Advances in Urological Diagnosis and Imaging - AUDI (Vol. 4 - n. 1 - 2021)

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. 4 - n. 1 - 2021

ADVANCES

IN

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) Advances in Urological Diagnosis and Imaging - 2021; 4, 1

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

General Information

Contents

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“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.

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Andrea Fandella, Umberto Barbaresi, Pietro Pepe, Lorenzo Bianchi, Riccardo Schiavina, Alessandro Bertaccini

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Correlation of clinical and sonographic characteristics in patients with unilateral subclinical varicocele and normospermia Georgios Tsampoukas, Athanasios Dellis, Ali Gharib, Mohamad Moussa, Dominic Brown, Konstantinos Deliveliotis, Noor Buchholz, Athanasios Papatsoris

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Cost analysis of ultrasound guided fusion-targeted prostate biopsy in the era of multiparametric MRI: Results from an Italian private health center

A new therapeutic strategy in the treatment of pelvic chronic pain Lorenzo Montesi, Carmine Franzese, Angelo Antezza, Simone Scarcella, Erika Palagonia, Lucio Dell’Atti

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Salvage radiotherapy following radical prostatectomy: Long term oncological and functional outcomes (median 96 months) in 108 patients Pietro Pepe, Marinella Tamburo, Michele Pennisi, Dario Marletta, Francesco Marletta

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Surgical treatment of locally advanced urachal cancer: A single case with a long-term follow up and literature review Alessandro Bertaccini, Umberto Barbaresi, Alessandro Colella, Fabio Manferrari, Riccardo Schiavina

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Advances in Urological Diagnosis and Imaging - 2021; 4, 1

ORIGINAL

PAPER

Cost analysis of ultrasound guided fusion-targeted prostate biopsy in the era of multiparametric MRI: Results from an Italian private health center Andrea Fandella 1, Umberto Barbaresi 2, Pietro Pepe 3, Lorenzo Bianchi Alessandro Bertaccini 2, 4.

1 2 3 4

2, 4,

Riccardo Schiavina

2, 4,

Urology Unit, Casa di Cura Rizzola, San Donà di Piave (VE), Italy; Department of Urology, S. Orsola Malpighi University Hospital, Bologna (BO), Italy; Urology Unit, Canizzaro Hospital, Catania (CT), Italy; Department of Experimental, Diagnostic, and Specialty Medicine - University of Bologna, Bologna (BO), Italy.

Objectives. Multiparametric magnetic resonance (mpMRI) of the prostate is recommended before performing a prostate biopsy, in order to improve the diagnosis of clinically significant prostate cancer and to reduce unnecessary procedures. The aim of this work is to quantify the overall costs of systematic prostate biopsy combined with MRI/TRUS fusion targeted biopsy.

Material and methods. The overall costs were determined by referring to the experience of 289 procedures performed in Italy in 2019 in a private Urological Centre. The following cost factors were assessed: personnel, materials, maintenance-equipment depreciation, energy consumption and common costs of structure.

Results. The overall cost of systematic plus mpMRI-guided biopsy was 581.00 EURO (€) if performed with MRI/TRUS fusion technique; data were obtained by summing up the costs of mpMRI, of personnel, hospital care, disposable items, use of the machine and costs of the structure. It can be assumed that the impact of a mpMRI fusion device can add from € 40 to € 120 to each procedure according to the initial cost of the machine, maintenance, any dedicated consumables, and operator time.

Conclusions. MRI/TRUS fusion biopsy represents an accepted method for the diagnosis of PCa, with the most beneficial cost/effective rate. The feasibility of the procedure, in the immediate future, could be affected by the inhomogeneous use of mpMRI in the common clinical practice.

SUMMARY

KEY WORDS: Prostate cancer; targeted biopsy; fusion biopsy; imaging; cost analyses.

INTRODUCTION Prostate Cancer (PCa) is the most common neoplasm in men in Europe and USA (1).The diagnosis of PCa is differs from most of the other solid cancers in which imaging is vital to identify those patients who could require a biopsy and, often, to guide a targeted biopsy. Indeed, random and systematic sampling of the prostate have represented the gold standard to diagnose PCa (2). Transrectal ultrasound (TRUS) guided prostate biopsy has been the cornerstone of prostate cancer diagnosis. Systematic sextant biopsy protocol with 12 cores has been the gold standard for many years, despite a detection rate of about 40–45 at first biopsy setting (3). Until a few years ago, TRUS guided biopsy was indicated for 16% of the male population over 50 years old, with obvious economic consequences (4, 5).

The introduction of multiparametric Magnetic Resonance

Imaging (mpMRI) of the prostate has deeply changed the diagnostic and therapeutic path for PCa (6-8). Compared to clinical evaluation with PSA dosage, digital rectal examination (DRE), TRUS and random biopsy, mpMRI enables accurate assessment of the location, size, and stage of the suspicious lesions within the prostate (9). With the aim of reducing unnecessary biopsies and increasing PCa detection rates, several techniques have been developed, with similar accuracy (10). The purest form of utilizing mpMRI to guide prostate biopsies is performing mpMRI and subsequent in-bore MRI-guided biopsy of the index lesions (11). While this approach demonstrates high quality performance characteristics, resource availability will likely limit its widespread use (12). A valid alternative is represented by the use of mpMRI and transrectal ultrasound Advances in Urological Diagnosis and Imaging - 2021; 4,1

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A. Fandella, U. Barbaresi, P. Pepe, L. Bianchi, R. Schiavina, A. Bertaccini Figure 1. MRI/TRUS Fusion biopsy matching example.

(TRUS) fusion hardware and software packages that allow the mpMRI data to be superimposed over live ultrasound images, guiding the operator during the biopsy (10, 13).

The fusion approach involves use of software that overlays an mpMRI image on a “real-time” ultrasound (mpMRI/ TRUS) images allowing assessment of the accuracy of the biopsy in relation to the mpMRI (Figure 1).

A third option widely adopted is the “cognitive fusion” technique, in which imaging comparison is is used to cognitively target the MRI identified lesion using TRUS guidance, without software assistance (14). In the last years, mpMRI has been strongly recommended in men with a previous negative biopsy (15-17). It is also being suggested as “triage test” also in biopsy naïve patients to improve cost-effectiveness of prostate biopsy, though its economic benefits are still a matter of debate (18, 19). Conversely, the feasibility of the procedure, in the immediate future, could be affected by the inhomogeneous availability of the mpMRI and of trained uroradiologists, often even within the same country.

The purpose of this study was to assess how the introduction of mpMRI and MRI/TRUS fusion biopsy have affected the costs of PCa diagnostic process.

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MATERIALS

AND METHODS

The full cost to perform the biopsy is the sum of the costs of all the resources involved the process, including personnel and cost amortization of the hardware, considering it used also for other procedures. The overall cost of mpMRI-guided biopsy was determined referring to the experience on 289 procedures run in 2019 in a Urological private center, submitted to systematic 12 samples plus 24 targeted biopsy cores. The overall cost of TRUS-guided prostate biopsy (12 sample) without mpMRI and fusion devices, was still around € 250 euro as in 2011 (20).

The cost of targeted only biopsies was also calculated. The following factors have been evaluated: 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). 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, many phases of activity: a preliminary examination, such as the acceptance; real execution and, after execution, such as reporting.

Cost analysis of fusion targeted biopsies.

Table 1. Average cost per-procedure of a MRI/TRUS fusion biospy.

mpMRI € 281.00

TRUS systematic biopsy Personnel

Corrective

Indirect business

€ 98.40

€ 34.80

€ 26.80

Fusion biopsy platform and disposable items

Supplementary cores (if added, each)

€ 120.00

€ 20.00

MRI/TRUS fusion biopsy total cost**

€ 581.00

*: 12 systematic cores + 1 targeted core

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/TRUS guided biopsy was set at optimal operating conditions: cooperative patient, experienced operator, logistics and environmental well suited. Furthermore, 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) was also considered.

Moreover, 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), was determined (21). Finally, a review of the literature was carried out in order to verify the correspondence of our data with those of other international realities in the context of the broader debate about the “cost-effectiveness” of strategies for early detection of PCa (20, 22, 23).

RESULTS The average costs for mpMRI were calculated resulting equal to € 281 corresponding to the staff cost (a radiologist and a radiology technician: € 163.00) and equipment cost (€ 119.00), but these data were not included in our study. Systematic TRUS biopsy was around € 250 per procedure, as previously stated. In detail, personnel costs weights € 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. In the case of supplementary biopsy cores, there was a relative increase in costs due to increased unloading time and reading time. This resulted in about € 20.00 increase, bringing the total sum at € 270.00 per procedure, assuming 1 targeted core for each fusion procedure (Table 1).

The overall cost of the systematic biopsy plus mpMRIguided targeted biopsy was € 581.00 if performed with MRI/TRUS fusion technique, related to the initial purchase expense and the annual number of biopsy procedures. If ultrasound equipment is not dedicated to biopsies only, costs are mitigated. It can be assumed that, for 300 procedures a year, the impact of fusion device platform can add from 40.00 to € 120.00 to each procedure according to the initial cost of the machine, maintenance, any dedicated consumables, and operator time. This last parameter is usually tripled in performing MRI/TRUS fusion biopsies (loading of the mpMRI exam, extrapolation of the images,

choice of target, synchronization of mpMRI and TRUS images; Table 1).

DISCUSSION Performing mpMRI before prostate biopsy can help avoid unnecessary procedures, saving economic resources as, according to literature, more than a half of random biopsies result negative (5). In fact, nowadays mpMRI is recommended both for the diagnosis of clinically significant PCa (csPCa) in men candidate to repeat prostate biopsy for persistent suspicious of PCa, and in biopsy naïve patients8.

