patients treated at the hospital during the study timeframe underwent both transperitoneal PN according to mass location and, for those, sutures were used only for the more complex neoplasms, or to repair damaged collecting systems. Hemoglobin was dosed preoperatively, then 24 hours after intervention to detect potential postoperative bleeding. Renal function was assessed using the estimated glomerular filtration rate (eGFR), calculated with the modification of diet in renal disease (MDRD) equation (15) preoperatively, at discharge and at 3-mo post-operative visit. Study endpoint Primary endpoint was to assess feasibility and safety of retroperitoneal zero ischemia sutureless partial nephrectomy, secondary endpoint was renal function preservation and short-term oncologic outcomes. Surgical technique Patient’s position and access to the retroperitoneum The patient was placed on flank position, angled at IX-X coastal level for the left side and angled at X-XI coastal level for the right side to better expose the triangle of Petit (Figure 1). The first incision was performed 3 cm above the iliac ridge, on the mid-auxiliary line. A blunt dissection of the anterior component of the lumbar-dorsal fascia with Mayo scissors and subsequently digital dissection is performed until the identification of the postero-lateral surface of the psoas muscle and the distal portion of Gerota’s fascia. An inflatable space maker balloon is used to develop the retroperitoneal space. The remaining 2 trocars are placed under digital guide: the anterior one (10 mm) 2 cm above the optical trocar, keeping as

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Figure 1. Flank position, angled at IX-X coastal level for the left side and angled at X-XI coastal level for the right side to better expose the triangle of Petit.

much distance as possible from the peritoneal reflection. The posterior trocar, 2 cm higher than the optical trocar, on the posterior axillary or in some cases (depending on the body shape) between the angular line of the scapula and the posterior axillary line. As this trocar is placed through the mass of the large dorsal muscle limiting movements in laterality we prefer to use a 5-mm trocar. A 4th trocar, usually placed at the apex of the 12th coast is inserted during the intervention. An intra-abdominal pressure between 12 and 15 mmHg was used during the entire intervention. Identification of the mass and resection The peritoneal reflection until the vena cava (right side) or ureter (left side) is identified. Subsequently, the surface of the psoas muscle is released, under the Gerota capsule, up to its proximal insertion on the diaphragm (Figure 2a). Laterally, the lateral-conal fascia is freed until the diaphragmatic insertion, to achieve posterior and lateral mobilization of the pre-renal fat. Gerota’s fascia is bluntly dissected cranially, along the renal convexity, starting from its lower apex. The dissection of the perinephric fat is continued until the mass is identified (Figure 2b).

Figure 2. A) surface of the psoas muscle is released; B) dissection of the perinephric fat until the mass is identified; C) identifying the vascular pole of the neoplasm; D) coagulation with bipolar forceps along the enucleation margin.

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Figure 3. Fibrin-based glue is applied on the resection area.

Surgical specimen is removed using an endo-bag through the anterior trocar: this to avoid further stress, at the margins of the lumbar-dorsal fascia, which would lead to greater risk of hernial failure. No drain is left in place. Postoperative measures Pathological examination was performed by a dedicated uro-pathologist according to the 2016 World Health Organization criteria (16) and to the Fuhrman classification (17). Positive surgical margin was defined as cancer cells at the level of the inked parenchymal excision surface. The severity of complications was reported according to the modified Clavien Classification (18). The Trifecta rate was calculated as the combination of warm ischemia time < 25 min, negative surgical margins and no complications (up to 90-day follow-up)(11). Patients were followed in outpatient setting 3 months after surgery and every 6 months for the first two years, then yearly. The follow-up protocol included: clinical visit, physical examination and a metabolic panel at 1, 3 and 6 month, annually thereafter; computed tomography (CT) at 6 and 12 month, annually thereafter. Patients were planned to be discharged at 4th post-operative day as per hospital protocol, eGFR was assessed at discharge and at 3 months post-operative visit.

Identification of the vascular supply and hemostasis The resection of the mass is performed with the aim of tumor enucleation whenever possible, using monopolar scissors and suction. This step is performed totally clampless, for this reason, identifying as soon as possible the vascular pole of the neoplasm, whoâ&#x20AC;&#x2122;s generally represented by an arterial branch lying on the resection burden, is crucial. Useful for this purpose is the blunt dissection performed with the tip of the suction device or with the bipolar forceps (Figure 2c), rising the lesion bottom to top, while the scissor proceeds with mechanical detachment, pandering RESULTS to the convexity of the lesion. The vascular pole of the renal The indication for nephron-sparing surgery was elective tumor is usually coagulated with bipolar forceps, except for some cases where the use of a titanium clip is mandatory due Table 1. to the presence of larger vessels. The Preoperative characteristics. margins of the enucleation are not parSutureless Transperitoneal Overall P ticularly bloody when the neoplasm is retroperitoneal (n = 15) (n = 25) (n = 40) value located at the lower pole, on the conAge, years, mean (SD) 64.0 (13.70) 61.4 (11.71) 62.0 (10.94) > 0.05 vexity (along the Brodel line, at whose BMI, Kg/m2, mean (SD) 25.03 (2.11) 25.9 (2.14) 26.00 (2.12) > 0.05 level the interlobar vessels are thinner Sex m/f 8/7 17/8 25/15 > 0.05 and fold medially towards the renal ASA score, n (%) > 0.05 sinus), or at the upper pole. In these 1 3 (20) 7 (28) 10 (25) cases, coagulation with bipolar forceps 2 11 (73) 16 (64) 27 (67.5) is sufficient along the enucleation mar3 1 (7) 2 (8) 3 (7.5) gin (Figure 2d). Conversely, when CCI, median (IQR) 4 (3-4) 4 (3-4) 4 (3-4) > 0.05 lesions are located on the posterior surAffected kidney > 0.05 face of the kidney, the risk to have more Right 5 (33) 14 (56) 19 (47.5) than one vascular pole is higher. In Left 10 (67) 11 (44) 21 (52.5) those cases, clipping of larger arterial Tumor size, mm, median (IQR) 25 (20-35) 28 (2.5-4) 30 (25-35) > 0.05 branches could be necessary. RENAL Score > 0.05 Final remarks At the end of the procedure the pneumoretroperitoneum is lowered until 5 mm Hg to check for any residual bleeding. Thereafter, fibrin-based glue (Floseal Baxter, USA) or gauze (Tabotamp Ethicon, Inc., Somerville, NJ) is applied on the resection area (Figure 3). In our experience this practice resulted more useful for lesions on the posterior surface of the kidney, where intra-renal vascular branches are more extensive.

<5 5-6 7 >7 Tumor location Polar Hilar Exophitic rate < 50% â&#x2030;Ľ 50% PN indication Imperative Elective

3 (20) 8 (53) 4 (27) -

2 (8) 11 (44) 6 (24) 6 (24)

5 (12.5) 19 (47.5) 10 (25) 6 (15)

13 (87) 2 (13)

18 (72) 7 (28)

31 (77.5) 9 (22.5)

5 (33) 10 (67)

7 (28) 18 (72)

12 (30) 28 (70)

4 (27) 11 (73)

2 (8) 23 (92)

6 (15) 34 (85)

> 0.05

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Sutureless retroperitoneal (n = 15) Operative time, min, mean (SD) 100 (31.5) Length of stay, d, mean (SD) 4.13 (0.37) Estimated blood loss, ml, mean (SD) 370 (299) Histology, n (%) Oncocytoma 4 (26.6) Renal Cell carcinoma 11 (73.4) Positive surgical margin, n (%) 0 (0) Maximal tumour-kidney margin, 4.1 (0.7) mm, mean (SD) pT Stage T1a 9 (60) T1b 2 (13.3) ≥T2 0 (0) Fuhrman grade (for RCC), n (%) I 2 (13.3) II 7 (46.7) ≥III 2 (13.3) Complications* I 3 (20) II ≥III 1 (6.7) Mean (SD) eGFR Preoperative 85.23 (29.95) Discharge 74.77 (23.22) 3-Mo post-OP 81.78 (16.77)

Transperitoneal Overall (n = 25) (n = 40) 130 (31.4) 115 (33.2) 4.7 (0.88) 4.55 (1.45) 425 (285) 410 (275) 2 (8) 23 (92) 0 4.6 (1.2)

6 (15) 34 (85) 0 (0) 4.4 (0.8)

18 (72) 3 (12) 2 (8)

27 (67.5) 5 (12.5) 2 (5)

3 (12) 18 (72) 2 (8)

5 (12.5) 25 (62.5) 4 (10)

2 (8) 1 (4) 1 (4)

5 (12.5) 1 (2.5) 2 (5)

> 0.05

> 0.05 81.34 (24.22) 80.59 (24.28) 72.34 (21.24) 71.89 (21.31) 79.12 ( 17.10) 69.25 (16.52) Simone et al. Minervini et al. 380 100 101(26.6) 32 (32) 101 (26.6) N.A. N.A. 101 (100) 18 (56.3) 94 (93.1) 7 (6.9) 24 (15-40)

N.A. N.A. N.A. 19 (15-21)

N.A. N.A. 63/38

5 (17) 27 (83) N.A.

45 (44.6) 30 (29.7) 26 (25.7) 59 (45-73) N.A.

N.A. N.A. N.A. 62 (46-80) 26 (19.5-35)

96 (95.1) 5 (4.9) 60 (45-160)

32 (100) 115 (80-180)

0.9 (0.6-1.3) 1 (0.6-1.4)

N.A. N.A. N.A.

96 (60-120) 93 (58-125) 97 (96)

N.A. N.A. N.A. 32 (100) §

§ Supposed, as no clear statement for the authors is available in the manuscript.

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> 0.05 > 0.05

*According to Clavien-Dindo classification.

Present study Overall study population, n 15 Overall sutureless procedures, n (%) 15 (100) Transeritoneal Retroperitoneal 15 (100) Clampless Procedures, n (%) 15 (100) RENAL score <5 3 (20) 5-6 8 (53) 7 4 (27) Tumour size, mm, median (IQR) 25 (20-35) Exophytic rate, n (%) <50% 5 (33) ≥50% 10(67) Sex m/f 8/7 ASA score 1 3 (20) 2 11 (73) 3 1 (7) Age, years, median (range) 68 (28-70) BMI, Kg/m2, meadian (IQR) 25.0 (24.2-27.6) Tumour location Polar 13 (87) Hilar 2 (13) Operative time, min, median (range) 90 (40-150) sCr, mg/dL, median (range) Preoperative 0.8 (0.6-1.7) At discharge 0.9 (0.6-1.8) 3-mo post-op 0.9 (0.6-1.9) eGFR, ml/min, median (range) Preoperative 88 (40-135) At discharge 79 (37-124) 3-mo post-op 90 (36-121) Completed sutureless 15 (100)

P value > 0.05 > 0.05 > 0.05 > 0.05

Table 2. Post-operative outcomes.

in 11 (73%) patients and imperative in 4 (27%), of those 3 presented a solitary kidney and one had impaired renal function. Preoperative median (IQR) eGFR was 88 (40-135) ml/min/1.73 m2. Median RENAL score was 5 (IQR: 5-7), median tumor diameter 25 mm (IQR: 20-35); 4 (27%) patients presented a mass with a RENAL score of 7. The tumor was located polar in 13 (87%) cases and hilar in 2 (13%) cases. Further patients’ characteristics for the study population compared to the entire cohort of treated patients are listed in Table 1. All interventions were successfully completed, with no report of intraoperative complication. No vascular lesions occurred during the procedure; no cases were converted to radical nephrectomy, in no case the use of parenchymal suture was necessary. Median (IQR) operative time was 90 (40150) min. All procedures were completed with zero ischemia technique as in no case clamping of the renal artery was necessary. Mean (SD) hospital stay was 4.1 (0.4) days. Median (IQR) GFR was 79 (37-124) at discharge and 90 (36121) at 3-month post-operative visit. Median IQR GRF median (IQR) EBL was 310 (180-500) ml. Pathological analysis showed renal cell carcinoma in 11 patients (73%), 9 (60%) staged T1a and 2 (13%) T1b. In 4 (27%) an oncocytoma was found. There were no positive surgical margins. One patient (7%) developed a major postoperative complication, post-operative renal bleeding requiring super-selective embolization, while 3 (20%) developed minor complications (Clavien I). Trifecta was achieved in 93% of the patients treated with sutureless retroperitoneal approach. Furthermore, oncologic and functional results were similar when compared to the transperitoneal cohort (Table 2). Comment The reports on lower incidence of postoperative acute kidney injury and chronic kidney disease (CKD) after off-clamp PN in the solitary kidney model led to an increased use of this approach for all patients, possibly to avoid the detrimental effect of ischemia on RF (19). Whereas the functional benefit of the off-

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clamp technique has been suggested by several authors both for patients with solitary and normal contralateral kidney (20-23), most of the studies do not include data on resection and reconstruction technique thus potentially either underestimate or overrate the actual effect of arterial clamping. Pure tumor enucleation, for those reasons, could help in preserving the maximal amount of healthy parenchyma granting comparable oncologic and surgical outcomes of conventional partial nephrectomy in T1 renal cancer, as previously reported (24), facilitating a better recovery of post-operative renal function (25), although no general consensus exists yet. Clampless approach, avoids on one side ischemia-related renal damage (26, 27) and on the other side, it permits to avoid any possible vascular damage related to hilum dissection reducing the time of the intervention. Additionally, in experienced hands, clampless approach could facilitate the surgeon to identify major arterial branches and seal it during enucleation. Renal function was assessed at discharge and at 3months post-op visit as per-hospital protocol, after this period, as previously described, no intervention related variations in RF should occur (28). Renal function was not particularly affected as reported in Table 2, no de novo CKD grade ≥ 3a occurred. Additionally, the only two patients with a GFR in the range of CKD stage 3 did not experience any notable decrease in RF. The transitory decrease in RF evidenced at discharge, and the complete restoration of the original GFR values for most of the patients in our series could be considered a consequence of the off-clamp approach, as well as the enucleative technique. Previous experiences with sutureless PN were reported, showing that under certain conditions it is a safe and effective procedure (29, 30) (Table 3). This study confirms previous experiences, demonstrating that this technique may also be applicable for masses with a RENAL score up to 7, without compromising oncologic and functional outcomes. Main limitations of this study include small sample size and retrospective nature of the analysis, although data collection was prospective. Nonetheless, present study is unique as it represents the first, to our knowledge, description of this technique. Furthermore, our series investigates feasibility and safety retroperitoneoscopic clampless sutureless partial nephrectomy, reporting functional outcomes and trifecta rate with a minimum follow-up length of 6 mo. Further studies, employing renal scintigraphy may help determine the real impact of the technique on the operated kidney parenchyma especially in case of imperative indication. Although not comparable with larger series of PN, due to the very selective nature of the cohort and the short follow up period, our preliminary experience showed feasibility and safety of sutureless retroperitoneal zero ischemia LPN for the treatment of low-complexity (up to RENAL 7 score) posterior renal masses. Longer follow-up and higher numbers of patients are, however, warranted to draw definitive conclusions.

REFERENCES

1. Ljungberg B, Albiges L, Bensalah K, et al. EAU guidelines on Renal Cell Carcinoma [Internet]. Uroweb. 2018 [cited 2018 Mar 27]. Available from: https://uroweb.org/guideline/renal-cell-carcinoma/ 2. Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol. 2011; 59:543-52. 3. Marchioni M, Preisser F, Bandini M, et al. Comparison of partial versus radical nephrectomy effect on other-cause mortality, cancerspecific mortality, and 30-day mortality in patients older than 75 years. Eur Urol Focus. 2018 Feb 2. 4. Kunath F, Schmidt S, Krabbe L-M, et al. Partial nephrectomy versus radical nephrectomy for clinical localised renal masses. Cochrane Database Syst Rev. 2017; 5:CD012045. 5. Campbell S, Uzzo RG, Allaf ME, et al. Renal Mass and Localized Renal Cancer: AUA Guideline. J Urol. 2017; 198:520-9. 6. Ren T, Liu Y, Zhao X, et al. Transperitoneal approach versus retroperitoneal approach: a meta-analysis of laparoscopic partial nephrectomy for renal cell carcinoma. PloS One. 2014; 9:e91978. 7. Choo SH, Lee SY, Sung HH, et al. Transperitoneal versus retroperitoneal robotic partial nephrectomy: matched-pair comparisons by nephrometry scores. World J Urol. 2014; 32:1523-9. 8. Stroup SP, Hamilton ZA, Marshall MT, et al. Comparison of retroperitoneal and transperitoneal robotic partial nephrectomy for Pentafecta perioperative and renal functional outcomes. World J Urol. 2017; 35:1721-8. 9. Volpe A, Blute ML, Ficarra V, et al. Renal ischemia and function after partial nephrectomy: a collaborative review of the literature. Eur Urol. 2015; 68:61-74. 10. Zabell JR, Wu J, Suk-Ouichai C, Campbell SC. Renal ischemia and functional outcomes following partial nephrectomy. Urol Clin North Am. 2017; 44:243-55.. 11. Hung AJ, Cai J, Simmons MN, Gill IS. “Trifecta” in partial nephrectomy. J Urol. 2013; 189:36-42. 12. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004; 351:1296-305. 13. 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. 14. Doyle DJ, Garmon EH. American Society of Anesthesiologists Classification (ASA Class). In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018 [cited 2018 Jun 4]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK441940/ 15. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999; 130:461-70. 16. Moch H, Cubilla AL, Humphrey PA, et al. The 2016 WHO classification of tumours of the urinary system and male genital organs-Part A: renal, penile, and testicular tumours. Eur Urol. 2016; 70:93-105. 17. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982; 6:655-63. 18. Dindo D, Demartines N, Clavien P-A. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004; 240:205-13.

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19. Mir MC, Ercole C, Takagi T, et al. Decline in renal function after partial nephrectomy: etiology and prevention. J Urol. 2015; 193:1889-98.

25. Dong W, Gupta GN, Blackwell RH, et al. Functional comparison of renal tumor enucleation versus standard partial nephrectomy. Eur Urol Focus. 2017; 3:437-43.

20. Lane BR, Russo P, Uzzo RG, et al. Comparison of cold and warm ischemia during partial nephrectomy in 660 solitary kidneys reveals predominant role of nonmodifiable factors in determining ultimate renal function. J Urol. 2011; 185:421-7.

26. Porpiglia F, Bertolo R, Amparore D, et al. Evaluation of functional outcomes after laparoscopic partial nephrectomy using renal scintigraphy: clamped vs clampless technique. BJU Int. 2015; 115:606-12.

21. Thompson RH, Lane BR, Lohse CM, et al. Every minute counts when the renal hilum is clamped during partial nephrectomy. Eur Urol. 2010; 58:340-5.

27. Simone G, Gill IS, Mottrie A, et al. Indications, techniques, outcomes, and limitations for minimally ischemic and off-clamp partial nephrectomy: a systematic review of the literature. Eur Urol. 2015; 68:632-40.

22. Kim EH, Tanagho YS, Sandhu GS, et al. Off-clamp robot-assisted partial nephrectomy for complex renal tumors. J Endourol. 2012; 26:1177-82.

28. Porpiglia F, Fiori C, Bertolo R, et al. Long-term functional evaluation of the treated kidney in a prospective series of patients who underwent laparoscopic partial nephrectomy for small renal tumors. Eur Urol. 2012; 62:130-5.

23. Kaczmarek BF, Tanagho YS, Hillyer SP, et al. Off-clamp robotassisted partial nephrectomy preserves renal function: A multi-institutional propensity score analysis. Eur Urol. 2013; 64:988-93. 24. Cao D-H, Liu L-R, Fang Y, et al. Simple tumor enucleation may not decrease oncologic outcomes for T1 renal cell carcinoma: A systematic review and meta-analysis. Urol Oncol. 2017; 35:661.e15661.e21.

Correspondence Emanuele Corongiu, MD (Corresponding Author) emanuele.corongiu@libero.it Angelo Di Santo adisanto1978@gmail.com Giorgio Pagliarella giorgiopagliarella@hotmail.com Stefano Squillacciotti stefano.squillacciotti@gmail.com Emanuele Liberati emanuele.liberati@libero.it Alessandra Zampelli a.zampelli@libero.it Flavio Forte flavioforte@hotmail.com Department of Urology, M.G. Vannini Hospital Via di Acqua Bullicante 4 - 00177 - Rome (Italy) Pietro Grande grandepietro@gmail.com Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Pitié Salpétière, Urology Department, Paris (France) Valerio Olivieri valerio.olivieri@uniroma1.it Department of Urology, Ivrea Hospital, ASL TO 4, Ivrea (Italy) Michele Innocenzi innocenzi.michele@gmail.com Department of Urology, Bambin Gesù Hospital, Rome (Italy)

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29. Simone G, Papalia R, Guaglianone S, Gallucci M. “Zero ischaemia”, sutureless laparoscopic partial nephrectomy for renal tumours with a low nephrometry score. BJU Int. 2012; 110:124-30. 30. Minervini A, Siena G, Tuccio A, et al. Sutureless hemostatic control during laparoscopic NSS for the treatment of small renal masses. Surg Innov. 2014; 21:32-8.

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DOI: 10.4081/aiua.2019.3.163

ORIGINAL PAPER

Assesment of anogenital distance as a marker in diagnosis of prostate cancer Aytac Sahin, Musab Ali Kutluhan, Tuncay Toprak, Yasin Vural, Ahmet Ürkmez, Serkan Akan, Ayhan Verit Urology Department, Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey.

Summary

Objectives: Anogenital distance (AGD), the distance from the sexual organs to the anus, is a sexually dimorphic feature in mammals. In this study, we investigated the relationship between anogenital distance and prostate cancer (PCa). Methods: 52 patients diagnosed with PCa and 60 patients with benign prostate hyperplasia as a control group were included in the study. AGDAP (cephalad insertion of the penis to the center of the anus) and AGDAS (posterior base (first fold) of the scrotum to the center of the anus) measurements of patients were done and noted before biopsy. Results: The mean ages of 52 patients diagnosed with PCa and 60 patients with benign prostatic hyperplasia (BPH) were 67.70 ± 7.74 and 67.03 ± 7.89, respectively. There was no statistically significant difference in terms of age and serum testosterone levels of the patients diagnosed with prostate cancer or BPH (p > 0.05). Mean PSA values of patients diagnosed with prostate cancer wto be statistically higher than patients with BPH (p = 0.000). The mean AGDAP measurements of patients diagnosed with prostate cancer were statistically higher than those diagnosed with BPH (p = 0.000) and there was no significant difference in AGDAS measurements.(p = 0.823; p > 0.05). Conclusions: Androgen exposure is thought to play a role in the development PCa. Also AGD may be an indicator of prenatal androgen activity. In our study, we found a direct correlation between AGDAP and PCa. In order to reach a definitive conclusion, randomized controlled trials with larger sample number are needed.

KEY WORDS: Anogenital distance; Prostate cancer; Benign prostate hyperplasia; Androgens. Submitted 12 June 2019; Accepted 26 July 2019

INTRODUCTION

Anogenital distance (AGD), the distance from the sexual organs to the anus, is a sexually dimorphic feature in mammals (1). The researchers used AGD as a measure of genital development and androgen status to measure reproductive toxicity in both experimental animals and humans. AGD is androgen dependent and males have longer AGD measures than females (2-4). Studies showed that AGD is determined in utero and persists during adulthood (5). However, it has been shown that in rats AGD shows a plasticity that can be mediated by local androgen/estrogen effect (6). In animals, it has been shown that anogenital distance can change with the effect of fetal androgens. Exposure to

chemicals, such as dioxins that exhibit antiandrogenic activity results in shorter AGD distances in rat models (7). Further exposure to prenatal androgen causes longer AGD development. Therefore, AGD may be an indicator of prenatal androgen activity (8). In human models studies have shown that, exposures to endocrine disruptors, such as dichlorodiphenyltrichloroethane metabolites, phthalates, dioxins and bisphenol A have been related with shorter AGD (9-12). Additionally, it was founded that children who had cryptorchidism orhypospadias have shorter AGD (13). Men with prostate cancer also have shorter AGD compared to a control group (14). In this study, we investigated the relationship between anogenital distance and prostate cancer.

MATERIALS

AND METHODS

The study was conducted in accordance with the Helsinki Declaration. All participants gave informed consent for participation. The study was approved by the ethics committee of Fatih Sultan Mehmet Training and Research Hospital. Patients diagnosed with prostate cancer with transrectal prostate biopsy due to PSA elevation (PSA > 2.5 ng/dl) in the urology clinic of Fatih Sultan Mehmet Training and Research Hospital were included in the study. The control group consisted of patients with lower urinary tract complaints who were diagnosed with benign prostate hyperplasia with transrectal prostate biopsy due to PSA elevation (PSA > 2.5 ng/dl). Body mass index (BMI) was calculated as weight in kilograms divided by squared height in meters. Two AGD variants; AGDAP, (from the center of the anus to the cephalad insertion of the penis) and AGDAS, (from the center of the anus to the posterior base of the scrotum) were evaluated (15-16). A digital caliper was used for measuring AGD variants in lithotomy position with his thighs at a 45° angle to the examination table. AGDAP and AGDAS was measured by two separate physicians and each AGD variant was measured three times. The average was calculated. Adjustment was made for body mass index instead of weight and height.

