Advances in Urological Diagnosis and Imaging - AUDI (Vol. 2 - n. 2 - 2019) by Edizioni Scripta Manent

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ISSN 2612-7601

ADVANCES IN UROLOGICAL DIAGNOSIS AND IMAGING EDITOR IN CHIEF Andrea B. Galosi CO-EDITOR Pasquale Martino

OFFICIAL JOURNAL of

S.I.E.U.N.

Italian Society of Integrated Diagnostic in Urology, Andrology, Nephrology

Vol. 2 - n. 2 - 2019

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ADVANCES

UROLOGICAL DIAGNOSIS AND IMAGING

Official Journal of S.I.E.U.N. EDITOR in CHIEF Andrea B. Galosi, Ancona (IT)

CO-EDITOR

Pasquale Martino, Bari (IT)

ASSISTANT EDITOR Lucio Dell’Atti, Ancona (IT)

EDITORIAL BOARD Urology

Ahmed Hashim, London (GB), Artibani Walter, Verona (IT) Battaglia Michele, Bari (IT), Bucci Stefano, Trieste (IT) Carini Marco, Firenze (IT), Carrieri Giuseppe, Foggia (IT) De Nunzio Cosimo, Roma (IT), Fandella Andrea, Treviso (IT) Ficarra Vincenzo, Messina (IT), Finazzi Agrò Enrico, Roma (IT) Franzese Corrado, Nola (IT), Gunelli Roberta, Forlì (IT) Kastner Christof, Cambridge (GB), Lapini Alberto, Firenze (IT) Miano Roberto, Roma (IT), Mirone Vincenzo, Napoli (IT) Montorsi Francesco, Milano (IT), Morgia Giuseppe, Catania (IT) Muller Stefan, Bonn (GE), Palazzo Silvano, Bari (IT) Pavlovich Christian, Baltimore, Maryland (USA) Pepe Pietro, Catania (IT), Rocco Bernardo, Modena (IT) Salomon George, Hamburg (GE) Schiavina Riccardo, Bologna (IT), Scattoni Vincenzo, Milano (IT) Volpe Alessandro, Novara (IT), Waltz Joachen, Marseille (FR)

Andrology

Bettocchi Carlo, Bari (IT), Bitelli Marco, Roma (IT) Cai Tommaso, Trento (IT), Cormio Luigi, Foggia (IT) Fusco Ferdinando, Napoli (IT), Gontero Paolo, Torino (IT) Liguori Giovanni, Trieste (IT), Lotti Francesco, Firenze (IT) Pizzocaro Alessandro, Milano (IT), Trombetta Carlo, Trieste (IT)

Nephrology

Boscutti Giuliano, Trieste (IT), D’Amelio Alessandro, Lecce (IT), Fiorini Fulvio, Rovigo (IT), Gesualdo Loreto, Bari (IT), Granata Antonio, Agrigento (IT), Ranghino Andrea, Ancona (IT)

Radiology

Barozzi Libero, Bologna (IT), Bertolotto Michele, Trieste (IT) Giuseppetti Gian Marco, Ancona (IT), Giovagnoni Andrea, Ancona (IT), Valentino Massimo, Tolmezzo (IT)

Pathology

Beltran Antonio Lopez, Lisbon (PT) Fiorentino Michelangelo, Bologna (IT) Liang Cheng, Indianapolis (USA), Montironi Rodolfo, Ancona (IT)

Bio-Medical Engineering Wijkstra Hessel, Eindhoven (NL)

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Official Journal of S.I.E.U.N.

General Information

Contents

AIMS and SCOPE

“Advances in Urological Diagnosis and Imaging” (AUDI) has the purpose of promoting, sharing and favorite technical-scientific research on echography and imaging diagnosis, in diagnostic and terapeutical field of Urology, Andrology and Nefrology. AUDI publishes original articles, reviews, case reports, position papers, guidelines, editorials, abstracts and meeting proceedings. AUDI is Open Access at www.issuu.com Why Open Access? Because it shares science at your finger tips with no payment. It is a new approach to medical literature, offering accessible information to all readers, becoming a fundamental tool, improving innovation, efficiency and interaction among scientists.

Pietro Pepe, Andrea Fandella, Andrea Benedetto Galosi

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How much for the fusion biopsy. Cost analysis of the prostate ultrasound guided biopsy in the era of multiparametric MRI, preliminary results Andrea Fandella, Pietro Pepe

Association between urological and cardiovascular malformations in non-identical twins

Clelia Tripaldi, Marcello Campagna, Ottavio Colamonico, Alessandro Mastrorosa, Pasquale Martino, Silvano Palazzo

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Multiparametric MRI/TRUS fusion prostate biopsy:The transperineal approach

Ultrasound in the management of a non sexual-related penile blunt trauma Andrea Fabiani, Luca Lepri, Emanuele Principi, Cristiana Biondi, Emanuele Rossi, Lucilla Servi

Complete regression of metastatic bladder carcinoma following chemotherapy Alessia Cimadamore, Matteo Tallè, Paola Fulvi, Andrea Benedetti Galosi, Rodolfo Montironi

Contemporary use of pelvic drain after robot assisted radical prostatectomy: is always mandatory?

Simone Scarcella, Lucio Dell’Atti, Andrea BenedettoGalosi

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ORIGINAL

PAPER

Multiparametric MRI/TRUS fusion prostate biopsy: The transperineal approach Pietro Pepe1, Andrea Fandella2, Andrea Benedetto Galosi3 1 2 3

Urology Unit â&#x20AC;&#x201C; Prostate Cancer Unit - Cannizzaro Hospital, Catania, Italy; Urology Unitâ&#x20AC;&#x201C; Giovanni XXIII Clinic, Monastier di Treviso, Italy; Department of Urology, Polytechnic University of Marche, Ancona, Italy.

Objectives: To evaluate the detection rate for clinically significant prostate cancer (csPCa) of transperineal multiparametric MRI/TRUS (magnetic resonance imaging/transrectal ultrasound) fusion targeted biopsy (TPBx). Materials and Methods. We previously reported our experience in the detection for csPCa (Gleason score > 6 and/or more than two positive cores and or GPC > 50%) performing TPBx; from 1032 men (median age 63 years) with negative digital rectal examination and previous negative biopsy underwent repeat transperineal saturation biopsy (SPBx; reference test) for the suspicion of cancer. All the patients underwent pelvic mpMRI and in the lesions characterized by a PI-RADS score > 3 (524 cases) a TPBx (four cores) was added to SPBx. Results: None had significant complications (Clavien-Dindo grade I) from prostate biopsy that needed hospital admission; a T1c PCa was found in 372/1032 (36%) patients and 272 (73.1%) of them were classified as csPCa. The detection rate for overall cancers vs csPCa using SPBx vs TPBx PIRADS > 3 vs TPBx PIRADS > 4 was equal to 90.3 and 95.6% vs 72% and 83.8% vs 48.4 and 60.3%, respectively; SPBx missed 12 (4.5%) suggestive as being csPCa vs 44 (16.2%) and 108 (39.7%) missed by TPBx PI-RADS > 3 and TPBx PI-RADS > 4, respectively. In detail, 40/228 (17.5%) csPCa were diagnosed in the anterior zone of the gland by TPBx. Conclusions: Although mpMRI is mandatory to improve the accuracy of prostate biopsy in the diagnosis of csPCa, still today, the systematic biopsy should be performed, anyway, in addition to targeted cores (PIRADS score > 3) or alone (negative mpMRI) in the presence of clinical parameters suspicious for cancer; in this respect, the transperineal approach reset the risk of sepsis and improve the diagnosis of csPCa located in the anterior zone of the gland.

SUMMARY

KEY WORDS: Prostate cancer; multiparametric MRI; transrectal fusion biopsy; transperineal fusion biopsy; saturation prostate biopsy.

INTRODUCTION Prostate cancer (PCa) is the most frequent tumor diagnosed in older men with more than 1 million biopsies a

year performed in the United States (1). The transrectal prostate biopsy approach is associated with an increased risk of infection with an estimated hospital admission and sepsis equal to 2.5 (3) and 3.5% (4), respectively; in addition, the rate of overdiagnosis in men enrolled in screening protocols is equal to 50% of the cases (2). Therefore, the main goal is to reduce the number of unnecessary biopsies and diagnose only clinically significant PCa. In this respect, multiparametric magnetic resonance imaging (mpMRI) combined with TRUS (transrectal ultrasound) fusion targeted biopsy has improved the accuracy of standard biopsy schemes in detecting clinically significant prostate cancer (csPCa), especially, in case of a repeat biopsy (5-7) and in the reevaluation of men enrolled in active surveillance (AS) programs (8-10). Although the accuracy of mpMRI/fusion targeted biopsy has been evaluated in a lot of series, very few papers have compared the detection rate for PCa or/and complications of the different MRI/TRUS fusion platforms and/or approaches in the same population (11-14); in this respect, the standard transperineal biopsy in comparison with the transrectal procedure has demostrated a higher accuracy in diagnosing PCa located in the anterior zone of the gland (15) resetting the risk of sepsis (16). In this report, the advantages of the transperineal fusion targeted biopsy (TPBx) in the diagnosis of csPCa (17) have been evaluated.

MATERIALS

AND

METHODS

We previously reported our experience in the detection for csPCa performing TPBx (18); from January 2011 to Febraury 2018 1032 men (median age 63 years) with negative digital rectal examination and previous negative biopsy underwent repeat transperineal saturation biopsy (SPBx; reference test) for the suspicion of cancer (increasing or persistently elevated PSA values). All the patients underwent pelvic mpMRI; SPBx (median of 30 cores; range: 28-34 cores) was performed transperineally using a GE Logiq P6 ecograph (General Electric; Milwaukee, WI, USA) supplied with a bi-planar trans-rectal probe (5-7.5 Advances in Urological Diagnosis and Imaging - 2019; 2,2

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P. Pepe, A. Fandella, A.B. Galosi

MHz) using a tru-cut 18 gauge needle (Bard; Covington, GA, USA) under sedation and antibiotic prophylaxis (one tablet daily of levofloxacin 500 mg for 3 days) (18). All mpMRI examinations were performed using a 3.0 Tesla scanner, (ACHIEVA 3T; Philips Healthcare Best, the Netherlands) equipped with surface 16 channels phasedarray coil placed around the pelvic area with the patient in the supine position; multi-planar turbo spin-echo T2weighted, axial diffusion weighted imaging, axial dynamic contrast enhanced MRI were performed for each patient. The mpMRI lesions characterized by a PI-RADS score > 3 were considered suspicious for cancer; moreover, two radiologists blinded to pre-imaging clinical parameters evaluated the mpMRI data separately and independently. In the presence of mpMRI lesions suggestive of cancer (524 cases) a fusion targeted biopsy (four cores) was added to SPBx: cognitive transperineal fusion biopsy in 229 cases, mpMRI TRUS fusion biopsy (GE Logiq E9, General Electric; Milwaukee, WI, USA) in 169 cases and transperineal fusion guided-biopsies (Hitachi 70 Arietta ecograph, Chiba, Japan) in 126 cases, respectively (7); the targeted biopsies of the anterior zone lesions were always performed transperineally. The GE Logiq E9 and Hitachi Arietta 70 platforms allowed processing of a softwarebased rigid registration of pelvic mpMRI and TRUS (endfire probe and biplanar probe, respectively) by the use of a fusion device; moreover, an electromagnetic tracking system showed the needle localization. The data were collected following the START criteria (13).

RESULTS

sity were equal to 45 grams and 0.21 vs. 63 grams and 0.15 in men with PCa vs. normal parenchyma, respectively. A normal parenchyma was diagnosed in the remaining 660/1032 (64%) men. The detection rate for overall cancers vs csPCa using SPBx vs. TPBx PIRADS > 3 vs. TPBx PIRADS > 4 was equal to 90.3 and 95.6% vs 72% and 83.8% vs 48.4 and 60.3%, respectively; in detail, SPBx missed 12 (4.5%) suggestive as being csPCa vs 44 (16.2%) and 108 (39.7%) missed by TPBx PI-RADS > 3 and TPBx PI-RADS > 4, respectively (18). The detection rate for csPCa performing cognitive transperineal fusion biopsy vs transrectal vs transperineal MRI/TRUS fusion biopsy was superimposable and equal to 35.8% (82/229) vs 35.5% (60/152) vs 36.5% (46/126), respectively (18); in detail, 40/228 (17.5%) csPCa were diagnosed in the anterior zone of the gland by transperineal targeted approach. In definitive, in our series (18), mpMRI significantly reduced the number of unnecessary repeat prostate biopsies (about 50% of the cases using a PI-RADS score > 3); on the other hand, our results suggested that the patients should be informed of the significantly false-negative rate for csPCa of TPBx in the presence of PI-RADS > 3 (16.2%) or > 4 (39.7%).