Anyway, the inclusion of MRI/TRUS fusion biopsy in a routine diagnostic process can be limited by highest costs per procedure (18). The actual costs per-patient at his first biopsy would include many parameters: medical instruments; surgery room (when used); mpMRI machine and the evaluation performed by an experienced and skilled uroradiologist; systematic TRUS-guided biopsy plus MRI/TRUS fusion-guided biopsy. Although the pooled baseline resource costs were 2.3 times higher in the United States than in other countries, in our esperience the overall cost of mpMRI cognitive fusion biopsy resulted equal to € 531, substantially corresponding to data reported in the literature (11, 24). This value is mainly influenced by the cost of the health personnel (about 64%); on this item will therefore focus attention on identifying and streamlining procedures to reduce spending. Furthermore, although not evaluated in this study, reported resource costs for performing mpMRI and/or biopsy should include the cost of complications resulting from these procedures.

Complications from prostate biopsy are similarly expensive and methods to decrease incidence may be costeffective; the risk of sepsis (and its related hospitalization costs) is included between 2% and 3.5% (25, 26). In addition, the overall costs of follow up for indolent PCa (Active Surveillance) should be calculated. As mpMRI techniques continue to refine and mpMRI use in PCa management grows, mpMRI before prostate biopsy is likely to become increasingly common; although, recently, Kasivisvanathan et al. reported that the use of MRI-targeted biopsy was superior to standard transrectal ultrasonography-guided biopsy in men who previously had not undergone biopsy, this approach should be adopted with caution as it appears that systematic biopsies still add value and detect some clinically relevant cancers in this setting (8, 27). At the same time, recent studies have reported encouraging results on the performance of mpMRI to optimize cost-effectiveness of prostate biopsy procedure. In the Prostate MR Imaging Study (PROMIS), the largest accuracy study on the use of Advances in Urological Diagnosis and Imaging - 2021; 4,1

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A. Fandella, U. Barbaresi, P. Pepe, L. Bianchi, R. Schiavina, A. Bertaccini

mpMRI in men candidate to initial prostate biopsy, authors concluded that mpMRI is cost effective as the first test for the diagnosis of PCa, when followed by an MRI/TRUS targeted biopsy on mpMRI suspect lesions (18). Recently, Pawha et al showed that mpMRI followed by a targeted MRI-guided biopsy in biopsy naïve patients is cost-effective compared with the standard prostate biopsy technique for the detection of csPCa (28). This conclusion is similar to what stated in a paper by Pepe et al underling that patients should be informed of the false-negative mpMRI rate for csPCa8. Although mpMRI could reduce both the cost of the biopsy and potential risks of serious complications, the omission of systematic TRUS guided biopsies may lead to about 15% of csPCa missed diagnosis and may not reflect common clinical practice (29, 30).

In definitive, mpMRI improve the cost-effectiveness of prostate biopsy, but false negative rate of mpMRI (about 20% of the cases) in diagnosing csPCa should be taken into serious account in the clinical management of patients; for that, the use of risk calculators that include mpMRI plus more clinical parameters (i.e., age, familiarity for PCa, initial or repeat biopsy, PSA values and its kinetics, DRE, genetic markers) could represent useful tools in better defining the risk of csPCa presence.

CONCLUSIONS MRI/TRUS fusion biopsy is becoming the accepted method for the diagnosis of PCa, with the most beneficial cost/effective rate when done with proper instructions.

The overall cost per-patient of a fusion plus systematic biopsy (€ 531.00 E + € 40.00/120.00) could be evaluated under the light of the cost-effectiveness of mpMRI in reducing the number of unnecessary prostate biopsies.

Other problems could influence the use of mpMRI in daily practice as the availability of mpMRI machine, MRI/TRUS fusion device and skilled uroradiologists.

REFERENCES 1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6):394-424.

2. Mottet N, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol. 2017; 71(4):618-629.

3. Schoots IG, Roobol MJ, Nieboer D, et al. Magnetic resonance imaging-targeted biopsy may enhance the diagnostic accuracy of significant prostate cancer detection compared to standard transrectal ultrasound-guided biopsy: a systematic review and meta-analysis. Eur Urol. 2015; 68(3):438-450.

4. Fandella A, Scattoni V, Galosi A, et al. Italian Prostate Biopsies Group: 2016 Updated Guidelines Insights. Anticancer Res. 2017; 37(2):413-424.

5. 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. 1990. J Urol. 2002; 167(2 Pt 2):966-973; discussion 973-965.

6. Bianchi L, Schiavina R, Brunocilla E. How can mpMRI help surgical

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planning in high risk prostate cancer? Prostate Cancer Prostatic Dis. 2019.

7. Zhang F, Liu CL, Chen Q, et al. Accuracy of multiparametric magnetic resonance imaging for detecting extracapsular extension in prostate cancer: a systematic review and meta-analysis. Br J Radiol.

2019; 92(1104):20190480.

8. Pepe P, Garufi A, Priolo GD, et al. Is it Time to Perform Only Magnetic Resonance Imaging Targeted Cores? Our Experience with 1,032 Men Who Underwent Prostate Biopsy. J Urol. 2018; 200(4):774-778.

9. Turkbey B, Brown AM, Sankineni S, et al. Multiparametric prostate magnetic resonance imaging in the evaluation of prostate cancer. CA Cancer J Clin. 2016; 66(4):326-336.

10. Wegelin O, van Melick HHE, Hooft L, et al. Comparing Three Different Techniques for Magnetic Resonance Imaging-targeted Prostate Biopsies: A Systematic Review of In-bore versus Magnetic Resonance Imaging-transrectal Ultrasound fusion versus Cognitive Registration. Is There a Preferred Technique? Eur Urol. 2017; 71(4):517-531.

11. Schiavina R, Vagnoni V, D'Agostino D, et al. “In-bore” MRI-guided Prostate Biopsy Using an Endorectal Nonmagnetic Device: A Prospective Study of 70 Consecutive Patients. Clin Genitourin Cancer.

2017; 15(3):417-427.

12. Bissoli E, Fandella A, La Torre E, et al. [Cost analysis of ultrasoundguided transrectal needle biopsy in prostatic carcinoma]. Radiol Med. 1998; 95(4):353-356.

13. Verma S, Choyke PL, Eberhardt SC, et al. The Current State of MR Imaging-targeted Biopsy Techniques for Detection of Prostate Cancer. Radiology. 2017; 285(2):343-356.

14. Puech P, Rouviere 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(2):461-469.

15. Perera M, Manning T, Finelli A, Lawrentschuk N. Management of men with previous negative prostate biopsy. Curr Opin Urol. 2016; 26(5):481-487.

16. Bjurlin MA, Meng X, Le Nobin J, et al. Optimization of prostate biopsy: the role of magnetic resonance imaging targeted biopsy in detection, localization and risk assessment. J Urol. 2014; 192(3):648658.

17. Drost FH, Osses DF, Nieboer D, et al. Prostate MRI, with or without MRI-targeted biopsy, and systematic biopsy for detecting prostate cancer. Cochrane Database Syst Rev. 2019; 4:Cd012663.

18. Ahmed HU, El-Shater Bosaily A, Brown LC, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet. 2017; 389(10071):815-822.

19. 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(1):22-29.

20. Fandella A. Analysis of costs of transrectal prostate biopsy.

Urologia. 2011; 78(4):288-292.

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(2):343-351.

22. 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(3):430-436.

Cost analysis of fusion targeted biopsies.

23. 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(6):266.e269-216.

multiparametric MRI avoid unnecessary prostate biopsies before holmium laser enucleation of the prostate? Preliminary results of a multicentric cohort of patients. Minerva Urol Nefrol. 2019; 71(5):524-530.

24. Barnett CL, Davenport MS, 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.

28. Pahwa S, Schiltz NK, Ponsky LE, et al. Cost-effectiveness of MR Imaging-guided Strategies for Detection of Prostate Cancer in Biopsy-Naive Men. Radiology. 2017; 285(1):157-166.

25. Borghesi M, Ahmed H, Nam R, et al. Complications After Systematic, Random, and Image-guided Prostate Biopsy. Eur Urol.

2017; 71(3):353-365.

29. Hanna N, Wszolek MF, Mojtahed A, et al. Multiparametric Magnetic Resonance Imaging-Ultrasound Fusion Biopsy Improves but Does Not Replace Standard Template Biopsy for the Detection of Prostate Cancer. J Urol. 2019; 202(5):944-951.

26. Loeb S, Vellekoop A, Ahmed HU, et al. Systematic review of complications of prostate biopsy. Eur Urol. 2013; 64(6):876-892.

27. Giampaoli M, Bianchi L, D’Agostino D, et al. Can preoperative

30. Celma A, Lopez R, Roche S, et al. Are targeted prostate biopsies ready to replace systematic prostate biopsies? Actas Urol Esp. 2019; 43(10):573-578.

CORRESPONDENCE Umberto Barbaresi, MD Department of Urology, S.Orsola Malpighi University Hospital Via Palagi, 9 – 40138 Bologna Phone: 0512142942 e-mail: ubarbaresi@libero.it

Advances in Urological Diagnosis and Imaging - 2021; 4,1

5

ORIGINAL

PAPER

Correlation of clinical and sonographic characteristics in patients with unilateral subclinical varicocele and normospermia Georgios Tsampoukas 1, 2, 3, Athanasios Dellis 1, 4, Ali Gharib 2, Mohamad Moussa 5, Dominic Brown 2, Konstantinos Deliveliotis 6, Noor Buchholz 1, Athanasios Papatsoris 1, 6.