RESULTS

A total of 112 patients with age ranging 47-86 years of age were included in the study between April 2018 and

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 3

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May 2019. The mean age of 52 patients diagnosed with prostate cancer was 67.70 ± 7.74; The mean age of 60 patients with benign prostate hyperplasia (BPH) was 67.03 ± 7.89. There was no statistically significant difference in terms of age of the patients diagnosed with prostate cancer or BPH (p > 0.05). Mean PSA values of patients diagnosed with prostate cancer were found to be statistically higher than patients with BPH (p = 0.000) and there was no statistical difference in terms of serum testosterone levels (p > 0.05). The mean AGDAP measurements of patients diagnosed with prostate cancer was statistically higher than those diagnosed with BPH (p = 0.000) whereas there was no significant difference in AGDAS measurements.(p = 0.823; p > 0.05) (Table 1). There was a statistically significant difference between patients with prostate cancer and BPH in terms of BMI averages (p = 0.043; p < 0.05). Adjusted AGDAP values obtained by dividing the AGDAP by BMI values were significantly higher in the prostate cancer group than in the BPH group (p = 0.007). On the other hand there was no statistically significant difference in adjusted AGDAS (AGDAS/BMI) values (p > 0.05).

exposed to prenatal androgens and their findings are consistent with hypothesis suggesting a relationship between testosterone levels and severity of PCa (21). Studies reported that there was a relationship between AGDAS and testosterone levels in both men and women (22, 23). A longer AGDAS is an indicator of more androgenic prenatal hormonal environment. Therefore, it may affect the proliferation of Leydig cells, which will cause higher androgen levels in adulthood (24). For this reason, having a longer AGDAS may increase the possibility that testosterone will be higher in adulthood, resulting in a greater risk of developing a more severe prostate cancer. On the other hand a review (25) reported that, there is no obvious indication that endogenous testosterone is positively correlated with prostate cancer and because of that it does not directly correlate with the aggression of the prostate cancer. There are also additional reports that prostate cancer development is independent of endogenous testosterone levels (26). Data obtained from the current literature indicate that testosterone replacement therapy (TRT) can be given with the condition that close follow-up is applied to symptomatic hypogonadal patients who underwent radical prostatecStatistical analysis tomy, brachytherapy or external radiotherapy because of While evaluating the findings obtained in the study, IBM prostate cancer (27). SPSS Statistics 25 program was used for statistical analyIn our study there was no statistical significant difference sis.The fit of the parameters to normal distribution was between groups in terms of serum testosterone levels evaluated by ShapiroWilks test. In addition to descriptive (p > 0.05). Also there was no significant difference statistical methods (mean, standard deviation), Student's between groups in terms of AGDAS measurements (p = t-test was used for comparison of quantitative data 0.823; p > 0.05) and adjusted AGDAS (AGDAS/BMI) between two groups of parameters that were normally values. (p > 0.05). In our study, AGDAP measurements distributed. Significance was determined as p < 0.05. were significantly higher in the prostate cancer group. Also according to adjusted AGDAP (AGDAP/BMI) values obtained by dividing AGDAP by BMI, it was found to be DISCUSSION statistically higher in PCa group compared to BPH group We investigated the relationship between AGD, which is (p = 0.007). a biological marker of prenatal androgen exposure, and However, it is difficult to establish a relationship PCa. Anogenital distance is a sexually dimorphic feature, between testosterone and PCa because it is difficult to which is longer in males than in females (17). Androgens predict the current testosterone levels of an individual in are necessary for normal development of prostate (18, clinical practice. Firstly the methods used to measure 19). In a study by Castano et al., men with prostate cantestosterone are variable. Secondly testosterone levels in cer showed shorter AGD compared to control group an individual can be variable at any time of the day. (14). Maldonado et al. found that patients with longer Therefore singular measures are not a good indicator of AGDAS had higher cancer severity (20). Boyle et al. normal testosterone levels. Porcaro et al. (28) reported reported that prostate cancer patients were more that PCa was significantly associated with serum total testosterone. Another study from Spain reported that longer AGD was associatTable 1. ed with lower risk of PCa (14). Comparison of patients diagnosed with prostate cancer and BPH. Hsieh et al. showed that shorter AGDAS measurements is associated with genital Prostate Ca (n = 52) BPH (n = 60) P anomalies (cryptorchidism or hypospaMean ± SD Mean ± SD dias) in men and established a link Age (years) 67.70 ± 7.74 67.03 ± 7.89 0.498 between normal genital development PSA (ng/mL) 13.78 ± 10.44 8.22 ± 3.23 0.000** and AGD in humans (29). Testosterone (ng/mL) 4.06 ± 117 4.37 ± 1.77 0.292 Furthermore, in many studies, AGDAP BMI (kg/m2) 28.23 ± 3.0 27.05 ± 3.04 0.043* measurements have been found to be AGDAP (cm) 13.9 ± 1.31 12.58 ± 1.73 0.000** associated with prenatal exposure and AGDAS (cm) 4.91 ± 1.20 4.96 ± 0.89 0.823 prostate cancer to endocrine disruptors Adjusted AGDAP (AGDAP/BMI) 0.49 ± 0.07 0.46 ± 0.04 0.007* (30-34, 14). AGDAS measurements were associated Adjusted AGDAS (AGDAS/BMI) 0.17 ± 0.04 0.18 ± 0.03 0.312 with semen quality and other reproIndependent Student t test *p<0.05 **p<0.001 ductive hormones (15, 22 to 23).

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Assesment of anogenital distance as a marker in diagnosis of prostate cancer

As can be seen, many studies have been conducted in different areas related to anogenital distance and there are no clear results yet. Therefore, it is not true to hold only androgens responsible for the development of prostate cancer. Further experimental studies are needed for relationship between AGD (AGDAP and AGDAS) and fetal androgen exposure.

7. Faqi AS, Dalsenter PR, Merker HJ, Chahoud I. Reproductive toxicity andtissue concentrations of low doses of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin inmale offspring rats exposed throughoutpregnancy and lactation . Toxicol Appl Pharmacol. 1998; 150:38392.

Limitations of the study The main limitation of our study was that although the patients with PSA values of 2.5 ng/dL and above were taken in both groups and histologically differentiated as benign prostatic hyperplasia and prostate cancer by transrectal biopsy, the mean PSA value of the control group was statistically lower than the prostate cancer group. Choosing patients with similar PSA values and prostate volumes in both groups could be better in terms of excluding androgen exposure and AGD relationship. Additionally, the methods used to measure testosterone are variable. Testosterone levels in an individual can be variable at any time of the day.Therefore, singular estimates are not a good indicator of normal testosterone levels. So, it is difficult to state anything definite about testosterone levels.

9. Suzuki Y, Yoshinaga J, Mizumoto Y, et al. Foetal exposure to phthalate esters and anogenital distance in malenewborns. Int J Androl. 2012; 35:236-44.

CONCLUSIONS

There is a scarce number of studies in the literature about the relationship between anogenital distance and prostate cancer. Androgen exposure is thought to play a role in the development of PCa, but recent studies demonstrated that there is no relationship between androgens and prostate cancer. On the other hand there are different conclusions about relationship between AGD and prostate cancer. In our study, we found a direct correlation between AGDAP and prostate cancer. In order to reach a definitive conclusion, randomized controlled trials with larger sample number are needed.

REFERENCES

1. Sathyanarayana S, Beard L, Zhou C, Grady R. Measurement and correlates of ano-genital distance in healthy, newborn infants. Int J Androl. 2010; 33:317-23. 2. Salazar-Martinez E, Romano-Riquer P, Yanez-Marquez E, et al. Anogenital distance in human male andfemale newborns: a descriptive, crosssectional study. Environ Health. 2004; 3:8. 3. Scott HM, Hutchison GR, Jobling MS, et al. Relationship between androgen action in the “maleprogramming window”, fetal Sertoli cell number, and adult testis sizein the rat. Endocrinology. 2008; 149:5280-7. 4. Swan SH. Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans. Environ Res. 2008; 108:177-84. 5. Hotchkiss AK, Parks-Saldutti LG, Ostby JS, et al. A mixture of the ‘anti-androgens’ linuron and butyl benzyl phthalate alters sexual differentiation of the male rat in a cumulative fashion. Biol Reprod. 2004; 71:1852-61. 6. Mitchell RT, Mungall W, McKinnell C, et al. Anogenital distance plasticity in adulthood: implications for its use as a biomarker of fetal androgen action. Endocrinology. 2015; 156:24-31.

8. Gray LE Jr, Wilson VS, Stoker T, et al. Adverse effects of environmental anti-androgens and androgens on reproductive development in mammals. Int J Androl. 2006; 29:96-104.

10. Bustamante-Montes LP, Hernandez-Valero MA, FloresPimentel D, et al. Prenatal exposure to phthalates is associated with decreased anogenital distance and penile size in male newborns. J Dev Orig Health Dis. 2013; 4:300-6. 11. Bornehag CG, Carlstedt F, Jonsson BA, et al. Prenatal phthalate exposuresand anogenital distance in Swedish boys. Environ Health Perspect. 2015; 123:101-7. 12. Miao M, Yuan W, He Y, et al. Inutero exposure to bisphenol-A and anogenital distance of maleoffspring. Birth Defects Res A Clin Mol Teratol. 2011; 91:867-72. 13. Jain VG, Singal AK. Shorter anogenital distance correlates with undescended testis: a detailed genital anthropometric analysis in human newborns. Hum Reprod. 2013; 28:2343-9. 14. Castano-Vinyals G, Carrasco E, Lorente JA, et al. Anogenital distance and the risk of prostate cancer. BJU Int. 2012; 110:E70710. 15. Mendiola J, Stahlhut RW, Jørgensen N, et al. Shorter anogenital distance predicts poorer semen quality in young men in Rochester, New York. Environ Health Perspect. 2011; 119:958-63. 16. Parra MD, Mendiola J, Jørgensen N, et al. Anogenital distance and reproductive parameters in young men. Andrologia. 2016; 48:3-10. 17. Kurzrock EA, Jegatheesan P, Cunha GR, Baskin LS. Urethral development in the fetal rabbit and induction of hypospadias: a model for human development. J Urol. 2000; 164:1786-92. 18. Wilson JD. The Critical Role of Androgens in Prostate Development. Endocrinol Metab Clin N Am. 2011; 40:577-90. 19. Yassin A, AlRumaihi K, Alzubaidi R, et al. Testosterone, testosterone therapy and prostate cancer. Aging Male. 2019; 7:1-9. 20. Maldonado-Cárceles AB, Sánchez-Rodríguez C, Vera-Porras EM, et al. Anogenital Distance, a Biomarker of Prenatal Androgen Exposure Is Associated With ProstateCancer Severity. Prostate. 2017; 77:406-11. 21. Boyle P, Koechlin A, Bota M, et al. Endogenous and exogenous testosterone and the risk of prostate cancer and increased prostatespecific antigen (PSA) level: A meta-analysis. BJU Int. 2016; 118:731-41. 22. Eisenberg ML, Jensen TK, Walters RC, et al. The relationship between anogenital distance and reproductive hormone levels in adult men. J Urol. 2012; 187:594-8. 23. Eisenberg ML, Hsieh MH, Walters RC, et al. The relationship between anogenital distance, fatherhood, and fertility in adult men. PLoS ONE 2011; 6:e18973. 24. Wilson Jean D. Role of androgens in prostate development. Endocrinol Metab Clin North Am. 2011; 40:577-590. 25. Endogenous Hormones and Prostate Cancer Collaborative Group, Roddam AW, Allen NE et al: Endogenous sex hormones and Archivio Italiano di Urologia e Andrologia 2019; 91, 3

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prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst 2008; 100: 170 26. Xu X, Chen X, Hu H, et al. Current opinion on the role of testosterone in the development of prostate cancer: a dynamic model. BMC Cancer. 2015; 15: 806. 27. Morgentaler A, Conners III WP. Testosterone therapy in men with prostate cancer: literature review, clinical experience, and recommendations. Asian J Androl. 2015; 17:206-11.

31. Miao M, Yuan W, He Y, et al. In utero exposure to bisphenol-A and anogenital distance of male offspring. Birth Defects Res A Clin Mol Teratol. 2011; 91:867-72. 32. Bustamante-Montes LP, Hernandez-Valero MA, FloresPimentel D, et al. Prenatal exposure to phthalates is associated with decreased anogenital distance and penile size in male newborns. J Dev Orig Health Dis. 2013; 4:300-6.

28. Porcaro AB, Petroziello A, Brunelli M, et al. High testosterone preoperative plasma levels independently predict biopsy gleason score upgrading in men with prostate cancer undergoing radical prostatectomy. Urol Int. 2016; 96:470-8.

33. Stamatiou K, Pierris N. Could testosterone have a therapeutic role in prostate cancer? Urol J. 2013; 10:747-54.

29. Hsieh MH, Eisenberg ML, Hittelman AB, et al. Caucasian male infants and boys with hypospadias exhibit reduced anogenital distance. Hum Reprod. 2012; 27:1577-80.

34. Vafeiadi M, Agramunt S, Papadopoulou E, et al. In utero exposure to dioxins and dioxin-like compounds and anogenital distance in newborns and infants. Environ Health Perspect. 2013; 121:125-30.

Correspondence Aytac Sahin, MD draytacsahin@gmail.com Musab Ali Kutluhan, MD dr.musab151@gmail.com Tuncay Toprak, MD drtuncay55@hotmail.com Yasin Vural, MD yasin_vural@windowslive.com Ahmet Ă&#x153;rkmez, MD ahmeturkmez@hotmail.com Serkan Akan, MD drserkanakan@hotmail.com Ayhan Verit, MD veritayhan@yahoo.com Urology Department, Fatih Sultan Mehmet Training and Research Hospital, Istanbul (Turkey)

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DOI: 10.4081/aiua.2019.3.167

ORIGINAL PAPER

Role of sterile pyuria in association to elevated PSA values in the diagnosis of non-palpable prostate cancer? Selamettin Demir Department of Urology, The Ministry of Health, University of Health Sciences, Van Education and Research Hospital, Van, Turkey.

Summary

Objectives: Although cancer is believed to develop and progress with the involvement of inflammation, it is still unclear what the correlation between inflammation and prostate cancer is. This study based on results of transrectal ultrasound-guided prostate biopsies aimed to determine whether C-reactive protein (CRP) and sterile pyuria were clinically useful in the evaluation of patients with suspect of prostate cancer. Materials and methods: This study is a cross-sectional prospective study of patients without clinical prostatitis symptoms. Characteristics of the 200 consecutive patients recruited were 3-20 ng/mL value of serum prostate-specific antigen (PSA), normal digital rectal examination finding, and sterile urine culture result. All patients underwent 12-core prostatic biopsy. 163 of the 200 patients had benign prostatic hyperplasia confirmed through histology, while the residual 37 patients had prostate cancer. Patients with pre-treatment urinary leukocyte count â&#x2030;¤ 3/high power field were categorized as non-pyuria, whilst those with pre-treatment urinary leukocyte count > 3/high power field were categorized as pyuria. The serum CRP level was also used to differentiate patients before the biopsy. Subgroups were compared regarding a number of clinical variables. Results: Histology revealed that 70% of pyuria patients and 38.5% of non-pyuria patients presented inflammation (p = 0.001). The pyuria group exhibited significantly higher total PSA compared to the non-pyuria group (p = 0.044). The two groups did not differ significantly regarding cancer detection rate (p = 0.752). CRP groups were similar regarding cancer detection and histologically-detected inflammation rates. Conclusion: In patients with no evidence of clinical prostatitis, sterile pyuria should be considered as a cause of increased PSA. Although sterile pyuria cannot predict non-palpable prostate cancer, it should be taken into account in urological evaluation in order to demonstrate minute prostatic inflammation due to its simplicity, convenience and non-invasiveness.

KEY WORDS: Prostate cancer; Inflammation; Biopsy; C-reactive protein; Pyuria. Submitted 16 February 2019; Accepted 2 April 2019

INTRODUCTION

In the US, prostate cancer (PCa) continues to be the cancer with the second highest mortality rate in men, despite the fact that the number of men dying because of it is not as high as the number of those dying with it for other causes (1, 2). PCa risk is believed to be heightened by genetic and environmental factors, but the exact etiology remains unclear (3). Nevertheless, PCa and partic-

ularly non-palpable PCa has been increasingly identified at an early stage thanks to the common practice of screening for serum prostate-specific antigen (PSA). However, some have argued that biopsies should not be performed unnecessarily (4, 5), because, besides PCa, non-malignant prostate conditions, such as inflammation, may be associated with high serum PSA as well (6, 7). The general assumption is that PCa develops and progresses due to inflammatory processes that disrupt the function of oncogenes and tumor inhibitors, thus damaging DNA and activating processes that can trigger tumor cells to grow and proliferate (8, 9). Therefore, PCa risk is considered to be elevated in men with intraprostatic conditions like proliferative inflammatory atrophy, prostatic intraepithelial neoplasia, and prostatitis, which may be induced by acute or chronic inflammation and are believed to be PCa precursors (9, 10). Abnormal digital rectal examination (DRE) results and/or PSA higher than 4.0 ng/mL are among the main markers warranting a prostate biopsy. If DRE suggests that PCa is likely, then biopsy is vital. On the other hand, PSA is the sole basis for deciding performance on non-palpable case biopsy, although it frequently yields false positives because its levels are increased by inflammation (11). Thus, it is important to prevent performing unnecessary biopsy for non-palpable case, and for this purpose, a number of PSA derived parameters have been considered, including free-to-total PSA ratio, PSA density (PSAD) and PSA velocity (12, 13). This study sought to determine the extent to which the impact of inflammation on detection of cancer in specimens of prostate biopsy could be gauged based on serum C-reactive protein (CRP) level and urinary leukocyte count.

MATERIALS

AND METHODS

Ethics committee approval was received for this study from the hospita ethics committee (number: 218/13). Written informed consent was obtained from patients who participated in this study. A number of 200 consecutive patients were recruited for this study. All of them had serum PSA levels in the range 3-20 ng/mL, normal DRE findings and sterile urine culture results and underwent transrectal ultrasound-guided 12-core prostatic biopsy (TRUS-bx) beetwen Januray 2018 and February 2019. The study did not include patients with clinical signs of

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 3

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prostatitis, macroscopic pyuria, bacteria isolated in urine provided in Table 1. PCa patients had a mean age of culture or systemic inflammatory conditions with poten65.47 ± 7.84 years, while BPH patients had a mean age tial impact on serum CRP. The medication regimen conof 63.12 ± 7.73 years (p = 0.197). PCa patients had sigsisted of 500 mg ciprofloxacin administered orally twice nificantly higher total PSA compared to BPH patients (p daily over a period of one week, with the first dose being = 0.001), but the two groups were similar in terms of given 24 hours before the procedure. Patients with prefree-to-total PSA ratios. Furthermore, PCa patients had treatment urinary leukocyte count ≤ 3/high power field significantly lower mean prostate volumes (p = 0.040), (h.p.f.) were categorized as non-pyuria, whilst those with the PSAD values were significantly higher in the PCa pre-treatment urinary leukocyte count > 3/h.p.f. were than in the BPH group (p = 0.001). However, histology categorized as pyuria. Furthermore, a positive group did not show a significant difference between the groups with serum CRP of 0.30 mg/dL or higher and a negative regarding inflammation (p = 0.738). group with serum CRP of less than 0.30 mg/dL were disA proportion of 35% of patients (n = 70) exhibited pyuria, tinguished as well (25). Elecsys PSA kit (Roche Cobas 411, while the other 65% (n = 130) did not, as revealed by the Tokyo, Japan) was used for measurement of free and total distribution of the urinary leukocyte count. A comparison PSA values. Alongside the blood sample, urine culture of these two groups in terms of clinical variables, cancer and urine samples were also acquired prior to DRE. detection rates, and histologically-detected inflammation Latex CRP immunoturbidimetric kit (CRP-Latex ‘CRPLX’, is provided in Table 2. The groups were similar regarding Roche, Germany, and Model no. 6000; Hitachi, Tokyo, age, free-to-total PSA ratio, prostate volume, and PSAD Japan) permitted measurement of serum CRP before value, although the pyuria group exhibited significantly treatment, with 0.30 mg/dL cut-off value with 93% higher total PSA compared to the non-pyuria group (p = specificity (25). Furthermore, a centrifugal automatic 0.044), as well as significantly higher serum CRP (p = analyzer and a light microscope (Roche Miditron® Junior 0.001). Furthermore, the groups were similar in terms of II, Germany) was used for urine analysis, while a scanner histological cancer detection rate (p = 0.752), but the with a 6.5 MHz transrectal probe enabled performance of pyuria group displayed greater histological inflammation prostate transrectal ultrasonography (TRUS). Prostate (70% vs 38.5%; p = 0.001). scanning was performed in both transverse and sagittal planes whilst the patient was lying on his left side. The formula for a prostate Table 1. ellipsoid (width × length × height × Characteristics of recruited patients. 0.523) helped to calculate the prostate volume and the total PSA was divided BPH ( n = 163) PCa (n = 37) P by the prostate volume to obtain the Age (years) 63.12 ± 7.73 (40-79) 65.47 ± 7.84 (45-80) 0.637 PSAD. Moreover, an automatic biopsy Urinary leukocyte count (n°/h.p.f.) 9.44 ± 19.18 (1-80) 10.71 ± 21.25 (1-90) 0.288 gun and an 18-gauge needle were CRP (mg/dL) 1.23 ± 1.55 (0.10-8.00) 0.85 ± 0.63( 0.10-3.12) 0.520 employed to conduct the 12-quadrant T-PSA (ng/mL) 5.84 ± 2.54 (3.11-14) 8.72 ± 4.48 (3.65-20.00) 0.001* biopsy under TRUS guidance. Prostate Prostate volume (mL) 57.77 ± 34.65 (17-260) 41.2 ± 20.36 (20-120) 0.040* chronic inflammation was considered Free to total PSA ratio (%) 19 ± 7 (5-38) 22 ± 23 (3-58) 0.752 to be present when inflammatory cells, PSAD 0.12 ± 0.07 (0.03-0.34) 0.25 ± 0.21 (0.07-0.85) 0.001* lymphocytes, plasma cells and/or histiHistologically-detected ocytes infiltrated prostatic biopsy specinflammation rate 49.7% (81/163) 48.6% (18/37) 0.738 imens (14). †Mean ± SD range; ‡BPH versus PCa. BPH: benign prostatic hyperplasia; CRP: C-reactive protein; PCa: prostate cancer; Data were expressed as means ± SD. T-PSA: total prostate-specific antigen; PSAD: PSA density. SPSS (IBM SPSS for Windows, ver.24) was used for comparison of the variables associated with the different groups via Student’s t-test and Chi- Table 2. Square test. Statistical significance was Clinical variables, cancer detection rates and histologically-detected inflammation rates in pyuria and non-pyuria groups. indicated by P value of less than 0.05.