DISCUSSION The improvement of diagnostic imaging by mpMRI has allowed to perform targeted biopsies of suspicious area increasing the accuracy in the diagnosis of csPCa (19) resulting predictive of definitive Gleason score with a higher detection rate of cancer for each core in comparison with standard prostate biopsy schemes.The detection rate for PCa of mpMRI is between 39% and 59% (20) with an incidence of cancer located only in the anterior zone

The median total PSA and prostate weight was 8.6 ng/ml (range: 3.5-46 ng/ml) and 57 grams (range: 20-135 grams), respectively; a mpMRI PIRADS score > 3 vs > 4 was Figure 1. Transperineal stereotactic fusion prostate biopsy. found in 524/1032 (50.7%) vs 272/1032 (26.3%) cases, respectively (18). None had significant complications (Clavien-Dindo grade I) from prostate biopsy that needed hospital admission; moreover, the mpMRI procedure was well tolerated and successfully performed in all cases (men with claustrophobia, cardiac pacemaker and hip replacement were not included in the study). A T1c PCa was found in 372/1032 (36%) patients and 272 (73.1%) of them were classified as csPCa: a Gleason score 3 + 4 vs 4 + 3 vs 4 + 4 vs 4 + 5 was found in 112 (41.1%) vs 60 (22.1%) vs 50 (18.4%) vs 50 (18.4%) cases. The Gleason score was directly correlated with PI-RADS score; moreover, the median prostate weight and PSA den-

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Multiparametric MRI/TRUS fusion prostate biopsy: The transperineal approach

Figure 2. Report of stereotactic transperineal fusion targeted biopsy.

CONCLUSIONS Although mpMRI is mandatory in order to improve the accuracy of prostate biopsy in the diagnosis of csPCa, still today, the systematic biopsy should be performed, anyway, in addition to targeted cores (PIRADS score > 3) or alone (negative mpMRI) in the presence of clinical parameters suspicious for cancer; in this respect, the transperineal approach reset the risk of sepsis and improve the diagnosis of csPCa located in the anterior zone of the gland.

REFERENCES 1. Loeb B, Carter HB, Berndt SI, et al. Complications after prostate biopsy: data from SEE-Medicare. J Urol. 2011; 186:1830-1844.

equal to 20% (21, 22). Although mpMRI is strongly recommended in men candidate to repeat biopsy or enrolled in AS protocols, still today, extended or SPBx should be always combined with mpMRI/TRUS fusion biopsy because the false negative rate of mpMRI (15-20% of PCa with low volume and Gleason score > 7) and the variable diagnostic accuracy reported using the different mpMRI/TRUS fusion biopsy platforms (18). The targeted biopsy of mpMRI suspicious areas could be performed using “in-bore” mpMRI-guidance, real-time mpMRI/TRUS imaging fusion or performing cognitive mpMRI/TRUS biopsies; although the detection rate for csPCa is superimposable performing cognitive vs fusion targeted biopsy (23), many papers have demonstrated a higher accuracy in favour of the fusion technique (24); in fact, the detection rate for csPCa is directly correlated with the expertise of the surgeon and the accuracy of the MRI/TRUS fusion platforms. In addition, few data have been reported regarding the accuracy of transrectal vs transperineal mpMRI/TRUS fusion approach in diagnosing clinically significant PCa (12). In this respect, the two approaches are provided of a superimposable detection rate for PCa, but, at the same time, the transperineal approach allows to easily and better reach the anterior zone of the gland (16, 25) resetting the risk of sepsis (15, 26, 27). The estimated targeting error of transperineal stereotactic biopsies is below 1 millimeter (28); therefore, the higher accuracy in the diagnosis of csPCa using the template combined with stereotactic fusion platforms (Figures 1, 2) improve the accuracy in the reevaluation of men enrolled in Active Surveillance (29) protocols and/or the treatment and reevaluation of men enrolled in clinical trials and candidate to focal therapy (30).

2. Pinkhasov GI, Lin YK, Palmerola R, et al. Complications following prostate needle biopsy requiring or emergency department visits- experience from 1000 consecutive cases. BJU Int. 2012; 110:369-374. 3. Ehdaie B, Vertosick E, Spaliviero M, et al. The impact of repeat biopsies on infectious complications in men with prostate cancer on active surveillance. J Urol. 2014; 191:660-664. 4. Schröder FH, Hugosson J, Roobol MJ, ERSPC Investigators. Prostatecancer mortality at 11 years of follow-up. N Engl J Med. 2012; 366:981-990. 5. Pepe P, Garufi A, Priolo G, Pennisi M. Can 3 Tesla pelvic phase-array MRI avoid unnecessary repeat prostate biopsy in patients with PSA below 10 ng/ml? Clinical Genitourinary Cancer. 2015; 13:e27-30. 6. Roethke MC, Kuru TH, Schultze S, et al. Evaluation of the ESUR PIRADS scoring system for multiparametric MRI of the prostate with targeted MR/TRUS fusion-guided biopsy at 3.0 Tesla. Eur Radiol. 2014; 24:344-352. 7. Pepe P, Garufi A, Priolo G, et al. Prostate cancer detection at repeat biopsy biopsy: can pelvic phased-array multiparametric MRI replace saturation biopsy? Anticancer Res. 2013; 33:1195-1199. 8. Hoeks CM, Somford DM, van Oort IM, et al. Value of 3-T multiparametric magnetic resonance imaging and magnetic resonance-guided biopsy for early risk restratification in active surveillance of low-risk prostate cancer: a prospective multicenter cohort study. Invest Radiol. 2014; 49:165-172. 9. Pepe P, Garufi A, Priolo G, Pennisi M. Can MRI/TRUS fusion targeted biopsy replace saturation prostate biopsy in the re-evaluation of men in active surveillance? World J Urol. 2016; 34:1249-1453. 10. Barrett T, Haider MA. The Emerging Role of MRI in Prostate Cancer Active Surveillance and Ongoing Challenges. AJR Am J Roentgenol. 2017; 208:131-139. 11. Westhoff N, Siegel FP, Hausmann D, et al. Precision of MRI/ultrasound-fusion biopsy in prostate cancer diagnosis: an ex vivo compariAdvances in Urological Diagnosis and Imaging - 2019; 2,2

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P. Pepe, A. Fandella, A.B. Galosi son of alternative biopsy techniques on prostate phantoms. World J Urol. 2017; 35:1015-1022. 12. Pepe P, Garufi A, Priolo G, Pennisi M.Transperineal Versus Transrectal MRI/TRUS Fusion Targeted Biopsy: Detection Rate of Clinically Significant Prostate Cancer. Clin Genitourin Cancer. 2017; 15:e33-e36. 13. Kongnyuy M, George AK, Rastinehad AR, Pinto PA. Magnetic Resonance Imaging-Ultrasound Fusion-Guided Prostate Biopsy: Review of Technology, Techniques, and Outcomes. Curr Urol Rep. 2016; 17(4):32. 14. Rastinehad AR, Abboud SF, George AK, et al. Reproducibility of Multiparametric MRI and Fusion-Guided Prostate Biopsy: MultiInstitutional External Validation by a Propensity Score Matched Cohort. J Urol. 2016; 195:1737-1783.

23. Wegelin O, Exterkate L, van der Leest M, et al. The FUTURE Trial: A Multicenter Randomised Controlled Trial on Target Biopsy Techniques Based on Magnetic Resonance Imaging in the Diagnosis of Prostate Cancer in Patients with Prior Negative Biopsies. Eur Urol. 2019; 75(4):582-590. 24. Cornud F, RoumiguiĂŠ M, Barry de Longchamps N, et al. Precision Matters in MR Imaging-targeted Prostate Biopsies: Evidence from a Prospective Study of Cognitive and Elastic Fusion Registration Transrectal Biopsies. Radiology. 2018; 287(2):534-542.

15. Pepe P, Aragona F. Morbidity following transperineal prostate biopsy in 3,000 patients submitted to 12 VS. 18 VS. more than 24 needle cores. Urology. 2013; 81:1142-1146.

25. Hansen N, Patruno G, Wadhwa K, et al. Magnetic Resonance and Ultrasound Image Fusion Supported Transperineal Prostate Biopsy Using the Ginsburg Protocol: Technique, Learning Points, and Biopsy Results. Eur Urol. 2016; 70:332-340.

16. Pepe P, Dibenedetto G, Pennisi M, et al. Detection rate of anterior prostate cancer in 226 patients submitted to initial and repeat transperineal biopsy. Urol Int. 2014; 93:189-192.

26. Grummet J, Pepdjonovic L, Huang S, et al. Transperineal vs. transrectal biopsy in MRI targeting. Transl Androl Urol. 2017; 6:368-375.

17. Epstein J, Walsh P, Carmichael M. Pathological and clinical findings to predict tumor extent of non palpable (stage T1c) prostate cancer. JAMA. 1994; 271:368-374.

27. Stefanova V, Buckley R, Flax S, et al. Transperineal Prostate Biopsies Using Local Anesthesia: Experience with 1,287 Patients. Prostate Cancer Detection Rate, Complications and Patient Tolerability. J Urol. 2019; 201(6):1121-1126.

18. Pepe P, Garufi A, Priolo GD, et al. Is it time to perform only MRI targeted biopsy? Our experience in 1032 men submitted to prostate biopsy. J Urol. 2018; 200:774-778. 19. Shoji S. Magnetic resonance imaging-transrectal ultrasound fusion image-guided prostate biopsy: Current status of the cancer detection and the prospects of tailor-made medicine of the prostate cancer. Investig Clin Urol. 2019; 60(1):4-13. 20. Fandella A, Scattoni V, Galosi A, et al. Italian prostate biopsies group. Anticancer Res. 2017; 37:413-424. 21. Filson CP, Natarajan S, Margolis DJ, et al. Prostate cancer detection with magnetic resonance-ultrasound fusion biopsy: The role of systematic and targeted biopsies. Cancer. 2016; 122:884-892.

CORRESPONDENCE Pietro Pepe, MD Urology Unit - Cannizzaro Hospital, Via Messina 829, Catania, Italy E-mail: piepepe@hotmail.com Phone: + 39 957263285 Fax: + 39 957263259

22. Pepe P, Pennisi M. Prostate Cancer Diagnosis and Management Across Twenty Years of Clinical Practice: A Single-center Experience on 2,500 Cases. Anticancer Res. 2019; 39:1397-1401.

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28. Kuru TH, Roethke M, Popeneciu V, et al. Phantom study of a novel stereotactic prostate biopsy system integrating preinterventional magnetic resonance imaging and live ultrasonography fusion. J Endourol. 2012; 26:807-13. 29. Voss J, Pal R, Ahmed S, et al. Utility of early transperineal templateguided prostate biopsy for risk stratification in men undergoing active surveillance for prostate cancer. BJU Int. 2018; 121:863-870. 30. Mortezavi A, Krauter J, Gu DA, et al. Extensive histological sampling following focal therapy of clinically significant prostate cancer with highintensity focused ultrasound. J Urol. 2019 May 1:101097JU0000000000000298. [Epub ahead of print]

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ORIGINAL PAPER

How much for the fusion biopsy. Cost analysis of the prostate ultrasound guided biopsy in the era of multiparametric MRI, preliminary results Andrea Fandella1, Pietro Pepe2 1 2

Divisione Urologia – casa di Cura Rizzola San Donà di Piave - Ve, (Italy); Prostate Cancer Unit - Urology Unit - Cannizzaro Hospital Catania, (Italy).

Introduction. Prostate cancer has an important incidence and mortality yet the best diagnostic procedure is to be defined. The latest scientific works aim at the use for diagnostic purposes of multiparametric magnetic resonance (mpMRI) according to the Pirads 2 criteria. The aim of the work is to quantify the overall cost of the diagnosis obtained with the use of mpMRI before the transrectal eco-guided prostate biopsy and to evaluate the economic impact of some current-use prostate biopsy strategies such as cognitive fusion biopsy, software fusion and with the Target or Target strategy with a systemic scheme. Material and methods. The total cost of mpMRI-guided transrectal biopsy was determined by referring to the experience of 289 procedures performed in 2017. The following cost factors were assessed: personnel, materials, maintenance - equipment depreciation, energy consumption and common costs of structure. A review of the literature was also performed to verify the correspondence of the costs that we extrapolated with those of other international operating entities and to consider the “cost of the mpMRI-guided transrectal agobiopsy” in the context of the broader debate on the effectiveness of the strategies for the early diagnosis of prostate cancer. Results. The overall cost of the transrectal mpMRI guided biopsy was 531,00 if performed with cognitive fusion; data obtained by adding together the costs of: personnel (E. 243,00); materials (E. 178,00); maintenance - depreciation of equipment (E. 72.30); energy consumption (E. 0.20); general costs of hospital care (E. 37.500), to be added the cost of amortization of hardware and software for computer-assisted fusion, this depends on the initial purchase cost and the number of annual biopsy procedures, if the ultrasound is not dedicated only to biopsies but is also used for other procedures the costs are spread over a greater number of procedures and so they go down. It can be assumed that for 300 procedures a year the impact of a fusion machine can add from 40 to 120 E to each procedure according to the initial cost of the machine, maintenance, any dedicated consumables, and operator time.

SUMMARY

KEY WORDS: Prostate cancer, fusion biopsy, ultrasound, mpMRI. No conflict of interest declared.