1 2 3 4 5 6

U-merge Ltd.* (Urology for emerging countries), London, UK; Department of Urology, Princess Alexandra Hospital, Harlow, UK; Department of Urology, General Hospital of Patras, Patras, Greece; Department of Urology, Aretaieion Academic Hospital, Athens, Greece; Al Zahraa Hospital, University Medical Center, Lebanese University, Beirut, Lebanon; 2nd Department of Urology, University Hospital of Athens, Athens, Greece.

*U-merge Ltd. (Urology for Emerging Countries) is an academic urological platform dedicated to facilitate knowledge transfer in urology on all levels from developed to emerging countries. U-merge Ltd. is registered with the Companies House in London/ UK. www.U-merge.com

Objective. Subclinical varicocele carry uncertain significance and the optimal management is unknown. In this prospective study, we evaluated correlations between clinical and sonographic characteristics in patients with subclinical varicocele and normospermia.

Material and methods. Men with unilateral, left subclinical varicocele and normospermia were included; men with clinical varicocele, surgery, infections, cancer or fertility issues were excluded. Age, Body Mass Index (BMI), left maximal vein diameter, grade of reflux, left, right and mean intratesticular Resistive Index (RI), right, left and total testicular volume (TTV), follicle-stimulating hormone (FSH), testosterone and total motile sperm count (TMSC) were recorded. A statistical analysis was performed to identify correlations between the parameters.

Results. Thirty-three patients were included. No statistically significant correlation was found between mean RI and TTV, FSH, testosterone and TMSC (p>0.05); between left RI values and left testicular volume, FSH, testosterone and TMSC (p>0.05); between TTV and TMSC and between TTV and serum testosterone (p>0.05); between left maximal vein diameter and left testicular volume, testosterone and TMSC (p>0.05). Moreover, BMI and left vein diameter and BMI and testosterone showed no significant correlation (p>0.05). A statistically significant difference was found for RI (0.52 vs 0.48, p<0.05) and testicular volume (12.9 vs 15.4, p<0.05) comparing left and right side. Fourteen men with reflux ending before ending of Valsava formed group 1 and 19 men with reflux lasting during all Valsava maneuver formed group 2. Maximal vein diameter was significantly higher in group 2 (2.88 vs 3.19 mm, p<0.05); no difference was found in terms of age, BMI, left testicular volume and TMSC. Conclusions. No significant correlations were found between sonographic and clinical characteristics in our population. However, the left testicles had altered hemodynamics and decreased testicular volume. Moreover, subclinical varicoceles exhibiting higher reflux grade were associated with larger vein diameter.

SUMMARY

KEY WORDS: Subclinical varicocele, unilateral, normospermia, ultrasound.

INTRODUCTION Varicocele constitutes one of the commonest conditions being encountered in male infertility (1). It can be seen often in healthy adults whereas it is one of the most common andrological conditions in the pediatric and adolescent population (2, 3). Epidemiologically, varicocele seems to be a dynamic condition as the prevalence and grading increases with ageing (4, 5). The diagnosis of the earliest or

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Advances in Urological Diagnosis and Imaging - 2021; 4,1

mildest forms defined as subclinical varicocele (SV) are varicoceles non-apparent in clinical examination but being diagnosed through imaging modalities (6). Moreover, evidence have shown that the combination of young age and sports might also increase the risk of clinical progression (7). Apart from the potential of the condition though, its impact on male infertility is unclarified (8). Laboratory studies have shown that the detrimental effect of SV on semen oxidation capacity and DNA integrity is uncertain whereas the results of prospective trials dealing with the

Unilateral subclinical varicocele and normospermia

treatment effect of SV in terms of fertility success are conflicting at best (9-11). However, in the appropriate clinical context subclinical varicoceles carries significance and they might be considered as possible treatment target.The bilaterality of SV and specific sonographic markers have been associated with dyspermia and might be associated with risk of subfertility (12, 13). Additionally, the correction of right subclinical varicocele together with a left clinical one is associated with increased pregnancy rates in comparison to left varicocelectomy alone in infertile patients (14).

On the other hand, little is known regarding the optimal follow-up of males with SV, although monitoring is advisable by experts and international panels (15). In this prospective study, we present correlations of clinical and sonographic characteristics in men with subclinical varicocele and normospermia.

MATERIAL

AND METHODS

This study was performed as an individual part of a prospective cohort for men with subclinical varicocele approved by the Scientific Board of our institutions (General Hospital of Patras & Sismanoglio University Hospital of Athens). We recruited men with unilateral disease and normospermia during a period of 2 years (November 2016 – December 2018) attending in our clinics for other common urological diseases. The inclusion criteria were men with unilateral subclinical varicocele and normospermia. The exclusion criteria were clinical varicocele, history of surgery in the area, current or past couple infertility issues, active or chronic urogenital infections, signs and symptoms of primary hypogonadism, testicular microlithiasis, background of cancer and history of intake of gonadotoxic medications or steroids. The subclinical varicocele was defined as a negative clinical examination for clinical varicocele but maximal venous dilatation of the pampiniform plexus larger than 2 mm demonstrating reflux during the Valsava manoeuvre in ultrasound (16).

The record of maximal vein diameter and the documentation of the Valsava were performed in the standing position. The Valsava was classified in 3 grades as per Hirsch classification (Valsava induced, spontaneous intermittent and spontaneous continuous reflux) (17).

Moreover, Grade I would be divided into pattern 1 (ending before the end of Valsava) and pattern 2 (reflux lasting as long as the Valsava) (17). The grade and pattern of the reflux will be forming groups for comparative analysis.

Additionally, the testicular volume was measured automatically by the machine by the formula volume = 0.53 × length × width × height. Also, the resistive index (RI) of at least 3 intratesticular arteries was recorded in each side and the mean value was calculated for both sides. The total motile sperm count was used as a reference of the fertility potential (obtained by multiplying the volume of the ejaculate by the sperm concentration by the proportion of progressive motile sperm divided by 100%) (18).

The recorded parameters for analysis were age, body mass index (BMI), left maximal vein diameter, left and right testicular volume, left, right and mean resistive index and TMSC.

STATISTICAL ANALYSIS All statistical analyses were performed using statistics software (Graphpad Prism 8.4.2). A Shapiro-Wilk test were used to test the normality of the data distributions. A t-test was performed for the comparison of data with normal distribution; a non-parametric Mann-Whitney test was used in non-normal distributed data. A p value < 0.05 was regarded as statistically significant. A Spearman correlation analysis was preferred to examine the monotonic association of mean RI, left maximal vein diameter and left RI with several parameters. A Mann-Whitney test was used to compare age, BMI, maximal vein diameter, left testicular volume and TMSC of men in different groups according to reflux.

RESULTS Thirty-three patients were included in the study. No men were carrying abnormal echogenicity, testicular microlithiasis and no intratesticular varicocele was found. The descriptive characteristics are illustrated in Tables 1, 2.

No statistically significant correlation was found between mean RI with TTV, FSH, testosterone and TMSC and left RI values with left testicular volume, FSH, testosterone and TMSC (Tables 3, 4, respectively). No significant statistical correlation was found between total testicular volume and total motile sperm count (r=-0.19, 95% CI -0.51 to 0.16, p=0.27) and total testicular volume and serum testosterone (r=-0.13, 95% CI -0.46 to 0.23, p=0.46). Moreover, no correlation was found between left maximal vein diameter and ipsilateral testicular volume, testosterone and TMSC (Table 5). Body mass index and maximal vein diameter (r=0.17, CI -0.19 to 0.49, p>0.05) and BMI and testosterone (r=0.12, CI -0.23 to 0.45, p>0.05) showed no significant correlation as well. Comparing the varicocele-affected and right side a statistically significant difference was found in terms of resistive index and testicular volume (Table 6). All men were classified as Grade I as per Hirsch classification (reflux induced my Valsava maneuver). Two groups were formed: 14 men with pattern 1 varicocele formed group 1 and 19 men with pattern 2 formed group 2. Comparing the groups, a statistically significant difference was noted in terms of maximal vein diameter for group 2 (2.88 vs 3.19 mm, p<0.05); no difference was found in terms of age, BMI, left testicular volume and TMSC (Table 7).

DISCUSSION Clinical grading is the cornerstone for the diagnosis and management of varicoceles but it does not take into consideration the non-palpable forms (19). Moreover, anatomic particularities of the scrotum’s skin, such as obesity or vivid movements of the cremasteric muscle or the dartos during the Valsava maneuver may change the significance of low-grade varicoceles (20). Others might be missed whereas others might be overdiagnosed as clinical ones changing the clinical framework. Therefore, there is a need for an in-depth evaluation and ultrasound has been proven helpful (21). The scope of our study was to invesAdvances in Urological Diagnosis and Imaging - 2021; 4,1

7

G. Tsampoukas, A. Dellis, A. Gharib, M. Moussa, D. Brown, K. Deliveliotis, N. Buchholz, A. Papatsoris Table 1.

Patients’ characteristics.

Age (years)

BMI

FSH (mUI/mL)

Testosterone (ng/dl)

TMSC (millions)

No.

33

33

33

33

33

Minimum

19

19

1.7

368

20

Maximum

34

29

4.3

683

125

Range

15

10

2.6

315

105

Mean

26

24

2.7

525

49

Std. Deviation

4.2

2.9

0.71

82

27

Std. Error of Mean

0.74

0.51

0.12

14

4.8

BMI: Body mass index, FSH: Follicle-stimulating hormone, TMSC: Total motile sperm count.

Table 2.

Sonographic characteristics of patients with unilateral subclinical varicocele.

Maximal Diameter-L (mm)

Left Testicular volume (cc)

Right Testicular volume (cc)

Total Testicular volume (cc)

RI Left

RI Right

Mean RI

No.