RESULTS

The characteristics of every recruited patient are shown in Table 1. A proportion of 81.5% of patients (n = 163) was histologically confirmed to have benign prostatic hyperplasia (BPH), while the other 18.5% of patients (n = 37) had PCa. Histology also showed inflammation in biopsy specimens of a proportion of 49.5% of patients (n = 99). A comparison of PCa and BPH patients in terms of clinical variables is

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Age (years) CRP (mg/dL) T.PSA (ng/mL) Prostate volume(mL) Free to total PSA ratio (%) PSAD Histologically-detected inflammation rate Cancer detection rate

Non-pyuria group (n: 130) Pyuria group (n: 70) 60.45 ± 7.51 (40-80) 64 ± 6.07 (50-78) 0.75 ± 0.78 (0.10-3.22) 2.39 ± 2.09 (0.28-8.00) 6.42 ± 2.41 (3.29-15.07) 7.85 ± 3.88 (3.11-20.00) 50.3 ± 34.4 (17-260) 55.4 ± 26.5 (30-130) 17 ± 9 (3-35) 20 ± 11 (11-58) 0.14 ± 0.07 (0.04-0.61) 0.15 ± 0.12 (0.03-0.85) 38.5% (50/130) 17.6% (23/130)

70% (49/70) 20% (14/70)

Mean ± SD range; ‡non-pyuria, urinary leukocyte count ≤ 3/h.p.f.; pyuria, urinary leukocyte count > 3/h.p.f.; CRP: C-reactive protein; h.p.f.: high power field; T-PSA: total prostate specific antigen; PSAD: PSA density.

p 0.637 0.001* 0.044* 0.208 0.814 0.288 0.001* 0.752

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Urinary inflammation and prostate cancer

Table 3. Clinical variables, cancer detection rates and histologically-detected inflammation rates in positive- and negative- C-reactive protein groups.

inflammation, especially interleukin 6 (IL-6) (22), have a significant influence on systemic inflammation markers like CRP (23). However, IL-6 is not only CRP negative (n: 57) CRP positive (n: 143) P involved in the mobilization of inflamAge (years) 63.15 ± 7.20 (40-77) 60± 6.37 (43-80) 0.245 matory cells but is also believed to be T-PSA (ng/mL) 6.80 ± 2.45 (3.23-14.58) 7.15 ± 3.63 (3.11-20.00) 0.991 mitogenic in the case of prostate cells Prostate volume(mL) 55.10 ± 37.32 (17-120) 59.88 ± 29.53 (20-260) 0.200 (24). In a retrospective study on 284 patients showing no cancer signs in Free to total PSA ratio (%) 19 ± 7 (3-55) 16 ± 8 (4-58) 0.738 sextant ultrasound-guided biopsies, PSAD 0.15 ± 0.06 (0.03-0.35) 0.17 ± 0.12 (0.04-0.85) 0.490 Morote et al. reported that 23.2% of Histologically-detected inflammation rate 49.1% (28/57) 49.6% (71/143) 0.857 patients had non-malignant tissue Cancer detection rate 12.3% (7/57) 20.1% (30/143) 0.248 without inflammation, 68.3% disMean ± SD range; ‡Negative, serum CRP < 0.30 mg/dL; positive, serum CRP ≥ 0.30 mg/dL; CRP, C-reactive protein; played chronic prostatitis, and 8.4% T-PSA, total prostate specific antigen; PSAD, PSA density. displayed acute prostatitis, which implied that BPH specimens had a high Two groups of positive CRP (71.5%, n = 143) and negarate of prostatic inflammation (11). tive CRP (28.5%, n = 57) were also distinguished based In a different retrospective study, Tomonori et al. found on the manner in which pre-treatment serum CRP levels that 53.5% of BPH patients and 14.1% of PCa patients were distributed. A comparison of these two groups in had inflammation (25). terms of clinical parameters, cancer detection rates, and In the present study, histology revealed that 49.7% of histologically-detected inflammation is provided in Table BPH patients and 48.6% of PCa patients had inflamma3. It was observed that the groups were similar regarding tion. Asymptomatic prostatitis are diagnosed when age, free-to-total PSA ratio, prostate volume, cancer inflammatory cells are present in histological prostate detection rates, and histologically-detected inflammation biopsy specimens according to the National Institute of and PSAD values. Health (NIH) (14). It was noted that serum PSA was significantly higher in pyuria patients with a urinary leukocyte count exceeding 3/h.p.f. (p = 0.044), but the two DISCUSSION groups were similar regarding the cancer detection rate Since the first isolation of serine protease PSA from (p = 0.752). Histology revealed that pyuria patients had prostate epithelial cells that was accomplished by Wang a high inflammation rate, even though clinical symptoms et al. in 1979, PCa began to be diagnosed and treated of prostatitis were absent (p = 0.001) (Table 2). based primarily on PSA measurement (15). There are sigFurthermore, NIH-IV prostatitis is often accompanied by nificant challenges involved in differentiating PCa from prostate hyperplasia (11, 25-27). However, the results BPH, especially in cases with intermediate levels of PSA. obtained in this study did not determine that serum CRP Furthermore, PSA is not associated exclusively with PCa was clinically useful in PCa screening. Pyuria patients but is expressed by malignant as well as normal prostate had higher levels of serum CRP compared with nonglands. pyuria patients (Table 3). Efforts to make prostate biopsy more efficient directed High levels of both PSA and CRP may be due to inflamattention to a number of factors associated with PSA, mation. Meanwhile, CRP positive and negative groups including the free-to-total PSA ratio, PSAD and PSA did not differ in terms of inflammation rate and cancer velocity (12, 13). Particular focus was put on serum detection rate. It was deduced that prostatic inflammamarkers like p53 antibody and insulin-like growth factor tion was more reliably signaled by urinary leukocyte 1 (IGF-1) with the purpose of enhancing positive precount than serum CRP and that serum CRP and elevated dictive value (16, 17), which has also benefitted from PSA were not closely correlated. PCa visualisation innovations, including magnetic resoAccording to Tomonori et al., non-palpable PCa and BPH nance spectroscopic imaging, dynamic contrastmight be differentiated based on an inflammatory index enhanced magnetic resonance imaging, positron emislike urinary leukocyte count applied in a clinical setting sion tomography and transrectal power Doppler imaging (25). However, the present study did not support this (18, 19). Reduction of negative biopsy rate as much as claim, despite observing that minute prostatic inflammapossible should be a key priority of management since tion could be reliably identified based on the urinary prostate biopsy can entail a great deal of pain and could leukocyte count. Meanwhile, in a different study conresult in considerable morbidity. ducted on 61 patients displaying PSA in the range 4-10 Besides PCa, benign conditions like benign prostatic ng/mL, normal DRE outcomes and inflammation in hyperplasia, prostatic manipulation, and even asymptoexpressed prostate secretion, Karazanashvili et al aimed matic and chronic prostatitis are associated with elevated to come up with solutions for making PCa screening levels of serum PSA (6, 7). It is well-known that the more accurate (28). To that end, they used PSA value development and progression of numerous cancers are modification following treatment with antibiotics as a associated with the risk factor of inflammation (20), with diagnostic approach. PCa was detected in only 6% of pre-malignant modifications and adenocarcinoma of the patients with reduced PSA values, whereas all patients prostate having been found to be underpinned by exhibited prostate inflammation. On the other hand, PCa inflammatory processes (21). Cytokines stimulating was detected in 83% of patients with unaltered or eleArchivio Italiano di Urologia e Andrologia 2019; 91, 3

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vated PSA values and prostate inflammation was observed in 17% of these patients. The authors concluded that PCa screening could be made more accurate by evaluating PSA value modification following treatment with antibiotics since high PSA was determined to a significant extent by chronic prostatitis.

CONCLUSIONS

Male individuals are at high risk of asymptomatic prostatitis if their levels of PSA are high and they present normal DRE outcomes. Prior to biopsy, antibiotics or antiphlogistics should be given to pyuria patients and it is advisable to measure PSA repeatedly as well. In patients without evidence of clinical prostatitis, sterile pyuria should be kept in mind as a cause of increased PSA. Although urine leukocyte count cannot predict non-palpable prostate cancer, it should be incorporated in routine urological evaluation to demonstrate minute prostatic inflammation due to its simplicity, convenience and non-invasiveness.

AUTHOR

CONTRIBUTION

Selamettin Demir: Concept, design, supervision, researches and material, data collection, literature search, writing manuscript, critical review, analysis, interperation.

REFERENCES

1. Cooperberg MR, Broering JM, Carroll PR. Risk assessment for prostate cancer metastasis and mortality at the time of diagnosis. J Natl Cancer Inst. 2009; 101:878-887. 2. Pishgar F, Ebrahimi H, Saeedi Moghaddam S, et al. Global, Regional and National Burden of Prostate Cancer, 1990 to 2015: Results from the global burden of disease study 2015. J Urol. 2018; 199:1224-1232. 3. Gann PH. Risk factors for prostate cancer. Rev Urol. 2002; 5:3-10. 4. Hernandez J, Thompson IM. Prostate-specific antigen: a review of the validation of the most commonly used cancer biomarker. Cancer. 2004; 101:894-904. 5. Gosselaar C, Roobol MJ, SchrĂśder FH. Prevalence and characteristics of screen-detected prostate carcinomas at low prostate- specific antigen levels: aggressive or insignificant? BJU Int. 2005; 95:231-7. 6. Oesterling JE. Prostate specific antigen: a critical assessment of the most useful tumor marker for adenocarcinoma of the prostate. J Urol. 1991; 145:907-23. 7. 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; 317:909-16. 8. Marzo AM, Platz EA, Sutcliffe S, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007; 7:256-69. 9. Sfanos KS, Hempel HA, De Marzo AM. The Role of inflammation in prostate cancer. Adv Exp Med Biol. 2014; 816:153-81. 10. Palapattu GS, Sutcliffe S, Bastian PJ, et al. Prostate carcinogenesis and inflammation: emerging insights. Carcinogenesis. 2005; 26:1170-81. 11. Morote J, Lopez M, Encabo G, de Torres IM. Effect of inflammation and benign prostatic enlargement on total and percent free serum prostatic specific antigen. Eur Urol. 2000; 37:537-40.

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12. Catalona WJ, Southwick PC, Slawin KM, et al. Comparison of percent free PSA, PSA density, and age-specific PSA cutoffs for prostate cancer detection and staging. Urology. 2000; 56:255-60. 13. Brawer MK, Cheli CD, Neaman IE, et al. Complexed prostate specific antigen provides significant enhancement of specificity compared with total prostate specific antigen for detecting prostate cancer. J Urol. 2000; 163:1476-80. 14. Krieger JN, Nyberg L Jr, Nickel JC. NIH consensus definition and classification of prostatitis. JAMA 1999; 282:236-7. 15. Wang MC, Valenzuela LA, Murphy GP, Chu TM. Purification of a human prostate specific antigen. Invest Urol. 1979; 17:159-63. 16. Suzuki H, Akakura K, Igarashi T, et al. Clinical usefulness of serum antip53 antibodies for prostate cancer detection: a comparative study with prostate specific antigen parameters. J Urol. 2004; 171:182-6. 17. Renehan AG, Zwahlen M, Minder C, et al. Insulin-like growth factor (IGF) -I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet. 2004; 363:1346-53. 18. Hersh MR, Knapp EL, Choi J. Newer imaging modalities to assess tumor in the prostate. Cancer Control. 2004; 11:353-7. 19. Inahara M, Suzuki H, Nakamachi H, et al. Clinical evaluation of transrectal power doppler imaging in the detection of prostate cancer. Int Urol Nephrol. 2004; 36:175-80. 20. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer related inflammation. Nature. 2008; 454:436-444. 21. De Marzo AM, Platz EA, Sutcliffe S, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007; 7:256-269. 22. Kushner I. The phenomenon of the acute phase response. Ann N Y Acad Sci. 1982; 389:39-48. 23. Guthrie GJ, Roxburgh CS, Horgan PG, McMillan DC. Does interleukin-6 link explain the link between tumour necrosis, local and systemic inflammatory responses and outcome in patients with colorectal cancer? Cancer Treat Rev. 2013; 39:89-96. 24. Malinowska K, Neuwirt H, Cavarretta IT, et al. Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor. Endocr Relat Cancer. 2009; 16:155-169. 25. Kato T, Suzuki H, Komiya A, et al. Clinical significance of urinary white blood cell count and serum C-reactive protein level for detection of non-palpable prostate cancer. Int J Urol. 2006; 13:915-919. 26. Stancik I, LĂźftenegger W, Klimpfinger M, et al. Effect of NIH-IV prostatitis on free and free-to-total PSA. Eur Urol. 2004; 46:760-4. 27. Irani J, Levillain P, Goujon JM, et al. Inflammation in benign prostatic hyperplasia: correlation with prostate specific antigen value. J Urol. 1997; 157:1301-3. 28. Karazanashvili G, Managadze L. Prostate-specific antigen (PSA) value change after antibacterial therapy of prostate inflammation, as a diagnostic method for prostate cancer screening in cases of PSA value within 4-10 ng/mL and nonsuspicious results of digital rectal examination. Eur Urol. 2001; 39:538-43.

Correspondence Selamettin Demir, MD (Corresponding Author) drselami1978@hotmail.com The Ministry Of Health, University of Health Sciences, Van Education and Research Hospital, Van (Turkey)

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DOI: 10.4081/aiua.2019.3.171

ORIGINAL PAPER

The comparative analysis of the three dilatation techniques in percutaneous nephrolithotomy: Which one is safer? Aytac Sahin, Fatih Uruc Department of Urology, Fatih Sultan Mehmet Research and Training Hospital, Istanbul, Turkey.

Summary

Objectives: Introduction of the “access sheath” is one of the most important steps of the percutaneous nephrolithotomy (PNL) intervention. In creating the access tract, various dilatators (balloon, metal) are used and different need-based dilatation tools were developed. In this study, we aimed to compare the mechanical Amplatz dilatation (AD), balloon dilatation (BD) and one-shot dilatation (OSD) methods in a retrospective manner. Methods: A total of 182 patients (127 males and 55 females), who underwent PNL surgery in Urology Department of Fatih Sultan Mehmet Research and Training Hospital between January 2016 and September 2018, were included in this study. Results: The average age was 47.34 ± 12.68 years (age range 15-80) and average BMI was 27.15 ± 5.01 kg/m2 (range between 17.12 and 40.75 kg/m2). There was a prominent difference in terms of operation duration (p = 0.032). Meaningful difference was found among the groups in terms of dilation fluoroscopy time (p = 0.001), with a notable shorter time in OSD group than the others (p < 0.05). Beside this, there was no difference between the AD and BD groups in terms of fluoroscopy times (p > 0.05). Also, there was no difference among the groups by Clavien complication rate (p > 0.05). There was a prominent difference among the groups in terms of hemoglobin decrement (p = 0.012; p < 0.05). The hemoglobin decrease in OSD group was significantly lower than in AD and BD groups (p < 0.05; p < 0.01). On the contrary, there was no meaningful difference between AD and BD groups with this regard (p > 0.05). Conclusions: As a result, we have concluded that the use of OSD modality in PNL interventions could be superior to other methods with respect to its feasibility, cost-effectiveness, shorter radiation exposure / fluoroscopy time and it could be a preferable way of treatment especially in developing countries.

kidney excision and removal of the kidney stones by inserting an access sheath between the kidney and subcutaneous region. PNL has become an important alternative to open surgery approach in urolithiasis treatment, with respect to its minimal invasive feature (3). In current clinical practice, extracorporeal shock wave lithotripsy (ESWL), PNL, retrograde intrarenal surgery (RIRS), combined approach of these methods and other laparoscopic methods are used. Due to minimal complication rates, fast elimination of big stones, quicker recovery, short hospitalization periods, increased quality of life and minimal loss of working capacity, the European Association of Urology (EAU) has recommended the PNL method as primary option for treatment of kidney stones larger than two cm in diameter (2). Introduction of the “access sheath” is one of the most important steps of the PNL intervention. In creating the access tract, various dilatators (balloon, metal) are used and different need-based dilatation tools were developed. In this study, we aimed to compare the mechanical Amplatz dilatation (AD), balloon dilatation (BD) and one-shot dilatation (OSD) methods in retrospective manner.

MATERIALS

AND NETHODS

A total of 182 patients (127 males and 55 females), who underwent PNL surgery at Urology Department of Fatih Sultan Mehmet Research and Training Hospital between January 2016 and September 2018, were included in this study. All participants were thoroughly examined KEY WORDS: Percutaneous nephrolithotomy; Dilatation techniques; and evaluated prior to surgical intervention. Patients who have positive bacterial contamination in urinary One shot dilatation. culture, hemorrhagic diathesis condition or any systemic Submitted 30 May 2019; Accepted 26 July 2019 comorbidity were previously treated according to the diagnosed disorder and subsequently included to the INTRODUCTION study. Only individuals with serious coagulopathy were Urolithiasis is a frequently encountered illness with excluded. Retrograde pyelography imaging was taken prevalence rates highly variable according to region and from all the patients. PNL surgery was applied to all population worldwide (1). Urolithiasis treatment can be patients in prone position with assisted retrograde pyelapplied by using conservative, medical or surgical methography imaging. After calyceal access to kidney, AD ods according to the patient’s status and characteristics of method was applied to 66 patients, BD method in 55 the stone (2). patients and OSD in 61 patients. Average age, calculi Percutaneous nephrolithotomy (PNL) can be defined as diameter, body mass index, operation duration, radiation No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 3

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exposure during the surgical intervention, hemoglobin decrement rate, Clavien complication score and treatment costs were compared in the three groups, Radiation exposure time elapsed during dilatation was defined as the time period between the insertion of the 18 Gauge needle and the placement of Ampltaz sheath. Surgical operation was carried out by two urology specialists. In OSD method, renal cavities were punctured by using 18 Gauge needle and guide-wire was inserted into collecting system after urinary flow was observed. Following this initial step, co-axial dilator of 10 F of diameter was pushed forward through the guide-wire. Amplatz dilators up to 30 F were further pushed into the kidney with rotation movement and access sheath was placed over Amplatz dilator, which enables a wide entry tract for nephroscopic examination.

for Clavien complication rates (p > 0.05). There was a prominent difference among the groups in terms of hemoglobin decrement (p = 0.012; p < 0.05). The hemoglobin decrease in OSD group was significantly lower than in AD and BD groups (p < 0.05; p < 0.01). On the contrary, there was no statistically significant difference between the AD and BD groups with this regard (p > 0.05) (Table 2).

DISCUSSION

With the development of minimally invasive treatment of urinary calculi, PNL has become one of the main treatments for large kidney and upper ureteral stones (4). One of the most fundamental steps of PNL surgery is to establish safe and effective access. However, complications in this process such as tract dilation failure, hemorStatistical analysis rhage and perforation of the renal parenchyma or colSPSS Statistics 22 (IBM SPSS, Turkey) program was used lecting system are not uncommon (5). for statistical analysis of the data obtained. Descriptive The dilation of the nephrostomy tract is a central step of statistical data were obtained (average, standard deviaPNL intervention, and is usually performed by three dilation, frequency), Kruskall Wallis test was used to comtion methods: Ssemi rigid fascial dilators (Amplatz) over pare non-normal parameters for more than 2 groups and an 8F guide catheter, metal telescopic dilatators (MTD) Mann Whitney U testwas used to compare differences and nephrostomy balloon dilatators (BD). Each dilation between two independent groups. method has advantages and disadvantages. In the past, there have been many attempts and modifications to obtain the best results with minimal kidney damage (6RESULTS 8). When it comes to the radiation exposure issue, BD The mean age was 47.34 ± 12.68 years (range 15-80) and OSD methods have an obvious superiority to MD and average BMI was 27.15 ± 5.01 kg/m2 (range between and AD methods, attributed to their easy-to-use aspect 17.12 and 40.75 kg/m2) (Table 1). There was a promiwith one-pass dilation technique and shorter intervennent difference in terms of operation time (p = 0.032). tion time. In addition to this, there are also some cons of Significant difference was found among the groups in the latter mechanical methods including the displaceterms of dilation fluoroscopy time (p = 0.001), with a ment of guide-wire and access sheath during the multinotable shortening in OSD group than the others (p < pass dilation entries, perforation in collecting tubule sys0.05). Beside this, there was no difference between the tem and hemorrhage (9). AD and BD groups in terms of fluoroscopy times (p > Although there is a general consensus that BD is a more 0.05). Also, there was no difference among the groups reliable and efficient method than the metallic and plastic dilator use in the literature, it has been reported in a multi-centric study that there was longer mean operation Table 1. time, more bleeding amount and higher transfusion rates Demographic data. with BD (10). In a meta-analysis study in which four different dilation Mechanical Balloon One-shot dilatation dilatation dilatation methods have been evaluated in 6820 patients submitted Average age (years) 48.86 45.94 46.5 to PNL, it has been reported that OSD method requested shorter fluoroscopy time and less hemoglobin loss, Male/female (n) 48/18 39/16 40/21 when compared with the MTD method. In the same Body mass index (kg/m2) 27.06 27.28 27.13 study, a statistically remarkable difference has been Stone surface area (cm2) 5.4 4.8 4.28 reported between BD and MTD in terms of blood transfusion rates and it has also been mentioned that BD had an Table 2. advantage over MTD approach Evaluation of the parameters according to the operations carried out. in terms of shorter intervention Mechanical Balloon One-shot P times and lower transfusion rate dilatation dilatation dilatation in patients who have not underMean ± SD (median) Mean ± SD (median) Mean ± SD (median) gone open kidney surgery operSurgery time (mins) 117.73 ± 49.53 (120) 104.92 ± 35.86 (120) 99.1 ± 39.34 (90) 0.032* ation before. This meta-analysis Scopy time in dilatation (sec) 30.05 ± 6.87 (28) 27.02 ± 4.06 (27) 25.39 ± 3.23 (25) 0.001** research has also pointed out Clavien score 1.35 ± 0.62 (1) 1.29 ± 0.58 (1) 1.15 ± 0.36 (1) 0.197 that OSD could be preferred in Hemoglobin level (mg/dL) 1.44 ± 1.3 (1) 1.39 ± 1.24 (1) 0.92 ± 0.44 (0,8) 0.012* most patients that have to be operated by PNL (11). Likewise, Kruskall- Wallis Test *p < 0.05 **p < 0.01 we have observed less fluo-

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Dilation in percutaneous nephrolithotomy

roscopy use and hemoglobin decrement in OSD method in the current study. In a meta-analysis study including large series of participants, it has been reported that bleeding was significantly higher with balloon dilation method (9.4%), when compared with telescopic/serial dilation (6.7%). It has also been mentioned in the same study that there was a need for more transfusions for balloon dilation interventions (7.0%) than telescopic/serial dilations (4.9%) (12). Moreover, hemorrhage risk gets higher when a consecutive dilator is displaced to insert a larger one, because of the space remained after the removal. In some papers, single-increment dilation has been suggested as an easyto-apply and safe method to achieve better outcomes (13). In a study by Frattini et al., it has been reported that there was a significant decrement in fluoroscopy time in comparison of the MTD, BD and OSD groups (14). Li et al. found that OSD was a more reliable method, because of shorter insertion and fluoroscopy times (15). In another prospective series with 320 participants, Harrech et al. reported that OSD was also a reliable and feasible method, which could also be used in PNL procedures performed in supine position (16). It has been emphasized in the literature that tract dilation failure was a crucial issue, which could be encountered especially in cases with renal hypermobility condition. Harrech et al. reported the dilation tract failure rate as three percent (16). In our study, we did not had failures of access tract dilation with OSD orocedure. Consequently, in our retrospective study, average fluoroscopy time and decrease in hemoglobin were found better by using OSD technique than AD and BD. Consequently our opinion is that OSD method is the safer and simpler technique.

CONCLUSIONS

As a result, we conclude that the use of OSD modality in PNL interventions could be superior to other methods with respect to its feasibility, cost-effectiveness, shorter radiation exposure/fluoroscopy times and it could be a preferable way of treatment especially in developing countries.

6. Patil AV. A novel 5-part percutaneous access needle with guidewire technique (5-PANG) for percutaneous nephrolithotomy: our initial experience. Urology. 2010; 75:1206-8. 7. Baldwin DD, Maynes LJ, Desai PJ, et al. A novel single step percutaneous access sheath: the initial human experience. J Urol. 2006; 175:156-61. 8. Maynes LJ, Desai PJ, Zuppan CW, et al. Comparison of a novel one-step percutaneous nephrolithotomy sheath with a standard twostep device. Urology. 2008; 71:223- 7. 9. Hajiha M, Baldwin DD. New technologies to aid in percutaneous access. Urol Clin North Am. 2019; 46:225-243. 10. Yamaguchi A, Skolarikos A, Buchholz NP, et al. Operating times and bleeding complications in percutaneous nephrolithotomy: a comparison of tract dilation methods in 5,537 patients in the Clinical Research Office of the Endourological Society Percutaneous Nephrolithotomy Global Study. J Endourol. 2011; 25:933-9. 11. Dehong C, Liangren L, Huawei L, Qiang W. A comparison among four tract dilation methods of percutaneous nephrolithotomy: a systematic review and meta-analysis. Urolithiasis. 2013; 41:523-30. 12. Lopes T, Sangam K, Alken P, et al. Clinical Research Office of The Endourological Society Percutaneous Nephrolithotomy Study Group. The Clinical Research Office of the Endourological Society Percutaneous Nephrolithotomy Global Study: tract dilation comparisons in 5537 patients. J Endourol. 2011; 25:755-62. 13. Xiong J, Shi Y, Zhang X, et al. Chinese one shot dilation versus sequential fascial dilation for percutaneous nephrolithotomy: a feasibility study and comparison.Urol J. 2019; 16:21-26. 14. Frattini A, Barbieri A, Salsi P, et al. One shot: A novel method to dilate the nephrostomy access for percutaneous lithotripsy. J Endourol. 2001; 15:919-23. 15. Li Y, Yang L, Xu P, et al. One-shot versus gradual dilation technique for tract creation in percutaneous nephrolithotomy: a systematic review and meta-analysis. Urolithiasis 2013; 41:443-8. 16. El Harrech Y, Abakka N, El Anzaoui J, et al. One-shot dilation in modified supine position for percutaneous nephrolithotomy: experience from over 300 cases. Urol J. 2014; 11:1575-82.

REFERENCES

1. Stoller ML. Urinary Stone disease; in Tanagho EA Mc Aninch JW 17th edition Smithâ&#x20AC;&#x2122;s general urology, McGraw Hill Medical 2008. 2. TĂźrk C, Skolarikos A, Neisius A, et al. Guidelines on Urolithiasis: European Association of Urology, 2019. 3. Peng PX, Lai SC, Ding ZS, et al. One-shot dilation versus serial dilation technique for access in percutaneous nephrolithotomy: a systematic review and meta-analysis. BMJ Open. 2019; 9:e025871. 4. Tomaszewski JJ, Smaldone MC, Schuster T, et al. Factors affecting blood loss during percutaneous nephrolithotomy using balloon dilation in a large contemporary series. J Endourol. 2010; 24:20711. 5. Ozok HU, Sagnak L, Senturk AB, et al. A comparison of metal telescopic dilators and Amplatz dilators for nephrostomy tract dilation in percutaneous nephrolithotomy. J Endourol. 2012; 26:630-4.

Correspondence Aytac Sahin, MD (Corresponding Author) draytacsahin@gmail.com Fatih Uruc, MD drfatihguruc@gmail.com Department of Urology, Fatih Sultan Mehmet Research and Training Hospital, Istanbul, Turkey

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DOI: 10.4081/aiua.2019.3.174

ORIGINAL PAPER

Transurethral endoscopic approach for large bladder diverticula: Evaluation of a large series Mauro Pacella 1, Nicolò Testino 1, Guglielmo Mantica 2, Matteo Valcalda 1, Rafaela Malinaric 1, Carlo Terrone 1 1 Department 2 Department

of Urology, Policlinico San Martino Hospital, University of Genova, Genova, Italy; of Urology, San Raffaele Turro Hospital, San Raffaele University, Milan, Italy.