INTRODUCTION The literature review points out transrectal ultrasound guided biopsy (TRUSB) as an invasive tool for diagnosing prostatic carcinoma clinically and economically controversial. Post mortems report the presence of cancer cells in the prostate of 50% of 70-year-old men, while extrapolations calculate a morbidity from prostatic carcinoma in 9.5% of 50-year-old men (1, 2). It is therefore obvious that randomised prostatic biopsies, methods apart, have a good probability of being positive (1, 2). This probability varies with the patient\quote and age, the level of prostate specific antigen (PSA), the density of PSA/cm3 of prostate volume (PSAD), detection by digital exploration and/or positive transrectal ultrasound (2). Despite severe application of all these criteria and critical assessment of the patient\quotes general conditions, TRUSB was indicated for 16% of the male population over 50 years old, with obvious economic consequences (1, 2). The introduction of multiparametric Magnetic Resonance Imaging of the prostate (mpMRI) is deeply changing the diagnostic path for prostate cancer (3-9). A biopsy is the only way for a definitive diagnosis of prostate cancer (1). In Italy the cost of transrectal prostate biopsy was calculated in 1998 and based on the sextant scheme in use in those years and the “Lire” the old Italian currency (10). Then It was calculated the costs in Euro in 2011 ( 11) The purpose of this study was to assess how the introduction mpMRI, and the platform for fusion biopsy have affected the costs of the procedure. The procedure need a mpMRI analized by an expert Radiologist, the biopsy device, with or without a fusion device a transrectal ultrasound probe, the needle and some disposable items (glove, plastic sheet, needle guidance, gel). The full cost to perform the biopsy is the sum of the costs of all resources involved in performing this biopsy method. The cost of mpMRI is the real cost of the execution of the Advances in Urological Diagnosis and Imaging - 2019; 2,2

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A. Fandella, P. Pepe.

procedure, the costs of personnel and the amortization of the hardware used for other procedures (12, 13). Were analyzed and reported costs of each element that is involved in fusion prostatic biopsy separately.

METHODS The total cost of mpMRI -guided biopsy was determined referring to the experience on 289 procedures run in 2017; with standard 12 samples plus 2-4 target biopsy, we calculated the cost of target only biopsy too, there were evaluated the following cost factors: personnel, materials (principals,drugs and films), maintenance and depreciation of equipment, energy consumption and cost of the property (imputed rent of the premises and participation in the overall costs of the hospital). All resource costs involved in the process were calculated on a purchasing power of the EURO 2017. Indirect costs such as lost work time from the patient, the cost related to the loss of free time, the cost of transporting the patient, the time to reach the hospital and the costs related to complications were not calculated. This kind of costs are theoretical and go further the purpose of this analysis and dealing with uncertainty are very difficult to estract. So only direct costs are examined (12, 13). As for the cost of personnel, are involved in the procedure as more professionals, it’s down in the detail of the implementing rules by identifying, for each individual operator, 3 phases of activity: 1) a preliminary examination, such as the acceptance (phase A); 2) real execution (phase B); 3) after execution, such as reporting (phase C). For each of these phases and for each professional has been computed the execution time, its cost and the cost

arising from the sum of all these phases and operators: cost of direct labor (13). The execution time of mpMRI ultrasound-guided biopsy was set at optimal operating conditions: cooperative patient, experienced operator, logistics and environmental well suited. In addition to the cost of work done for the direct execution of the procedure (direct labor costs) were also counted any additions or corrections due to operational difficulties for patients poorly collaborating to unpredictable environmental disruptions, weariness of the professionals operating (cost of average time burden). Finally it was also considered the cost of time to activities not directly related to the execution of the procedure, but indispensable to the life and service management: inventory management, archive, scientific activities, updating, management (labor costs indirect) (12, 13). It ‘was also carried out a review of the literature in order to verify the correspondence of our data compared with those of other international and operational realities that figure “cost fusion biopsy ultrasound-guided” in the context of the broader debate about the’ cost-effectiveness of strategies for early detection of prostate cancer (14-20).

RESULTS The overall cost of TRUS-guided prostate biopsy (12 sample) without mpMRI and fusion devices, was still around € 250 euro as in 2011 (11) (Table 1). In detail, personnel costs are € 98.40 for the results of direct business, which must be added € 34.80 for corrective (average cost of a burden) and more € 26.80 for the indirect business. These data were obtained by adding up the costs of: a) personnel (doctor sampler, pathologist, pathology technician,nurse and secretary) of E. 160,000; b) materials (cutting needle, syringe, gloves, prepared slides; and 8 tablets of cotrimoxazole) equal to E. 59,000 (addi-

Table 1. Overall costs of systematic and targeted prostate biopsy (cognitive vs mpMRI/TRUS fusion procedure).

Procedure costs EURO (€)

Systematic prostate biopsy (12 cores) €

Targeted “cognitive” fusion biopsy €

mpMRI/TRUS fusion biopsy €

Personell*

160.00

243.00

Materials**

78.00

178.00

maintenance and depreciation of equipment

12.30

72.30

energy consumption°

0.20

overhead costs of the hospital°°

17.50

27.5

energy consumption

0.20

49/120.00

250.50

531.00

571/651.00

Ultrasound fusion device/platform Overall cost €

*doctor sampler, pathologist, pathology technician, nurse and secretary; ** cutting needle, ultrasound, optical microscope, computer, printer, furnishing of the premises, syringe, gloves, prepared slides and antibiotic; °ultrasound, optical microscope, computer, printer, furnishing of the premises; °°proportion of use of the ambulance service, anesthesia and resuscitation service, salaries of health care and administrative leadership

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How much for the fusion biopsy. Cost analysis of the prostate ultrasound guided biopsy in the era of multiparametric MRI, preliminary results

tional 19,000 are added to E if the appeals echogenic needle Chiba; c) maintenance and depreciation of equipment (ultrasound, optical microscope, computer, printer, furnishing of the premises, etc.) equal to E.12,300; d) energy consumption at a flat rate of E. 0,20; e) overhead costs of the hospital (proportion of use of the ambulance service, anesthesia and resuscitation service, salaries of health care and administrative leadership, etc.) equal to E. 17,500. In detail, personnel costs are 98,400 euros for the results of direct business, which must be added E. 34,800 for corrective (average cost of a burden) and more E. 26,800 for the indirect business. In the case of supplementary biopsies, exceeding the maximum of 12 standardized methodology “to the sextant,” there was a relative increase in costs due to increased unloading time and reading time. In fact, this possibility of little impact on the average total duration of the sampling procedures and preparation of samples will be prepared if you sent in the box associated with the transport (up to 3 carrots for “cage”, so do not affect the average total consumption of materials and of medical devices, its cost has been calculated under “corrective” to direct work. It would be calculated in about E 20,00 more expense, bringing the total sum at E. 270,00 for the procedure. The average cost for mpMRI was 281 E (staff cost Radiologist and radiologic technician 163,00 E, equipment cost (119,00 E). Results. The overall cost of the transrectal mpMRI guided biopsy was 531,000 if performed with cognitive fusion; data obtained by adding together the costs of: personnel (E. 243,000); materials (E. 178,000); maintenance - depreciation of equipment (E. 72.300); energy consumption (E. 0,20); general costs of hospital care (E. 37.500), to be added the cost of amortization of hardware and software for computer-assisted fusion, this depends on the initial purchase cost and the number of annual biopsy procedures, if the ultrasound is not dedicated only to biopsies but is also used for other procedures the costs are spread over a greater number of procedures and so they go down. It can be assumed that for 300 procedures a year the impact of a fusion platform can add from 40,00 to 120,0 E to each procedure according to the initial cost of the machine, maintenance, any dedicated consumables, and operator time that it is usually tripled in the fusion method (loading of the mpMRI exam, extrapolation of the images, choice of target, synchronization of the mpMRI and ultrasound images).

DISCUSSION The total cost of mpMRI cognitive fusion biopsy (21, 23) is in our esperienze E. 531 E, substantially corresponding to data reported in the literature (24). For diagnostic tests and staging methods, the variations in the resource costs between the United States and other countries were mixed. The pooled baseline resource costs

were 2.3 times higher in the United States than in other countries (24). The item that affects more (64%) between the cost factors is related to personnel; on this item will therefore focus attention on identifying and streamlining procedures to reduce spending, especially with regard to the corrective work is directed (14% of total) and indirect (10%). Another possible area of spending restraint, certainly more effective, is the rational use for mpMRI: in this sense moves the search for guidelines in the diagnosis of prostate cancer (1). The inclusion of fusion biopsy mpMRI-guided as a step in a protocol of early diagnosis of prostate cancer is controversial from economic points of view (5-7), because reported resource costs for performing biopsy and clinical staging represented combined resource costs from several procedures, they should be interpreted with caution. Furthermore, reported resource costs for performing mpMRI and/or biopsy did not include the cost of complications resulting from these procedures. It has been reported that complication costs are directly correlated to the biopsy rate. Resource costs associated with complications arising from biopsy should be reported separately from those for diagnostic procedures because the cost of complications depends on the number of infections, which ranges from 5% to 6%, and their severity (25, 26). The only way to reduce costs is reducing the number of negative (useless biopsy), in this way mpMRI could give some help (8, 9). The actual costs for the average patient seeking a first-line biopsy would actually include: • The costs for the initial MRI; • The costs for the evaluation of the results of that MRI (as evaluated by an experienced and skilled uroradiologist); • The costs for the systematic, 12-core, TRUS-guided biopsy, and; • The costs for the MRI/TRUS fusion-guided biopsy. Despite the rigorous application of all these criteria and the critical evaluation of the general state of the patient, as many as 16% of the male population over 50 years old only with PSA and the rectal findings maintain the indication to the eco-guided transrectal agobiopsy prostate, which has a reasonable economic weight. Recently, the use of mpMRI as a strategy to reduce the use of biopsy and increase its diagnostic efficacy would appear to be of clinical utility. We have calculated the costs of this approach. It is more difficult to calculate the effects of this approach at a distance, to check whether reducing the number of samples obtained reduces complications. If you decide not to biopsy negative mpMRI patients (21% or more of the population examined) the savings would be 250 E per patient (calculated on all patients who would have been biopsy candidates). Reducing the number of samples obtained at each biopsy would halve the costs of pathological anatomy. These phases are evaluated and an aggregate risk for a particular lesion being cancerous is given by the radiologist, commonly as a PI-RADs score (6). Using this score, MRI provides an accurate diagnostic tool in prostate cancer with high specificity for high grade disease (6). The negative predictive value of MRI also provides an opportunity to Advances in Urological Diagnosis and Imaging - 2019; 2,2

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A. Fandella, P. Pepe.

delay or avoid a biopsy in cases where no lesion is detected (8, 9). This could reduce both the cost of the biopsy and the potential risk of serious complications, such as sepsis, whose incidence is rising due to increasing rates of quinolone resistance (25, 26). Post-biopsy sepsis, while rare, is serious for those patients affected and costly to the healthcare system (27). Many cost studies assume that MRI negative patients would not undergo biopsy, however omission of systematic ultrasound guided biopsies may miss relevant cancers and may not reflect real-world practice (15). An earlier Dutch study examined the cost case of using MRI and in bore MRI-guided biopsy as the primary initial diagnostic modality in the management of prostate cancer and found the approach to be nearly cost-equivalent to current management with a significant improvement in QALYs. A number of assumptions in this study may limit its generalizability including the low costs associated with multiparametric MRI (€300) and MRI-guided prostate biopsy (€800) (4). Another concern with the current models is that they assume that no biopsy is performed on men with negative imaging. The impact of “missed cancer” will need to be assessed in prospective studies. External to the issue of cost is that of value derived by the patient, especially in the indication of initial biopsy; even if an MRI-based initial evaluation of prostate cancer is noncost effective it may still be desirable as approximately one third of ultrasound biopsies are upgraded when subsequently evaluated with MRI guidance (7). Studies of mpMRI guided biopsy in men with prior negative ultrasound biopsy have shown an increased rate of detection of high grade tumors, especially in the anterior prostate, a region often poorly sampled in ultrasoundguided biopsy (28). A study from 2015 showed both cost savings in using MRI to inform repeat biopsy and that a large portion of repeat biopsies could be avoided (16). In patients undergoing mpMRI-guided biopsy after negative prior biopsy the possibility of avoiding systematic (non-targeted) biopsies as a cost saving measure has been raised. This approach should be used with caution as it appears that systematic biopsies still add value and detect some clinically relevant cancers in this setting (15). As MRI techniques continue to refine and MRI use in prostate cancer management grows, MRI before repeat prostate biopsy is likely to become increasingly common. Three different cost analyses of prostate MRI used different costs for MRI. A study from a Dutch group used a cost of MRI at €345, an American study using medicare reimbursement rates of $524 and a Canadian study using hospital expense of $900 (16, 17, 28). The determination of baseline costs can result in significantly different conclusions especially if one considers using MRI in every patient with an elevated PSA. Such factors may limit the ultimate conclusion of a cost analysis to its nation of origin. In many healthcare environments, the limiting factor for MRI use may not be cost but availability (29). The purest form of utilizing MRI information in prostate biopsy is performing multiparametric MRI and subsequent in-bore MRI-guided biopsy of suspicious lesions. While this approach demonstrates high quality performance characteristics (30), resource availability will likely limit its

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widespread use. An intermediate option is the use of MRIultrasound fusion hardware and software packages that allow the MRI data to be superimposed over live ultrasound images, guiding the provider during the biopsy. The utility of MRI-fusion software and hardware is itself a point of controversy. In theory a provider could review relevant MRI images and target a region of interest using ultrasound guidance, a practice used elsewhere in the body for the biopsy of metastases. This practice of viewing the MRI and targeting with ultrasound is generally referred to as “cognitive fusion” (31). The fusion approach involves use of software that overlays an MRI image on a “realtime” ultrasound image allowing assessment of the accuracy of the biopsy in relation to the MRI. A 2015 study in an ex vivo model showed greatly improved detection of relevant lesions using MRI machine-based fusion versus cognitive fusion (22), however a prospective, blinded inhuman study failed to show a difference in cancer detection between the two modalities (21). Similar results were found in another in-human 2013 prospective study which found no difference in cancer detection between machine-based fusion and cognitive fusion (23).