33

33

33

33

33

33

33

Minimum

2.4

8.7

10

16

0.41

0.31

0.38

Maximum

3.7

19

21

40

0.69

0.72

0.67

Range

1.2

10

11

24

0.28

0.41

0.29

Mean

3

13

16

29

0.53

0.48

0.51

Std. Deviation

0.34

2.4

2.5

5.2

0.069

0.084

0.065

Std. Error of Mean

0.059

0.42

0.44

0.91

0.012

0.015

0.011

Std. Deviation: Standard Deviation, Std Error of mean: Standard error of mean, RI: Resistive index.

Table 3.

Correlation of mean RI and testicular volume, FSH, testosterone and TMSC.

r 95% Confidence intervals p Summary

TTV (cc)

FSH (mUI/mL)

Testosterone (ng/dl)

TMSC (millions)

0.07

0.02

-0.25

0.08

-0.28 to 0.41

-0.33 to 0.37

-0.55 to 0.10

-0.27 to 0.42

0.68

0.90

0.14

0.63

ns

ns

ns

ns

TTV: Total testicular volume, FSH: Follicle-stimulating hormone, TMSC: Total motile sperm count.

Table 4.

Correlation of left RI and left testicular volume, FSH, testo and TMSC.

Left testicular Volume (cc)

FSH (mUI/mL)

Testosterone (ng/dl)

TMSC (millions)

-0,11

-0.13

-0.23

-0.06

-0,44 to 0,25

-0.46 to 0.23

-0.54 to 0.12

-0.4 to 0.29

0.53

0.46

0.18

0.73

ns

ns

ns

ns

r 95% Confidence intervals p Summary

TTV: Total testicular volume, FSH: Follicle-stimulating hormone, TMSC: Total motile sperm count.

Table 5.

Correlation left maximal vein diameter and left testicular volume, FSH, testosterone and TMSC.

Left testicular Volume (cc)

FSH (mUI/mL)

Testosterone (ng/dl)

TMSC (millions)

-0,03

-0.18

0.04

0.07

-0.38 to 0.32

-0.50 to 0.17

-0.31 to 0.39

-0.28 to 0.41

0.84

0.29

0.81

0.69

ns

ns

ns

ns

r 95% Confidence intervals p Summary

TTV: Total testicular volume, FSH: Follicle-stimulating hormone, TMSC: Total motile sperm count.

8

Advances in Urological Diagnosis and Imaging - 2021; 4,1

Unilateral subclinical varicocele and normospermia

study of suspected varicoceles, the recorded venous size in Resistive Index Testicular volume (cc) standing position was significantly larger whereas the detection of Left Right Left Right bilateral varicocele surged to Mean 0.48 0.52 55% from 28% in the supine position (24). In our study, we Median 12.90 15.40 measured venous size in the p 0.017* <0.0001* standing position which facilitated at the same time both the t,df t=2.449, df=64 diagnosis of varicocele and the U documentation of the reflux.

We found that varicocele-affectSun of ranks 784, 1427 ed testicles have significantly Summary Yes Yes increased resistive index in their intratesticular arteries. If this dif*statistically significant. ference corresponds to tissue Table 7. Comparison of pattern I and II characteristics. changes caused by the presence of SV is uncertain. Future search evaluation with novel modalities Reflux such as elastography or Magnetic Pattern 1 (n=14) Pattern 2 (n=19) P value U Resonance Imaging (MRI) might unmask the effect of SV on tesAge (median, years) 26 27 0.96 131.5 ticular tissue like in clinical forms BMI (median) 23.4 23.5 0.53 115.5 (25, 26). Also, the mean readings of RI (0.51) were normal and far Maximal vein diameter (median, mm) 2.88 3.19 0.0411* 77 below the proposed cutoff of 0.6 Left testicular volume (median, cc) 13.2 12.9 0.19 97 in cases of dyspermia (27, 28).

RI (median) These findings are compatible 0.50 0.54 0.96 131.5 with the clinical context as our TMSC (median, millions) 37.43 37.44 0.78 125 study population were young men with normospermia. Finally, *statistically significant difference. left and mean RI showed no correlation between testicular volume, levels of testosterone tigate possible correlations between clinical and sonoand FSH and sperm count. Although the exact role of RI graphic characteristics in asymptomatic patients with uniis uncertain, we would advise to be included in future follateral SV and normospermia. Although the optimal manlow-up as it has been associated with dyspermia in agement is unknown, experts argue in favour of a regular patients with SV (12, 13). follow-up in selected groups of men (15).

Moreover, we investigated the role of testicular volume Firstly, we evaluated the correlation of venous size and the and we found that varicocele-bearing testicles were signifpattern of reflux. We found that SVs exhibiting a continuicantly smaller than the right ones (12.9 vs 15.40, p<0.05). ous reflux during Valsava (pattern 2) are significantly larger Previously, SV has been associated with testicular hypotrothan those recorded as pattern 1 (2.88 vs 3.19 mm, phy, although this is conflicting (29, 30). Also, in our cohort, p<0.05).This finding might imply ongoing incompetence of men with pattern 1 reflux had slightly larger left testicles the venous valves and might be relevant in terms of proin comparison to those with pattern 2, but the difference gression to a CV. It has been shown that presence of reflux was not significant (13.2 vs 12.9 cc, p>0.05). It could be is associated with maximal diameter larger than 3 mm stated that SV might be associated with smaller testicular (22) and varicocele size larger than 3 mm is helpful to dissize, but the clinical importance of the finding is doubtful. criminate palpable from non-palpable varicoceles (23).

If these readings represent an ongoing testicular hypotroTherefore, we believe that SVs larger than 3 mm exhibitphy needs to be addressed in future follow-up. Finally, we ing non-reducible reflux during Valsava are coming closer found no correlation of total testicular volume with total to become clinically apparent. In the appropriate clinical motile sperm count and serum testosterone. As expected, context, these men might be benefited from a follow-up the findings reflect the normospermia and the eugonadal as their clinical status might change in the future. state of the men in our cohort.

Also, we examined the role of maximal vein diameter and We need to acknowledge the limitations in our study. First, we found no correlation with left testicular volume, FSH it includes only a small population of well and fit individuand testosterone. Although sonographic size alone is helpals. Moreover, although there was no evidence to imply ful for the diagnosis, its significance is uncertain in this any infertility issues to these men, we did not correlate group of men. We would also advise a systematic ultrawith pregnancy rates which is the primary endpoint in sonographic protocol to be followed in terms of docuvaricocele patients. Also, our methodology did not include mentation and reproducibility as size reading might be the calculation of relative risks for progression and our staaffected by minor but meaningful details. For example, in a tistical observations cannot imply causation, but they need Table 6. Comparison of testicular characteristics.

Advances in Urological Diagnosis and Imaging - 2021; 4,1

9

G. Tsampoukas, A. Dellis, A. Gharib, M. Moussa, D. Brown, K. Deliveliotis, N. Buchholz, A. Papatsoris

to be utilized in the appropriate clinical context. Finally, the appreciate that our data are static; a future follow-up would have given more information regarding the significance of our findings.

CONCLUSIONS In this cohort, the testicles carrying SV were found with significantly elevated resistive index of the intratesticular arteries and lower testicular volume comparing to the contralateral ones. Also, subclinical varicoceles exhibiting a continuous reflux during Valsava were found to be larger than those showing a faint reflux, which might be relevant in terms of clinical progression. Future studies should evaluate the importance of these findings at the long-term.

Finally, no significant correlations were found between sonographic and clinical characteristics in men with left unilateral varicocele and normal semen quality.

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2. Lotti F, Frizza F, Balercia G, et al. The European Academy of Andrology (EAA) ultrasound study on healthy, fertile men: clinical, seminal and biochemical characteristics. Andrology. 2020.

3. Zampieri N, Camoglio F. Pediatric-adolescent andrology: Single centre experience. Arch Ital Urol Androl. 2020; 92(2).

4. Levinger U, Gornish M, Gat Y, Bachar GN. Is varicocele prevalence increasing with age? Andrologia. 2007; 39(3):77-80.

5. Besiroglu H, Otunctemur A, Dursun M, Ozbek E.The prevalence and severity of varicocele in adult population over the age of forty years old: A cross-sectional study. Aging male Off J Int Soc Study Aging Male.

2019; 22(3):207-213.

6. Belay R, Huang G, Shen J-C, Ko EK. Diagnosis of clinical and subclinical varicocele: how has it evolved? Asian J Androl. 2016; 18(2):182.

7. Zampieri N, Dall’Agnola A. Subclinical varicocele and sports: a longitudinal study. Urology. 2011; 77(5):1199-1202.

8. Majzoub A, Agarwal A, Esteves SC. Sperm DNA fragmentation testing in patients with subclinical varicocele: Is there any evidence? 2017; 6(Suppl 4):459-461.

9. Unal D, Yeni E, Verit A, Karatas OF. Clomiphene citrate versus varicocelectomy in treatment of subclinical varicocele: A prospective randomized study. Int J Urol. 2001; 8(5):227-230.

10. Cantoro U, Polito M, Muzzonigro G. Reassessing the Role of Subclinical Varicocele in Infertile Men with Impaired Semen Quality: A Prospective Study. Urology. 2015; 85(4):826-830.

11. Yamamoto M, Hibi H, Hirata Y, et al. Effect of varicocelectomy on sperm parameters and pregnancy rate in patients with subclinical varicocele: A randomized prospective controlled study. J Urol. 1996; 155(5):1636-1638.

12. Tsampoukas G, Dellis A, Papatsoris A. Bilateral disease and intratesticular haemodynamics as markers of dyspermia in patients with subclinical varicocele: A prospective study. Arab J Urol. 2019; 17(4):298-304.

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15. Freeman S, Bertolotto M, Richenberg J, et al. Ultrasound evaluation of varicoceles: Guidelines and recommendations of the European Society of Urogenital Radiology Scrotal and Penile Imaging Working Group (ESUR-SPIWG) for detection, classification, and grading. Eur Radiol. 2020; 30(1):11-25.