Summary

Objective: To present the results of the largest series of patients with bladder diverticula > 4 cm managed with an endoscopic approach and give tips about the execution of the procedure. Materials and methods: Data of male patients undergone the endoscopic approach for an acquired bladder diverticula > 4 cm from December 2004 to August 2018 were prospectively collected and retrospectively analyzed. The description of the monopolar and bipolar techniques are provided. The success of the procedure was defined as the reduction of the diverticula for more of the 80% of its initial diameter documented at the 3months follow-up imaging. Continuous variables with nonparametric distribution were compared using the Mann-Whitney test, while frequencies of categorical variables were compared between groups by Fisher’s exact test with significance level set at 0.05. Results: Thirty-nine patients with a mean (+/- SD) age at surgery of 69.4 ± 8.8 years were enrolled, for an equal number of diverticula managed. The mean diverticular size was 75.1 ± 24.5 millimeters. The mean operative time was 65 ± 21.9 minutes including the prostate surgery. Twelve patients (30.8%) were managed with bipolar energy, the others with monopolar. The success of the procedure was achieved in 30 patients (76.9% - 7 bipolar and 23 monopolar - p = 0.66). Conclusions: The endoscopic approach might be considered as a useful option for patients with a large bladder diverticulum who are at risk for major or laparoscopic procedures.

KEY WORDS: Bladder diverticula; BPH; Urinary retention; HoLEP; TURP. Submitted 21 April 2019; Accepted 2 May 2019

INTRODUCTION

Acquired bladder diverticula are a herniation of the mucosa through the detrusor muscle and are mainly secondary to an outlet obstruction typically caused by benign prostate enlargement, bladder neck contracture and urethral stenosis. For these reasons, acquired bladder diverticula are usually a disease affecting the elderly male population. The surgical management of a bladder diverticulum itself is not always mandatory but often, especially if of big dimensions, they can lead to post void residual urine, lithiasis, urinary tract infections and ureteral compression. Mandatory should be the resolution of the obstruction, while the surgical management of the diverticula is mostly carried out through an open,

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laparoscopic or robotic approach. The endoscopic approach using the Orandi technique is usually reserved, during other endoscopic procedures, to diverticula less than 4 cm diameter, which are less likely to cause symptoms (1-3). Recently, some authors have proposed the endoscopic management with good success also for large diverticula (4-6). We aim to present the results of the largest series of patients with bladder diverticula > 4 cm managed with an endoscopic approach and give tips about the execution of the procedure.

MATERIALS

AND METHODS

The characteristics, intra- and perioperative data, as well as the follow-up of male patients undergone the endoscopic approach for an acquired bladder diverticula from December 2004 to August 2018 were prospectively collected and retrospectively analyzed. The inclusion criteria were the presence of at least a diverticulum with a major diameter > 4 cm in a patient with comorbidities, an American Society of Anesthesiology Score (ASA Score) ≥ 2 and a Charlson Comorbidity index ≥ 3. The preoperative assessment included routine blood tests with serum creatinine, urinalysis, Trans-rectal Ultrasound (TRUS), and CT scan or conventional cystogram, uroflometry, International Prostatic Symptoms Score (IPSS), serum Prostate Specific Antigen (PSA), serum creatinine, urinalysis and urine culture. At a 3 months follow-up all patients included in the study underwent a control cystogram or Kidney-Ureter-Bladder (KUB) ultrasound. The success of the procedure was defined as the reduction of the diverticula for more of the 80% of its initial diameter. Complications were graded using the ClavienDindo classification (7). Surgery is carried out with the patient in lithotomic position. A meticulous cystoscopy is performed and the subsequent step consist in the fulguration of the whole diverticular mucosa with a rollerball electrode using either the monopolar or bipolar energy source, with a coagulation setting respectively of 60-70 W and 70-80 W. The following step is the incision of the diverticular neck in four different cardinal points (12-3-6-9) and then the flattening of the entire diverticular neck circumference with the same rollerball electrode using plasma vaporization No conflict of interest declared.

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(160 W for monopolar, 180 W for bipolar). Subsequently the management of the primary obstruction is carried out (either with a TURP, TUIP, or other endoscopic procedures) and a 3 ways catheter inserted. All cases were performed by a single urologist (M.P.). An antibiotic prophylaxis (cefazolin 1000 mg), or according to the urinalysis, was started 30 min before surgery. Antithrombotic prophylaxis with low-molecular weight heparin was administered when needed according to our Department protocol. A 3 months follow up included conventional or CT cystography and abdominal, in addition to physical examination, uroflowmetry and IPSS. Demographic and clinical characteristics and perioperative data were expressed as the mean ± standard deviation (SD), median with interquantile range (IQR) or as count with percentage. Continuous variables with nonparametric distribution were compared using the Mann-Whitney test, while frequencies of categorical variables were compared between groups by Fisher’s exact test with significance level set at 0.05. Data were analyzed with Sofastat TM for windows.

procedure was achieved in 30 patients (76.9% - 7 bipolar and 23 monopolar - p = 0.66 - Groups not significantly different in terms of age, ASA, Charlson, prostate size, diverticular size, IPSS). The tendency of the diverticulum was to progressively decrease in the first 12 weeks after surgery and during following months (Figures 1-2). The catheter was removed at a median time of 10 (8-12) days and the median length of stay was 5 (4-6) days. None of the patients required a blood transfusion. No major complications (Clavien-Dindo > 2) were seen, while 2 patients (5.1%) developed postoperative fever managed with antibiotic therapy. The median IPSS change was - 62% (-74% to -46%).

DISCUSSION

The genesis of the diverticula in obstructed patients is determined by the high pressures generated into the bladder during the voiding contraction of the detrusor muscle. During this process, the mucosa extrude through the weakest points of the bladder muscular wall leading to the formation of the bladder diverticula. The need for treatment of secondary bladder diverticula RESULTS is a debated topic. Large bladder diverticula may lead to Thirty-nine patients with a mean (+/- SD) age at surgery post void residual urine, lithiasis, urinary tract infections of 69.4 ± 8.8 years were enrolled, for an equal number of and ureteral compression. For these reasons, some diverticula managed. The mean diverticular size was authors have proposed several open or mini-invasive 75.1 ± 24.5 millimeters. Six patients (15.4%) underwent laparoscopic and robotic surgical approaches (8-12). general anesthesia while 33 (84.6%) spinal anesthesia. These approaches showed to be successful both in terms Eight patients (20.5%) had a TUIP while 31 (79.5%) a of disappear of the diverticulum and symptoms improveTURP. The mean operative time was 65 ± 21.9 minutes ment despite often very high operative times. Obviously, including the prostate surgery. they were associated to endoscopic surgery in order to Twelve patients (30.8%) were managed with bipolar manage the causing obstruction. energy, the others with monopolar. The success of the On the contrary, other authors do not see the need to intervene surgically for these benign pathologies, and they Figure 1. place surgical attention only on Patient A – Progressive reduction of the diverticular diameter. Images at 0-6-12 weeks. the underlying cause (13). Agarwal et al. evaluated the results of patients with bladder diverticula and outlet obstruction undergone HoLEP alone (13). They found a significant improve in the post-void residual, peak flow and symptoms at a 15 months follow-up, and only 6% of patients requiring diverticulectomy. They concluded that most of patient, even with large diverticula, can Figure 2. avoid more invasive surgical Patient B – Complete disappearance of a bladder diverticulum at a CT-Scan performed approaches whether the outlet 3 years later for other reasons. obstruction has been relieved. Recently, an in vivo study on rats showed how large bladder diverticula can alter bladder storage and emptying and can lead to dysfunctional voiding (14). Furthermore, bladder diverticula with a diameter > 5 cm seems to increase the risk of acute urinary retention in Archivio Italiano di Urologia e Andrologia 2019; 91, 3

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benign prostatic hyperplasia (BPH) patients (15). These studies suggest that, in some cases, the surgical management of large bladder diverticula may be necessary. Several reports in literature have described the use of endoscopic management of bladder diverticula. Orandi et al. published the first report on a series of 17 patients who underwent transurethral fulguration: a complete resolution was achieved in five patients and a decrease in volume in nine (1). Likewise, Clayman et al. managed six patients obtaining a complete disappear of the diverticulum in five of them and a size reduction in the other (3). Yamaguchi et al. reported the most recent and largest series of bladder diverticula fulguration in 1992: twentysix out of thirty-one patients showed a complete resolution (16). In all these studies the size of the managed diverticula was heterogeneous. Recently, some authors have proposed the endoscopic management with good success also for large diverticula (4-6). The complete disappearance of the diverticulum may take several months and it depends mainly on the initial dimensions of the diverticulum itself. The pathophysiological process behind these results is not completely clear. The effect of the fulguration of the mucosa may involves also the underlying submucosa, causing ischemia of the diverticular wall and leading to a consequent progressive atrophy. This may determine the progressive retraction and the final disappearance of the diverticulum. Data from our study shows that it’s effective in terms of symptoms improvement, with low complication rate and a very short operative time. It adds only few minutes to the mandatory management of the causing obstruction (TUIP/TURP/HoLEP/ThuLEP/etc), it’s safe, cost-effective and if it fails it doesn’t preclude a subsequent further management through a laparoscopic or robotic approach. With the limit of the small samples, it showed similar outcomes whether performed with monopolar or bipolar energy. The fact that is retrospective and the absence of a group of control undergone another procedure are the main limits of the study. However, we believe it has been successful in showing the possible role of this mini-invasive surgical approach.

CONCLUSIONS

Although the endoscopic management of large bladder diverticula doesn’t guarantee the same successful rate and radicality of other open or minimally-invasive procedures it showed some advantages such a very short operative time and the possibility to be performed under spinal anesthesia (8-10). Furthermore, patients in which the procedure fail can still be further managed with a subsequent different and more radical approach. For these reasons we believe it should be considered as a useful option for patients at risk for major or laparoscopic procedures.

REFERENCES

1. Orandi A. Transurethral fulguration of bladder diverticulum: new procedure. Urology. 1977; 10:30-32. 2. Vitale PJ, Woodside JR. Management of bladder diverticula by transurethral resection: re-evaluation of an old technique. J Urol. 1979; 122:744.

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3. Clayman RV, Shahin S, Reddy P, et al. Transurethral treatment of bladder diverticula. Alternative to open diverticulectomy. Urology. 1984; 23:573. 4. Pham KN, Jeldress C, Hefty T, et al. Endoscopic management of bladder diverticula. Rev Urol. 2016; 18:114-117. 5. Chandhoke RA, Ghoniem GM. Transurethral electrovaporization of bladder diverticulum: an alternative to open or laparoscopic bladder diverticulectomy. J Endourol Case Rep. 2015; 1:11-13. 6. Pacella M, Mantica G, Maffezzini M, et al. Large bladder diverticula: a comparison between laparoscopic excision and endoscopic fulguration. Scand J Urol. 2018; 52:134-138. 7. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004; 240:205-213. 8. Rifaioglu MM, Warman I, Rassweiler J, Gözen AS. Robotic-assisted bladder diverticulectomy. Cent European J Urol. 2016; 69:238. 9. Cacciamani G, De Luyk N, De Marco V, et al. Robotic bladder diverticulectomy: step-by-step extravesical posterior approach technique and outcomes. Scand J Urol. 2018; 52:285-290. 10. Altunrende F, Autorino R, Patel NS, et al. Robotic bladder diverticulectomy: technique and surgical outcomes. Int J Urol. 2011; 18:265-271. 11. Tufek I, Mourmouris P, Argun OB, et al. Robot-Assisted Bladder Diverticulectomy with Concurrent Management of Bladder Outlet Obstruction. Urol Int. 2016; 96:432-7. 12. Porpiglia F, Tarabuzzi R, Cossu M, et al. Is laparoscopic bladder diverticulectomy after transurethral resection of the prostate safe and effective? Comparison with open surgery. J Endourol 2004; 18:73-76. 13. Agarwal DK, Krambeck AE. Holmium laser enucleation of the prostate is an effective treatment in patients with concomitant bladder diverticula and outlet obstruction. World J Urol. 2018; 36:87-90. 14. Celebi S, Kuzdan Ö, Özaydın S, et al. The effect of bladder diverticula on bladder function: An experimental study in rabbits. J Pediatr Surg. 2016; 51:1538-42. 15. Iscaife A, Dos Anjos G, Barbosa C Neto, et al. The role of bladder diverticula in the prevalence of acute urinary retention in patients with BPH who are candidates to surgery. Int Braz J Urol. 2018; 44:765-770. 16. Yamaguchi K, Kotake T, Nishikawa Y, et al. Transurethral treatment of bladder diverticulum. Urol Int. 1992; 48:210-212.

Correspondence Guglielmo Mantica, MD guglielmo.mantica@gmail.com Department of Urology, San Raffaele Turro Hospital, San Raffaele University Via Stamira d’Ancona 20, 20127 Milano (Italy) Mauro Pacella mauropacella@virgilio.it Nicolò Testino nicolo.testino@live.it Matteo Valcalda matteo.valcalda@gmail.com Rafaela Malinaric rafaela.malinaric@gmail.com Carlo Terrone carlo.terrone@med.uniupo.it Department of Urology, Policlinico San Martino Hospital, University of Genova, Genova (Italy)

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DOI: 10.4081/aiua.2019.3.177

ORIGINAL PAPER

Chronic prostatic infection: Microbiological findings in two Mediterranean populations Konstantinos Stamatiou 1, Vittorio Magri 2, Gianpaolo Perletti 3, 4, Vaia Papadouli 5, Nectaria Recleiti 5, Vassiliki Mamali 5, Olympia Zarkotou 5 1 Urology

Department, Tzaneion Hospital, Piraeus, Greece; Secondary Care Clinic, ASST-Nord, Milan, Italy; 3 Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, Università degli Studi dell'Insubria, Varese, Italy; 4 Faculty of Medicine and Medical Sciences, Ghent University, Ghent, Belgium; 5 Microbiology Department, Tzaneion Hospital, Piraeus, Greece. 2 Urology

Summary

Introduction/Aim: Despite accumulated knowledge, several microbiological aspects of chronic bacterial prostatitis (CBP) remain uncertain. The aim of our study was to determine microbiological characteristics on our CBP population. Materials: The material of this retrospective study consisted in bacterial isolates from urine and/or prostatic secretions or sperm cultures (total ejaculate) obtained from individuals with prostatitis symptoms and from patients with febrile relapses of CBP visiting our department, from 03/2009 to 03/2015. Retrospective data from an Italian single-center database (years 2009-2015) were also collected for a tentative comparison of pathogen prevalence between chronic bacterial prostatitis cases assessed in Greece and Italy. Results: A total of 389 bacterial isolates obtained from eligible Greek patients constituted the material of the study. While E coli was the most frequent individual pathogen, Gram-positive species were overly more frequent than Gram-negative. Besides the high frequency of E. coli and E. faecalis isolates the most remarkable similarity between Greek and Italian databases was the wide array of different Gram-positive and Gram-negative species isolated from CBP patients. Conclusions: In Greece, the incidence of CBP is possibly higher than that reported in international surveys. Similarities between Greek and Italian databases suggest geographical trends in CBP epidemiology.

KEY WORDS: Chronic prostatitis; Prostate; Infection; StameyMeyers. Submitted 19 June 2019; Accepted 21 July 2019

INTRODUCTION/AIM

Chronic bacterial prostatitis (CBP) is an inflammatory condition of the prostate, characterized by pain in the genital or the pelvic area, which can lead to urinary disorders and may cause sexual dysfunction. Despite the extensive knowledge accumulated over time, several microbiological aspects remain uncertain. The aim of our study was to describe the microbiological characteristics of patients referring to a single Hellenic tertiary care center with symptoms of prostatitis combined with symptoms in the genitourinary tract.

METHODS Material The material of this retrospective study consisted in bacterial isolates from urine and/or prostatic secretions or sperm cultures (total ejaculate) obtained from individuals with reported pelvic discomfort and genital pain, with or without lower urinary tract symptoms and sexual dysfunction, and from patients with febrile relapses of CBP, visiting our department from 03/2009 to 03/2015. Retrospective data from an Italian single-center database (years 2009-2015) were also collected for a tentative comparison of pathogen prevalence’s between CBP cases assessed in Greece and Italy. Patients assessment Demographic, microbiological and clinical history of each assessed patient were reviewed. Patients suffering from conditions that influence bacterial virulence or host response (eg. immunodeficiency, abnormalities of the urogenital system) and patients who received antibiotics or immunosuppressive treatment within 4 weeks of the visit were excluded from the study. Included patients were clinically evaluated and underwent the Meares-Stamey “4-glass” test. Few cases underwent the “two-glass” test, assessing the sole VB2 and VB3 specimens. Depending on medical history and specific symptoms, urethral smear cultures and total ejaculate cultures were additionally obtained from several patients. Patients presenting with febrile prostatitis were investigated by a midstream urine culture (MUC) only. Appropriate antimicrobials were administered to confirmed cases of CBP accordingly to antibiogram for a period of 4 weeks. Follow-up included interview, physical examination and the Meares-Stamey test. Microbiological evaluation The Meares-Stamey test was considered positive when: 1) bacteria grew in the culture of expressed prostatic secretion (EPS) and VB3 urine sample and did not in VB1 and VB2 sample; 2) bacterial colonies in VB3 were higher in num-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 3

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ber compared to VB1 and VB2 samples. Given that no standard cut-off level of the number of bacteria in both urine and prostate secretion samples is defined by consensus for the diagnosis of chronic bacterial prostatitis, we defined no lower acceptable level for either one. Cultures, identification and semi-quantitative assay for Mycoplasma hominis and Ureaplasma urealyticum were performed using the Mycoplasma IST 2 kit (bioMerieux). Chlamydia trachomatis was detected by direct immune-fluorescence (monoclonal antibodies against lipopolysaccharide membrane, Kallestad). Urine samples were cultured undiluted in blood and MacConkey agar plates (Kallestad Lab., TX, USA) and subjected to centrifugation for microscopic examination of the sediment. Evaluation of culture results was performed by two specialist microbiologists. Identification of traditional pathogens was performed by conventional methods and the Vitek-2 Compact (bioMerieux, France) system and susceptibility testing was performed by disc diffusion and/or the Vitek-2 system. Interpretation of susceptibility results was based on Clinical and Laboratory Standards Institute (CLSI) guidelines. The local Ethical Committee approved the research protocol for the present retrospective study.

RESULTS

A total of 548 bacterial isolates were obtained from eligible Greek patients assessed in 1324 visits and recorded during a period of 6 years (2009-2015). In 114 cases the colonies counted in VB2 cultures were as many as those assessed in VB3. In 44 cases the EPS/VB3 cultures were negative despite the presence of bacteria in the specimens. These cases were excluded from the study. Finally, 389 bacterial isolates were recognized as CBP cases and constituted the material of our study. Demographic and microbiological data are presented in Table 1. Microbiological findings A vast variety of pathogens, including rare bacteria, was found in both mono and polymicrobial cultures from both EPS and VB3 samples. The most common were E. coli, coagulase negative staphylococci (CoNS) (mainly S. hominis and S. haemolyticus) and Enterococcus faecalis. The most common combination in polymicrobial isolates composed of two different species was that of E. coli and Table 1. Patient demographic and microbiological data. Clinical sample Number of patients Median age Microbiological sample Cultures of prostatic secretions Urine samples collected after prostate massage Mid-stream urine only cultures (febrile cases) Sperm cultures (total ejaculate) monomicrobial infection polymicrobial infection

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Number 389 34.7 92 343 46 43 297 92

CoNS (21 cases) while in polymicrobial isolates composed of three different species was that of Escherichia coli, Enterococcus faecalis and Proteus mirabilis (4 cases). 29 out of 43 sperm cultures were performed complementary to EPS/VB3. Thirteen of them were identical to EPS/VB3 cultures. The remaining 16 cultures allowed diagnosing bacterial infection while the EPS/VB3 cultures were negative. The most frequently assessed isolates were Enterococcus spp. (19 monomicrobial and 3 polymicrobial). Urethral discharge cultures and cultures from urethral swab samples have diagnosed 48 cases of coexisting urethral infection mainly caused by CoNS and Chlamydia trachomatis (Table 2). Table 2. Pathogens found in monomicrobial and polymicrobial isolates. Pathogen Escherichia Coli Coagulase negative staphylococcus Enterococcus faecalis Streptococcus spp. Proteus spp. Staphylococcus aureus Klebsiella spp. Gemella Morbilorum Raoultella planticola Haemophilus parainfluenzae Enterobacter aerogenes Citrobacter freundii Mycoplasma hominis Acinetobacter baumannii Staphylococcus lugdunensis Haemophilus influenzae Pseudomonas aeruginosa Brevundimonas diminuta/vesicularis Candida non albicans Candida albicans Chlamydia trachomatis N. gonorrhoeae TOTAL

EPS/VB3 142 108 102 31 28 21 9 4 3 3 2 2 1 1 1 1 1 1 2 2

465

Sperm 5 16

Urethral 1 15 4

1 1 5 1 1

13 4 40

Follow-up visits and outcome As far as the outcomes of follow-up visits are concerned, 263 patients reported elimination of symptoms/clinical improvement, though only 149 were completely cured. Bacterial persistence occurred in 111 cases. In 17 patients pus was found in EPS and/or VB3 in the absence of symptoms. In 6 cases EPS/VB3 cultures were negative despite the presence of bacteria in the same samples. Six patients were diagnosed with another disease during follow-up. In most non-treated cases, the pathogens found in the follow-up cultures were different from those isolated in the initial visit (usually Enterococcus faecalis, CoNS and E. coli). Relapses occurred in 53 patients and almost half of them were caused by microorganisms other than those causing the initial infection. The average time interval between episodes of chronic prostatitis is 13.9 months (minimum 2 and maximum 56 months). The pathogens most commonly associated with clinical relapses were Enterococcus faecalis, CoNS and E. coli.

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DISCUSSION

rently considered the diagnostic standard for CBP, while PCR techniques are cumbersome and have little use in the daily clinical setting. For this reason Magri et al. introduced the 'five-glass' test (four-glass plus post-VB3 semen culture), which showed 3.6- or 6.5-fold increases in relative sensitivity and lesser reductions (-13.2% or 14.7%) in relative specificity for traditional and unusual pathogens (Mycoplasmata and others) compared with the four-glass or two-glass test, respectively (9). The significance and diagnostic value of complementary semen culture is supported by two other studies (10. 11), though further studies are needed to determine whether a 'five-glass' test may represent a better diagnostic tool. Similarities between Greek and Italian databases may indicate geographical trends in CBP epidemiology. In fact, similar policies in antibiotic usage and common factors that influence male sexuality and sexual behaviour may contribute to such trends. To our knowledge, a high CBP incidence (26.9%) has been also demonstrated in a previous Greek study (12) while higher incidences were found in central and southern regions of Italy (13).