CONCLUSIONS mpMRI fusion biopsy is becoming the accepted method for diagnosing prostate cancer that allows the most cost/effective beneficial when done with proper instructions. The costs (531,00 E + 40,00 - 120,00 E for fusion platform each patient) are a problem as the availability of mpMRI and of skilled uroradiologists, but we urologists have to be prepared to face this challenge, so the health system.

REFERENCES 1. Fandella A, Scattoni V, Galosi A, et al. Italian Prostate Biopsies Group: 2016 Updated Guidelines Insights. Anticancer Res. 2017; 37:413-424. 2. Cooner WH, Mosley BR, Rutherford CL Jr, et al. Prostate cancer detection in a clinical urological practice by ultrasonography, digital rectal examination and prostate specific antigen. J Urol. 1990; 143:1146-54. 3. Thompson JE, Moses D, Shnier R, et al. Multiparametric magnetic resonance imaging guided diagnostic biopsy detects significant prostate cancer and could reduce unnecessary biopsies and over detection: a prospective study. J Urol. 2014; 192: 67-74. 4. Fütterer JJ, Briganti A, De Visschere P, et al. Can clinically significant prostate cancer be detected with multiparametric magnetic resonance imaging? A systematic review of the literature. Eur Urol. 2015; 68: 1045-1053. 5. Weinreb JC, Barentsz JO, Choyke PL, et al. PI-RADS Prostate Imaging-Reporting and Data System:2015,Version 2. Eur Urol. 2016; 69:16-40. 6. de Rooij M, Hamoen EH, Fütterer JJ, et al. Accuracy of multiparametric MRI for prostate cancer detection: a meta-analysis. AJR Am J Roentgenol. 2014; 202:343-51. 7. Siddiqui MM, Rais-Bahrami S, Truong H, et al. Magnetic resonance imaging/ultrasound-fusion biopsy significantly upgrades prostate can-

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How much for the fusion biopsy. Cost analysis of the prostate ultrasound guided biopsy in the era of multiparametric MRI, preliminary results cer versus systematic 12-core transrectal ultrasound biopsy. Eur Urol. 2013; 64:713-9.

ic transrectal ultrasound, direct in-bore MRI, and image fusion. AJR Am J Roentgenol. 2017; 22:1-6.

8. Veeru Kasivisvanathan, Antti S. Rannikko, Marcelo Borghi, et al. PRECISION Study Group Collaborators* MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis N Engl J Med. 2018; 378:1767-1777.

20. Hutchinson R, Lotan Y. Cost consideration in utilization of multiparametric magnetic resonance imaging in prostate cancer. Transl Androl Urol. 2017; 6(3):345-354.

9. Hashim U Ahmed, Ahmed El-Shater Bosaily, Louise C Brown, et al. PROMIS study group† Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study Lancet. 2017; 389(10071):815-822. 10. Bissoli E, Fandella A, La Torre E, et al. Cost analysis of ultrasoundguided transrectal needle biopsy in prostatic carcinoma. Radiol Med. 1998; 95(4):353-6. 11. Fandella A. Analysis of costs of transrectal prostate biopsy. Urologia. 2011; 78:288-92. 12. Gold MR, Siegel JE, Russell LB, Weinstein MC, et al. Cost-effectiveness in health and medicine. New York (NY): Oxford University Press; 1996. 13. Dalla Palma F, Peterlongo P, Moser E, et al. Il controllo di gestione nelle Unità Operative di /Radiologia Diagnostica. Promosan, Trento, 1994. 14. de Rooij M, Crienen S, Witjes JA, et al. Cost-effectiveness of magnetic resonance (MR) imaging and MR-guided targeted biopsy versus systematic transrectal ultrasound-guided biopsy in diagnosing prostate cancer: a modelling study from a health care perspective. Eur Urol. 2014; 66:430-6. 15. Salami SS, Ben-Levi E, Yaskiv O, et al. In patients with a previous negative prostate biopsy and a suspicious lesion on magnetic resonance imaging, is a 12-core biopsy still necessary in addition to a targeted biopsy? BJU Int. 2015; 115:562-70. 16. Lotan Y, Haddad AQ, Costa DN, et al. Decision analysis model comparing cost of multiparametric magnetic resonance imaging vs. repeat biopsy for detection of prostate cancer in men with prior negative findings on biopsy. Urol Oncol. 2015; 33:266.e9-16. 17. Cerantola Y, Dragomir A, Tanguay S, et al. Cost-effectiveness of multiparametric magnetic resonance imaging and targeted biopsy in diagnosing prostate cancer. Urol Oncol. 2016; 34:119.e1-9. 18. Barnett CL, Davenport M, Montgomery JS, et al.Cost-effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer. BJU Int. 2018; 122(1):50-58. 19. Venderink W, Govers TM, de Rooij M, et al. Cost-effectiveness comparison of imaging-guided prostate biopsy techniques: systemat-

21. Wysock JS, Rosenkrantz AB, Huang WC, et al. A prospective, blinded comparison of magnetic resonance (MR) imaging-ultrasound fusion and visual estimation in the performance of MR-targeted prostate biopsy: the PROFUS trial. Eur Urol. 2014; 66:343-51. 22. Cool DW, Zhang X, Romagnoli C, et al. Evaluation of MRI-TRUS fusion versus cognitive registration accuracy for MRI-targeted, TRUSguided prostate biopsy. AJR Am J Roentgenol. 2015; 204:83-91. 23. Puech P, Rouvière O, Renard-Penna R, et al. Prostate cancer diagnosis: multiparametric MR-targeted biopsy with cognitive and transrectal US-MR fusion guidance versus systematic biopsy-prospective multicenter study. Radiology. 2013; 268:461-9. 24. Haffner J, Lemaitre L, Puech P, et al. Role of magnetic resonance imaging before initial biopsy, comparison of magnetic resonance imaging-targeted and systematic biopsy for significant prostate cancer detection BJU int. 2011; 108:1-8. 25. Loeb S, Vellekoop A, Ahmed HU, et al. Systematic review of complications of prostate biopsy. Eur Urol. 2013; 64:876-92. 26. Roth H, Millar JL, Cheng AC, et al. The state of TRUS biopsy sepsis: readmissions to Victorian hospitals with TRUS biopsy-related infection over 5 years. BJU Int. 2015; 116(Suppl 3):49-53. 27. Adibi M, Hornberg B, Bhat D, et al. Reduction in hospital admissionrates due to post-prostatte biopsy infections after augmenting standard antibiotic prophylaxis. JUrol. 2013; 189: 35-40. 28. Radtke JP, Boxler S, Kuru TH, et al. Improved detection of anterior fibromuscular stroma and transition zone prostate cancer using biparametric and multiparametric MRI with MRI-targeted biopsy and MRI-US fusion guidance. Prostate Cancer Prostatic Dis. 2015; 18:288-96. 29. Emery DJ, Forster AJ, Shojania KG, et al. Management of MRI wait lists in Canada. Healthc Policy. 2009; 4:76-86. 30. Pokorny MR, de Rooij M, Duncan E, et al. Prospective study of diagnostic accuracy comparing prostate cancer detection by transrectal ultrasound-guided biopsy versus magnetic resonance (MR) imaging with subsequent MR-guided biopsy in men without previous prostate biopsies. Eur Urol. 2014; 66:22-9. 31. Puech P, Ouzzane A, Gaillard V, et al. Multiparametric MRI-targeted TRUS prostate biopsies using visual registration. Biomed Res Int. 2014; 2014:819:360.

CORRESPONDENCE Andrea Fandella, MD Divisione Urologia Casa di Cura Rizzola San Donà di Piave Ve Via Gorizia, 1 - 30050 San Donà di Piave (VE) Italy E-mail: afandella@libero.it

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C ASE REPORT

Association between urological and cardiovascular malformations in non-identical twins Clelia Tripaldi1, Marcello Campagna2, Ottavio Colamonico2, Alessandro Mastrorosa2, Pasquale Martino3, Silvano Palazzo2 1 2 3

UOSVD Pediatria, Ospedale “San Giacomo”, Monopoli, ASL BA - (Italia); UOC Urologia, Ospedale “A. Perrino”, Brindisi, ASL BR - (Italia); Università degli Studi di Bari.

It has long been known that in twins the incidence of congenital abnormalities is greater than in single newborns. This occurs especially in monochorionic ones. The higher incidence of hypospadias in monozygotic twins has already been described and so also the association between hypospadias and heart anomalies. We illustrate the case of two twin brothers both affected by hypospadias, whose clinical history represents an example of association between minimal anomalies of cardiovascular system and hypospadias in twins. The first fetus had first degree hypospadias and unique umbilical artery, while the second one presented first degree hypospadias and bilateral cryptorchidism. In the first twin echocardiogram was normal. In the second baby echocardiogram had been diagnosed oval forame patency. The interest in this case we reported is linked to the association between a concordant urogenital malformation (phenotypically identical first degree hypospadias) and a minor anomaly of cardiovascular apparatus, different in the two infants (single umbilical artery in a twin and oval forame patency in the other), in two dichorionic twins.

SUMMARY

KEY WORDS: Congenital abnormalities, twins, hypospadias.

INTRODUCTION It has long been shown that in twin pregnancies the incidence of congenital abnormalities is greater than in singleton ones (1). This is particularly the case for monozygotic twins, as in the dizygotic this incidence does not differ significantly from the single newborns (1, 2). The malformative pathology that can be observed in multiple pregnant women is very heterogeneous, both in clinical and eziopathogenetic terms, including similar conditions to single and other typical of multiple pregnancies (3). In some cases, the twins have the same malformation and are therefore defined as concordant; they are discordant

Advances in Urological Diagnosis and Imaging - 2019; 2,2

when one only has morphogenetic defects or both have congenital abnormalities, which are distinguishable, however, from the clinical and embryological point of view (4). The rate of concordance varies widely in relation to the type of twin pregnancy and the etiopathogenesis of the defect (4, 5). Monozygotic twins are gender-compatible and phenotypic, but full 100% concordance can only be theoretical in relation to possible genotypic differences or the role of environmental factors in different modes and at different moments (4). The prototype of phenotypic discordance for malformations between monozygotic twins is represented by vascular disruption that results in absolute discordance for phenotypic and prognosis characteristics (6). In recent years, thanks to the records for congenital malformations, it has been possible to document an increased risk of malformations in the in-vitro fertilization techniques (7) This increase is extreme in the different cases and according to the type of anomaly considered. Numerous factors seem to contribute, both intrinsic to the couple with hypofertility, and related to the medically assisted procreation method used. In particular, with the increasing spread of intracytoplasmic sperm injection, a significant role has been attributed to the absence of natural selection of male gamete (6, 7). More recently, the possibility that the manipulation and conservation of gametes and embryos, which occurs with assisted procreation, interferes with essential epigenetic mechanisms for early stages of the replanting stage and for the proper development of the embryo and fetus (8). The conservation and culturing conditions of gametes and embryos may result in modification of DNA methylation and chromatin structure, thereby increasing the risk of pathologies due to altered expression of imprinted genes (9). The clinical history we describe, represents a synthesis of all possible malformative problems associated with hypospadias in twins. Anomalies most commonly associated with hypospadias in bicorial twins, in 10% of the cases are urogenital tract pathologies (unilateral renal agenesis,

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Association between urological and cardiovascular malformations in non-identical twins

bladder-ureter reflux, pyelo-ureteral joint stenosis, megaureters). Malformations of the urogenital apparatus, in a variable percentage of non-syndromic cases, are associated with malformations of the cardiovascular and musculoskeletal system (3, 5). Hypospadias is a congenital malformation with multifactorial etiology, whose incidence has increased considerably in recent years (7). It represents a defect in the virilization of external genitalia in the embryo, and as such may have several manifestations ranging from major anatomical alterations to minimal abnormalities such as the foreskin (7). The key element in its genesis consists in stopping the closure of the urethral shower, resulting in incomplete formation of the urethra (9). This central anomaly is associated with alterations of the other constituent elements of the penis, such as buck band development, dartos, and cute of ventral penis. There are various levels of hypospadias, which in the most serious forms can lead to erroneous gender attribution if they are not properly evaluated. Malformation affects 1 out of 300 males born (8, 10). There is no mendelian transmission of this defect. The family trend has hypothesized through retrospective studies a model of autosomal multifactorial inheritance with varying penetration, so for every affected child there is 20% of the chance of having another affected first degree family (11). Frequent is the association with other urogenital pathologies, which are present in about 3-15% of cases (5).

Figure 1. The first twin.

Figure 2. The second twin.

CASE REPORT We describe the case of a pair of twins affected by hypospadias admitted to our neonatal nursery. The twins were born from mother at first pregnancy, with caesarean section at 36th week of gestation. The pregnancy was spontaneous, bicameral, with negative maternal infection history. The ultrasound determination of sex during 20week ultrasound was remarkably difficult in both twins. The first fetus, with adequate weight for the gestational age, feet presentation, had a unique umbilical artery and first degree hypospadias (Figure 1). The second fetus, small for gestational age, cephalic presentation, presented first degree hypospadias and bilateral cryptorchidism (Figure 2). For the presence of hypospadias and other associated malformations (single umbilical artery in the first twin and cryptorchidism in the second), both infants were submitted to diagnostic examinations such as urinary ultrasound, brain ultrasound and echocardiogram during the first week of life. In the first twin, which had a unique umbilical artery, brain, heart and urinary ultrasound had been found in the standard. In the second twin, which featured bilateral cryptorchidism, ultrasound of the brain, and urinary tract were normal, while echocardiogram had been diagnosed with oval foramen patency.