16. Gonda RL, Karo JJ, Forte RA, O’Donnell KT. Diagnosis of subclinical varicocele in infertility. Am J Roentgenol. 1987; 148(1):71-75.

17. Hirsh AV, Cameron KM, Tyler JP, et al. The Doppler assessment of varicoceles and internal spermatic vein reflux in infertile men. Br J Urol. 1980; 52(1):50-56.

18. Hamilton JAM, Cissen M, Brandes M, et al. Total motile sperm count: a better indicator for the severity of male factor infertility than the WHO sperm classification system. Hum Reprod. 2015; 30(5):1110-1121.

19. Valentino M, Bertolotto M, Derchi L, Pavlica P. Children and adults varicocele: Diagnostic issues and therapeutical strategies. J Ultrasound.

2014; 17(3):185-193.

20. Liguori G,Trombetta ÆC, Garaffa ÆG, Belgrano ÆE. Color Doppler ultrasound investigation of varicocele. 2004; 378-381.

21. Bertolotto M, Freeman S, Richenberg J, et al. Ultrasound evaluation of varicoceles: systematic literature review and rationale of the ESURSPIWG Guidelines and Recommendations. J Ultrasound. 2020.

22. Hoekstra T, Witt MA.The correlation of internal spermatic vein palpability with ultrasonographic diameter and reversal of venous flow. J Urol. 1995; 153(1):82-84.

23. Sujenthiran A, Abumelha S,Yap T, et al. Maximum Venous Diameter is a Simple and Objective Measurement to Characterize Clinical Varicoceles. Ann Urol Res. 2017; 1(1).

24. Ebubedike UR, Enukegwu SU, Nwofor AM. Ultrasound evaluation of testicular vein diameter in suspected cases of varicocele: Comparison of measurements in supine and upright positions. Niger J Clin Pract. 2020; 23(7):1004-1007.

25. Salama N, Samir M, Blgozah S. Evaluation of Normal and Varicocele-Bearing Testes Using Real-time Strain Elastography. J Ultrasound Med. 2019; 38(3):621-627.

26. Karakas E, Karakas O, Cullu N, et al. Diffusion-weighted MRI of the testes in patients with varicocele: A preliminary study. AJR Am J Roentgenol. 2014; 202(2):324-328.

27. Hillelsohn JH, Chuang KW, Goldenberg E, Gilbert BR. Spectral doppler sonography: A noninvasive method for predicting dyspermia. J Ultrasound Med. 2013; 32(8):1427-1432.

28. Pinggera GM, Mitterberger M, Bartsch G, et al. Assessment of the intratesticular resistive index by colour Doppler ultrasonography measurements as a predictor of spermatogenesis. BJU Int. 2008; 101(6):722-726.

29. Zini A, Buckspan M, Berardinucci D, Jarvi K. The influence of clinical and subclinical varicocele on testicular volume. Fertil Steril. 1997; 68(4):671-674.

30. Sakamoto H, Ogawa Y, Yoshida H. Relationship Between Testicular Volume and Varicocele in Patients With Infertility. Urology. 2008; 71(1):104-109.

CORRESPONDENCE Georgios Tsampoukas U-merge scientific office 1, Menandrou Street Athens 14561 - Greece

13. Chen SS-S. Significant predictive factors for subfertility in patients with subclinical varicocele. Andrologia. March 2017.

Email: scientific-Office@u-merge.com

14. Ou N, Zhu J, Zhang W, et al. Bilateral is superior to unilateral varicocelectomy in infertile men with bilateral varicocele: Systematic review and meta-analysis. Andrologia. 2019; 51(11):e13462.

Tel: +30 213045 5951

Advances in Urological Diagnosis and Imaging - 2021; 4,1

(personal mail: tsampoukasg@gmail.com)

ORIGINAL

PAPER

A new therapeutic strategy in the treatment of pelvic chronic pain Lorenzo Montesi, Carmine Franzese, Angelo Antezza, Simone Scarcella, Erika Palagonia, Lucio Dell’Atti Division of Urology, University Hospital “Ospedali Riuniti”, School of Medicine, Department of Clinical, Special and Dental Sciences, Marche Polytechnic University, Ancona, Italy.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) remains a mysterious medical disorder.

Creation of the Chronic Prostatitis Collaborative Research Network (CPCRN) funded by the National Institutes of Health (NIH) has increased a refreshed interest in the research and clinical aspects of CP/CPPS. The therapeutic efficacy for CP/CPPS is currently unsatisfactory. Often the side effects of the medications used (antiinflammatory drugs, antibiotics, alpha blockers) far outweighs the benefits gained with their administration.

The choice of nutraceutical medications is preferred for their effectiveness, that has been accepted and proven by the scientific community and for the low incidence of side effects.

This single blind study shows the therapeutic efficacy of the glycerophosphoinositol in terms of reduction of symptoms, and in the average waiting time of the variation of the National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI).

SUMMARY

KEY WORDS: Chronic prostatitis, chronic pelvic pain syndrome, glycerophosphoinositol, nutraceutical medica-tions, anti-inflammatory drugs.

INTRODUCTION Prostatic inflammation and related symptomatology like lower urinary tract symptoms (LUTS) and pelvic pain are common in men with a prevalence of 8.2% in the general population. Prostatitis are classified using the definition of National Institute of Health (NIH) The classification devised is illustrated in Table 1 and consists of four item including: acute bacterial prostatitis (ABP), chronic bacterial prostatitis (CBP), chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and asymptomatic inflammatory prostatitis (AIP) (1). The National Institutes of Health Chronic Prostatitis Index (NIH-CPSI) is used to objective assess prostatitis-like symptoms. Epidemiologic data shows a rate of prostatitis-like symptoms that ranges from 2.2% to 9.7% with a mean prevalence of 8.2% (2). “Prostatitis” is a term generally used to refer to different and separate entities. In addition the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) is widely used to objective assess prostatitis-like symptoms (3).

Among prostatitis in less than 10% of men it is possible to identify a causative pathogen and it is estimated that after ABP in 10% of the cases the patient will develop a CBP while in a further 10% of cases it will lead to CPPS. Overall CPPS accounts for more than 90% of men with prostatitis-like symptoms (4). While the treatment of bacterial prostatitis relies on the use of specific antimicrobial agents tar-

geted to the identified uropathogen, the therapeutic management of CPPS remains controversy.

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. The aim of our study is to evaluate the efficacy of suppositories of Glycerophosphoinositol (GPI) compared to placebo in role to reduce the pain, LUTS symptoms, anorectal symptoms in patient with prostatitis and pelvic and anorectal pain symptoms.

MATERIALS

AND METHODS

From June 2019 to December 2019, we enrolled sixtynine consecutive patients affected by CP/CPPS III from our institution. Patients with symptoms of pelvic pain and a total National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score ≥ 12 points were included in the study protocol. At baseline subjects underwent digital rectal exploration for the evaluation of pain based on Visual analogue scale (VAS), urine examination and calculation of NIH-CPSI index. We have considered patients with positive and negative urine culture.

The patients were randomized in two groups. In single blind we administered for ten days one rectal suppository Advances in Urological Diagnosis and Imaging - 2021; 4,1

11

L. Montesi, C. Franzese, A. Antezza, S. Scarcella, E. Palagonia, L. Dell’Atti Table 1. National Institute of Health Classification of prostatitis.

Table 2. Results of the DRE VAS and NIH-CPSI data of GPI and placebo group.

NIH-CP/CPPS classification

GPI group

Placebo group

Type I: ABP Acute bacterial prostatitis

DRE VAS first

7,0 (4-10)

7,1 (4-10)

A painful condition typically associated with fever and chills

NIH-CPSI first

21,8 (11-31)

22,5 (12-31)

Type II: CBP Chronic bacterial prostatitis

DRE VAS final

4,5 (2-8)

6,2 (3-9)

A recurring problem of symptoms associated with infection

NIH-CPSI final

13,9 (4-24)

18,9 (8-28)

Type IIIa: CP/CPPS Chronic prostatitis/Chronic pelvic pain syndrome

DRE VAS improvement

2,4

1,0

Not bacterial symptomatic inflammation of the prostate

Urine culture positive

2,1

1,1

Type IIIb: P/CPPS Non-inflammation chronic pelvic pain syndrome

Urine culture negative

2,5

0,8

Not bacterial and not inflammation of the prostate

NIH-CPSI improvement

7,9

3,5

Type IV: AIP Asymptomatic inflammation of the prostate

Urine culture positive

7,2

3,6

Detected during evaluation and/or treatment for other conditions

Urine culture negative

8,1

3,3

The average NIH-CPSI index was 21,8 for GPI’s group and 22,5 for the Placebo’s group.

In the GPI’s group 16/33 patients had positive Patient characteristics Total GPI group Placebo group urine culture versus 18/31 of the Placebo’s Number pz 64 33 31 group. In this case antibiotic therapy was assoAGE y ciated with the suppositories. After 10 days of 50.1 (31-68) 49.7 (31-65) 50.5 (33-68) therapy, the final visit average VAS was 4,5 for Anorectal symptoms pz 44 22 22 the GPI's group versus 6,2 for the Placebo’s Improve anorectal symptoms pz 15 10 5 group with a mean reduction of 2,4 points in the GPI’s group versus 1,0 in the Placebo’s Urine culture positive pz 34 16 18 group. The NIH-CPSI index after treatment Urine culture negative pz 30 17 13 was 13,9 for the GPI’s group and 18,9 for the Placebo’s group with a mean reduction of 7,9 point in the GPI’s group versus 3,5 in the with GPI for the study group and placebo for the control Placebo’s group. 44 patients had anorectal symptoms group. Fans for pain control and antibiotics for positive (69% of the population). urine culture were dispensed.