Epidemiological and diagnostical issues According to the general perception a progression of prostatic inflammation and its consequences from acute to chronic occur resulting on CBP pathogenesis (1). Actually, after an episode of acute bacterial prostatitis approximately 5-10% of patients progress to chronic infection (2, 3). In accordance to the above, in our study 10.52% of the patients presented with episodic or persistent relapsing urinary tract infections and all reported a previous diagnosis of prostatitis. CBP is considered a relatively infrequent disease, since it comprises only 10% of all prostatitis cases (4). Nevertheless, from the currently available epidemiologic studies, it appears that CBP is more common since many patients may have bacterial infection despite negative urine cultures: while less than 10% of men worldwide have a proven bacterial infection of the prostate, up to 25% receive a diagnosis of prostatitis in their lifetime (5). Negative culture results occur for various reasons including, the presence of fastidious organisms, initiation of Microbiological and pathophysiological issues antibiotics prior to obtaining an EPS sample, high bacterBesides the high frequency of E. coli and E. faecalis isoial count cut-offs established by laboratories (e.g., 50 000 lates the most remarkable similarity between Greek and CFU), or insufficient sample volumes. Since we defined Italian databases was the wide array of different species no lower acceptable level for bacterial colonies in both like Coag. Neg. Staphylococcus, Streptococcus spp., S. aureus, urine and prostate secretion samples for the diagnosis of Haemophylus spp., Citrobacter Spp., Mycoplasma hominis, chronic bacterial prostatitis, the bacteriologically proven Haemophylus spp., P. aeruginosa and Candida spp. isolated incidence of CBP in this study was 29.45%. Moreover, the from both Greek and Italian CBP patients (Tables 2-4). fact that we recognised certain Gram-positive bacteria as In our study Enterococcus faecalis was by far the most frepathogenic may have also contributed to this difference. In quent bacterial isolate from sperm cultures. In the Italian fact, the literature strongly suggests that urologic diseases cohort, this species was the third most common isolate involving Gram-positive bacteria may be easily overlooked in sperm cultures after E. coli and U. urealyticum (Tables due to limited culture-based assays typically utilized for urine in hospital microTable 3. biology laboratories (6). Monomicrobial isolates in an Italian cohort of 151 consecutively assessed Insufficient sample volumes explain the Italian patients (years 2009-2015). low number of assessable EPSs in this study. This fact may indicate the need Pathogen Isolated Isolated Isolated TOTAL of better preparing (e.g. abstain from from EPS/VB3 from total from both sexual intercourse for 3 to 5 days) only ejaculate only specimens before the Meares-Stamey test. Escherichia coli 26 13 6 45 On the other hand, the presence of fasProteus mirabilis 2 1 / 3 tidious organisms, anaerobic pathogens Klebsiella spp. 1 2 / 3 or bacteria not detectable with the usual Morganella morganii 1 5 / 6 tests may explain the 44 cases whose Pseudomonas aeruginosa / / 2 2 EPS/VB3 cultures were negative despite Haemophilus parainfluenzae / 2 / 2 the presence of bacteria. As a matter of Citrobacter koseri / 1 / 1 fact, traditional culture procedures Neisseria subflava / 1 / 1 show lower specificity and sensitivity in Enterococcus faecalis 11 6 3 20 detection of bacteria in prostatic speciStaphylococcus aureus 3 / / 3 mens than polymerase chain reaction Staphylococcus coagulase-negative 1 5 1 7 (PCR)-based techniques. Choi et al. Streptococcus beta-haemolyticus gr. B / / 1 1 found an 11.4% incidence of bacterial Streptococcus agalactiae 1 / / 1 infection in routine EPS or VB3 culSteptococcus anginosus / 1 / 1 tures, while PCR detected bacterial Kocuria kristinae / / 1 1 infection in 40.9% of cases (7). Chlamydia trachomatis 3 / / 3 Similarly, Krieger and Riley found a subUreaplasma Urealyticum 4 21 2 27 stantial proportion of positive broadMycoplasma hominis / 2 / 2 spectrum PCR assays (8). Regardless of TOTAL 53 60 16 129 its drawbacks, the four-glass test is curArchivio Italiano di Urologia e Andrologia 2019; 91, 3

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K. Stamatiou, V. Magri, G. Perletti, V. Papadouli, N. Recleiti, V. Mamali, O. Zarkotou

3, 4). Several other studies provided clear evidence of a Gram-positive predomination in bacteriospermia (14, 15), while other found a very high proportion of Gram-negative microorganisms with Escherichia coli being the commonest isolate in positive cultures (22.2 to 75%) (16-18). Urethral discharge cultures and cultures from urethral swab samples revealed coexisting CoNS and/or Chlamydia trachomatis-induced urethral infection. Interestingly, in the Italian cohort, whereas Mycoplasmata were found mainly in ejaculate cultures, C. trachomatis was isolated mainly from EPS/VB3 samples (Table 4). Since the urinary tract acts as a nest of infection for the seminal tract, these microorganisms are capable of causing classical infections of the urogenital tract such as epididymitis and prostatitis as well as subclinical reproductive tract infections.

Table 4. Polymicrobial isolates in an Italian cohort of 151 consecutively assessed Italian patients (years 2009-2015). Pathogen

Isolated Isolated Isolated TOTAL from EPS/VB3 from total from both only ejaculate only specimens E.coli + Enterococcus faecalis 1 1 2 4 E.coli + Klebsiella spp. / 1 / 1 E.coli + Streptococcus beta-haemolyticus gr. B 1 / / 1 E.coli + Ureaplasma urealyticum / / 1 1 E.coli + Mycoplasma hominis / / 2 2 E.coli + Peptostreptococcus spp. / / 1 1 E.coli + Candida albicans / / 2 2 E. faecalis + Klebsiella spp. / 2 / 2 E. faecalis + Citrobacter spp. / / 1 1 E. faecalis + Ureaplasma urealyticum / / 1 1 E. faecalis + Staphylococcus coagulase negative 1 / / 1 P. aeruginosa + Proteus mirabilis 1 / / 1 P. aeruginosa + Staphylococcus coagulase negative / 1 / 1 M. morganii + Haemophilus parainfluenzae / 1 / 1 Streptococcus mitis + Staphylococcus coagulase negative / / 1 1 Chlamydia trachomatis + Ureaplasma urealyticum / / 1 1 E. coli + E. faecalis + Staphylococcus coagulase negative / / 1 1 TOTAL 4 6 12 22

Outcome related issues Differences in isolated microorganisms in VB3/EPS cultures between follow-up and initial visits of untreated/relapsed cases reinforce the new appreciation of chronic prostatitis as a biofilm disease. Pathogen eradication rates, as high as 80%, have been reported in the pastin CBP patients treated with various fluoroquinolones (19). Our bacterial eradication rate (68.15%) is similar with that reported in a previous Greek study (64.7%) (12) and this fact may be attributed to the quinolones overuse in Greece.

CONCLUSIONS

In Greece, the incidence of CBP is possibly higher than that reported in international surveys. Similarities between Greek and Italian databases suggest geographical trends in CBP epidemiology. The fact that Gram-positive species were the most frequent isolates in both Greek and Italian databases support the role of Gram-positive bacteria in CBPs pathogenicity. Regardless of its drawbacks, the Meares-Stamey is the main tool for the diagnosis of CBP. The significance and diagnostic value of complementary semen culture is supported by our findings, though further studies are needed to determine whether a 'five-glass' test may represent a better diagnostic tool.

REFERENCES

1. Nickel JC, Olson ME, Barabas A, et al. Pathogenesis of chronic bacterial prostatitis in an animal model. Br J Urol. 1990; 66:47-54. 2. Nickel CJ. Inflammatory and pain conditions of the male genitourinary tract: prostatitis and related pain conditions, orchitis, and epididymitis. Campbell-Walsh Urology. 11th ed. Elsevier; 2016.

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3. Yoon BI, Kim S, Han DS, et al. Acute bacterial prostatitis: how to prevent and manage chronic infection? J Infect Chemother. 2012; 18:444-450. 4. Krieger JN, Egan KJ. Comprehensive evaluation and treatment of 75 men referred to chronic prostatitis clinic. Urology. 1991; 38:11-19. 5. Lipsky BA, Byren I, Hoey CT. Treatment of bacterial prostatitis. Clin Infect Dis. 2010; 50:164152. 6. Kline KA, Lewis AL. Gram-positive uropathogens, polymicrobial urinary tract infection, and the emerging microbiota of the urinary tract. Microbiol Spectr. 2016; 4(2). 7. Choi YS, Kim KS, Choi SW, et al. Microbiological etiology of bacterial prostatitis in general hospital and primary care clinic in Korea. Prostate Int. 2013; 1:133-8. 8. Krieger JN, Riley DE. Prostatitis: what is the role of infection. Int J Antimicrob Agents. 2002; 19:475-9. 9. Magri V, Wagenlehner FM, Montanari E, et al. Semen analysis in chronic bacterial prostatitis: diagnostic and therapeutic implications. Asian J Androl. 2009; 11:461-77. Table 5. Clinical and microbiological outcome. Cured Bacterial persistence - Symptom persistence Bacterial eradication - Symptom persistence Clinical improvement -Unknown microbiological outcome Elimination of symptoms - Bacterial persistence Developed asymptomatic chronic nonbacterial prostatitis Non-recognizable bacteria in EPS/VB3 cultured samples Diagnosed with another disease during follow-up Developed cystitis (VB3 cultures were identical to VB2) TOTAL

146 63 54 53 44 17 6 6 4 389

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Chronic prostatic infection: Microbiological findings in two Mediterranean populations

10. Zegarra Montes LZ, Sanchez Mejia AA, Loza Munarriz CA, Gutierrez EC. Semen and urine culture in the diagnosis of chronic bacterial prostatitis. Int Braz J Urol. 2008; 34:30-7. 11. Cai T, Pisano F, Nesi G, et al. Chlamydia trachomatis versus common uropathogens as a cause of chronic bacterial prostatitis: Is there any difference? Results of a prospective parallel-cohort study. Investig Clin Urol. 2017; 58:460-467.

15. Sheikh AF, Mehdinejad M. Identification and determination of coagulase-negative Staphylococci spp and antimicrobial pattern of isolates from clinical specimens. Afr. J. microbiol. 2012; 6: 16691674 16. Panackal A, Panackal A. Semen Culture a Diagnostic Tool in the Diagnosis of Bacterial Prostatitis. Transl Biomed. 2017; 8:114.

12. Panagopoulos P, Antoniadou A, Kanellakopoulou K, et al. Fluoroquinolone treatment of chronic bacterial prostatitis: a prospective cohort study. J Chemother. 2009; 21:317-21.

17. Budía A, Luis Palmero J, Broseta E, et al. Value of semen culture in the diagnosis of chronic bacterial prostatitis: a simplified method. Scand J Urol Nephrol. 2006; 40:326-31.

13. Rizzo M, Marchetti F, Travaglini F, et al. Prevalence, diagnosis and treatment of prostatitis in Italy: a prospective urology outpatient practice study. BJU International. 2003; 92:955-959.

18. Ostrowski A, Banas M, Brzóska Ret al. Semen culture in bacterial prostatitis – retrospective analysis of microbiological profile, antibiograms and clinical utility Eur Urol Suppl 2017; 1:e2949

14. Ibadin, OK, Ibeh IN. Bacteriospermia and sperm quality in infertile male patient at University of Benin Teaching Hospital, Benin City, Nigeria. Mal J Microbiol. 2008; 4:65-67.

19. Weidner W, Ludwig M, Brähler E, Schiefer HG. Outcome of antibiotic therapy with ciprofloxacin in chronic bacterial prostatitis. Drugs. 1999; 58 (Suppl 2):103-6.

Correspondence Konstantinos Stamatiou, MD stamatiouk@gmail.com Urology Dpt, Tzaneion Hospital, Piraeus (Greece) Vittorio Magri, MD Urology Secondary Care Clinic, ASST-Nord, Milan, Italy Gianpaolo Perletti, PhD Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences Università degli Studi dell'Insubria, Varese (Italy) Vaia Papadouli, MD Nectaria Recleiti, MD Vassiliki Mamali, MD Olympia Zarkotou, MD Microbiology Dpt, Tzaneion Hospital, Piraeus (Greece)

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DOI: 10.4081/aiua.2019.3.182

ORIGINAL PAPER

How much do people know about male sexual problems? A survey in a selected population sample Edoardo S. Pescatori 1, Anna Baldini 2, Fabio Parazzini 3, 4, Nicola Ghidini 5, Giovanni L. Briganti 2 1 Andrology

Service, Hesperia Hospital, Modena, Italy; Bologna, Italy; 3 Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Italy; 4 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy; 5 Urology Department, Hesperia Hospital, Modena, Italy. 2 Cittadinanzattiva,

Summary

Objectives: Our purpose has been to investigate by an ad hoc questionnaire the knowledge of several aspects of male sexual dysfunction in a significant sample of men and women (largely not physicians) attending an International Health Care Exhibition, held in Italy. Materials and methods: The survey took place during Exposanità, 2018 edition, aimed at medical and non-medical professionals. We devised as investigation tool an ad hoc anonymous questionnaire in two versions, one for each sex. Object of this report are questions addressing subject’s knowledge of prevalence of erectile dysfunction (ED), ED causes, ED as early sign of coronary heart disease/myocardial infarction, available ED treatments and attitudes towards penile prosthesis, and reimbursement of ED treatments. Results: As many as 1094 Convention attendees (495 men, 599 women) participated to the survey (about 4% of total attendees). Mean sample age was 40.5 years in men and 39.9 years in women. Forty-three percent of the sample worked in healthrelated professions, 5.9% being physicians. Respondents globally over-estimated the prevalence of ED. Both responding men and women rated psychologic and lifestyle factors as the most frequent ED causes. The majority of responders did not regard ED as a possible predictor of cardiovascular events. Oral pills resulted the most known ED treatment by both men (77.2%) and women (79.1%). Psychotherapy ranked as the second most known treatment approach. Other effective ED treatments (intracavernosal injections, vacuum erection device, penile prostheses) were known by a minority of men (22.2-27.9%) and women (19.2-20.2%). Roughly half of the sample (50.7% of men and 48.4% of women) were willing to choose (men) or to support (women) the penile prosthesis option in cases of severe ED; majority of both sexes (71.3% of men and 76.3% of women) expressed no resistances to the perspective of penile prosthesis use. Vast majority of men (80.3%) and women (80.4%) considered that coverage for ED treatments should be provided by the National Health System. Conclusions: The outcomes of our survey show both an elevated prevalence of misconceptions on the role of organic factors in the etiology of ED, and ignorance of the implications of ED on cardiovascular health. Knowledge of available second level ED treatments resulted scanty. Nonetheless, when confronted with the most aggressive treatment, penile prosthesis, majority of both genders responders would undergo/support this surgery, should it be the only way to solve the erectile problem. In this perspective, population appears ready and overall keen to a treatment option that too often is not addressed by majori-

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ty of the medical community when counseling men with severe ED not responsive to conservative approaches.

KEY WORDS: Erectile dysfunction; Awareness; Penile prosthesis; Risk factors; Impotence. Submitted 18 May 2019; Accepted 21 May 2019

INTRODUCTION

Male sexual dysfunctions have been significantly acknowledged by the medical community in recent years only: elucidation of male sexual pathophysiology and availability of effective treatments date no more than 3 decades (1, 2). Even more recent is the acquisition that erectile dysfunction (ED) can allow early diagnosis, or be a predictor/sentinel event for future cardiovascular events [i.e. ischemic heart disease (IHD), myocardial infarction (MI)] and dysmetabolic conditions (i.e. diabetes) (3, 4). These concepts are well acknowledged by specialists (Andrologists, dedicated Urologists/Endocrinologists), but seldom by the rest of the medical community. The general population appreciates even less all the above, and too often men with sexual problems bypass medical consultations for improper embarrassment, turning to Internet for both online information and self-medication. Some detrimental consequences of such scenario include: overlooking underlying specific risk factors and/or medical conditions that are consequently not identified and not addressed, and lack of exposure to some second and third line effective treatments (i.e. intracavernosal vasoactive drugs and penile prostheses). The purpose of this survey has been to investigate by an “ad hoc” questionnaire the knowledge of several aspects of male sexual dysfunctions in a significant sample of men and women (largely non physicians) attending an International Health Care Exhibition, held in Italy. Members of two regional associations for people rights tightly cooperated for the realization of this project: Cittadinanzattiva - Bologna section (www.cittadinanzattivaer.it) (AB, ESP, GLB) and ASSERTIVO (Associazione per la SaluteSEssuale e RiprodutTIVa dell’uOmo) (ESP, NG). Funding has been provided by a unrestricted grant by Boston Scientific.

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How much people know about male sexual problems?

MATERIALS

AND METHODS

Setting The International Health Care Exhibition where the survey took place was Exposanità (www.exposanita.it), held in Bologna (Italy) from 18 to 21 April, 2018. Exposanità is the second largest European International Health Care Exhibition in terms of number of exhibitors and product range; it is held in Bologna every two years since 1982. It is dedicated to health care and assistance, and it is aimed at all medical and non-medical professionals who operate in various ways in the public and private sectors. The total number of visitors attending the 2018 edition has been 30199. Survey tool: the questionnaire An ad hoc anonymous questionnaire has been created (ESP, FP) for the purpose of this survey; the questionnaire had two versions, one for each sex. It consisted of a preliminary section with three questions on age, occupation, relational status, and a question for men only if they ever suffered of uro-andrologic conditions. This tool was preliminarly evaluated by experts for its content, and a limited number of questionnaries was administered to non-experts to ascertain questions comprehension. A formal validation was not deemed appropiate as this questionnaire simply investigates the level of knowledge of specific areas. The ensuing 11 core questions addressed the following areas: – subject’s knowledge on frequency, causes, consequences and treatment modalities/reimbursement for ED; attitudes toward penile prosthesis surgery in case of severe ED. These areas will constitute the focus of this report; the respective questions (male version) are reported in Appendix (see Supplementary Materials). – knowledge of frequency of premature ejaculation, risks linked to penile trauma during intercourse, attitudes towards sexual/reproductive screening for female versus male children. Such areas will be addressed in future reports. Questionnaire administration Cittadinanzattiva volunteers handed out the questionnaire to men and women attending Exposanità during the first three days of the event; the questionnaire was self-administered. Participants were asked to fold the completed questionnaires and place them in dedicated boxes, located in several spots in the convention area. Data analysis Mean (standard deviation, SD), median (range) or frequency (percent, %) were computed as appropriate. When appropriate confidence limits at 95% of the proportions were computed. Differences in proportions were tested using the chi-square test.

RESULTS

Out of 30199 Exposanità attendees 1094 (495 men and 599 women) filled the questionnaire.

Table 1. Characteristics of study participants according to gender. Women No. (%)* Age (years) Mean (SD) 39.9 (13.4) < 30 184 (30.7) 30-<45 185 (30.9) 45-<65 207 (34.6) 65 or more 23 (3.8) Occupation Medical doctor 25 (4.2) Nurse 98 (16.4) Other health professions 135 (22.5) Other non health professions° 333 (55,6) Missing 8 (1.3) Married/common-low wife/husband Yes 372 (62.1) No 215 (35.9) Missing 12 (2.0) History of uro andrologic diseases Yes --No Missing

------

Men No. (%)

Chi square value

40.5 (15.4) 154 (3.1) 156 (31.5) 143 (28.9) 42 (8.5) 40 (8.1) 47 (9.5) 110 (22.2) 294 (59,4) 1.37 (p = ns)°° 4 (0.8) 257 (51.9) 224 (45.3) 0.80; p < 0.01 14 (2.8) 120 (24.2) 367 (74.1) 7 (1.4)

* The sum does not add up the total due to missing values. ° Including retired subjects. °° Health vs non health professions. SD = Standard deviation.

Table 1 details the characteristics of study participants according to gender. Mean sample age was 40.5 years (15.4 SD) in men and 39.9 years (13.4 SD) in women. Forty-three percent of the sample worked in health-related professions without a significant difference between men and women; physicians represented 5.9% of the sample. A stable couple relation was present in 51.9% of men and 62.1% of women. A history of uro-andrologic diseases was reported by 24% of men. Table 2 shows the answer to questions about knowledge towards ED: 28.1% of men estimated a prevalence of ED in the general population < 10%, and 16.3% responders > 40%. The corresponding figures in women were 24.7% and 22.5% (Chi square heterogeneity p = 14.19, p < 0.05). Both responding men and women rated psychologic and lifestyle factors as the most frequent causes of ED. The subset of responders that most acknowledged organic conditions and radical pelvic surgery as frequent ED causes is represented by health care professionals. The majority of responders of both sexes and all ages did not regard ED as a possible predictor of IHD. The subset of responders that most acknowledged ED as a predictor of such condition is represented by health care professionals (data not shown in table). Oral pills are the most known ED treatment by both men (77.2%) and women (79.1%). Psychotherapy is the second most known treatment approach for both sexes: 38.4% in men, and 41.9% in women, respectively. Archivio Italiano di Urologia e Andrologia 2019; 91, 3

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Table 2. Knowledge/awareness about erectile dysfunction (ED).

How often do you think ED is common? 3 out of 100 men 10 out of 100 men 20 out of 100 men 30 out of 100 men 40 out of 100men 50 out of 100 men Which do you think are the most frequent causes of ED?** Psycological conditions

Women No. (%)*

Men No. (%)

40 (6.7) 108 (18.0) 132 (22.0) 158 (26.4) 97 (16.2) 38 (6.3)

46 (9.3) 93 (18.8) 148 (29.9) 122 (24.6) 58 (11.7) 23 (4.6)

333 (67.3)

475 (79.3)

Chi square value

Health professions

Non health professions

14.19, p < 0.05

38 (8.4) 77 (16.9) 113 (24.8) 128 (28.1) 68 (14.9) 21 (4.6)

47 (7.5) 47 (7.5) 163 (26.0) 163 (26.0) 86 (13.7) (39 (6.2)

316 (69.5)

482 (76.9)

108 (23.7)

129 (20.6)

119 (26.2)

99 (15.8)

167 (36.7)

193 (30.8)

259 (56.9)

388 (61.9)

59 (13.0)

48 (7.7)

179 (39.3)

196 (31.3)

211 (46.4)

315 (50.29

131 (28.8)

135821.5)

112 (24.6) 59 (13.0)

118 (18.8) p = 0.02 72 (11.5)

172 (37.8)

193 (30.8)

173 (38.0)

289 (46.1)

64 (14.1)

70 (11.2)

196 (43.1)

244 (38.9)

356 (78.2)

491 (78.3)

119 (26.2)

105 (16.7)

148 (32.5)

122 (19.5)

143 (31.4)

112 (17.9)

20.30, p < 0.01 Hypertension 121 (24.4) 117 (19.5) 3.84, p = 0.05 Diabetes 107 (21.6) 111 (18.5) 1.61, p = ns Vascular diseases 180 (36.4) 182 (30.4) 4.37, p = 0.04 Unhealthy lifestyles 279 (56.4) 373 (62.3) 3.93, p = 0.05 Infectious diseases 63 (12.7) 45 (7.5) 8.28, p < 0.01 Radical pelvic surgery for prostate / bladder cancer 171 (34.5) 210 (35.1) 0.03, p = ns Old age 258 (52.1) 274 (45.7) 4.41, p = 0.04 Trauma of the penis 109 (22.0) 157 (26.2) 2.58, p ns Do you think that the presence of ED can be an â&#x20AC;&#x153;alarm bellâ&#x20AC;? for subsequent development of which of the following diseases?** Obesity 110 (18.4) 123 (24.8) 6.79 p = 0.01 Kidney diseases 80 (13.4) 53 (10.7) 0.18 p = ns Myocardial infarction/coronary hearth diseases 191 (31.9) 177 (35.8) 0.18 p = ns None 270 (45.1) 196 (39.6) 0.07 p = ns What treatments for ED do you know?** Supplements 67 (11.2) 69 (13.9) 0.21 p = ns Psychotherapy 251 (41.9) 190 (38.4) 0.24 p = ns Oral drugs 474 (79.1) 382 (77.2) 0.43 p = ns Intracavernosal injections 115 (19.2) 110 (22.2) 0.22 p = ns Vacuum erection devices 134 (22.4) 137 (27.7) 0.04 p = ns Penile prosthesis 121 (20.2) 138 (27.9) 0.00 p = ns

Chi square value

7.51 p < 0.05 1.54 P0ns 17.60 p < 0.01 4.16 p < 0.05 2.70 p < ns 8.35 p < 0.05 7.60 p < 0.05 1.58 p = ns 7.50 p < 0.05 5.29 0.55 p = ns 5.81 P < 0.05 7.02 p < 0.05 2.74 p = ns 1.89 p = ns 0.00 p = ns 14.21 p < 0.05 24.05 p < 0.01 26.97 p < 0.01

* The sum does not add up the total due to missing values. ++ Multiple answers were allowed.

The other listed effective ED treatments (intracavernosal injections, VED, penile prostheses) are known by a minority of men (22.2-27.9%) and women (19.220.2%). Dietary supplements are referred as possible ED treatment by 13.9% of men and by 11.2% of women. No significant differences in terms of answers emerged among different age ranges and different occupations. Two questions addressed the perspective of treatment of severe ED by penile prostheses (Table 3). The first explored the willingness to choose (men) or to support (women) the penile prosthesis option: roughly

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half of the sample (50.7% of men and 48.4% of women) was in favor of this choice. The second question investigated possible resistances to the use of penile prostheses, leaving the possibility of a free comment on the reason/s for such resistances. Majority of both sexes expressed no resistances (71.3% of men and 76.3% of women). The main reason for resistance was concerns related to the surgical procedure. The majority of both responding men (80.3%) and women (80.4%) considered that coverage for ED treatment should be provided by the National Health System.