DISCUSSION The possible inheritance at the base of the association between cryptorchidism and hypospadias in patients with

both pathologies had already been reported by examining twin populations, but without a definite conclusion (12). Of all the congenital anomalies associated with hypospadias in twins, those of the urogenital apparatus are undoubtedly the most common, along with those of the cardiovascular apparatus (10). Several studies have reported the association of hypospadias, premature births and low birth weight, all of these phenomena as an expression of reduced androgenic recruitment (11). According to the court study published by Schnack in 2008, the risk of family recurrence of hypospadias among twin brothers would be 50.8%, and would gradually decrease in the first, second and third degree relatives. In this study, however, the risk of recurrence was not related to the chronicity (10). Instead, according to the Visser study of 2015, the incidence of hypospadias in monochorionic twins would be four times Advances in Urological Diagnosis and Imaging - 2019; 2,2

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C. Tripaldi, M. Campagna, O. Colamonico, A. Mastrorosa, P. Martino, S. Palazzo.

greater than in dichorionic (9). The association of hypospadias with malformations of the cardiovascular apparatus has already been described in monochorionic twins, particularly aortic coarctation. The prevalence of the single umbilical artery in twins is approximately three times higher than single pregnancies (8, 10). The uniqueness of the clinical case we reported is due to the association of a phenotypically identical urogenital malformation (first degree hypospadias) in combination with an anomaly of cardiovascular apparatus, different in the two infants (single umbilical artery in a twin and oval forame patency in the other), in two non-monochorionic twins. Therefore, the first twin, weight-appropriate for the gestational age, with hypospadias and unique umbilical artery had a double risk factor for the hypospadias itself, familiarity and unique umbilical artery. The anatomy of the penile lesion (first degree hypospadias) was absolutely identical in the two babies, although they were bichorionic and biamniotic. Unfortunately, no genetic investigation has been carried out in this case (4, 6).

REFERENCES 1. Corsello G, Giuffrè M, Piccione M. Newborn with multiple congenital anomalies: diagnostic classification and nosology. The Doctor and the Child. Vol 43, n. 171, pag 149-157.

CORRESPONDENCE Silvano Palazzo UOC Urologia, Ospedale “A. Perrino”, Brindisi, ASL BR- Italia e-mail: silvano.palazzo@alice.it

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2. Klatt J, et al. Single umbilical artery in twin pregnancies. Ultrasound Obstet nGynecol. 2012; 39(5):505-9. 3. HsiehMH, Alonzo DG, Gonzales ET, et al. Ex-premature infant boys with hypospadias are similar in size to age-matched, ex-premature infant boys without hypospadias. Journal of Pediatric Urology. 2011; 7, (5):543-547. 4. Beleza-Meireles A, Lundberg F, Lagerstedt K, et al. FGFR2, FGF8, FGF10 and BMP7 as candidate genes forhypospadias. Eur J Hum Genet. 2007; 15(4):405-10. 5. Schnack TH, Poulsen G, Myrup C, et al. Familial coaggregation of cryptorchidism and hypospadias. Epidemiology. 2010; 21(1):109-13. 6. Remco V, Nienke C, Burger M et al. Higher incidence of hypospadias in monochorionic twins. Twin Research and Human Genetics. 2015; 18 (5): 591-594. 7. Ramos-Arroyo MA. Birth defects in twins: study in a Spanish population. Acta Genet Med Gemellol (Roma).1991; 40(3-4):337-44. 8. Van Nesselrooii BP, Spliet W, Beemer FA. Unusual association of congenital malformations:craniosynostosis, heart defect, abnormal intestinal innervations and urogenital abnormalities. Clin Dysmorphol. 1998; 7(1): 51-3. 9. Visser R, et al. Higher Incidence of Hypospadias in Monochorionic Twins. Twin Res Hum Genet. 2015; 18(5):591-4. 10. Schnack TH1, Zdravkovic S, Myrup C, et al. Familial aggregation of hypospadias: a cohort study. Am J Epidemiol. 2008; 167(3):251-6. 11. Weidner IS1, Møller H, Jensen TK, Skakkebaek NE. Risk factors for cryptorchidism and hypospadias. J Urol. 1999; 161(5):1606-9.

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Ultrasound in the management of a non sexual-related penile blunt trauma Andrea Fabiani1, Luca Lepri2, Emanuele Principi2, Cristiana Biondi3, Emanuele Rossi4, Lucilla Servi5 1

Section of Urology ASUR Marche Area Vasta 3, Macerata Hospital, (Italy); Surgery Dpt, Section of Urology, ASUR Marche Area Vasta 3, Macerata Hospital, (Italy); 3 Emergency Dpt, ASUR Marche Area Vasta 3, Macerata Hospital, (Italy); 4 Emergency Dpt, Chief of Emergency Room, ASUR Marche, Area Vasta 3, Macerata Hospital, (Italy); 5 Surgery Dpt, Chief of Section of Urology ASUR Marche Area Vasta 3, Macerata Hospital, (Italy). 2

Penile albuginea fracture of the corpora cavernosa is a relatively uncommon emergency. It results from a blunt trauma that commonly mandates immediate surgical exploration. Urethral injury may also accompany penile fracture. Frequently, it is a sexual intercourse the situation in which the trauma occurs, but it is reported the possibility of a non sex-related penile trauma. Although the diagnosis of penile fracture is mainly clinical imaging can play a role in confirming it, identifying the exact location of the tunica tear and ruling out the presence of urethral involvement. Ultrasound can be very helpful especially when the urologist work in a peripheric center. Other radiologic evaluation methods, such as Magnetic Resonance or retrograde uretrography, may not be quickly available, especially in an emergency situation, in a non-tertiary center. The Radiologist may not be able to provide the right information necessary for choosing the therapeutic strategy, which must be early and surgical. Urologist must perform itself ultrasound as first instrumental diagnostic exam. We present a non sex-related penile fracture case of 47-year-old with bilateral rupture of the corpora cavernosa with urethral injury who diagnosed by ultrasound and treated by early surgery.

SUMMARY

KEY WORDS: Penile trauma, penile fracture, ultrasound, diagnosis, complete urethral rupture.

INTRODUCTION Penile fracture is a relatively uncommon urological emergency which results from traumatic injury to the erect penis. In western countries it is typically associated with injury incurred during vaginal intercourse when the erect penis strikes the pubic symphysis. High incidences have been reported in Middle Eastern word where it is associated with self-manipulation to achieve detumescence (1). Penile fracture has only rarely been associated with a direct blow to the erect penis as reported in the literature (2, 3). A blunt trauma may be responsible of penile fracNo conflict of interest declared.

ture in 3% of cases (4,5) but it is rare the association with urethral rupture , which, in these cases, would be more commonly isolated (6). We report the management of a patient with a bilateral disruption of corpora cavernosa associated with complete urethral section, due to a non sex related blunt trauma occurred during the working time. We describe the diagnostic ultrasonographic work up and the subsequent immediate surgical reconstruction.

CASE

REPORT

A 47-years-old-man presented at our Emergency Department complaining a penile swelling associated with pain and difficult to micturition. He refers that during working time, his penis got stuck in an extendable ladder, with a consequent blunt injury. On physical examination there was the classic appearance of a discolored, fractured penis (7) with a right sided deviation. Penis was untouchable for the pain. Urethral bleeding was present. No hematoma was in the scrotum and pubis. Ultrasound investigastion showed an extended hematoma in the proximal ventral shaft of the penis, with a discontinuity of the tunica albuginea straddling both cavernous bodies and edema of the subcutaneous tissue (Figure 1). No color Doppler ultrasonography was performed. The patient was taken to the operating room for immediate emergency surgery. Under the subaracnoideal anesthesia, penile subcoronal circumcisional incision was made.To allow a better penile degloving, a longitudinal ventral incision along cutaneous rafe was made (Figure 2). The Buck fascia was incised, and hematoma was evacuated. After cleaning the surgical bed from the cloths, a partial ventral defect of both two cavernosal bodies and a complete urethral transection have been highlighted (Figures 3, 4). To minimize the blood loss, a tourniquet has been positioned at the base of the penis. A 16 ch catheter was inserted into the urethra in order to facilitate the proximal and distal mobilization of the stumps. Defect of both cavernosal bodies were repaired by 2-0 Maxon running sutures, previous Advances in Urological Diagnosis and Imaging - 2019; 2,2

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apposition of a collagen fleece (8) (Figure 5). A end-toend anastomosis of the urethra was performed with tension free 2-0 monocryl sutures. The final result is shown in Figure 6. A subcutaneous Penrose drainage was placed. A compressive dressing was always left in place for 24 hours to minimize haematoma formation and postoperative oedema. Epicystostomy was inserted. Circumcision was carried out. The patient was discharged 5 days after surgical intervention with foley catheter, antibiotic (cephalosporine) and anti fibrosis prophilaxys (tadalafil 5 mg once a day). Urethral catheter and epicystostomy

Figure 3. The partial ventral defect of both cavernosal bodies and the complete urethral transaction as they appeared just after evacuation of the hematoma.

Figure 1. Ultrasound findings of the extended hematoma (arrow) in the proximal ventral shaft of the penis, with a discontinuity of the tunica albuginea straddling both cavernous bodies and oedema of the subcutaneous tissue. The exam was performed at the patient admission.

Figure 4. The bilateral tunica albuginea defect and the urethral stumps mobilized for the anastomosis.

Figure 2. The circumcisional (Bold arrow) and longitudinal ventral (thick arrow) incision, seven days after the surgery. The star indicates the exit point of the drainage.

Figure 5. The tunica albuginea defect covered by the collagen fleece (arrow).

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Ultrasound in the management of a non sexual-related penile blunt trauma Figure 6. The final result before penile shaft reconstruction layer by layer.

were removed at the 21-th post operative day with resumption of spontaneous urination. Ultrasound perfomed with penis in the flaccid state revealed the complete restitution ad integrum. There was no penile deformity in physical examination. Only a minimal induration was palpated at the fracture repair line (Figures 7, 8). The patient was advised to abstain from sexual intercourse for at least 4 weeks. Than, one month later, patient referred normal erectile function.

DISCUSSION

Figure 7. Longitudinal ultrasound penile ventral shaft appearance at the site of surgical reconstruction. The thick arrow indicates the extramucosal urethral stitch. The bold arrow indicates the albugineal ventral patch.

Figure 8. Another ultrasound longitudinal ultrasonographic view of urethral anastomosis.

Penile fracture, defined as rupture of the tunica albuginea of the corpora cavernosa, can occur in association with a urethral tear in 1% to 38% of cases (4). This is a relatively uncommon emergency in Urology that urologist must know to decide the correct management (9-10). The mechanisms of penile fracture are sexual related, frequently. The direct trauma to penis outside of sexual intercourse is rarely described in literature. While we could not definitively elicit from the patient whether his penis was erect at the time of the accident, we expect that the trauma was given by the severity of the injury (1). Although the diagnosis of penile fracture is mainly clinical, imaging can play a role in confirming the diagnosis, identifying the exact location of the tunica tear, and ruling out the presence of urethral involvement (11). Although operator dependent, in experienced hands, ultrasound has been found to be a very useful tool. In our described case, the emergency department doctors preferred to bring the patient directly to the urologistâ&#x20AC;&#x2122;s attention bypassing the radiologistâ&#x20AC;&#x2122;s evaluation, understanding the need for a timely assessment not so much diagnostic as pre surgical. Ultrasound provided all the information needed. The presence and the location of the tunica albuginea tear and the urethral involvement. Relatively to the tear location, as expected, also in our case the rupture was ventral and transverse. In fact, the thickness of the tunica albuginea during flaccidity is 2 mm and decreases to 0.25 to 0.50 mm at erection. The thinnest area is on the ventral side, with only a single layer. In this side, the event could be frequent and reported in 80% of penile trauma case (13). Thus, performing penile ultrasound in an emergency setting, we must take into account these pathophysiological considerations expecting the rupture in the ventral side. Ultrasound demonstrates a focal discontinuity in the tunica albuginea with an associated hematoma beneath the deep fascia of the penis (14). Only when ultrasound provide equivocal results, the magnetic resonance (MRI) can be used to obtain the information needed. However, the high costs and unavailability in emergency settings represent a significant limitation to the use of MRI (1). Gross haematuria or microscopic haematuria are indicative signs of urethral involvement in 50 % of cases (15). In case of these signs, in order to avoid the urethral injury with a catheter, it is advisable to drain the bladder via suprapubic cystostomy, especially in case of inability to urinate. Invasive diagnostics, as retrograde urethrography, are considered time consuming and not cost effective, as the urethral injury tends to be located at the same level as the corpoAdvances in Urological Diagnosis and Imaging - 2019; 2,2

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ral tear. Any delay of surgical treatment may potentially lead to poorer outcomes (16). De Luca and co-workers emphasized the role of preoperative ultrasound to exclude a concomitant urethral involvement. Surgical repair was carried out within 24 h from the time of the trauma in 62 patients (81.5%) and between 24 and 72 h in the remainder. The ultrasonographer was able to clearly identify the exact location of the albugineal rupture in 76 out of 78 patients; the two patients who had an inconclusive ultrasound scan were therefore excluded from the analysis. The intraoperative findings showed a ventral and transverse tear located in the midshaft or proximal shaft in 93.5% of cases. These patients were therefore easily managed through a minimal penoscrotal incision at the level of the tear. Since proximal shaft tears were addressed through a penoscrotal approach, a complete degloving of the shaft was never necessary (17). They also reported an urethral involvement in nearly one-quarter of the patients, always associated with a bilateral corporeal tear and located at the same level of the tunical rupture. Preoperative ultrasonographic findings were confirmed intraoperatively in all patients, allowing a minimally invasive access and avoiding the morbidity of unnecessary complete degloving in all cases. In our reported case, we localized the albuginea tear in the proximal part of the ventral penile shaft. Considering our low experience with these urological emergency, the complete penile degloving was necessary to allow an exposure of urethra in order to perform an end-to-end tension free anastomosis. However, penile fractures can be properly diagnosed and treated to achieve the best outcomes in terms of healing and quality of life postoperatively. Ultrasound may be the preferred imaging technique for evaluation of penile trauma before surgery, because its improved spatial resolution permits evaluation of normal and pathologic anatomic structures (18).