Of them 19 were from the group with positive urine culThe patients underwent to a control visit two weeks later ture (57%) and 25 were from the group with negative the first visit and after the end of the medical therapy. urine culture (81%).After treatment the number of Each subject underwent digital rectal exploration for the patients with anorectal symptoms and negative urine culevaluation of pain based on VAS index and calculation of ture was reduced from 15 to 8 in the GPI’s group (reducNIH-CPSI index. Exclusion criteria were patient who don’t tion of 46,7%) and from 10 to 7 in the Placebo’s group respect the drugs regimen, patient don’t come at final visit. (reduction of 30%); when the urine culture was positive All visits were performed in our center. we observed a reduction from 7 to 4 in the GPI’s group All result were analyzed with statistical analysis system (reduction of 43%) and from 12 to 10 in the Placebo's SPSS. Our first goal was to test the GPI in patient with or group (reduction of 16%). No serious side effects were without LUTS or anorectal symptoms in role of DRE VAS observed in the whole population. and NIH-CPSI score. Second goal was test if were difference in case urine culture at baseline were positive or RESULTS IN POSITIVE URINE CULTURE negative.

The average age was 48,3 years for GPI’s group and 51,7y for Placebo’s group. The average VAS at the DRE in the recruitment visit was 7,4 for GPI’s group and 7,4 for the RESULTS Placebo’s group.

The average NIH-CPSI index was 22,9 for GPI’s group and We enrolled 69 patients in our study, 64 were considered 23,6 for the Placebo’s group. After 10 days of therapy, the for the study, 5 did not respected the inclusion criteria. In final visit average VAS was 5,1 for the GPI's group versus 33 cases was dispensed GPI suppositories (Prospidol), in 6,4 for the Placebo’s group with a mean reduction of 2,1 the other 31 cases was dispensed the Placebo suppositopoints in the GPI’s group versus 1,1 in the Placebo’s group. ries. The average age was 50,1 years for GPI’s group and The NIH-CPSI index after treatment was 15,6 for the 49,7 y for Placebo’s group (Table 2). The average VAS at GPI’s group and 18,8 for the Placebo’s group with a mean the DRE in the recruitment visit was 7,0 for GPI's group reduction of 7,3 point in the GPI’s group versus 3,6 in the and 7,1 for the Placebo’s group.

Placebo’s group.

Table 3. Patient characteristics.

12

Advances in Urological Diagnosis and Imaging - 2021; 4,1

Glycerophosphoinositol suppositories for pelvic chronic pain Figure 1. Flowchart showing patient selection and results.

From this perspective a novel 6point clinical phenotyping system UPOINTs for the manage69 patients ment of CP/CPPS has been 5 patient exit for introduced in clinical practice. incompliance in therapy The six UPOINTs domains comprise Urinary symptoms, 44 with anorectal 64 patients Psychological dysfunction, symptoms (69%) Organ-specific symptoms, !"#$%&'(%"#) Infection, Neurologic/systemic conditions, Tenderness of mus33 in PGI group 31 in Placebo group cles and Sexual Dysfunction.

In agreement with recent clinical !"#$%&'()*("% trials this classification system appears to correlate with symp16 positive 17 negative 18 positive 13 negative toms severity and duration of disease. This multimodal treat+,-&./0&#12"34%1%$* ment guided by UPOINTs leads to a significant improvement of !"# ("% !") #"# both symptomatology and quality of life (9). GPI taken by sup56789:06&#12"34%1%$* positories was demonstrated safety, there were no side effects '"! %"# $"$ $"& in our population. We observed a better grade of improving for the VAS index and uro-anorectal symptoms in group with GPI therapy versus the placeRESULTS IN NEGATIVE URINE CULTURE bo. Particularly this improvement was observed in the The average age was 49,4 years for GPI’s group and 48,8 y population with negative urine culture, similarly we for Placebo’s group. The average VAS at the DRE in the observed a reduction of anorectal symptoms in the group recruitment visit was 7 for GPI’s group and 6,8 for the with negative urine culture and GPI therapy. This therapy Placebo’s group. The average NIH-CPSI index was 20,6 for could be associate with other drugs as alpha blockers, antiGPI’s group and 22,4 for the Placebo’s group. inflammatory, antibiotics in multi drugs therapy (10).

After 10 days of therapy, the final visit average VAS was 4,1 Drugs taken as local therapy could reduce systemic side for the GPI’s group versus 6,0 for the Placebo’s group with a effect of systemically drug therapy took by oral suspenmean reduction of 2,5 points in the GPI’s group versus 0,8 sion. In a meta-analysis published on 2011 on three studies in the Placebo’s group. The NIH-CPSI index after treatment comparing phytotherapy with placebo (n = 223), authors was 12,5 for the GPI’s group and 19,1 for the Placebo’s demonstrated a reduction of pain score (standard mean group with a mean reduction of 8,1 point in the GPI’s group difference (SMD: -0.5) and in voiding symptoms (SMD: versus 3,3 in the Placebo’s group. Data are in Table 3 and -0.4). Moreover, phytotherapy exhibited the second highFigure 1. est response rate after alpha-blockers, showing a risk ratio of 1.6 compared with placebo (11).

Many drugs and plant were tested in piratical clinic in DISCUSSION chronic pelvic pain syndrome and bacterial prostatitis syndrome. Morgia et al. tested Curcumin and Calendula as The use of antibiotics showed suboptimal results in suppositories in ironic pelvic syndrome type III (12, 13).

CP/CPPS with a significant long-term improvement in only In their study Curcumin and Calendula token for 1 month 50-65% of men. Moreover, multiple medications have been as suppositories can improve pain and urinary symptoms tested but the majority of pharmacotherapies utilized in compared to placebo. The choice of nutraceutical medicaCP/CPPS did not improve symptoms significantly (5, 6). tions is preferred for their effectiveness, that has been The lack of a widely shared and accepted treatment algoaccepted and proven by the scientific community and for rithm is due to the complex and heterogeneous pathothe low incidence of side effects. physiology of CPPS which is still incompletely known.

For this reason, the management of this condition remains challenging. Many meta-analysis evaluating data of randomCONCLUSIONS ized controlled trials (RCTs) pointed out the variable efficacy of different therapeutic options related to the hetGlycophosphoinositol taken as suppository (Prospidol) is erogeneity of clinical features among patients (7). safety and effectiveness in reduction pain and urinary and According to the guidelines a multimodal therapeutic anorectal symptoms, associated with antibiotic and approach is mandatory and therapy should be individualNSAIDs therapy, in patient with prostatitis like symptoms. ized to target the specific symptom(s) presented by each Effectiveness seems better in case of bacterial prostatitis patient (8). and pelvic chronic pain.

Advances in Urological Diagnosis and Imaging - 2021; 4,1

13

L. Montesi, C. Franzese, A. Antezza, S. Scarcella, E. Palagonia, L. Dell’Atti

REFERENCES

phate increase during haemopoietic cell differentiation. BBA - Mol Cell Res. 1994; 1222(1):101-8.

1. Bozzini G, Provenzano M, Buffi N, et al. An observational study of the use of beclomethasone dipropionate suppositories in the treatment of lower urinary tract inflammation in men. BMC Urol. 2016; 16(1).

8. Narita K, Kubota M, Nakane M, et al. Therapeutic time window in the penumbra during permanent focal ischemia in rats: Changes of free fatty acids and glycerophospholipids. Neurol Res. 2000; 22(4):393-400.

2. Hedelin H, Fall M. Controversies in chronic abacterial prostatitis/pelvic pain syndrome. Scandinavian Journal of Urology and Nephrology. 2008; 42:198-204.

3. Bartoletti R, Cai T, Mondaini N, et al. Prevalence, Incidence Estimation, Risk Factors and Characterization of Chronic Prostatitis/Chronic Pelvic Pain Syndrome in Urological Hospital Outpatients in Italy: Results of a Multicenter Case-Control Observational Study. J Urol. 2007; 178(6):2411-5.

4. Gurunadha Rao Tunuguntla HS, Evans CP. Management of prostatitis. Vol. 5, Prostate Cancer and Prostatic Diseases. 2002; 172-9.

5. Pavone C, Caldarera E, Liberti P, et al. Correlation between chronic prostatitis syndrome and pelvic venous disease. A survey of 2554 urologic outpatients. Eur Urol. 2000; 37(4):400-3.

6. Westesson KE, Shoskes DA. Chronic prostatitis/chronic pelvic pain syndrome and pelvic floor spasm: Can we diagnose and treat?

Current Urology Reports. 2010; 11:261-4.

7. Mountford JC, Bunce CM, French PJ, et al. Intracellular concentrations of inositol, glycerophosphoinositol and inositol pentakisphos-

9. Corda D, Zizza P, Varone A, et al. The glycerophosphoinositols: Cellular metabolism and biological functions. Cellular and Molecular Life Sciences. 2009; 6:3449.67.

10. Cucullo L, Hallene K, Dini G, et al. Glycerophosphoinositol and dexamethasone improve transendothelial electrical resistance in an in vitro study of the blood-brain barrier. Brain Res. 2004; 997(2):147-51.

11. Zazzara M, Nazaraj A, Colamonico O, et al. Could pollen extract in association with vitamins be favorable in the reduction of chronic prostatic inflammation? A case-series analysis. Arch Ital di Urol e Androl. 2019; 91(2):84-6.

12. Morgia G, Privitera S. Phytotherapy in Benign Prostatic Hyperplasia. In: Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia. 2018; 135-75.