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Table 3. Attitude towards the use of penile prosthesis. Women Men Chi square No. (%) No. (%) value If you or your partner had an ED not responding to drugs, what would you choose/recommend? Live with the problem 249 (41.6) 222 (44.8) I would like to solve the problem with penile prosthesis 290 (48.4) 251 (50.7) 0.06; p = 0.81 Missing 60 (10.0) 22 (4.1) Would you have any concern about the use of prosthesis? None 457 (76.3) 353 (71.3) Yes 142 (23.7) 142 (28.7) 3.50; p = 0.06 Do you think that the costs related to the treatment of ED should be paid by the national health service? Yes 481 (80.3) 398(80.4) No 85 (14.2) 84 (17.0) 0.00; p = ns Missing 33 (5.5) 13 (2.6)

DISCUSSION

Male sexual dysfunctions represent a medical area that has been, and is, heavily investigated in many perspectives: dysfunctions prevalence, specific risk factors, impact of distinct dysfunctions on quality of life, treatment modalities and related patient/partner satisfaction and compliance, etc. A recurrent issue among caregivers is the limited access of sufferers to appropriate treatment options, and how to overcome it. Surprisingly, minimal attention has been given by the scientific community on what lay people know of male sexual dysfunctions: specific scientific reports are scanty, at best (5, 6). This is a potential significant bias when planning effective strategies to promote male sexual health and better access to effective treatments, as we feel it should be known upfront what people know and what do not know, what people expect, fear, wish, in order to devise targeted interventions. The purpose of our study has been to explore the knowledge of some key aspects of male sexual dysfunctions in a selected population sample expected to have a knowledge of andrologic problems not inferior to the average general population, being professionals working in the health care area, a very minor part only represented by physicians (less than 6%). In order to do so we devised a questionnaire structured in an epidemiologic perspective. A questionnaire investigating the simple knowledge does not require a formal validation, but an expert evaluation and the administration of a few questionnaires to assess the comprehensibility of the questions. This phase was conducted prior to the investigation by the working group. On the other hand, to interview for example the same group of subjects after a period of time with the same questionnaire is biased by the fact that it is possible that many respondents tend to gather information on the topic of the survey after the first administration of the questionnaire. Following, we analyze the outcomes of our survey. Respondents globally over-estimated the prevalence of ED, in fact about 70% of responders declared that the frequency of ED is 20% or more. Published studies refer to an overall ED prevalence in Italy of 10% (7, 8). One possible reason for this finding is that sexuality issues

draw the attention of lay public, to the extent that they can be perceived more prevalent than their reality. When requested their opinion on the most frequent ED causes, responders incorrectly selected psychological issues, while as many as 80% of them did not regard diabetes and hypertension as leading ED causes. It is of no surprise that the correct answers of organic conditions and radical pelvic surgery have been more frequently selected by health care professionals. Similarly, the majority of responders of both sexes and all ages did not regard ED as a possible predictor of IHD; other Authors reported similar findings (9, 10). The subset of responders that most acknowledged ED as a predictor of such condition was again represented by health care professionals. Oral pills are the most known ED treatment by both men (77.2%) and women (79.1%). Psychotherapy is the second most known treatment approach for both sexes: 38.4% of men, and 41.9% of women, respectively. The other listed effective ED treatments (intracavernosal injections, VED, penile prostheses) are known by a minority of men (22.2-27.9%) and women (19.2-20.2%) only. Interestingly, the penile prosthesis option as treatment for severe ED is conceptually accepted by half of the sample of both men and women, we can assume largely not directly/indirectly involved in this condition. Furthermore, a sharp majority of the sample would not foresee any problem/resistance in having intercourse by means of the penile prosthesis; of the minority that would have concerns with the prosthesis option the main emerging reason is some sort of fear related to the surgical procedure. Such outcomes clash with the attitude of the medical community not dedicated to penile surgery that too often negatively depicts the prosthesis option, despite its key role in treating severe ED cases as those resulting from radical prostatectomy, diabetes, Peyronieâ&#x20AC;&#x2122;s disease (11). Vast majority of our sample, both men and women, considered that coverage for ED treatment should be provided by the National Health System. This suggests that ED is considered as a significant condition that deserves treatment, and that therapies for ED are not perceived as lifestyle issues. Study limitations and strengths We upfront elected to investigate a selected sample of professionals, and accordingly we do not aim to extend our findings to the general Italian population. A potential limitation of the study is that the interviewed subjects were randomly identified among exhibition participants, but it is possible that subjects who were present all the period of ExposanitĂ were more likely interviewed. In any case the distribution of participants was largely similar with the participants to the convention. Finally, the participation rate was very high and the missing value very few. The strengths of the study included the fact that it provides information from a large series of men and women, accounting for about 4% of all ExposanitĂ attendees. Despite the study design limitations, the results of this large survey give a general picture of the opinion about ED in the Italian population. Archivio Italiano di Urologia e Andrologia 2019; 91, 3

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CONCLUSIONS

Our investigation provides for the first time in Italy a view on what a large sample of men and women think of male sexual dysfunctions and related treatments. The population we investigated was represented by professionals involved in the health care area; it can be easily assumed that their knowledge of the questioned topics is at least not inferior of that of the general population. The outcomes of our survey show that also in this more-thanaverage knowledgeable sample there are misconceptions both on the prevalence of organic factors in the etiology of erectile dysfunction and on the implications of ED on IHD. Such findings underscore the need of educational programs aimed to promote population awareness on the real ED risk factors, and their tight correlation with cardiovascular conditions: it is expected that ultimately informed men can adopt healthy lifestyles that could promote both sexual and cardiovascular health. When enquiring the knowledge of available treatments for ED it emerged a scanty awareness of second level treatments. Nonetheless, when confronted also with the most aggressive treatment, i.e. penile prosthesis, majority of both genders responders would elect to undergo/support this surgery, should it be the only way to solve the erectile problem. In this perspective population appears ready and overall keen to a treatment option that too often is not addressed by the majority of the medical community when counseling men with severe erectile dysfunctions not responsive to conservative treatments.

AUTHORS’

CONTRIBUTIONS

Edoardo S. Pescatori: study ideation and study design, manuscript writing; Anna Baldini: study design, study conduction, manuscript reviewing; Fabio Parazzini: study design, statistical analysis, manuscript reviewing Nicola Ghidini: study conduction; Giovanni L. Briganti: study conduction

ACKNOWLEDGEMENTS

Authors would like to thank Stefano Piazza (President), and Mauro Angiolini (Secretary) of the Association ASSERTIVO

(ASsociazione per la Salute SEssuale e RiprodutTIVa dell’uOmo), for condivision of the study, support and strategic advices. REFERENCES

1. Kim N, Vardi Y, Padma-Nathan H, et al. Oxygen tension regulates the nitric oxide pathway. Physiological role in penile erection. J Clin Invest 1993; 91:437-42. 2. Virag R. About pharmacologically induced prolonged erection. Lancet. 1985; 1:519-20. 3. Jackson G. Prevention of cardiovascular disease by the early identification of erectile dysfunction. Int J Impot Res. 2008; 20 Suppl 2:S9-14. 4. Carrillo-Larco RM, Luza-Dueñas AC, Urdániga-Hung M, et al. Diagnosis of erectile dysfunction can be used to improve screening for Type 2 diabetes mellitus. Diabet Med. 2018; 35:1538-1543. 5. Laumann EO, Nicolosi A, Glasser DB, et al. Sexual problems among women and men aged 40-80 y: prevalence and correlates identified in the Global Study of Sexual Attitudes and Behaviors. Int J Impot Res. 2005; 17:39-57. 6. Low WY, Wong YL, Zulkifli SN, Tan HM. Malaysian cultural differences in knowledge, attitudes and practices related to erectile dysfunction: focus group discussions. Int J Impot Res. 2002; 14:440-5. 7. Parazzini F, Menchini Fabris F, Bortolotti A, et al. Frequency and determinants of erectile dysfunction in Italy. Eur Urol. 2000; 37:43-9. 8. Bortolotti A, Parazzini F, Colli E, Landoni M. The epidemiology of erectile dysfunction and its risk factors. Int J Androl. 1997; 20: 323-34. 9. Shabsigh R, Kaufman J, Magee M, et al. Lack of awareness of erectile dysfunction in many men with risk factors for erectile dysfunction. BMC Urol. 2010 5; 10:18. 10. Kałka D, Domagała Z, Rakowska A, et al. Modifiable risk factors for erectile dysfunction: an assessment of the awareness of such factors in patients suffering from ischaemic heart disease. Int J Impot Res. 2016;28:14-9. 11. Pescatori E, Alei G, Antonini G, et al. INSIST-ED: Italian Society of Andrology registry on penile prosthesis surgery. First data analysis. Arch Ital Urol Androl. 2016; 88:122-7.

Correspondence Edoardo S. Pescatori, MD (Corresponding Author) info@andrologiapescatori.it Andrology Service, Hesperia Hospital Via Arquà 80/B - 41100 Modena (Italy) Anna Baldini, Mrs a.baldini@cittadinanzattiva-er.it Giovanni L. Briganti (medical student) giovanni.briganti1990@gmail.com Cittadinanzattiva via Castiglione, 24 - 40124 Bologna (Italy) Fabio Parazzini, MD fabio.parazzini@unimi.it Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano Via Commenda 9/12 - 20122 Milano (Italy) Nicola Ghidini, MD info@nicolaghidini.it Urology Department, Hesperia Hospital Via Arquà 80/B - 41100 Modena (Italy)

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DOI: 10.4081/aiua.2019.3.187

ORIGINAL PAPER

Effects of antioxidant treatment on seminal parameters in patients undergoing in vitro fertilization Laura Gambera 1, Anita Stendardi 1, Camilla Ghelardi 1, 2, Benedetta Fineschi 1, 2, Rosamaria Aini 1 1 A.G.I.

Medica Center for Reproductive Medicine, Siena, Italy; of Molecular and Developmental Medicine, University of Siena, Siena, Italy.

2 Department

Summary

Objective: The aim of this non controlled trial was to assess whether a therapy with an antioxidant supplement may improve spermatozoa quality in terms of number, motility, morphology and a higher number of successful conceptions in patients with oligoasthenoteratozoospermia undergoing cycles of medically assisted reproduction by intracytoplasmic sperm injection (ICSI). Materials and methods: 32 patients registered at A.G.I. Medica (Siena) medically assisted reproduction centre affected by fertility problems associated with oligoasthenoteratozoospermia were included in the study. Semen analysis were evaluated according to World Health Organization 2010, before and after treatment. Moreover, we used colorimetric tests to assess oxidative stress. After evaluating oocyte fertilisation rate and the quality of embryos obtained, data were statistically analysed. Result: Microscopy examination after the therapy, showed a general improvement in sperm parameters (number of sperms, progressive motility, viability and normal morphology) in both baseline and capacitated; also the levels of oxidative stress was notably lower after the treatment. Morever we evaluated the outcome of the IVF treatment, the percentage of fertilization and the number of embryos obtained, all the parameters was significantly higher in the N1 group. Conclusions: The outcomes of this trial seem to suggest that the administration of our food supplement improve semen parameters and that the evaluation of oxidative stress levels may become a diagnostic tool to assess male infertility in patients undergoing ART cycle.

KEY WORDS: Assisted reproduction technology; Embryo quality; Male infertility; Oxidative stress; Reactive oxygen species; Semen quality. Submitted 16 May 2019; Accepted 25 July 2019

INTRODUCTION

Human infertility affects 15% of couples in their reproductive age, of which 30% is due to male factors. Alterations in spermatogenesis may be related to various clinical conditions such as varicocele, cryptorchidism, infections, nutrient deficiencies, traumas, cancer, smoke or exposure to environmental agents. However, in many cases aetiology is not clear and several studies have proved that such condition, defined as idiopathic, may be caused by oxidative stress (1). Reactive Oxygen Species (ROS) are chemically reactive molecules that, in physiological conditions, have positive

effects on sperm function (2). On the other hand, high levels of ROS may induce lipid peroxidation, damage sperm DNA (3) and protein modifications (4). Furthermore, significant negative relations between oxidative stress (OS) parameters and semen, fertilisation rate, development of embryos and pregnancy rates have been observed (5). Approximately 25% of men suffering from infertility show high levels of free radicals in semen (6). Increased concentration of free radicals may be due to several factors such as inflammation, cigarette smoke, ultraviolet rays, stress, alcohol, exposition to polluting agents, diets too rich in proteins and animal fats and drugs. Human ejaculate contains potential sources of ROS including leukocytes, germ cells or abnormal spermatozoa (7, 8). From a clinical point of view, all the aforesaid may result in lower fertilization rates, implantation failure, compromised embryo development, multiple abortions and low success in case of application of assisted reproduction techniques (9, 10). Considering the high number of factors that may increase oxidative stress and thus damage spermatogenesis and nemaspermic function, antioxidant oral supplements are widely used in patients affected by infertility. In our investigation, we especially observed the therapeutic effects of a food supplement containing LArginine, Coenzyme Q10, Vitamin C and E, Inositol and active principles from plants such as Ginseng and Tribulus terrestris. These substances are known to have positive effects on the motility and mitochondrial function of spermatozoa. Our non controlled trial was to assess whether a therapy with antioxidants may lead to actual improvement in the quality of spermatozoa as a result of a reduction in reactive oxygen species and consequently to an increase in the number of successful pregnancies in patients undergoing medically assisted reproduction.

MATERIALS

AND METHODS

32 patients enrolled in this study after 12-18 months of unprotected sexual intercourses without conception. Sexual development, medical history, physical examination and serum hormone levels were normal. Serological, virological and genetic tests which are necessary to start In Vitro Fertilization (IVF) cycle were performed. All selected patients underwent microbiological analysis

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 3

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of seminal fluid to search for common bacteria. Azoospermic patients and couples whose sterility was due to female factors were excluded from the study. All the patients were informed by the doctor about the use of supplement and written informed consent was obtained from each patient. Selected patients took a sachet a day of a food supplement (Argifast, San Marino, Italy) containing L-Arginine (3 g), Coenzyme Q10 (200 mg), Vitamin C (240 mg), Vitamin B3 (27 mg), Tribulus (Tribulus terrestris, 60 mg), Ginseng (Panax ginseng, 12 mg), Inositol (100 mg) and Vitamin E (36 mg), for a total of 65 days. Semen samples collected by masturbation after 3-4 days of sexual abstinence were examined after liquefaction for 30 minutes at 37°C. Volume, pH, concentration, viability and sperm motility were assessed according to parameters of the World Health Organization (WHO) manual (11). For each sample were counted one hundred sperm and morphological characteristics of sperm organelles (nucleus, acrosomal and tail) were evaluated using an optical microscope (Zeiss, magnification 100X). Eosin Y staining was used to detect necrotic sperm. Semen analysis was performed before (Time 0) food supplement treatment. The same tests, except for eosin test, were carried out on semen on the day of oocyte retrieval (Time 1) at the end of therapy. Swim-up selection was performed before and after therapy to compare sperm recovery in the two steps. A sample of semen was washed in Gamete Buffer (Cook Medical®, USA) and then centrifuged for 10 minutes at 161 rcf. Supernatant was removed and pellet was layered with a variable volume of medium proportional to the number and motility of the spermatozoa detected in the baseline evaluation. The sample was heated at 37°C for 45 minutes and then we controlled spermatozoa concentration, motility and morphology. Oxidative stress test Oxidative stress analysis was performed with a colorimetric test (Oxisperm®, AB Analitica, Italy) following the instructions of the manufacturer. The Reactive Gel (RG) was liquefied in a water bath at 90°C for 5 minutes and then the RG temperature was reduced to 37°C. The RG was mixed with the semen sample in an Eppendorf tube in order to have a final sperm concentration of 1 × 106/mL (volume proportion 1:1 semen-RG). The mix was gelified at 4°C for 5 minutes and then incubated for 45 minutes at 37°C. The resulting colour of the mix was compared with the colour scheme and the corresponding OS level was estimated. Samples were subsequently divided into two groups depending only on the OS level detected with Oxisperm®: low OS samples including levels N1 and N2 and high OS samples including levels N3 and N4. N1 and N2 samples have optimal/low levels of ROS considered not able to damage cells, whereas N3 and N4 samples have levels of ROS so high that may cause pathological effects on sperms such as DNA fragmentation. Assisted reproduction procedure Female partners underwent ovarian stimulation through the administration of gonadotropins, which aimed to

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trigger the growth of multiples follicles at the same time in order to obtain a higher number of fertilizable oocytes. Oocytes were recovered from follicular fluid immediately after follicle aspiration. ICSI was performed on mature oocytes as described by Palermo et al. (12). Eighteen hours after ICSI, the presence of two pronuclei and two polar bodies was checked to verify normal fertilization. Embryos were cultured until embryo transfer, at day 3, were transferred using a catheter into the uterus in an ultrasound-guided procedure. Clinical pregnancy was confirmed by ultrasound, which showed the presence of gestational sac and foetal heart beat at the seventh week Before transfer, the embryos were evaluated morphologically and graded in order to compare embryo quality in the two different categories of patients (N1 and N2). We gave them a score (13, 14) according to the number of cells and percentage of fragments (15). Statistical analysis We used Wilcoxon test (a non-parametric test) to compare the data of both groups before and after treatment. We used Mann-Whitney test (a non-parametric test) and chi-square test to compare groups with levels of OS rated N1 and N2. Statistical significance was set at P ≤ 0.05.

RESULTS

We selected 32 couples where the male partner was suffering from oligoasthenoteratozoospermia. Microbiological surveys did not detect the presence of common bacteria. None of the patients reported side effects and all experienced physical wellness after the 65-days therapy with antioxidants. Sperm analysis was performed before the treatment (T0) and about 65 days after therapy on the day of female oocyte retrieval (T1). Mean sperm count, progressive motility, normal sperm morphology and eosin Y were below the normal range in all patients (Table 1). At Time 1, semen parameters highlighted a significant improvement in all the categories observed. Light microscopy examination after the therapy, showed a general improvement in sperm parameters (number of sperms, progressive motility, viability and normal morphology). In particular, we observed a higher quantity of spermatozoa with a well-formed nucleus and normal flagella, even though the percentage of spermatozoa with good morphology does not exceed the 25th percentile (15). Subsequently we compared the data from the swim-up before and after therapy and it was observed a general improve of all sperm parameters examined (Table 1). The significant improvement of parameters after swimup proved to be important in order to undergo assisted reproduction techniques since these will be the spermatozoa selected for the ICSI. Eosin Y test on capacitated spermatozoa was carried out neither at Time 0 nor at Time 1. A colorimetric test was performed on all the samples collected for this trial to detect the presence of free radicals in the semen before and after the treatment with antioxidants (Figure 1). After therapy with antioxidants, it was observed that the levels of OS were notably lower and none of examined samples showed high or very high OS levels.

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Antioxidant treatment on seminal parameters

Table 1. Sperm parameters assessed in selected patients before and after treatment.

No. of spermatozoa (x10⁶/ml) No. of total spermatozoa(x10⁶) Progressive motility (a+b%) Normal morphology (%) Eosin test (%)

Baseline T0 9.45 ± 3.24 28.44 ± 13.75 23.68 ± 10.54 3.43 ± 1.68 68.43 ± 3.83

Baseline T1 13.39 ± 5.06 40.61 ± 18.80 37.65 ±10.06 4.93 ± 1.96 72.68 ± 3.15

Capacitated spermatozoa T0 3.80 ± 2.80 3.75 ± 2.84 65.15 ± 20.50 11.46 ± 5.79

Capacitated spermatozoa T1 5.83 ± 4.51 5.94 ± 4.43 75.87 ± 16.76 15.12 ± 5.76

WHO 2010 > 15 x10⁶ > 39 x10⁶ > 32% > 4% > 58%

WHO: world health organization.

Figure 1. Time 0: 5 patients showed no oxidative stress (N1); 12 patients had low levels of oxidative stress (N2); 12 patients had high levels of oxidative stress (N3) and 3 patients showed very high levels (N4). Time 1: the value of 23 patients tested after the treatment was nearly zero (N1) while 9 patients proved to have N2 levels.

Then we evaluated the outcome of the IVF treatment. The percentage of fertilization and the number of embryos obtained, was significantly higher in the N1 group; our comparison highlighted a significant improvement in the embryo quality in the group showing a lower OS level. The pregnancy rate was not significative in the two groups analysed (Table 2).

CONCLUSIONS

A lower number of free radicals in semen may influence positively the development of embryos. Table 2. Comparison of influence of oxidative stress between group N1 and group N2 (9 patients) on the outcome of ICSI treatments. No. of retrieved oocytes % of mature oocytes % of fertilization No. of embryos obtained % of cleavage No. of transferred embryos Embryo Score (ES) % of pregnancies

N1 (n = 23) 5.17 ± 2.90 82.35 92.85* 3.43 ± 2.14* 86.81 1.30 ± 0.47 10.22±1.86* 26.08

N2 (n = 9) 4 ± 2.17 83.33 70* 1.77 ± 1.30* 76.19 1.33 ± 0.5 6.94±1.8* 22.22

Many factors may influence treatment outcome and among them reactive oxygen species (ROS) have aroused great interest in the scientific literature of the last years. ROS play a fundamental physiologic role during the various phases of reproductive process. The presence of antioxidant systems, enzymatic or not, aims to control the excessive production of reactive oxygen species and the damage they may cause (17). A lack of balance results in a condition called OS, which leads to lipid peroxidation of plasm membranes, DNA fragmentation and cell apoptosis in spermatozoa (18). The manipulation of gametes in vitro during medically assisted reproduction may be influenced by their exposure to high levels of ROS, thus suggesting the importance of using antioxidants to neutralize negative effects of the latter. Antioxidant therapy has become quite a common treatment in case of male infertility. Number of studies describe general positive effects related to the intake of antioxidants. However, outcomes are highly variable depending on the kind of antioxidant used, its concentration or the synergy of several antioxidants administered together. Since oxidative stress seems to play a fundamental role in infertility, if antioxidant defence systems are increased, benefits comparable with those deriving from the use of traditional drugs may be obtained. We assessed the effects of a therapy with antioxidants on semen parameters of 32 patients affected by oligoasArchivio Italiano di Urologia e Andrologia 2019; 91, 3

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thenoteratozoospermia and oxidative stress. Morphology, motility and the number of normal spermatozoa are the parameters that significantly improved after 65 days of treatment, thus suggesting that oxidative stress may induce several alterations in the various parts of spermatozoa. The presence of ROS results in the break of plasma membranes and such effect may lead to sperm chromatin fragmentation, thus compromising male’s gene pool. The morphologic analysis of spermatozoa samples at Time 0 showed a high number of altered acrosomes, which were often missing or reacted. After the therapy with antioxidants, the nucleus was well formed with normal non-reduced acrosomes, thus suggesting that oxidative stress has negative consequences also at this level. The assessment of semen parameters was performed also after the application of swim up method. Increased motility rates and a higher number of spermatozoa with normal morphology was observed also after such test. This improvement proved to be significant for the application of assisted reproductive techniques since these spermatozoa will be selected for ICSI. The micro-environment of gametes and embryos during assisted reproduction is very different from physiological one: a higher oxygen concentration, temperature and pH surges, as well as prolonged exposition to light and media may be potential exogenous sources of oxidative stress (9). The lack of balance between antioxidant defence systems and reactive oxygen species may cause a damage that could affect the fertilization rates and embryo quality. The impact of oxidative stress seems to have some effects also on the number of embryos obtained. Such number was double in the patients with levels of oxidative stress close to zero (N1) compared to those with low levels of OS (N2). From such data we can deduce that oxidative stress may negatively influence both fertilization process and the development of embryos. Quality assessment of embryos, which is essential during medically assisted reproduction, confirmed that the best ones develop in an environment with almost no oxidative stress. The embryo score given to evaluate embryo quality made it easy to detect the best ones. This practical, non-invasive method allowed us to select the most suitable embryo to be transferred, which led to an increase in implantation rates and to a reduction in the number of multiple pregnancies and related risks. Since the production of ROS during assisted reproduction techniques cannot be completely eliminated, suitable strategies should be adopted to minimize their effects on the treatment. The observation of abnormal levels of oxidative stress makes clinical analysis clearer, especially when reduced sperm function is not related to known illnesses. The outcomes of this trial seem to suggest that the administration of our food supplement improve semen parameters and that the evaluation of oxidative stress levels may become a diagnostic tool to assess male infertility in patients undergoing ART cycle.

REFERENCES

1. Agarwal A, Majzoub A. Role of antioxidants in assisted reproductive techniques. World J Mens Health 2017; 35:77-93. 2. Agarwal A, Nallella KP, Allamaneni SS, Said TM. Role of antioxidants in treatment of male infertility: an overview of the literature. Reprod Biomed Online. 2004; 8:616-27.

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3. Aktan G, Dogru-Abbasoglu S, Küçükgergin C, et al. Mystery of idiopathic male infertility: is oxidative stress an actual risk? Fertil Steril. 2013; 99:1211-5. 4. Piomboni P, Stendardi A, Gambera L, et al. Protein modification as oxidative stress marker in normal and pathological human seminal plasma. Redox Rep. 2012; 17:227-32. 5. Tremellen K. Oxidative stress and male infertility- A clinical perspective. Hum Reprod Update. 2008; 14:243-58. 6. Zini A, San Gabriel M, Baazeem A. Antioxidants and sperm DNA damage: a clinical perspective. J Assist Reprod Genet. 2009; 26:427-32. 7. Gambera L, Campanella G, Piomboni P, et al. Ruolo di un’associazione tra antiossidanti e stimolanti immunitari naturali nel trattamento dell’astenoteratospermia con leucocitosi. Minerva Ginecol. 2007; 59:473-9. 8. Piomboni P, Gambera L, Serafini F, et al. Sperm quality improvement after natural anti-oxidant treatment of asthenoteratospermic men with leukocytospermia. Asian J Androl. 2008; 10:201-206. 9. Du Plessis SS, Makker K, Desai NR, Agarwal A. Impact of oxidative stress on IVF. Expert Rev Obstet Gynecol. 2008; 3:539-554. 10. Opuwari CS, Henkel RR. An Update on Oxidative Damage to Spermatozoa and Oocytes. Biomed Res Int. 2016; 9540142. 11. WHO laboratory manual for the Examination and processing of human semen. 2010; p.225. 12. PalermoG, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmatica injection of a single spermatozoon into oocyte. Lancet. 1992; 340:17-18. 13. Lee SH, Song H, Park YS, et al. Poor sperm quality affects clinical outcomes of intracytoplasmatic sperm injection in fresh and subsequent frozen-thawed cycles: potential paternal effects on pregnancy outcomes. Fertil Steril. 2009; 91:798-804. 14. Choi HW, Park YS, Lee SH, et al. Effects of maternal age on embryo quality and pregnancy outcomes using testicular sperm with intracytoplasmatic sperm injection. Clin Exp Reprod Med. 2016; 43:221-7. 15. Veek LL. An Atlas of the Human Gametes and Conceptuses. New York: Parthenon Publishing Group; 1999, pp.46-51. 16. Maizoub A, Agarwal A. Antioxidant therapy idiopathic oligoasthenoteratozoospermia. Indian J Urol. 2017; 33:207-214. 17. Aitken RJ, Clarkson JS, Fishel S. Generation of reactive oxygen species, lipid peroxidation, and human sperm function. Biol Reprod. 1989; 41:183-97. 18. Agarwal A, Majzoub A. Role of Antioxidants in Assisted Reproductive Techniques. World J Mens Health. 2017; 35:77-93. Correspondence Laura Gambera lauragambera@agimedica.it Anita Stendardi anitastendardi@agimedica.it Rosamaria Aini dr.aini@agimedica.it A.G.I. Medica Center for Reproductive Medicine Viale Toselli 94/F, 53100 Siena, Italy Camilla Ghelardi c.ghelardi@agimedica.it Benedetta Fineschi b.fineschi@agimedica.it Department of Molecular and Developmental Medicine, University of Siena, Siena (Italy)

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DOI: 10.4081/aiua.2019.3.191

CASE REPORT

A purely penoscrotal approach: Reservoir placement of an inflatable penile prosthesis (IPP) in an orthotopic neobladder patient. Case report Cumhur Yeşildal, Ahmet Tevfik Albayrak, Abdullah Hizir Yavuzsan, Musab !lgi, Sinan Levent Kireççi Department of Urology, Şişli Hamidiye Etfal Training and Research Hospital, University of Health Science, Istanbul, Turkey.