CONCLUSIONS A penile fracture is a rare urological emergency which may have devastating complications. The possibility of urethral injury must always be kept in mind. Although the diagnosis is essentially clinical, the penile ultrasound study must be considered the main exam which allow to identify the site of the injury and an associated urethral laceration. In expert hands, ultrasound plays a determinant role in facilitating the identification of the tunica laceration and excluding the alternative diagnosis. Urologist itself must perform the ultrasonographic evaluation, in order to plan the immediate surgical repair. Indeed, a low incidence of postoperative complications and full satisfactory functional outcomes are reported when early repair is performed.

REFERENCES

3. Zeki Bayraktar, Selami Albayrak. Non sex-related subtotal rupture of the corpus cavernosum without urethral injury: A case report and literature review. Arch Ital Urol Androl. 2016; 88,3,233-234. 4. Amer T, Wilson R, Chlosta P, et al. Penile fracture: A Meta-Analysis. Urol Int. 2016; 96(3):315-29. 5. Bhalaajee Meenakshi-Sundaram B, Coco CT, Furr R, et al. Penile Fracture Following a Fall in a Seven Year Old Male. Urology 2017; 106:200-202. 6. McArdle BJ, Wille MA, Hollowell Courtney MP. Isolated Spongy Urethral Rupture from Abrupt Coital Distractive Force Radiology Case. 2017; 11(2):23-27. 7. Whitworth PW, Ramchandani P, Dyer RB.The “eggplant penis” sign. Abdom Radiol. 2017; 42:332-333. 8. Fabiani A, Fioretti F, Filosa A, et al. Patch bulging after plaque incision and grafting procedure for Peyronie’s disease. Surgical repair with a collagen fleece. Arch Ital Urol Androl. 2015; 87(2):173-174. 9. Antonini G, Vicini P, Sansalone S, et al. Penile fracture: peno-scrotal approach with degloving of penis after Magnetic Resonance Imagin (MRI). Arch Ital Urol Androl. 2014; 86(1),39-40. 10. Tamhankar AS, Pawar PW, Sawant AS, et al. Fractured Penis: Not So Rare! Urol Int. 2017; 99:63-68. 11. Garofalo M, Bianchi L, Gentile G, et al. Sex-related penile fracture with complete urethral rupture: a case report and review of the literature. Arch Ital Urol Androl. 2015; 87:260. 12. Nomura JT, Sierzenski PR. Ultrasound diagnosis of penile fracture. J Emer Med. 2010; 38:362-5. 13. Gontero P, Muir GH, Frea B. Pathological findings of penile fractures and their surgical management. Urol Int. 2003; 71:77-82. 14. Avery LL, Scheinfeld MH. Imaging of penile and scrotal emergencies. Radiographics. 2013; 33:721. 15. Derouiche A, Belhaj K, Hentati H, et al. Management of penile fractures complicated by urethral rupture. Int J Impot Res. 2008; 20:111-114. 16. Ahmadnia H, Younesi Rostami M, Kamalati A, et al. Penile fracture and its treatment: is retrograde urethrograghy necessary for management of penile fracture? Chin J Traumatol. 2014; 17:338-340. 17. De Luca F, Garaffa G, Falcone M, et al. Functional outcomes following immediate repair of penile fracture: a tertiary referral centre experience with 76 consecutive patients. Scand J Urol. 2017; 51:170-175. 18. Dell’Atti L. The role of ultrasonography in the diagnosis and management of penile trauma. J Ultrasound. 2016; 19:161-166.

Authors’ contributions All authors participated in the design and conduct of the study. All authors reviewed and approved the final version of the manuscript. CORRESPONDENCE Andrea Fabiani, MD, Surgery Dpt Section of Urology ASUR Marche Area Vasta 3

1. Falcone M, Garaffa G, Castiglione F, et al. Current Management of Penile Fracture: An Up-to-Date Systematic Review. Sex Med Rev. 2018; 6:253-260.

Macerata Hospital - Italy

2. Unnikrishnan R, Goel R, Thupili C, et al. Ultrasound for acute penile fracture. J Urol. 2013; 190:2253-2254.

Mobile: +393474865381

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C ASE REPORT

Complete regression of metastatic bladder carcinoma following chemotherapy

Alessia Cimadamore1*, Matteo Tallè2*, Paola Fulvi2, Andrea Benedetti Galosi2, Rodolfo Montironi1 1 2 *

Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, (Italy); Institute of Urology, Marche Polytechnic University, School of Medicine, United Hospitals, Ancona, (Italy). Equally contributing authors

A 62-year-old man presented with recurrent macroscopic hematuria. Cystoscopy revealed an ulcerated tumor of 2 cm in diameter in the left bladder wall. The transurethral resection of the lesion was reported as highgrade urothelial carcinoma invading the muscularis propria. The tumor was cytokeratin 5/6 positive with a rich stromal chronic infiltrate. CT scan showed a cT3, cN1M0 bladder tumor. The patient underwent cisplatin-based neoadjuvant chemotherapy (NAC), followed by radical cystoprostatectomy and regional lymphadenectomy. The bladder showed absence of histologically identifiable residual cancer cells and extensive fibrosis with calcifications of the tumor bed. One lymph node (out of 29) showed extensive fibrosis with hemosiderin deposits, but not residual tumor. Prostate and seminal vesicles were benign. The tumor was staged as ypT0, ypN0. No residual tumor following NAC is seen in approximately 30% of patients with probability of 8-year RFS greater than 0.9.

SUMMARY

KEY WORDS: Bladder cancer, Urothelial carcinoma, Neoadjuvant chemotherapy, Tumor regression, Basal type, luminal type.

INTRODUCTION Neoadjuvant cisplatin-based chemotherapy (NAC) is the standard treatment in muscle-invasive bladder cancer (MIBC) prior to radical cystectomy. The inability to identify patients who could derive most benefit from NAC is the main reason why this treatment is vastly underutilized. Recent studies have demonstrated the promise of biomarkers of “response” to NAC based on somatic mutation or gene expression. Basal urothelial tumors, so called for the immunohistochemical expression of basal markers as cytokeratin 5/6 and characterized by the activation of p63, frequently present as metastatic disease at time of diagnosis (1). Patients with basal MIBC experienced shorter overall survival and poor outcomes with No conflict of interest declared.

cystectomy alone (median 14.9 months) and seemingly better outcomes with NAC followed by cystectomy (2). The case report we presented have experienced the maximum desirable benefit from NAC achieving a complete tumor regression.

CASE

REPORT

A 62-year-old man was referred to the Urology Department of United Hospital of Ancona for a single episode of macroscopic hematuria. Ultrasound imaging showed an intravescical lesion of the bladder wall with calcific aspects of about 3 cm suspicious for solid tumor (Figure 1). Cystoscopy revealed an ulcerated mass of 3 cm in diameter in the left bladder wall. A CT scan showed a bladder mass infiltrating the outer half of the muscolaris propria with extension into perivesical tissue; it also showed the presence of 22 mm right external iliac lymph node to be referred to lymphatic metastasis. (Figure 2A) A trans-urethral resection of bladder (TURB) was performed. Pathological examination reported high-grade urothelial carcinoma invading the muscularis propria (Figure 3A). Immunohistochemistry for Citokeratin (CK) 5/6 and Citokeratin 20 revealed a strong positivity for CK 5/6 and a focal positivity for CK20 (Figure 3B). The clinical stage was cT3 N1M0. After a multidisciplinary evaluations of the patient, taking into account the EAU guidelines, the tumor stage and patient comorbidities, a cisplatin-based neoadjuvant chemotherapy (NAC), followed by radical cystoprostatectomy and regional lymphadenectomy, was offered. The patient first underwent carboplatin-based chemotherapy that was suspended for the appearance of asymptomatic pulmonary embolism at the CT scan, treated with 3 months of full dose Seleparine; for this reason the patient was switched to a cisplatin-based chemotherapy Advances in Urological Diagnosis and Imaging - 2019; 2,2

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A. Cimadamore, M. Tallè P. Fulvi, AB. Galosi, R. Montironi.

for an overall duration of three months. (Schedule: Cisplatinum 35 mq/mg ev G1-8, every 21 – 3 cycles). After chemotherapy, restaging CT scan revealed “a modest reduction of the bladder lesion volume and a strong reduction of the lynphoadenopathy, in particular the right external iliac lymph node that goes from 22 mm to 11 mm” (Figure 2B). Surgery has been planned one month after the ending of the chemotherapy, in order to maximize the post-CHT Hb value and minimize the risk of DVT; the patient has been counselled prior to surgery about the risk of each type of urinary diversion, and the decision to go for neobladder was taken also according to the patient’s will. An open radical cistoprostatectomy was perfomed with bilateral nerve-sparing technique and posterior musculofascial reconstruction; extended lymphadenectomy was performed on the right side up to the common iliac vasa and simple lymphadenectomy on the left side, including external, internal iliac and obturatory lymph nodes. No abnormal introperative foundings was noticed either in perivescical fat or in lymph nodes dissection. A orthotopic neobladder reconstruction according to Studer’s technique was then performed with an ureteroileal anastomosis according to Wallace II. Macroscopically, the bladder mucosa was normal without significant alterations or identifiable lesions. Histological examination showed extensive stromal fibrosis with calcifications of the left bladder wall and cysts lined by reactive epithelium with no atypia. No evidence of residual cancer cells (Figure 4A). One lymph node (out of 29) showed extensive fibrosis with hemosiderin deposits, but not residual tumor (Figure 4B). Pathological stage was ypT0, ypN0. Tumor regression grade (TRG) was assessed accordingly to Fleischmann et al. (3) Separate TRGs were assigned for primary tumor and lymph nodes. Since there

were complete tumor regression in the post-NAC bladder specimen, a TRG 1 was assigned. No residual tumor following NAC is seen in approximately 30% of patients with probability of 8-year RFS greater than 0.9. During hospitalization no major complications has been Figure 1. Ultrasound showing bladder lesion.

Figure 2. A: Pre-TURV CT scan: Bladder tumor extension into perivescical fat and right external iliac lymph nodes (red circle) of 22 mm. B: Post-chemotherapy CT scan: Modest reduction of the lesion volume and strong reduction of the right external iliac lymph node that goes from 22 mm to 11 mm.

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Complete regression of metastatic bladder carcinoma following chemotherapy Figure 3. A: High grade urothelial carcinoma infiltrating muscle fibers of the muscular bladder wall. B: Immunohistochemistry for Citokeratin 5/6 reveals a strong and diffuse positivity in more than 50% of neoplastic cells.

Figure 4. A: Whole section of the bladder. Stromal fibrosis and calcifications are visible in the muscolaris propria of the left bladder wall (circle). B: Iliac lymph node with extensive fibrosis and hemosiderin deposits.

observed; recovery of bowel function occurred in 2 days and the patient started to feed in 3 days. Overall blood loss was 3,7 gr/dl of Haemoglobin that did not require emo transfusion. Drainages was removed in 5 days. The patient was discharged in six days after surgery with the catheter placed on and ureteral splints. Cistography after 14 days from surgery showed no contrast leak from the anastomosis and the ureteral splints were removed. Bladder catheter was removed after 21 days from surgery. After the removal the patients suffered fever, that required quinolones administration for 7 days. No major complications has been observed. The patient soon started to void the bladder by abdominal straining with an increasing perception of the bladder storage. After 3 months from surgery the patients was fully continent; functional outcome has been investigated with uri-

nary ultrasound and uroflowmetry that both showed a proper functioning of the neobladder (Qmax 25 ml/s, Vvoid 400 ml, PVR absent) and no hydronephrosis with a serum creatinine of 1.4 mg/dl and Hb value of 14.0 gr/dl. The patient reported a partial erectile disfuncion with decent response to sexual stimulation but insufficient for sexual intercourse; he is currently undergoing sexual rehabilitation with Alprostadil 10 mcg per week.

CONCLUSIONS NAC has been effective in optimizing oncological outcome and, despite the potentially severe complication, did not affect the surgical strategy and the decision for a neobladder reconstruction. No post-operative complications and no effect on functional outcome has been observed, Advances in Urological Diagnosis and Imaging - 2019; 2,2

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with a full urinary continence recovery, good urine stream and ongoing recovery of sexual function. Application of molecular and immunohistochemical markers able to identify patients responsive to NAC could be of great help in the management and treatment decision of bladder cancer patients.

Authors’ contributions Conceptualization: A.C., M.T.; P.F.; Writing—Original Draft Preparation: A.C., M.T.; P.F.; Figures and Tables: A.C., M.T.; Writing—Review & Editing: A.B.G. and R.M. All authors have approved the final version of the manuscript.

REFERENCES 1. Choi W, Porten S, Kim S, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell. 2014; 25(2):152-65. 2. Seiler R, Ashab HAD, Erho N, et al. Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy. Eur Urol. 2017; 72(4):544-554. 3. Fleischmann A, Thalmann GN, Perren A, Seiler R. Tumor regression grade of urothelial bladder cancer after neoadjuvant chemotherapy: a novel and successful strategy to predict survival. Am J Surg Pathol. 2014; 38(3):325-32.