13. Morgia G, Russo GI, Urzì D, et al. A phase II, randomized, singleblinded, placebo-controlled clinical trial on the efficacy of curcumina and calendula suppositories for the treatment of patients with chronic prostatitis/chronic pelvic pain syndrome type III. Arch Ital Urol Androl. 2017; 89(2):110-113.

CORRESPONDENCE Franzese Carmine Division of Urology, University Hospital “Ospedali Riuniti”, School of Medicine, Department of Clinical, Special and Dental Sciences, Marche Polytechnic University, Conca Street 71, 60126, Ancona, Italy E-mail: carminefranzese_@msn.com Phone. +39 0715966523

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Advances in Urological Diagnosis and Imaging - 2021; 4,1

ORIGINAL

PAPER

Salvage radiotherapy following radical prostatectomy: Long term oncological and functional outcomes (median 96 months) in 108 patients Pietro Pepe 1, Marinella Tamburo 2, Michele Pennisi 1, Dario Marletta 2, Francesco Marletta 2.

1 2

Azienda Ospedaliera Cannizzaro, Urology Unit; Azienda Ospedaliera Cannizzaro, Radiotherapy Unit.

Introduction. To evaluate oncological and functional outcomes in men submitted to salvage radiotherapy (sRT) following radical retropubic prostatectomy (RRP).

Materials and Methods. In the years 2003-2020, 108 patients received sRT because biochemical recurrence (BCR) defined as 2 consecutive prostate specific antigen (PSA) values than 0.2 ng/ml and rising after RRP (median 49 months). All patients have been treated up to 66.0-70.4 Gy with single dose of 1.8-2.0 Gy fractions. Predictive factors were analyzed to evaluate prostate specific antigen (PSA) and clinical response to radiotherapy.

Results. Median follow-up after sRT was 96 months (12-204 months); 54/108 (54.7%) men had PSA response (PSA value < 0.2 ng/ml), conversely 49/108 (45.3%) demonstrated BCR during follow up. Clinical stage (pT2 vs > pT3), pathological ISUP Grading Group (GG < 3 vs GG > 4), pre-radiotherapy median PSA value (0.55 vs 1.83 ng/ml) and pathological node-involvement were highly predictive for BCR (p < 0.05). Clinical complications following sRT were characterized by late gastrointestinal (GI) and genitourinary toxicity (GU) in 9 (9.5%) and 12 cases (11.8%), respectively.

Conclusions. Salvage RT following RP constitutes a curative therapy in about 50% of the cases with a low rate of GI (9.5%) and GU (11.8%) late complications. The oncological outcome is correlated with pathological stage, ISUP Grade Group, node-involvement and pre-sRT PSA value.

SUMMARY

KEY WORDS: Prostate cancer; salvage radiotherapy and prostate cancer; oncological outcome and radical prostatectomy.

INTRODUCTION Salvage radiation therapy (sRT) is considered the most common treatment option employed in case of biochemical recurrence (BCR) after radical prostatectomy (RP) and its effectiveness dependent on the PSA level at the time of treatment (1, 2). Many studies have shown that early sRT at a PSA level < 0.5 ng/ml (2) has been associated with improved BCR, metastasis-free survival, and cancer-specific survival (3). The potential benefit of sRT must be weighed against the potential deleterious effect on functional outcomes, particularly, erectile function, urinary continence (4), and bowel disease; in fact sRT affect long term continence and toxicity irrespective of time of initiation for RT (5, 6). Additionally, a considerable proportion of patients treated with post-surgery radiotherapy may experience early and late high-grade toxicity (7). The impact of sRT on the biochemical control varies according to the clinical and pathological features of patients; moreover, in the presence of unfavorable risk factors multimodal treatment is highly recommended (8).

In this study, we report long term functional and oncological outocomes in men submitted to sRT following radical retropubic prostatectomy (RRP).

MATERIALS

AND METHODS

In the years 2003-2020, 108 patients received sRT following RRP (9-11) because BCR defined as 2 consecutive PSA values than 0.2 ng/ml and rising (1). Nobody had suspicious rectal examination, in addition median number of nodes removed by surgery was equal to 12 (range: 3-27 nodes). Overall, median PSA value before starting sRT was 0.68 ng/ml (range: 0.17-4.2 ng/ml). All the patients with PSA value > 1 ng/ml underwent diagnostic imaging (lungabdominal CT or, in the last five years, choline PET-CT scan); none of the patients showed any clinical evidence of distant metastases before they received sRT. On the contrary, in the presence of PSA value below 1 ng/ml the patients underwent sRT without any imaging evaluation.

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P. Pepe, M. Tamburo, M. Pennisi, D. Marletta, F. Marletta

Clinical parameters of men submitted to sRT are listed in Table 1.

Image-guidate radiotherapy tecniques (IGRT) with daily CBCT were performed for all patients, 20/108 (18.5%) patients have been treated with 3-dimensional conformal RT (3D-CRT), 49/108 (45.4%) with intensity modulated RT (IMRT) and 39/108 (36.1%) volumetric modulated arc therapy (VMAT).

These techniques allow improved dose homogeneity and reduction in radiation dose to normal structures, such as the bladder and rectal wall; 43/108 (39.8%) patients subjected to whole-pelvic radiation therapy and 65/108 (60.2%) received bed prostate treatment. For all patients a median total dose of 68 Gy (range: 66-70.4 Gy) was delivered with single dose of 1.8-2 Gy. Clinical and pathological findings predictive of PSA response to sRT were evaluated. The long-term oncological and functional outcomes after sRT has been retrospectively evaluated.

A probability (p) level of less than 0.05 was considered statistically significant.

stable PSA response (< 0.2 ng/ml) during follow up, conversely 49 (45.3%) demonstrated BCR over the time.

Overall, median follow-up was 96 months (range: 12-204 months) resulting equal to 64 vs 50 months in men RT responders vs RT non responders. In men with complete PSA response median PSA before RT was 0.55 ng/ml (range 0.17-2 ng/ml) and 24/59 (40.7%) vs 35/59 (50.7%) had a PCa ISUP GG1 vs GG2-3, respectively. In the 49/108 (45.3%) patients who developed BCR following sRT median PSA was 1.83 ng/ml (range: 0.18-4.3), 4/49 (8.1%) had positive nodes and 39/49 (80%) of them needed androgen deprivation therapy (ADT). Pathological stage (pT2 vs > pT3) (Figure 1), pathological Grade Group (GG < 3 vs GG > 4), pre-radiotherapy PSA value (0.55 vs 1.83 ng/ml) and nodes involvement (Figure 2) were highly predictive of BCR (p < 0.05). Stereotassic radioterapy was administered in 6 men and only in 2 (33.3%) cases a temporary PSA response was recorded. Functional outcomes of men submitted to sRT are listed in Table 2; in detail 11.8% (12 cases) and 9.5% (9 cases) of the patients reported late G2/G3 genitourinary (GU) and gastrointestinal (GI) complications (Table 2).

RESULTS Salvage RT started about 4 years (median 49 months) from RRP: 59/108 (54.7%) patients had a complete and

DISCUSSION

BCR alone is not a surrogate of overall survival and/or PCa specific survival; therefore, a lot of Table 1. Clinical and pathological parameters in 108 patients submitted to salvage prognostic indicators are used in clinical practice to assess the patient level risk radiotherapy. to initiate early treatment or to adopt a strategy of surveillance; the decision pTNM GG 1 GG 2 GG 3 GG 4 GG 5 Median PSA making should be performed by multi(number of patients) (ng/ml) disciplinary team to adopt an informed individualised approach (12). BCR pT2 (70) 21 26 0.40 occurs in 27-53% of patients after pT3 (37) 3 14 27 10 6 1.2 definitive therapy (13); in detail 24-35% pT4 (1) 1 4.3 of men who develop BCR will experience clinical recurrence within 15 years N+ (4) 3 1 4.3 from surgery and 2-6% of them will die ADT (40) 23 10 7 2.6 from PCa (14). Pathological stage, preoperative PSA value, Gleason score < 8, ISUP GG: International Society of Urologic Pathology Grade Group; presence of positive surgical margins, PSA: prostate specific antigen; N+: positive nodes; pre sRT PSA value and PSA nadir < 0.1 ADT: antiandrogen deprivation therapy. ng/ml correlate with lower risk of recurrence (15). Kashihara et al. (16) in 120 Table 2. Functional outcome in 108 patients submitted to salvage radiotherapy (sRT) men submitted to sRT demonstrated in multivariate analysis that biochemical for PSA recurrence. response was significantly favourable in men with PSA value < 0.5 ng/ml and sRT complications Early complications Late complications pathological Gleason score < 7. Mishra within 6 months after 6 months et al. (17) in 186 men submitted to adjunumber of patients (%) number of patients (%) vant RT vs sRT demonstrated that the GU (dysuria, urinary urgency, 54 cases (50%) 10 cases (10%) G2 long-term outcomes (88-103 months) hematuria) 2 cases (1.8%) % G3 freedom from metastatic failure was superimposable; at the same time, GI (diarrhea, bowel disease, rectal 4 cases (4.3%) 8 cases (8.6%) G2 Fossati et al. (18) in 510 men pT3N0 bleedind) 1 case (0.9%) G3 demonstrated at long term follow up no significant defferences in term of overall GU: genitourinary; GI: gastrointestinal.

RTOG/EORTC: Late Radiation Morbidity Scoring (Grade 1-Grade 4) Scheme. survival between immediate postoperaAvailable at: www.rtog.org/ResearchAssociates/AdverseEventReporting/RTOtive adjuvant radiation therapy and early GEORTCLLateRadiationMorbidityScoringSchema.aspx sRT (PSA < 0.5 ng/ml). Galla et al. (19)

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Advances in Urological Diagnosis and Imaging - 2021; 4,1

Salvage radiotherapy following radical prostatectomy: long term oncological and functional outcomes (median 96 months) in 108 patients Figure 1. pT stages, antiandrogen deprivation theraphy (ADT), timing of salvage radiotherapy from retropubic radical prostatectomy (RRP) and follow up in 108 patients: correlation with PSA response.