Summary

Introduction: The inflatable penile prosthesis (IPP) is the last step in drug-resistant erectile dysfunction treatment. IPP implantation can be challenging, especially following a cystoprostatectomy with an orthotopic neobladder. There is no consensus about surgical techniques for placement of an IPP reservoir in such patients. In this paper, we present a case of an IPP and reservoir placement with a single penoscrotal incision. Case: A 55-year-old patient, who underwent radical cystoprostatectomy with an orthotopic neobladder seven years ago, presented with severe erectile dysfunction. His oncologic status was stable, and he was in remission. He also had high blood pressure and took medication for it. He previously used different medical treatments, such as oral phosphodiesterase-5 inhibitors (PDE5i), intraurethral prostaglandin E2 (PGE2) installations, and Trimix injections. As far as we know, he had no benefit from these treatments. A three-piece IPP was recommended. After a discussion of surgical techniques, we chose the penoscrotal approach, and the ectopic reservoir was placed through the inguinal canal, guided by a forefinger. Results: The total operative time was 60 minutes, and the estimated blood loss was minimal. There were no perioperative complications. The patient was discharged on postoperative day one. He could start to use the IPP in the first month. His sexual and urinary functions were normal, and there was no abdominal bulging from the ectopic reservoir at the three-month follow-up. Conclusions: In conclusion, ectopic placement of the reservoir through a single penoscrotal incision appears to be a safe and acceptable surgical technique for postoperative ED following a radical cystoprostatectomy with an orthotopic neobladder.

KEY WORDS: Penile prosthesis; Erectile dysfunction; Orthotopic neobladder. Submitted 9 February 2019; Accepted 13 February 2019

no one had attempted to place an IPP reservoir with a penoscrotal approach in a radical cystoprostatectomy patient with a neobladder. We describe a safe placement method for the reservoir of an IPP via a single penoscrotal incision in a neobladder patient who has a secondary erectile dysfunction due to a past radical cystoprostatectomy (Figure 1).

CASE

A 55-year-old bladder cancer patient, who had undergone radical cystoprostatectomy with an orthotopic Studer neobladder seven years ago, presented with severe erectile dysfunction (ED). He had already used medical treatments such as oral phosphodiesterase-5 (PDE5i) inhibitors, Trimix, and prostaglandin E2 (PGE2). He had hypertension and took medication. Our clinic recommended a three-piece inflatable penile prosthesis as an end-stage treatment. At that point, surgical techniques were discussed, and we agreed on the penoscrotal approach. The ectopic reservoir was placed from the inguinal canal, guided by a forefinger. Then the posterior wall of the inguinal canal was pricked, and the internal obliques and transversal muscles were separated, followed by circumferential sweeping using the forefinger. The Cloverleaf reservoir was established, filled with 65 mL Figure 1. An abdominal cross-section of the 55-year-old patient, showing the orthotopic bladder formed seven years ago.

INTRODUCTION

Although the retropubic and perivesical spaces are known to be the best locations for three-piece IPP reservoirs, the use of these locations becomes impossible with an underlying cause of fibrosis due to pelvic surgery, such as radical prostatectomy, cystectomy, or even radiotherapy to the pelvis. As an alternative to these locations, ectopic reservoirs can be placed between the transverse fascia and the abdominal muscles (1-3). However, as far as we know, No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 3

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saline solution, and then evaluated for back pressure. Finally, a narrowing suture was placed at the orifice of the inguinal canal to prevent the reservoir from slipping downward.

DISCUSSION

A surgeon should carefully plan how and where to place the IPP reservoir in ED patients with a neobladder. As we know, after radical cystoprostatectomy with an orthotopic neobladder, a significant part of the peritoneum cannot be closed. Therefore, a part of the small intestine can be found in the pelvic cavity. If the surgeon does not consider this possibility and tries to insert a reservoir

Figure 2. Postoperative third month. The reservoir can be seen under the external and internal oblique muscles.

with classical methods such as scrotal or infrapubic incision, it may damage the neobladder, the intestines, and even the inferior epigastric vessels (2, 3). There is one report that describes an alternative way to place the IPP reservoir (4). Jung Kwon Kim et al. placed the IPP reservoir with a separate longitudinal incision two fingerbreadths to the left and lateral to the umbilicus. Although this approach is feasible, it has no advantage against our technique since it is done with a secondary incision. In our procedure, we placed the IPP and its Cloverleaf reservoir using a single penoscrotal incision (Figure 2). The total operative time was 60 minutes. There were no perioperative complications, nor was there more blood loss than expected. On the fifteenth day after the surgery, we started to train the patient about how to use the IPP. We recommended abstaining from sexual intercourse for the first six weeks. He was able to begin using the IPP in the sixth week. His sexual and urinary functions were normal, and his sexual satisfaction was very high. There was no abdominal bulging from the ectopic reservoir at the three-month follow-up (Figure 3). The ectopic placement of a flat reservoir using only a penoscrotal incision appears to be a safe and feasible surgical technique for postoperative ED following radical cystoprostatectomy with orthotopic neobladder.

REFERENCES

1. Al-Enezi A, Al-Khadhari S, Al-Shaiji TF. Three-piece inflatable penile prosthesis: surgical techniques and pitfalls J Surg Tech Case Rep. 2011; 3:76-83. 2. Perito PE, Wilson SK. Traditional (retroperitoneal) and abdominal wall (ectopic) reservoir placement J Sex Med. 2011; 8:656-9. 3. Morey AF, Cefalu CA, Hudak SJ. High submuscular placement of urologic prosthetic balloons and reservoirs via transscrotal approach J Sex Med. 2013; 10:603-10. 4. Kim JK, Cho MC, Ku Ja Hyeon, et al. Preperitoneal placement of an inflatable penile prosthesis reservoir for postoperative erectile dysfunction after radical cystoprostatectomy with orthotopic neobladder Investig Clin Urol. 2016; 57:364-366.

Figure 3. Postoperative third month. Penoscrotal operation area. Single incision.

Correspondence Cumhur Yesildal, MD c_yesildal@hotmail.com Ahmet Tevfik Albayrak, MD atevfikalbayrak@gmail.com Abdullah Hizir Yavuzsan, MD hiziryavuzsan@hotmail.com Musab Ilgi, MD ilgimusab@gmail.com Sinan Levent Kirecci, MD sinankirecci@yahoo.com.tr University of Health and Sciences Sisli Etfal Traning and Research Hospital Urology Department Halaskargazi Cad., Etfal Sk., 34371 Şişli/Istanbul (Turkey)

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CASE REPORT

Priapism induced by use of tamsulosin: A case report and review of the literature Marcelo Marconi 1, Pablo Pavez 2, Ignacio San Francisco 2, Paulette Narvaez 3 1 Andrology

Unit, Department of Urology, Pontificia Universidad Catรณlica de Chile, Santiago, Chile; of Urology, Pontificia Universidad Catรณlica de Chile, Santiago, Chile; 3 Department of Urology, Hospital Dipreca, Santiago, Chile. 2 Department

Summary

Numerous medications have been associated to the development of priapism as an adverse reaction, the most common are intracavernosal vasoactive agents, antipsychotics and antidepressants. Alpha blockers, in particular tamsulosin which is widely used in different urological conditions, has been associated to priapism in only few case reports. We present the case of a healthy 45-year-old man who medicated himself with two doses of 0.4 mg of tamsulosin due to a renal colic with spontaneous passage of a 3 mm stone. Eight hours after the second tamsulosin dose the patient developed a persistent painful erection not associated to sexual stimulation that lasted for 6 hours. He was admitted to the emergency room, and after history taking and physical evaluation the diagnosis of ischemic priapism was made. The patient denied consumption of any other medication or drug during the last month, blood tests in particular hemogram were normal and no recent history of pelvic trauma was reported. To achieve detumescence, five boluses of 200 mcg of phenylephrine were injected directly in the corpora cavernosa, no further procedures were needed. In the follow-up the patient had no new priapism episodes and he reported no problems with erections in sexual intercourse. Tamsulosin is one of most indicated medications in urological general practice; though priapism has been rarely associated to its consumption the risk of this side effect exists, suggesting that patients should be counselled about it.

KEY WORDS: Priapism; Tamsulosin; Adverse effect. Submitted 24 April 2019; Accepted 6 May 2019

INTRODUCTION

Priapism is defined has a prolonged painful erection lasting for more than 4 hours in the absence of sexual stimulation and remaining despite orgasm (1). The three main subtypes are ischemic, non-ischemic and stuttering, being ischemic priapism the most common form, characterized by absence of intracavernous arterial inflow. The incidence of priapism in the general population is low (0.5-0.9 cases per 100,000 person-years); however, it is considered a medical emergency and should be treated promptly to avoid further complications, in particular corporal fibrosis and erectile dysfunction. Although a specific etiology cannot be found in up to one-third of the cases of ischemic priapism, defined conditions such as blood dyscrasias and neurological disorders have been associated to its development. Priapism

can also develop as a side effect of different medications and drugs, being the most common vasoactive intracavernosal injections, psychotropic medications and recreational drugs (i.e. alcohol, cocaine) (2). Alpha-blockers such as prazosin, terazosin and doxazosin have also been reported as an etiology of priapism. Tamsulosin, an alpha 1a blocker, has rarely been related to priapism; however, is one of the most indicated medications in general urological practice being the first therapeutic line for the management of benign prostatic hyperplasia (3) and treatment of distal ureteral stones (4). The objective of this case report is to present a case of tamsulosin induced ischemic priapism.

CASE

PRESENTATION

A healthy 45-year-old man with history of one renal colic episode with spontaneous stone elimination 12 months earlier, develops forty-eight hours before consultation a colic left flank pain and lower urinary tract symptoms, in particular urgency and increased urinary frequency, with no fever or macroscopic hematuria. The patient interpreted himself as developing a new renal colic episode so auto-medicated with ketorolac 10 mg three times a day and tamsulosin 0.4 mg once a day. The patient had no history of diabetes, hypertension, neurologic diseases, hematologic disease or any type of drug consumption or abuse. Thirty-six hours after the first symptoms and after two doses of tamsulosin the patient spontaneously eliminated a 3 mm stone with no other incidents. The night before consultation approximately eight hours after stone elimination the patient woke up at 6 AM with his usual morning erection, he urinated with no difficulties but the erection persisted during the following 5 hours without any sexual stimulation at that time or the night before. The patient tried to achieve detumescence by walking and local ice application with no success at home. He was admitted at noon with already six hours of a constant, painful and unrelated to sexual stimuli erection. At admission, the patient was evaluated by the emergency room physician, who collected a completed medical history excluding consumption of drugs (cocaine, marijuana), antidepressants, antipsychotics, narcotics, intracavernosal injection of vaso-active agents, phosphodiesterase 5 inhibitors, or any other substance associated

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with priapism risk. The patient had no history of pelvic trauma either major or minor. The only drugs the patient had consumed in the last 48 hours were five 10 mg separated doses of ketorolac and two 0.4 mg doses of tamsulosin. He had a visual analog visual for pain (range 010) of 7 secondary to the painful erection. At admission the physical examination showed: temperature 36,6Â°C, pulse 84/minute, respiratory rate 18/minute and blood pressure 137/88. Heart, lung, abdominal and neurologic examination were normal. Genital examination revealed no skin lesions, painless testicular examination with normal volume and a complete painful rigid erection with no tumescence of the glans. A urine analysis revealed microscopic hematuria with no other pathological signs, urine culture developed no bacterial growth 48 hours later, and hemogram was normal with no signs of hematologic disease. After evaluation, a consultation for urologic evaluation was asked. After history taking and physical evaluation, the urologist confirmed the diagnosis of ischemic priapism. To achieve detumescence, after administration of local anesthesia to the base of the penile shaft and while monitoring the heart rate and blood pressure of the patient, boluses of 200 microgram phenylephrine in a two milliliter solution were injected directly in the corpora cavernosa. After five boluses (1000 micrograms) and 20 minutes, detumescence was achieved. No further procedures were needed. The patient was send home with the indication to avoid tamsulosin intake and sexual intercourse for the next seven days. In the follow-up the patient had no new priapism episodes and reported no problems with erections and sexual intercourse.

DISCUSSION

Adverse events to different type of medications is one of the most important causes of priapism. The most common drugs involved in priapism development are vasoactive intracavernosal injections, anti-psychotics, antidepressants, cocaine, alcohol (Table 1). There are few published reports associating the consumption of alphablockers to the development of priapism, in particular tamsulosin. In a previous systematic review, 13 articles reported a cause-effect relation, among which only three cases were secondary to tamsulosin (5). In one of those cases, tamsulosin was associated to a partial thrombosis of the corpora cavernosa (6), and in a second case the association of tamsulosin to a drug (Boceprevir-CYP3A4) that inhibits its degradation triggered a priapism episode (7). When analyzing our case, we were not able to find any other etiology of priapism in our patient. He was healthy, with no hematological or neurologic diseases, and the only two medications he had consumed in the last 48 hours were ketorolac and tamsulosin. There are no reports in the literature associating ketorolac with the development of priapism. As an alpha-blocker tamsulosin would interfere with the detumescence mechanism that is mediated by adrenaline and nor-adrenaline acting on alpha-adrenergic receptors in the corpora cavernosa. Considering the previous case-reports and ours, it seems that the development of priapism would be independent of the number tamsulosin doses.

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Table 1. Drugs associated to the development of priapism. Intracavernosal vaso-active drugs Prostaglandin â&#x20AC;&#x201C; Papaverine - Phentolamine Antipsychotics Clozapine - Olanzapine - Risperidone - Chlorpromazin - Haloperidol Thoridazine Antidepressants Trazodone - Imipramine - Bupropion - Fluoxetine - Lithium Antianxiety agents Hydroxyzine Antihypertensives Ntiroglicerine - Hydralazine - Guanethidine - Propanolol - Verapamil Alpla-blockers Doxazosine - Prazosine - Terazosin - Tamsulosin Theophylline Vancomycin Heparin - Warfarin Erythropoietin Alcohol Cocaine Cannabis

Even though, tamsulosin related priapism has been rarely reported; the association is relevant considering that this medication is commonly prescribed by urologists to treat benign prostatic hyperplasia, which is an extremely frequent condition in general population. When prescribing tamsulosin, priapism is almost never mentioned as a potential side-effect, questionable our report together with previous ones suggest that patients should be counselled.

CONCLUSIONS Tamsulosin is one of most prescribed medications in urological practice, even though priapism has been rarely associated to its consumption, the risk exists, suggesting that patients should be counselled about it.

AUTHORS

CONTRIBUTION

MM and FP contributed to the writing of the first draft of the report and the initial discussion. MM was involved in the care and therapy of the patient. ISF and PN reviewed the manuscript. MM is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors read and approved the final manuscript.

REFERENCES

1. Salonia A, Eardley I, Giuliano F, et al. European Association of Urology guidelines on priapism. Eur Urol. 2014; 65:480-489 2. Muneer, A. Comparison of EAU and UK guidelines on priapism. Journal of Clinical Urology. 2017; 11:127-131.

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Priapism and tamsulosin

3. Foster HE, Barry MJ, Dahm P, et al. Surgical Management of Lower Urinary Tract Symptoms Attributed to Benign Prostatic Hyperplasia: AUA Guideline. J Urol. 2018; 200:612-619. 4. Turk C, Neisius AP, Seitz C,, et al. (2018) EAU guidelines on urolithiasis. https://uroweb.org/guideline/urolithiasis. Accessed 04 April 2019 5. Spagnul SJT, et al. Adrenergic a-blockers: an infrequent and over-

looked cause of priapism. International Journal of Impotence Research. 2011; 23:95-98. 6. Kilinc M, Piskin S, Guven R, et al. Partial priapism secondary to tamsulosin: a case report and review of the literature. Andrologia. 2009; 21:199-201. 7. Hammond KP, Nielsen C, Linnebur SA, et al. Priapism induced by boceprevir-CYP3A4 inhibition and Îą-adrenergic blockade: case report. Clin Infect Dis. 2014; 58:e35-8.

Correspondence Marcelo Marconi, MD (Corresponding Author) mmarconi@andro.cl Andrology Unit, Department of Urology, Pontificia Universidad Catolica de Chile, Cruz del Sur 177, Santiago (Chile) Pablo Pavez, MD info@andro.cl Ignacio San Francisco, MD isanfrancisco@med.puc.cl Department of Urology, Pontificia Universidad CatĂłlica de Chile, Santiago (Chile) Paulette Narvaez, MD kikinarvaez@gmail.com Department of Urology, Hospital Dipreca, Santiago (Chile)

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DOI: 10.4081/aiua.2019.3.196

CASE REPORT

A complicated case of recurrent Cowper’s gland abscess Pietro Pepe, Ludovica Pepe, Astrid Bonaccorsi, Paolo Panella, Michele Pennisi Urology Unit, Cannizzaro Hospital, Catania, Italy.

Summary

A Caucasian man 64 years old was admitted to our department for fever, strangury, frequency and pain in the perineum secondary to the relapse of Cowper’s gland abscess previously treated by antibiotic therapy and trans-perineal ultrasound-guided aspiration. At admission, the clinical parameters were suggestive of sepsis; moreover, the trans-perineal ultrasound detected an hypoechoic mass suspicious for the recurrence of Cowper’s gland abscess. A suprapubic catheter was positioned and a targeted antibiotic therapy (Colistin 9000.000 U intravenously every day for 8 days plus meropenem 500 mg intravenously every 8 hours for 10 days) was administered. The patient during the follow up presented long fibers of mucus in the urine and recurrent positive urine culture, therefore two months later underwent trans-perineal surgical asportation of the left Cowper’s gland. One month after surgery the patient was readmitted for the presence of a urinary fistula between bulbar urethra and perineum. A new suprapubic catheter was positioned and after three months was removed because a complete restitutio ad integrum was shown by retrograde cystourethrogram and uroflowmetry. In conclusion, the abscess of Cowper’s gland could represent a very rare but severe clinical event that need aggressive therapy and close follow up for its potentially high rate of early and late clinical complications; in the presence of recurrence the surgical asportation of the Cowper’s gland should be considered.

KEY WORDS: Cowper’s gland abscess; Urinary perineum fistula; Transperineal ultrasound; Cowper's gland surgery. Submitted 17 February 2019; Accepted 9 April 2014

INTRODUCTION

The abscess of the Cowper gland (1, 2) is associated with fever, malaise and severe pain in the perineum combined frequency, urgency, painful defecation and sometime acute urinary retention. We, previously, showed a case of Cowper’s gland abscess complicated by sepsis treated conservatively (targeted antibiotic therapy, trans-perineal ultrasound-guided aspiration of the abscess and suprapubic catheter) with an apparent restitutio ad integrum (3). We now report the clinical evolution and relapse of the same clinical case that needed the surgical asportation of the Cowper’s gland subsequently complicated by a urinary perineum fistula.

CASE

REPORT

A Caucasian man 64 years old was readmitted to our hospital for the presence of fever (40°C), strangury, frequency, pain in the perineum and long fibers of mucus in the

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urine. The patient had been treated with three cycles of antibiotics during hospitalization about nine months before for the presence of sepsis secondary to an abscess of the left Cowper’s gland; in addition, for the persistence of symptoms, a culture of trans-perineal ultrasound-guided aspiration of Cowper’s gland abscess showed the presence of Pseudomonas Aeruginosa sensitive to ciprofloxacin. A suprapubic catheter was positioned and antibiotic therapy (oral ciprofloxacin 1000 mg per day) was administrated for 4 weeks with apparent restitutio ad integrum (urine and urethral swab cultures were negative) and absence of clinical symptoms for the following three months from hospital discharge (3). At last hospital readmission, PSA was 1.8 ng/ml, kidney and bladder ultrasound were normal (absence of postvoid urinary residual); urological examination was characterized by normal prostate, penis and testicular findings with pain and skin redness in correspondence of the perineum. The trans-perineal ultrasound detected a hypoechoic mass suggestive for the relapse of the left Cowper’s gland abscess that was confirmed by pelvic magnetic resonance imaging. A suprapubic catheter was positioned; blood culture found presence of Escherichia coli and the patient underwent targeted antibiotic therapy (Colistin 9000.000 U intravenously every day for 8 days plus Meropenem 500 mg intravenously every 8 hours for 10 days) according to antibiogram results; seven days from the end of the therapy and in the absence of urinary symptoms the patient underwent 3 blood culture (negative), urine culture (negative), serum pro-calcitonin (negative) and was discharged from the hospital. The patient during the follow up presented again long fibers of mucus in the urine and recurrent positive urine cultures, therefore two months later underwent transperineal surgical asportation of the left Cowper’s gland. After the incision of perineum the gland was identified during surgery by metilene blue dye that was previously injected trans-perineally under transrectal ultrasound guidance; the Cowper’s gland was removed and the duct between the gland and the bulbar urethra was identified and closed in correspondence of the urethra (Figure 1). The transcutaneous drain was removed after four days and the patient was discharged after two weeks from surgery; two weeks later the urethral and suprapubic catheters were removed. Definitive histological specimen showed an abscess of the Cowper’s gland. One month from surgery the patient was readmitted again for the presence of a urinary fistula between bulbar urethra and No conflict of interest declared.

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Cowper’s gland abscess

Figure 1. Left Cowper’s gland (a) was removed by transperineal surgical approach (b).

CONCLUSIONS

The abscess of Cowper’s gland could represent a very severe clinical event that need aggressive therapy and close follow up for its potentially high rate of early and late clinical complications; in the presence of relapse the surgical asportation of the Cowper’s gland should be considered.

REFERENCES

1. Chwallar R. Cowperitis: a rarely diagnosed frequent disease, its diagnosis and treatment. Zeitschrift Fur Urologie. 1963; 56:155-166. 2. Martínez-Sagarra JM, Cuervo J, Cortiñas JR. Cowperitis. Actas Urológicas Españolas. 1981; 5:255-258. Figure 2. Transperineal ultrasound during urethral echography (saline solution injected through the urethra). In the correspondence of the spongiosum corpus is clearly showed a large hypoechoic zone (arrow) secondary to a cutaneous fistula between bulbar urethra and perineum.

3. Pepe P, Pepe L, Bonaccorsi A, et al. Sepsis secondary to Cowper's gland abscess. Urol Case Rep. 2017; 15:48-49. 4. Lo A, Upadhyay V, Teele RL. Syringocoele of the bulbourethral duct with additional lower genito-urinary anomalies. Pediatric Radiolology. 2011; 41:1201-1204. 5. Blasl F, Rösch WH, Koen M, et al. Cowper's syringocele: A rare differential diagnosis of infravesical obstruction in boys and young adults. J Pediatr Urol. 2017; 13:52.e1-52.e5. 6. Arena S, Scuderi MG, Arena F, Di Benedetto V. Management of "open" syringocele based on urodynamic findings. Pediatr Med Chir. 2008; 30:35-40. 7. Maizels M, Stephens FD, King LR, Firlit CF. Cowper's syringocele: a classification of dilatations of Cowper's gland duct based upon clinical characteristics of 8 boys. J Urol. 1983; 129:111-114. 8. Birnstingl J, Griffiths D, Nicol CS, Redmond A. Two cases of perineal fistula following cowperitis. Br J Vener Dis. 1957; 33:246-248.

perineum (Figure 2). A new suprapubic catheter was positioned and after three months was removed after complete restitutio ad integrum was showed (absence of fistula or urethral stenosis) by retrograde cystourethrogram and uroflowmetry.

DISCUSSION

Cowper’s gland abscess has been rarely reported (1, 2) but it should be considered in any male presenting with long persistent irritative or obstructive symptoms following many cycles of antibiotic therapy. Cowper's gland defect (i.e. syringocele) could be a focal point for bacterial persistence in the urinary tract following acute prostatitis (4-7). The treatment is appropriate antibiotic therapy, but in the presence of abscess direct aspiration is the most efficacious procedure; when underestimated, Cowper’s gland abscess could induce a perineal fistula (8). In the clinical case previously showed, to our knowledge the first reported in literature, we observed multiple acute recurrences requiring removal of the Cowper’s gland that was also complicated by a urinary fistula between bulbar urethra and perineum.