CORRESPONDENCE Alessia Cimadamore and Rodolfo Montironi Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Via Conca 71, I−60126 Ancona, Italy. E-mail: alessiacimadamore@gmail.com or r.montironi@univpm.it Phone: +390715964830 Fax: +39071889985

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LETTER TO THE

EDITOR

Contemporary use of pelvic drain after robot assisted radical prostatectomy: is always mandatory? Simone Scarcella, Lucio Dellâ&#x20AC;&#x2122;Atti, Andrea Benedetto Galosi Department of Urology, Polytechnic University of Marche Region, University Hospital â&#x20AC;&#x153;Ospedali Riunitiâ&#x20AC;?, Ancona, (Italy).

Radical prostatectomy is the reference standard surgery for localized prostate cancer and over the last two decades there has been consistent improvements of techniques leading to laparoscopic and robot assisted procedures. These improvements allowed a reduction of intraoperative bleeding, better and more precise dissection of tissue with overall reduction of morbidity and length of hospital stays. Despite all these advantages, the majority of urological centres still routinely use pelvic drain placement at the end of the procedure in all patients even with the absence of high-level evidence of clinical benefit reported in the literature. Aim of this work is to analyse over time the trend of pelvic drain use after radical prostatectomy and to report the last evidence acquired from the literature.

SUMMARY

KEY WORDS: Prostate cancer, radical prostatectomy, pelvic drain.

Radical Prostatectomy (RP) is the Gold Standard surgical treatment for localized prostate cancer. In the last 15 years we observed a constant improvement of the technique with the advent of laparoscopic and robot-assisted surgery. RP can be performed in association with extended pelvic lymph node dissection (ePLND) in all high risk cases and intermediate risk patients, when the probability of lymph-node invasion (LNI) is higher than 5% by nomograms (1). Since the initial description of the technique, in the early 1980s, many surgeons considered a standard component of the procedure the placement of a pelvic drain, to serve as conduit for removing urine, blood, lymph and other fluids. Nowadays, the majority of urological centres use pelvic drainage as a routine part of open and minimally invasive RP, even in the absence of high-level evidence of clinical benefit in all patients. RP is a safe procedure with low morbidity when performed by experienced hands. Moreover, Robot-assisted radical prostatectomy (RARP) represent the majority of surgery performed in Europe for localized prostate cancer. The advantages of the three dimensions vision, the optical magnification and the higher degrees of wrist range of motion due to robot assistance lead to a

precise, clean and sharp tissue dissection. Consequently, RARP has been associated with lower overall complications, less intraoperative bleeding and consequent fewer transfusions compared to an open approach. Contemporary series have shown that most frequent complications are anastomotic leakage, prolonged lymph drainage, rectal injury, symptomatic lymphocele, pelvic abscess or hematoma, occurring in less than 1-3% of cases (1). In this context thanks to the improvements of minimally invasive robot-assisted procedures, the necessity and benefit of a pelvic drainage after surgery has been questioned and its prophylactic placement is not routine anymore. Several prospective studies regarding non-urological surgical procedures, such as colon resection for cancer, perforated duodenum closure, elective cholecystectomy, hysterectomy, failed to demonstrate a positive impact of drain placement on rates of complications. The use of routine drain placement after surgery has been associated with higher rates of morbidity, surgical site infections, higher postoperative pain, injury to the inferior epigastric vessels, abdominall wall hematoma and increased length of hospital stays (2). Moreover, it has to be considered the necessity of an ulterior bedside procedure for drain removal with potential risks of breakage or retention of drains components that may represent a barrier to early discharge on an short-stay pathway for RP patients. However, the decision of drain placement has to be balanced between the benefit of not having a drain and the risk of requiring a later placement. Not all patients could benefit from drain placement omission. In case of concerns for anastomotic integrity or documented leakage after bladder irrigation, when the haemostasis is not excellent or when adjacent organs are injured during the procedure, pelvic drain placement is mandatory. The issue of not placing a pelvic drain after major urological procedure has been taken in consideration also in dated serie including patients treated with open radical retropubic prostatectomy. Savoie et al. showed how the decision of not placing a drain did not expose the patients at increased risk of complications with the condition that the bladder neck had to be preserved and accurately Advances in Urological Diagnosis and Imaging - 2019; 2,2

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reconstructed (2). Later studies examined the role of pelvic drains placement in laparoscopic and robot-assisted radical prostatectomy outlining how in most cases it is a matter of routine or tradition instead of being related to evidence based benefit. Moreover, according to these studies, it may delay discharge and have a negative impact on the patient with increased anxiety and morbidity (3). However, all these studies presented a selection bias related to the fact that only patients at higher risk of developing complications were selected for drain placement. At least, a recent non inferiority randomized clinical trial analysed similar cohorts of patients showing no differences in postoperative adverse events in the group without post-surgery drain placement compared to the one with pelvic drain placement (1). The main limit of these studies is that all of them have been conducted in highvolume experienced single centres so the reproducibility of theirs results could be questionable in low volume centres or when radical prostatectomy are performed by surgeons still in their learning curves. In conclusion, we can say that routinely pelvic drain placement policy after RARP, with or without ePLND, should be revised. All studies cited above suggested that no drain placement is equivalent, compared to drain placement, regarding complications rate, length of stays and morbidity. The option of drain placement at the end of the surgical

procedure remains a call depending to experienced surgeon’s judgement in regards of integrity of the urethrovesical anastomosis. In selected patients the omission of pelvic drain can be chosen safely without risk of additional morbidity with advantages regarding patients comfort and early hospital discharge. Further multicentre studies are required for the identification of specific and reproducible criteria in order to select, during surgery, the patients who benefit the most from the placement of a pelvic drain and spare those in which it does not provide any clinical benefit.

REFERENCES 1. Chenam A, Yuh B, Zhumkhawala A, et al. Prospective randomised non-inferiority trial of pelvic drain placement vs no pelvic drain placement after robot-assisted radical prostatectomy. BJU Int. 2018; 121(3):357-364. 2. Savoie M, Soloway MS, Kim SS, Manoharan M. A pelvic drain may be avoided after radical retropubic prostatectomy. J Urol. 2003; 170(1):112-114. 3. Porcaro AB, Siracusano S, Bizzotto L, et al. Is a drain needed after robotic radical prostatectomy with or without pelvic lymph node dissection? Results of a single center randomized clinical trial. J Endourol. 2018 doi: 10.1089/end.2018.0176.

CORRESPONDENCE Scarcella Simone, MD Department of Urology, Polytechnic University of Marche Region University Hospital “Ospedali Riuniti” Via Conca, 71 - 60126 Ancona - Italy Mail: simoscarc@gmail.com Tel.+39 3924677442 Fax: +39 071/5963367

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ORIGINAL PAPER

Glycerophosphoinositol rectal suppositories: rationale of application in male with chronic pelvic pain syndrome Lorenzo Montesi, Erika Palagonia, Angelo Antezza, Carmine Franzese, Simone Scarcella, Andrea Benedetto Galosi Department of Urology, Polytechnic University of Marche Region, University Hospital “Ospedali Riuniti”, Ancona, Italy.

Objectives. CP/CPPS is a chronic multi-faceted syndrome, that is frequently characterized by the association of urinary disorders with ano-rectal symptoms. Different rectal suppository compounds are empirically used in clinical practice without any clinical evidence. Only one study showed how the use of topic rectal therapy based on corticosteroids improved symptoms by both providing local soothing action and reducing dysfunctional symptoms. However, the absence of evidence-based therapies reflects the need to investigate new molecules. GlyceroPhosphoInositol (GPI) is derived from lipid catabolism of cellular membranes. Its reduce Phospo Lipase A2 (PLA2) activity and, leading to lower production of Arachidonic Acid and Prostaglandins. We evaluated the rational use of GPI as rectal suppositories and anti-inflammatory device. According to preliminary data it could be considered as alterative to the widespread use of corticosteroid suppositories. Material and methods. We reviewed all published articles in the literature regarding observational studies and clinical trials on the management of CP/CPPS with interest towards topical treatments and GlyceroPhosphoInositol. Results. CP/CPPS management remains a question of debate between urologists with a lack of shared therapeutic algorithm.

Different type of compounds including antibiotics, alpha-blockers, anti-inflammatory, phytotherapy, and corticosteroid rectal suppository are commonly used in clinical practice. Exogenous GPI showed effect in patients with psoriasis. Also experimental studies supports GPI inhibitory mechanism on pro-inflammatory molecules. Potential candidates are those men who have anorectal inflammatory disease associated with CP/CPPS. The best evidence based treatment of CP/CPPS should be a multimodal therapy tailored according to the specific clinical phenotype of the single patients. Conclusions. A significant proportion of men with CP/CPPS has functional or organic ano-rectal inflammatory disorders. GPI could be utilized to develop new class of PLA2 negative modulators also in men with pelvic inflammatory disease. We evaluated the rational use of GPI rectal suppositories as anti-inflammatory device to be combined with standard therapy. According to preliminary data it could be considered as an alterative to the widespread use of corticosteroid suppositories. However, further phase II studies on GPI profile safety and clinical efficacy are advised. Patients with non-bacterial prostatitis associated with ano-rectal symptoms should be accurately studied and evaluated.

INTRODUCTION

Table 1. National Institutes of Health classification system consensus definition and classification system for prostatitis.

SUMMARY

Male patients can be affected by lower urinary tract symptoms (LUTS) and pelvic pain related to conditions of the prostate at all ages. Epidemiologic data shows a rate of prostatitis-like symptoms that ranges from 2.2% to 9.7% with a mean prevalence of 8.2% (1). “Prostatitis” is a term generally used to refer to different and separate entities. However in 1999 the National Institutes of Health (NIH) established a consensus definition and classification system for prostatitis that is actually widely accepted in both research and clinical practice. The classification devised is illustrated in Table 1 and consists of four item including:

KEY WORDS: Glycerophosphoinositol, Rectal Suppository, Prostatitis, Chronic Prostatitis, Chronic Pelvic Pain Syndrome.

NOMENCLATURE

Category

Evidence Strengtha

Examples

Comments

Oral therapy Antibiotics

Ciprofloxacin, levofloxacin, tetracycline

4-6 weeks of therapy, repeating antibiotics only in patients who have positive urine cultures or partially respond to the first therapy

Alfa-blockers

Tamsulosin, alfuzosin, doxazosin or terazosin, silodosin

Efficacy on lower urinary tract symptoms

Phytotherapy

Rye pollen extract, quercetin

B59

Considered for patient with inadequate symptom control to initial antibiotics, alfa-blockers and analgesics

Analgesics

Nonsteroidal anti-inflammatory drugs (NSAIDs)

C60

Avoid narcotics

Neuromodulators

Amitriptyline, gabapentinoids, Serotoninenorepinephrine reuptake inhibitors (SNRIs)

B61

Early use of neuromodulating agents in pain of neuropathic origin

Hormonal agents

Finasteride, dutasteride

C62

Only if coexisting benign prostatic hypertrophy

5-phophodiesterase inhibitors

Sildenafil, tadalafil, mirodenafil

C63

In erectile dysfunction

(Level A: meta-analysis of well-designed randomized controlled trials. Level B: at least 1 well-designed randomized controlled trials. Level C: at least 1 well-designed observational study). Table 3. Clinical Phenotyping System for the management of CP/CPPS UPOINTs.

PHENOTYPING Urology

Psychology

Organ specific

Infection

Neurological

Tender muscle

Sexual Dysfunction

SYMTHOMPS

storage/voiding symptoms, high postvoid residual

depression, catastrophizing, anxiety

prostate tenderness, leukocystosis in prostatic fluid, hematospermia, extensive calcification, lower urinary obstruction

positive cultures in prostatic samples, previous UTI

pain beyond pelvis, irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome

pelvic floor spasm, muscle trigger points

ejaculatory dysfunction, erectile dysfunction, orgasmic dysfunction

ASSESSMENT

urinary flow, cystoscopy, micturition diary, ultrasound, uroflowmetry

Anxiety about pain, depression and loss of function, history of negative sexual experiences

gynaecological, gastrointestinal, ano-rectal, sexual complaints, gynaecological and/or rectal examination

Urine culture and semen culture, vaginal swab, stool culture

neurological complaints, neurological testing

palpation of the pelvic floor, abdominal and gluteal muscles

Erectile function, ejaculatory function, post-orgasmic pa in

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Glycerophosphoinositol rectal suppositories: rationale of application in male with chronic pelvic pain syndrome

patient (9). From this perspective a novel 6-point clinical phenotyping system UPOINTs for the management of CP/CPPS has been introduced in clinical practice. The six UPOINTs domains comprise Urinary symptoms, Psychological dysfunction, Organ-specific symptoms, Infection, Neurologic/systemic conditions, Tenderness of muscles and Sexual Dysfunction (Table 3). In agreement with recent clinical trials this classification system appears to correlate with symptoms severity and duration of disease.This multimodal treatment guided by UPOINTs leads to a significant improvement of both symptomatology and quality of life (10). In this scenario, recent evidences showed how the use of topic rectal therapies in combination with other treatments could improve the clinical presentation by both providing local soothing action and reducing dysfunctional symptoms (11-13).

PATHOPHYSIOLOGY Chronic pelvic pain syndrome (CPPS) is defined as chronic, persistent or recurrent pain in the pelvic region structures, associated with urinary symptoms and that involves genital, urinary, gastrointestinal, peripheral nervous and skeletal muscle systems, lasting for at least 3 of the previous 6 months. Nowadays, the etiology of CP/CPPS remains unclear. However, several putative mechanism have been hypothesized. Among these infection, trauma, dysfunctional voiding, autoimmune reaction, chemical irritant and psychiatric disease were the most investigated (14). These agents might cause inflammation/neurologic damage directly to the prostate or the pelvic floor, the bladder or the perineum. As consequence peripheral and central sensitization occurs, leading to the development of pelvic floor neuromuscular dysfunction (15). Once established this chronic neuropathic state can be associated with depression and anxiety (16). Moreover, it has been hypothesized a correlation between the rectal symptomatology observed in CP/CPPS and the inflammatory process related to the congestion of the prostatic plexus. In fact both CP/CPPS are characterized by a condition of hypertonicity of pelvic floor muscles as a consequence of inflammation at rectal level (17). Neuromuscolar activation is due to the presence of trigger points in the pelvic floor reacting to irritative stimuli through muscles contracture (18). CP/CPPS can also be sustained by haemorrhoidal congestion caused by perianal fissures and local contamination with intestinal microorganisms that increases the risk of lymphatic reabsorption of microorganisms themselves. Pavone et al. showed a strict correlation between the phlogistic condition of the rectum/haemorrhoidal plexus and the pathogenesis of prostatic inflammation (19).

DIAGNOSIS The diagnostic pathway of CP/CPPS is not well standardized and characterized (20). The first step should be the

Table 4. Common Ano-Rectal disorders.

Common Ano-Rectal Disease Organic • Fistulae • Colorectal Cancer • Abscess • Fistula • Inflammatory Bowel Disease (Crohn’s Disease – Ulcerative Colitis) Functional • Faecal Incontinence • Ano-rectal Pain: - Proctalgia Fugax - Levator Ani Syndrome - Unspecified Rectal Pain • Dissynergic Defecation • Solitary Rectal Ulcer Syndrome

assessment of the severity, duration, intensity and impact of symptoms by utilizing the visual-analogue scale (VAS) (scores from 1 to 10) for pain or the NIH-CPSI (level of evidence 2b; grade of recommendation B), both validated internationally. The International Prostate Symptom Score (IPSS) and the International Index of Erectile Function (IIEF) should be adopted for evaluation of the initial condition and for monitoring the response to treatment (21, 22). Physical examination of abdomen, genitalia and digital rectal exam (DRE) of the prostate are mandatory. The modified Meares-Stamey test with two glasses involves the analysis of pre- and post- prostate massage urine and can differentiate CP/CPPS from chronic bacterial prostatitis. It is a simpler and more reproducible test compared to the four glasses test (23). Chronic bacterial prostatitis is usually associated with a history of symptomatic recurrent urinary tract infections (UTI) documented by cultures with identification of uropathogenic bacteria. The absence of positive urine culture with symptomatic chronic pelvic pain supports the diagnosis of CP/CPPS. A complete laboratory testing should include blood count, inflammatory parameters while serum prostate-specific antigen (PSA) is not a clinically useful parameter for CP/CPPS but should be considered if the patient is at risk for Prostate Cancer (24). Imaging studies are not routinely performed, trans-rectal ultrasound should be performed in selected patients if an intra-prostatic abscess or obstructed ejaculatory duct are suspected. A detailed medical history is mandatory and should specifically look at possible co-occurring gastro-intestinal disorders. Visual and digital rectal examination is recommended to exclude common ano-rectal disorders that are summarized in Table 4.

TREATMENT

CP/CPPS

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L. Montesi, E. Palagonia, A. Antezza, C. Franzese, S. Scarcella, A.B. Galosi

urologist. Empiric antibiotics treatment was proposed as a first line therapy. However, three randomized clinical trials using different molecules (ciprofloxacin, levofloxacin, tetracycline) failed to demonstrate a statistically significant response to the active treatment compared to the placebo (25-27). Moreover, following the alert published in June 2019 by the EAU Urological Infections Guidelines Panel and the EAU Section of Infections in which restricted the use of fluoroquinolones to selected cases, the use of these antibiotics in CP/CPPS scenario is strongly discouraged (28). Due to the frequent association between CP/CPPS and voiding symptoms (e.g. urgency, frequency and incomplete voiding sensation) mimicking benign prostatic hyperplasia (BPH) condition, alpha-adrenergic blockers were investigated as possible treatment option. Seven RTCs analysed the treatment response of monotherapy with alfa-adrenergic receptor blockers versus placebo. However, the results were contrasting. In line with these findings, alfa blockers cannot be recommended as first-line mono-therapy. However, in selected CP/CPPS patients with recurrent urinary symptoms the use of these compounds in the context of a multimodal therapeutic regimen could improve the quality of life (29-33). Five RTCs outlined the important role played by inflammation in the pathophysiology of CP/CPPS using several anti-inflammatory agents. The variety of the compounds used and the controversial results of these trials demonstrated the inefficacy of these agents when used in monotherapy in producing an improvement of clinical symptoms (34-39). Two RTCs evaluated the use of hormonal agents in patient with CP/CPPS but no significant clinical improvement was reported (40, 41). On the contrary, two RTCs showed the potentiality of phytotherapeutic agents (Quercetin and Pollen extract) as treatment modality for CP/CPPS. In those trials, a significant improvement of the symptoms was evident both clinically and using validated questionnaires thus supporting the use of phytotherapeutic agents either as monotherapy or in combination with other compounds (42, 43). In addition to these oral administrated compounds recent evidences in the literature introduced the possibility of local treatment for CP/CPPS in form of rectal suppositories. One randomized clinical trial by Morgia et al. reported the clinical efficacy of suppositories of Curcumin and Calendula extract with a significant improvement of NIH-CPSI, IIEF-5, peak

flow and VAS score over the placebo group (44). Another observational study showed the effectiveness of Beclometasone di-propionate rectal suppositories in patients with CP/CPPS, with an improvement both of storage phase of urinary symptoms and clinical findings (45). All therapies described should be considered according to a multimodal treatment regimens based on the clinical phenotyping system UPOINTs described in the introductory section of this manuscript.

Figure 1. Metabolic pathway and GPI negative feedback.

GPI has an effective and selective inhibitory action on cPLA2.This has been showed by experimental studies both in vitro and in vivo settings (47). Furthermore, on these basis an important role of GPI in intracellular signalling has been hypothesized. It has been observed that exogenous supplementation of GPI led to an increase of its specific plasma membrane transporter. The consequence of this process is a higher accumulation of GPI within the cell cytoplasm where it contributes to cell homeostatic mechanisms (48).

GLYCEROPHOSPHOINOSITOL

MOLECULAR MECHANISM OF ACTION AND EXPERIMENTAL DATA Glycero-Phospho-Inositol (GPI) is derived from lipid catabolism of cellular membranes. GPI is synthesized by cytoplasmic Phospho-Lipase A2 (cPLA2) activity on phosphoinositides of the cellular membrane. Furthermore, the cPLA2 is a hydrolysing enzyme also involved in inflammatory processes mediated through the eicosanoid pathway (Figure 1). Eicosanoids are involved in a wide range of pathological disorders such as inflammation, allergy, skin inflammation, inflammatory bowel diseases and brain injury. These molecules are generated from Arachidonic Acid (AA) by cyclooxygenase (COX) and lipooxygenase (LOX) cycles. Therefore, the AA is derived from the cPLA2 activity on membrane phospholipids and Phosphatidyl-Inositol (PI). For this reason, eicosanoid production represents a target for the treatment of inflammatory diseases. Inhibition can occur selectively on one of the two enzymatic cycles that lead to the production of Prostaglandins (PG) or Leukotrienes (LT). However, this is associated with an increase of the Arachidonic Acid (AA) fraction produced by the other enzymatic cycle still active. This mechanism could lead to a worsening of the underlying pathological condition. To overcome this important disadvantage, an alternative approach has been proposed.That is the â&#x20AC;&#x153;inhibition of multiple pathwaysâ&#x20AC;? which allows to reduce the production of Arachidonic Acid (AA) by down-modulating cPLA2 activation through the GPI regulation (46).

GLYCEROPHOSPHOINOSITOL IN INFLAMMATORY DISEASE

[GPI: Glycero-Phospho-Inositol; cPLA2: Phospho-Lipase A2; AA: Arachidonic Acid; COX: cyclooxygenase; LOX: lipooxygenase; PI: Phosphatidyl-Inositol; PG: Prostaglandins; LT: Leukotrienes]

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Glycerophosphoinositol rectal suppositories: rationale of application in male with chronic pelvic pain syndrome

These studies support the hypothesis that exogenous GPI added to cultured cells reduces Arachidonic Acid (AA) and that GPI plays a role in the regulation of G protein effectors, including cPLA2, as part of a natural homeostatic negative feedback mechanism (Figure 1). According to this inhibitory mechanism GPI can be utilized to develop new class of cPLA2 negative modulators with reduction of pro-inflammatory molecules such as eicosanoids. Different promising synthetic/semi-synthetic GPIs derivatives have been recently introduced but only in ongoing clinical trial settings. An example of possible human clinical use of GPI derivatives is a topic cream for soothing psoriatic lesions. A preliminary clinical trial was conducted on 30 patients with active psoriatic lesions. GPI concentration was 1% and was topically applied on the affected skin area twice a day. Evaluation of clinical improvement was performed by objective dermatologic observation of psoriatic symptoms and photographic analysis. This preliminary clinical trial demonstrated the GPI efficacy in the reduction of lesions size, redness and itching. GPIs could be suggested as an adjuvant treatment in case of CP/CPPS, particularly in the presence of congestive phenomena and constipation of the ano-rectal apparatus. The product is manufactured in the form of rectal suppository, in order to avoid gastric inactivation with direct absorption and action on the rectal mucosae (49). This is a completely new field of research that could extend the potential therapeutic role of GPI and its derivatives.

CONCLUSIONS CP/CPPS is a chronic multi-faceted bothersome syndrome. The clinical presentation is frequently characterized by the association of urinary disorders with ano-rectal symptoms. Currently the absence of evidence-based therapies reflects the need to investigate new molecules and to improve actual management strategies. Different type of compounds including antibiotics, alpha-blockers, anti-inflammatory medications, phytotherapy and rectal suppository are commonly used in clinical practise. However the impact of these treatments is questionable due to heterogeneity and conflicting results of the clinical trials published in the literature. We evaluated the rational use of GPI rectal suppositories as anti-inflammatory device to be combined with standard therapy. According to preliminary data it could be considered as an alterative to the widespread use of corticosteroid suppositories. However, further phase II studies on GPI profile safety and clinical efficacy in patients with nonbacterial prostatitis are advised.

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CORRESPONDENCE Simone Scarcella, MD Department of Urology, Polytechnic University of Marche Region, University Hospital “Ospedali Riuniti”, Ancona, Italy E-mail: simoscarc@gmail.com Tel: +39 3924677442 Fax: +39 071/5963367

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The Authors must submit a long English summary (300 words, 2000 characters). Subheadings are needed as follows: Objective(s), Material and method(s), Result(s), Conclusion(s). After the Summary, three to ten key words must appear, taken from the standard Index Medicus terminology.

TEXT

For original articles concerning experimental or clinical studies, the following standard scheme must be followed: Summary - Key Words Introduction - Material and Methods - Results - Discussion - Conclusions - References - Tables - Legends - Figures. Case Report should be divided into: Summary - Introduction (optional) Case report(s) - Conclusions - References (Discussion and Supplementary Figures, Tables and References can be submitted for publication in Supplementary Materials).

SIZE

OF MANUSCRIPTS

Literature reviews, Editorials and Original articles concerning experimental or clinical studies should not exceed 3500 words with 3-5 figures or tables, and no more than 30 references. Case reports, Notes on surgical technique, and Letters to the Editors should not exceed 1000 words (Summary included) with only one table or figure, and no more than three references. No more than five Authors are permitted.

TABLES

Tables must be aimed to make comprehension of the written text easier. They must be numbered in Arabic digits and referred to in the text by progressive numbers. Every table must be accompanied by a brief title. The meaning of any abbreviations must be explained at the bottom of the table itself.

FIGURES

Figures are also graphics, algorithms, photographs, drawings. Figures must be numbered and quoted in the text by number. The meaning of all symbols, abbreviations or letters must be indicated. Histology photograph legends must include the enlargement ratio and the staining method. Legends must be collected in one or more separate pages. Please follow these instructions when preparing files: • Do not include any illustrations as part of your text file. • Do not prepare any figures in Word as they are not workable. • Line illustrations must be submitted at 600 DPI. • Halftones and color photos should be submitted at a minimum of 300 DPI.

MANUSCRIPT

REVIEW Only manuscript written according to the above mentioned rules will be considered. All submitted manuscripts are evaluated by the Editorial Board and/or by two referees designated by the Editors. The Authors are informed in a time as short as possible on whether the paper has been accepted, rejected or if a revision is deemed necessary. The Editors reserve the right to make editorial and literary corrections with the goal of making the article clearer or more concise, without altering its contents. Submission of a manuscript implies acceptation of all above rules.

MANUSCRIPT

PRESENTATION Authors must submit their manuscripts (MAC and WINDOWS Microsoft Word are accepted) to the Assistant Editor (dellatti@hotmail.com).

PROOFS

Authors are responsible for ensuring that all manuscripts are accurately typed before final submission. Galley proofs will be sent to the Corresponding Author. Proofs should be returned within seven days from receipt.

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