Correspondence Pietro Pepe, MD (Corresponding Author) piepepe@hotmail.com Ludovica Pepe, MD Astrid Bonaccorsi, MD Paolo Panella, MD Michele Pennisi, MD Urology Unit - Cannizzaro Hospital Via Messina 829, Catania (Italy) Archivio Italiano di Urologia e Andrologia 2019; 91, 3

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CASE REPORT

Vena cava defect repair using a polytetrafluoroethylene graft after a radical nephrectomy and vena cava resection: A case report Volkan Izol, Mutlu Deger, Mustafa Zuhtu Tansug Department of Urology, Faculty of Medicine, University of Çukurova, Adana, Turkey.

Summary

Introduction: The gold standard treatment for large renal masses is a radical nephrectomy and the removal of tumor thrombi from the large vessels. Here, we discussed the repair of a vena cava defect using a polytetrafluoroethylene (PTFE) graft after a radical nephrectomy and vena cava resection. Case: A 69-year-old male patient presented to our clinic with right-sided pain and 10 kg of weight loss over the previous 3 months. The computed tomography showed that the right kidney was 23 x 13 cm in size, with a 7 x 6 x 7 cm contrastenhanced mass at the renal ilum level. The patient underwent a radical nephrectomy, and the vena cava defect was repaired using a PTFE graft. There was also tumor infiltration in the proximal third of the left renal vein. The renal vein defect was also repaired using a PTFE graft, and the end of the graft was sutured to the vena cava graft at a right angle. The histopathological examination showed a Fuhrman grade 4 renal cell carcinoma (RCC) with focal sarcomatoid differentiation areas. Conclusions: The management of patients with RCCs and inferior vena cava (IVC) tumor thrombi should be planned with an experienced team, including a cardiovascular surgeon and liver transplantation team. In these patients, the comorbidities, life expectancy, and imaging methods should be considered for treatment planning in experienced centers. The tumor stage, probability of invasion, and patient’s performance status should also be determined using magnetic resonance imaging during the preoperative period. Finally, the needs for a graft or tubular patch, sternotomy, and chemotherapeutic agents after the nephrectomy should be discussed using a multidisciplinary approach.

KEY WORDS: Radical nephrectomy; Vena cava; Renal cell carcinoma; Polytetrafluoroethylene; Graft. Submitted 9 March 2019; Accepted 3 April 2019

INTRODUCTION

Renal cell carcinomas (RCCs) account for approximately 3% of all adult solid tumors and approximately 85% of all parenchymal kidney tumors.1 After prostate and bladder tumors, RCCs are the third most commonly seen urological tumors, and they exhibit the highest mortality rate of all urological cancers. Although an RCC diagnosis can be made during the early stages with the widespread use of imaging modalities, 25% of the patients may have metastatic and venous involvement, extending from the renal vein to the right atrium. This is seen in 4-

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10% of the cases at the time of the diagnosis (2-4). Evaluating the tumor size, location, inferior vena cava (IVC) thrombus presence, adjacent organ involvement, lymph node involvement, and any distant metastases before performing an intervention is very important for determining the surgical margin and the patient’s survival. Nephron sparing surgery or a radical nephrectomy, which is the standard treatment for an organ confined RCC, allows for a high-grade cure. Unfortunately, after a radical nephrectomy and tumor thrombus removal in the case of IVC tumors, the 5-year survival rate drops to 3264% (5-8). However, the survival rate in patients who have undergone only radical nephrectomies, without removing any thrombi, declines significantly, and most of these patients die within the first year. Despite the significant improvements that have been made in targeted therapy in recent years, the most effective treatment for these patients is still surgery. Although large renal masses can be removed safely with the developments that have been made in the preoperative diagnostic methods, anesthesia, and surgical techniques, especially after liver transplantation, morbidity and mortality rates ranging from 2.7-40% have been reported (9). There are three important stages involved in RCC and venous tumor thrombus surgery: renal artery ligation, avena cava tumor thrombectomy, and radical nephrectomy. Due to IVC tumor infiltration in certain rare cases, a resection of the infiltrating section of the IVC may also be necessary (10). After the resection and an adequate hepatic vena cava dissection, the vena cava can be anastomosed end to end, or the defect can be repaired with synthetic or homologous grafts. Here, we have discussed a vena cava defect repair case in which a polytetrafluoroethylene (PTFE) graft was used after a radical nephrectomy and vena cava resection.

CASE

REPORT

A 69-year-old male patient presented to our clinic with right-sided pain and 10 kg of weight loss over the previous 3 months. The ultrasonography showed that left kidney was normal, but a mass completely infiltrated the right kidney. The complete blood count and serum biochemistry values were normal, the Karnofsky Performance Scale Index was 80%, and the patient's medical history did No conflict of interest declared.

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the surgery began with a transperitoneal subcostal incision in right semi-lumbar position under general anesthesia. When the colon was turned over and the retroperitoneal area was reached, a mass extending proximally to the bottom of the liver with the IVC could be seen. There was also tumor infiltration in the proximal third of the left renal vein. The hepatic vena cava was dissected, and vascular clamps were placed on the distal and proximal sections of the vena cava and on the renal vein of the opposite kidney. After controlling the renal arteries, the renal mass was removed to uncover the inferior section of the IVC (Figure 2). An approximately 13-cm vena cava defect was repaired using a 16-mm not include any significant features, with the exception of diameter, 13-cm long PTFE graft, achieving continuity of hypertension and smoking 60 packs/years. the IVC. The defect in the renal vein was repaired with a Computed tomography (CT) scan showed that right kid10-mm diameter, 4-cm long PTFE graft, and the end of ney was 23 x 13 cm in size, with a contrast-enhanced the graft was sutured to the vena cava graft at a right mass at the renal ilum level of 7 x 6 x 7 cm in size. angle (Figure 3). The operation ended after the bleeding Magnetic resonance (MR) imaging was used to determine was controlled. the relationship between the mass surrounding the renal The operation time was 300 minutes, the estimated ilum and the vascular structures. The MR images blood loss was 5,000 ml, and 14 erythrocyte transfusion revealed a 10 cm mass compressing the liver at the right units were given. The patient, who was extubated during renal ilum level, which extended to the para-aortic midthe postoperative period, was admitted to the service line, filling the renal vein and vena cava, with suspected without any problems, and low molecular weight wall invasion (Figure 1). Bone scintigraphy and thorax heparin was administered. On the 3rd postoperative day, tomography showed no metastases. this patient was started on oral intake; however, he After patient evaluation, an experienced cardiovascular developed acute right-sided pain on the 6th postoperasurgeon and liver transplantation team planned a radical tive day, and a hematoma was detected in the operation nephrectomy, thrombectomy, and IVC resection and zone. The hematoma was evacuated under general anesreconstruction. Following the necessary preparations, thesia, and no bleeding focus was found. Two blood transfusion units were administered, and the procedure was terminated. The preoperative creatinine level was Figure 2. 0.8 mg/dl, the postoperative level increased to 2 mg/dl, The renal mass and upon discharge, it was 0.7 mg/dl. The patient underwas removed to went drainage on the 9th postoperative day, and he was show the inferior discharged on the 14th postoperative day. part of the inferior The histopathological examination showed a Fuhrman vena cava. grade 4 RCC with focal sarcomatoid differentiation areas. At the 1 month follow-up, the positron emission tomography CT of the operation region showed a large number of mass lesions consistent with metastases extending from the para-aortic region to the pelvic region. There was a recurrent mass in the posFigure 3. teromedial section of the liver, with suspicion Approximately 13 cm vena cava defect was repaired using a 16 mm of invasion. This patient was referred for a diameter x 13 cm long PTFE graft achieving continuity of the inferior vena consultation in the medical oncology departcava. The defect in the renal vein was repaired with a 10 mm diameter x ment, and interferon treatment was started. 4 cm long PTFE graft and the end of the graft was sutured to the vena However, this patient died due to metabolic cava graft at a right angle. causes during the 6th postoperative month.

Figure 1. MRI revealed a 10 cm mass compressing the liver at the right renal hilum level and extending to the midline paraaortic localization, filling the renal vein, vena cava with suspected wall invasion.

DISCUSSION

The gold standard treatment for large renal masses is a radical nephrectomy and tumor thrombus removal from the large vessels (if there are any). This process was first described by Berg in 1913, and since then, it has been applied as a standard treatment method (11, 12). When making surgical deciArchivio Italiano di Urologia e Andrologia 2019; 91, 3

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sions, the metastasis-related symptoms (e.g., IVC syndrome, weight loss, hematuria, edema, and side pain), comorbidities (e.g., hypertension, heart failure, diabetes mellitus, chronic obstructive pulmonary disease, and secondary malignancy), patient's performance status, and patient’s life expectancy must be taken into account. Thrombus removal with a radical nephrectomy may reduce the disease-related symptoms. This can lead to a better quality of life for the patient, even though it may not provide a curative treatment (12). Additionally, the administration of novel chemotherapeutic agents, such as tyrosine kinase inhibitors (e.g., sunitinib and sorafenib) and mammalian target of rapamycin kinase inhibitors (e.g., temsirolimus and everolimus or RAD001), after cytoreductive surgery can also extend the life expectancy of these patients (13). The most important issue when determining the prognosis involving a tumor thrombus is whether the tumor is invasive with regard to the vascular structures. If the tumor has invaded the vascular structures with a thrombus, the prognosis will be worse whether this patient has metastases or not. A good MR imaging examination and transesophageal echocardiography should be performed (during the operation, if necessary) to make this differentiation (14-16). Surgery is not difficult for renal tumors with tumor thrombi in the subcortical IVC, and in majority of cases, minimal vena cava invasion can be treated using standard surgical approaches. If the thrombus does not occupy much space in the IVC, a radical nephrectomy alone can be performed, while milking the thrombus to the renal vein. However, more complicated surgical approaches are needed when the thrombus is at a higher level or the right atrium is extended. Although various surgical thrombus resection methods have been suggested, a cardiopulmonary bypass, deep hypothermia, and transient circulatory arrest are the ones most commonly used. In addition, various surgical maneuvers, such as hepatic mobilization, the Pringle maneuver, or a venovenous bypass, may be required. If vascular invasion is suspected and a surgical decision is made, a partial or total IVC resection and synthetic vascular grafting can be performed. However, these should only be performed in tertiary hospitals using a multidisciplinary approach, including an anesthetist with sufficient experience, a vascular surgeon, a liver transplant team, and a urologist (10-16). When the tumor thrombus partially or totally infiltrates the IVC wall, the wall should be resected until a reliable surgical margin is reached; however, the indications for resection and the reconstructive methods to be used afterwards are not clearly defined. Some authors have argued against reconstruction after a suprarenal resection because collateral vessels, such as lumbar, epigastric, and vertebral arteries, may develop. However, other authors have suggested that major venous insufficiency may develop if it is not done. In general, if the IVC wall defect is less than 1/3 of the wall diameter, a direct repair should be performed; if it is excessive, reconstruction should be performed with a PTFE or tubular graft. The PTFE graft was first used by Sarti et al. in 1970, and it has been applied safely to patients with malignant tumors since that time (17).

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The increased laparoscopic renal surgery experience in recent years has brought with it the feasibility of this method for patients with widespread IVC thromboses. In the past, a laparoscopic approach seemed to be relatively contraindicated in cases with a renal vascular tumor thrombosis. Nowadays, in some clinics, especially those experienced in laparoscopic surgery, tumor surgeries including level I thromboses and some cases level II can be performed laparoscopically. In some studies (despite their small number) it has been argued that a handassisted laparoscopic nephrectomy is safe if the thrombus is in the renal vein, and it can even be comparable to an open radical nephrectomy (18, 19). Depending on the experience of the clinic, the patient’s risk factors, and the thrombus grade, an open or laparoscopic approach can be used in certain cases. Despite the advances that have been made in preoperative imaging methods and the increase in surgical experience, the mortality rates during this operation range between 2.7% and 13%. The most common causes of mortality are massive bleeding and pulmonary emboli (12, 20-22). In one study, 659 patients who underwent thrombectomies at the Mayo Clinic were evaluated retrospectively, and a 15% complication rate was reported. The subgroup analysis revealed an increase in the complication probability as the thrombus level increased; as a result, the need for a multidisciplinary approach to reduce morbidity was emphasized (23).

CONCLUSIONS

The management of patients with RCCs that include IVC tumor thrombi should include an experienced team consisting of a cardiovascular surgeon and liver transplantation team in an experienced center. A tumor burden reduction with minimal morbidity to a maximum extent is very important for the patient’s survival. Moreover, the tumor stage, invasion probability, patient’s performance status, comorbidities, and life expectancy should be evaluated using imaging methods, such as MR imaging, during the preoperative period. The needs for a graft or tubular patch, sternotomy, and chemotherapeutic agents after the nephrectomy should all be discussed with a multidisciplinary team. The patient should also be informed about the operation and the planned procedures both before and after surgery.

REFERENCES

1. Jacqmin D, van Poppel H, Kirkali Z, et al. Renal cancer. Eur Urol. 2001; 39:361-9. 2. Janzen NK, Kim HL, Figlin RA, et al. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am. 2003; 30:843-52. 3. Pagano F, Dal Bianco M, Artibani W, et al. Renal cell carcinoma with extension into the inferior vena cava: problems in diagnosis, staging and treatment. Eur Urol. 1992; 22:200-203. 4. Marshall F, Dietrick D, Baumgartner W, et al. Surgical management of renal cell carcinoma with intracaval neoplastic extension above the hepatic veins. J Urol. 1988; 139:1166-72.

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5. Padovan RS, Perkov D, Smiljanic R, et al. Venous spread of renal cell carcinoma. Abdom Imaging. 2007; 32:530-7.

after resection of renal cell carcinoma with venous involvement. Int Urol Nephrol. 2012; 44:1671-9.

6. Schimmer C, Hillig F, Riedmiller H, et al. Surgical treatment of renal cell carcinoma with intravascular extension. Interact Cardiovasc Thorac Surg. 2004; 3:395-7.

15. Boorjian SA, Sengupta S, Blute M. Renal cell carcinoma: vena caval involvement. BJU Int. 2007; 99:1239-44.

7. Wotkowicz C, Wszolek MF, Libertino JA. Resection of renal tumors invading the vena cava. Urol Clin North Am. 2008; 35:657-71. 8. Kaplan S, Ekici S, Dogan R, et al. Surgical management of renal cell carcinoma with inferior vena cava tumor thrombus. Am J Surg. 2002; 183:292-9. 9. Hallscheidt P, Pomer S, Roeren T, et al. Preoperative staging of renal cell carcinoma with caval thrombus: is staging in MRI justified? Prospective histopathological correlated study. Urologe A. 2000; 39:36-40. 10. Duckett JW, Lifland JH, Peters PC. Resection of the inferior vena cava for adjacent malignant diseases. Surg Gynecol Obstet. 1973; 136:711-6. 11. Okada Y, Kumada K, Terachi T, et al. Long-term followup of patients with tumor thrombi from renal cell carcinoma and total replacement of the inferior vena cava using an expanded polytetrafluoroethylene tubular graft. J Urol. 1996; 155:444-7. 12. Rigaud J, Hetet JF, Braud G, et al. Surgical care, morbidity, mortality and follow-up after nephrectomy for renal cancer with extension of tumor thrombus into the inferior vena cava: retrospective study since 1990s.Eur Urol. 2006; 50:302-10. 13. Procopio G, Verzoni E, de Braud F. Targeted therapies and survival: what we can learn from studies in advanced renal cell carcinoma. Oncology. 2013; 84:39-42. 14. Sidana A, Goyal J, Aggarwal P, et al. Determinants of outcomes

16. Kirkali Z, Van Poppel H. A critical analysis of surgery for kidney cancer with vena cava invasion. Eur Uro.l 2007; 52:658-662. 17. Sarti L. Total prosthetic transplantation of the inferior vena cava, with venous drainage restoration of the one remaining kidney on the graft, successfully performed on a child with Wilms’ tumor. Surgery. 1970; 67:851-5. 18. Henderson A, Murphy D, Jaganathan K, et al. Rané Handassisted laparoscopic nephrectomy for renal cell cancer with renal vein tumor thrombus. Urology. 2008; 72:268-72. 19. Hoang AN, Vaporcyian AA, Matin SF. Laparoscopy-assisted radical nephrectomy with inferior vena caval thrombectomy for level II to III tumor thrombus: a single-institution experience and review of the literature. J Endourol. 2010; 24:1005-12. 20. Steahler G, Brkovic D. The role of radical surgery for renal cell carcinoma with extension into vena cava. J Urol. 2000; 163:1671-5. 21. Skinner DG, Pritchett TR, Lieskovsky G, et al. Vena caval involvement by renal cell carcinoma: surgical resection provides meaningful long-term survival. Ann Surg. 1989; 210:387-94. 22. Nesbitt JC, Soltero ER, Dinney CPN, et al. Surgical management of renal cell carcinoma with inferior vena cava tumor thrombus. Ann Thorac Surg. 1997; 63:1592-600. 23. Karnes RJ, Blute ML. Surgery insight: management of renal cell carcinoma with associated inferior vena cava thrombus. Nat Clin Pract Urol. 2008; 5:329-39

Correspondence Volkan Izol, MD Mustafa Zuhtu Tansug, MD Department of Urology, Faculty of Medicine, University of Çukurova Adana (Turkey) Mutlu Deger, MD, FEBU (Correspondent Author) drmutludeger@gmail.com Department of Urology, Faculty of Medicine, University of Çukurova, Adana 01330 (Turkey)

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DOI: 10.4081/aiua.2019.3.202

CASE REPORT

Ureteral realignment with combined access as a treatment of complete ureteral transection Jorge Panach-Navarrete, Marcos Antonio Lloret-Durà, María Medina-González, José María Martínez-Jabaloyas Department of Urology, University Clinic Hospital of Valencia. Facultat de Medicina i Odontologia, Universitat de València, Valencia (Spain).

Summary

Ureteral realignment using a ureteral stent can be an alternative treatment in cases of complete ureteral transection and may avoid the need for reconstructive surgery. The combined access can help the passage of the guidewire through the injured area and the threading of the urinary system of the patient. We present a case of a 38-year-old man with multiples abdominal surgeries, who underwent a complete ureteral section treated with ureteral realignment with combined access. The subsequent evolution was favourable, with resolution of the ureteral injury at the acute time, and without the presence of long-term obstruction. Although we must accept that the standard treatment of the complete ureteral transection is reconstruction and anastomosis, in cases such as the one prsented, with multiple abdominal surgeries and whenever it is technically feasible, ureteral realignment may be a treatment option.

KEY WORDS: Ureteral transection; Ureteral trauma; Endourology; Ureteral realignment. Submitted 15 April 2019; Accepted 29 April 2019

INTRODUCTION

Within urogenital system injuries, those in the ureter are relatively infrequent, representing around 1-2.5% of urological traumas. The most frequent location is the distal third of the ureter (73% of cases); and the most frequent cause is surgical iatrogenic damage (75%), which can produce avulsion, perforation, ligature or burning (1). Along with gynecological surgery, distal ureter injuries happen most frequently in colorectal surgeries, with a reported incidence of unnoticed ureteral injury of between 0.11 and 0.24%. The diagnosis of these complications should be one of suspicion, as there are no specific signs. This fact implies that, sometimes, ureteral injuries are diagnosed in a deferred manner, in the postoperative period of surgeries (2). The clinical guidelines on urological trauma of the European Association of Urology and the American Association of Urology agree that small lesions or ureteral fistulas are subsidiary of conservative treatment with the use of a ureteral stent, a procedure that is safe and effective. On the other hand, larger lesions should be treated with surgical reconstruction followed by urinary diversion (1, 3). We present in this work a case of complete ureteral transection successfully treated by ureteral realignment.

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CASE

REPORT

A 38-year-old man with a history of perforated acute diverticulitis, having been treated at first with sigmodectomy and reconstruction of intestinal transit. In the postoperative period he presented with a leak of the intestinal anastomosis, requiring an emergency colostomy. During the postoperative period of the second surgery, he required emergency splenectomy for unnoticed splenic injury during the colostomy. At 12 months, during the scheduled colostomy closure, an inadvertent ureteral injury was produced. Due to the patient's paralytic ileus, a computed tomography (CT) scan was performed one week later, finding a contrast leak in the middle area of the distal ureter in the excretory phase (Figure 1) and a pelvic collection secondary to the leak. Percutaneous drainage of the collection and urgent double J stent placement was decided. In the ascending pyelography, complete extravasation of contrast outside the urinary tract was found about 4 cm above the bladder. In addition, it was not possible to raise the guidewire through the ureter. Ureterorenoscopy with a 9.5F semirigid instrument (Storz®) was decided, checking for a disheveled area and complete solution of continuity of the ureter, without reaching the proximal end of the ureter with any guidewire. At that time, given the history of multiple abdominal surgeries, the most Figure 1. UroCT at the time of diagnosis of the ureteral injury. Contrast leakage from the left pelvic ureter.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 3

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Ureteral realignment with combined access

Figure 2. Intraoperative images obtained during retrograde ureteroscopy.

recent a week before, ureteral realignment with combined access was decided. Then, after percutaneous puncture of the kidney, descending pyelography was performed, measuring a distance of about 2 cm between both ureteral ends. An anterograde guide coated with 0.035 "PTFE (Coloplast®)” was descended, outside of the urinary tract. Using the ureteroscope and with the help of a 0.035 "Sensor® guidewire (Boston Scientific®)”, the area of the injury was reached, visualizing the PTFE guidewire outside of the tract (Figure 2). Arriving with the ureteroscope to the edge of the distal end, the PTFE guidewire was lowered to the bladder by means of foreign body forceps and then extracted through the urethra. With the patient threaded, a double J 6F-26 cm Vortek® stent (Coloplast) was placed retrogradely. In a control uro-CT scan performed a week later, no contrast leakage was found. The ureteral stent was removed after two months. A CT scan and renogram four months after the realignment showed minimal evident pathway in the left kidney and absence of obstruction, with a differential function for the affected kidney of 46% (Figure 3).

DISCUSSION

The management of ureteral trauma should be initiated with the prevention of injury. The preoperative placement of a double J stent, the correct identification of the ureter and its proper dissection, are basic maneuvers for any surgery that develops in the proximity of the ureteral tract. In the case of injury, the ideal solution is immediate repair, although this action is not possible many times. That is why, sometimes, treatment must be individualized depending on the stability of the patient, the evolution time of the injury, its severity, or its exact location. Ureteral reconstruction with an ulterior temporary urinary diversion is the accepted treatment for major ureteral injuries (1, 3). In the case we present, it was decided to perform a realignment in spite of the intraoperative findings due to the patient's background. This procedure has been previously described by different authors in the context of a complete ureteral transection, with different approaches, number of stents used and maintenance period. Wang et al. used a retrograde approach, placing two stents for four months, and resolving the urine leak without long-term complications. In this case, the authors highlighted the difficulty of finding the proximal end under direct vision by retrograde ureteroscopy, solved with the combined approach that we carried out (4). On the other hand, Liu et al. reported eight cases of complete transection, treating them with combined access through flexible anterograde and rigid retrograde ureteroscope. This group placed three 5 Ch stents, solving the ureteral discontinuity in all cases, but with the development of stenosis in three of the eight cases (5). As far as we know, this work is the third one that describes this technique. Although we must accept that the treatment of the complete ureteral transection is reconstruction and anastomosis, in cases such as the one we present, with multiple abdominal surgeries and whenever it is technically feasible, ureteral realignment may be a treatment option.

REFERENCES

1. Bryk DJ, Zhao LC. Guideline of guidelines: a review of urological trauma guidelines. BJU Int. 2016; 117:226-34. 2. Eswara JR, Raup VT, Potretzke AM, et al. Outcomes of Iatrogenic Genitourinary Injuries During Colorectal Surgery. Urology. 2015; 86:1228-33.

Figure 3. CT and renogram four months after the realignment. They showed minimal patent pathway in the left kidney and absence of obstruction, with a differential function for the affected kidney of 46%.

3. Morey AF, Brandes S, Dugi DD, et al. Urotrauma: AUA guideline. J Urol. 2014; 192:327-35. 4. Wang D, Wan SP. Retrograde Endoscopic Management of Completely Transected Ureter Discovered Postoperatively. J Endourol Case Rep. 2018; 4:84-6. 5. Liu C, Zhang X, Xue D, et al. Endoscopic realignment in the management of complete transected ureter. Int Urol Nephrol. 2014; 46:335-40. Correspondence Jorge Panach-Navarrete, MD (Corresponding Author) - jorge.panach@uv.es Av. Blasco Ibáñez, nº 17, Valencia, CP 46010 (Spain) Marcos Antonio Lloret-Durà, MD - marcosant.lloret@gmail.com María Medina-González, MD - mariamedinagon@gmail.com José María Martínez-Jabaloyas, MD PhD - marjabaloyas@gmail.com Department of Urology. University Clinic Hospital of Valencia. Facultat de Medicina i Odontologia. Universitat de València, Valencia (Spain)

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