Figure 2. ISUP Grade Groups correlated to PSA response in the 108 patients submitted to salvage radiotherapy.

increased number of lymph nodes resected at RP had improved outcomes. Ying et al. (22) in 61 patients who underwent sRT at a median follow up of ten years reported a PSA failure and an overall survival equal to 56 vs 67%, respectively showing a worse prognosis in men with early PSA failure (< 1 year from radiotherapy).

Gandaglia et al. (23) in 525 men submitted to salvage RT reported a reduction in the rate of metastasis in men with more aggressive clinical characteristics (pT3b/4 and grade group > 4) when concomitant androgen deprivation therapy was added; Carrie et al. (24) in 743 men enrolled in a open-label multicentre randomised controlled trial demonstrated that adding short-term androgen suppression to sRT improved benefits in men who PSA rises after a postsurgical period when it is undetectable.

In our series, at median follow-up of 96 months (range: 12204), 59/108 (54.7%) patients had a complete and stable PSA response (< 0.2 ng/ml) during follow up, conversely 49 (45.3%) demonstrated over the time BCR. Pathological stage, PCa ISUP Grade Group, pre-radiotherapy PSA value and nodes involvement resulted highly predictive of BCR (p < 0.05). Finally, long term functional outcomes demonstrated late GU and GI complications only in 11.8% (12 cases) vs 9.5% (9 cases), respectively.

Regarding our results some considerations should be made. First, the study is retrospective. Second, although our results are in agreement with the literature data the long time of follow up (median 96 months) allows to better evaluate oncological and functional outcomes following sRT.Third, no conclusions could be made about stereotassic sRT because the very limited number of cases evaluated (25). Finally, the introduction in clinical practice of new diagnostic imaging (i.e., PSMA PET scan), probably, will improve targeted sRT treatment (26).

CONCLUSIONS sRT following RP constitutes a curative therapy in about 50% of the cases with a low rate of GI (9.5%) and GU (11.8%) late complications; the oncological outcomes are directly correlate with pathological stage, ISUP Grade Group, nodes involvement and pre-sRT PSA value.

REFERENCES ISUP GG: Grade Group International Society of Urologic Pathology

in 234 men with BCR who underwent sRT at a median follow of 117 months reported a PSA response and PCa specific survival equal to 54 and 94%; in detail, in multivariate analysis pathological stage, Gleason score and the last PSA value before RT were the best predictors of survival.

Buscariollo et al. (20) in 718 men submitted to adjuvant RT vs sRT at a median follow up of about 8 years showed an improved PSA response performing adjuvant RT but a superimposable overall survival. Fossati et al. (21) reported in 728 patients submitted to sRT that men who had

1. Cornford P, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing, Metastatic, and Castration- Resistant Prostate Cancer. Eur Urol. 2017; 71:630-642.

2. Mohler JL, Armstrong AJ, Bahnson RR, et al. Prostate Cancer, Version 1. 2016. J Natl Compr Canc Netw. 2016; 14:19-30.

3. Viani GA, Hamamura AC, Correa AC, Felipe Teles de Arruda.

Salvage radiotherapy for biochemical recurrence after radical prostatectomy: does the outcome depend on the prostate cancer characteristics? Int Braz J Urol. 2019; 45:237-45.

4. Zaffuto E, Gandaglia G, Fossati N, et al. Early Postoperative Radiotherapy is Associated with Worse Functional Outcomes in Patients with Prostate Cancer. J Urol. 2017; 197:669-75.

5. Nyarangi-Dix JN, Steimer J, Bruckner T, et al. Post-prostatectomy

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P. Pepe, M. Tamburo, M. Pennisi, D. Marletta, F. Marletta

radiotherapy adversely affects urinary continence irrespective of radiotherapy regime. World J Urol. 2017; 35:1841-47.

6. van Dessel LF, Reuvers SHM, Bangma CH, Aluwini S. Salvage radiotherapy after radical prostatectomy: Long-term results of urinary incontinence, toxicity and treatment outcomes. Clin Transl Radiat Oncol. 2018; 11:26-32.

7. Ost P, Fonteyne V, Villeirs G, et al. Adjuvant high-dose intensity-modulated radiotherapy after radical prostatectomy for prostate cancer: clinical results in 104 patients. Eur Urol. 2009; 56:669-75.

8. Shipley WU, Seiferheld W, Lukka HR, et al. Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer. N Engl J Med. 2017; 376:417-28.

17. Mishra MV, Scher ED, Andrel J, et al. Adjuvant Versus Salvage Radiation Therapy for Prostate Cancer Patients With Adverse Pathologic Features: Comparative Analysis of Long-Term Outcomes Am J Clin Oncol. 2015; 38:55-60.

18. Fossati N, Parker WP, Karnes RJ, et al. More Extensive Lymph Node Dissection at Radical Prostatectomy is Associated with Improved Outcomes with Salvage Radiotherapy for Rising Prostatespecific Antigen After Surgery: A Long-term, Multi-institutional Analysis. Eur Urol 2018; 74:134-37.

19. Galla A, Maggio A, Delmastro E, et al. Salvage Radiation Therapy After Radical Prostatectomy: Survival Analysis Minerva Urol. 2019; 71:240-48.

9. 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.

20. Buscariollo DL, Drumm M, Niemierko A, et al. Long-term results of adjuvant versus early salvage postprostatectomy radiation: A large single-institutional experience. .Pract Radiat Oncol. 2017; 7(2):e125e133.

10. Pepe P, Pennisi M, Fraggetta F. How Many Cores Should be Obtained During Saturation Biopsy in the Era of Multiparametric Magnetic Resonance? Experience in 875 Patients Submitted to Repeat Prostate Biopsy. Urology. 2020; 137:133-37.

21. Fossati N, Karnes RJ, Boorjian SA, et al. Long-term Impact of Adjuvant Versus Early Salvage Radiation Therapy in pT3N0 Prostate Cancer Patients Treated with Radical Prostatectomy: Results from a Multi-institutional Series. Eur Urol. 2017; 71:886-93.

11. Pepe P, Garufi A, Priolo GD, et al. Is it Time to Perform Only Magnetic Resonance Imaging Targeted Cores? Our Experience with 1,032 Men Who Underwent Prostate Biopsy. J Urol. 2018; 200:77478.

22. Ying J, Wang CJ, Yan J, et al. Long-term Outcome of Prostate Cancer Patients Who Exhibit Biochemical Failure Despite Salvage Radiation Therapy After Radical Prostatectomy. Am J Clin Oncol.

2017; 40:612-20.

12. Artibani W, Porcaro AB, De Marco V, et al. Management of Biochemical Recurrence after Primary Curative Treatment for Prostate Cancer: A Review. Urol Int. 2018; 100:251-62.

23. Gandaglia G, Fossati N, Karnes RJ, et al. Use of Concomitant Androgen Deprivation Therapy in Patients Treated with Early Salvage Radiotherapy for Biochemical Recurrence After Radical Prostatectomy: Long-term Results from a Large, Multi-institutional Series. Eur Urol. 2018; 73:512-18.

13. Mottet N, Cornford P, van der bergh RCN, et al. EAU Oncology guideline: Prostate Cancer. 2020.

14. Pound CR, Partin AW, Eisemberg MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999; 281:1591-97.

15. Bartkowiak D, Thamm R, Bottke D, et al. Prostate-specific antigen after salvage radiotherapy for postprostatectomy biochemical recurrence predicts long-term outcome including overall survival. .Acta Oncol. 2018; 57:362-67.

16. Kashihara T, Nakamura S, Wakita A, et al. Importance of the site of positive surgical margin in salvage external beam radiation therapy for biochemical recurrence of prostate cancer after radical prostatectomy. Cancer Med. 2018; 7:1723-30.

24. Carrie C, Hasbini A, de Laroche G, et al. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol.

2016; 17:747-56.

25. Pepe P, Garufi A, Priolo G, Pennisi M. Accuracy of pelvic multiparametric MRI in diagnosing local recurrence following radical prostatectomy. Case report and revision of the literature. Arch Ital Urol Androl 2016; 87:335-36.

26. Boreta L, Gadzinski AJ, Wu SY, et al. Location of Recurrence by Gallium-68 PSMA-11 PET Scan in Prostate Cancer Patients Eligible for Salvage Radiotherapy. Urology 2019; 129:165-71.

CORRESPONDENCE Pietro Pepe, MD Urology Unit - Cannizzaro Hospital, Via Messina 829, Catania (Italy) E-mail: piepepe@hotmail.com Phone. + 39 95 7263285 Fax. + 39 95 7263259

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Advances in Urological Diagnosis and Imaging - 2021; 4,1

C ASE

REPORT

Surgical treatment of locally advanced urachal cancer: A single case with a long-term follow up and literature review Alessandro Bertaccini 1, Umberto Barbaresi 2, Alessandro Colella 2, Fabio Manferrari 1, Riccardo Schiavina 1.

1

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Cardio-Nephro-Thoracic Sciences Doctorate, University of Bologna, Bologna, Italy; 2 Department of Urology, University of Bologna, Bologna, Italy.

Urachal carcinoma (UrC) is rare and it is related to a poor prognosis. We report the surgical treatment and the subsequent long-term follow up of a patient affected by advanced stage UrC. A 57-year-old patient presenting a voluminous expansive process >8cm, extensively infiltrating the posterior bladder wall was submitted to endoscopic resection with a diagnosis of UrC. Radical cystectomy with resection of the involved ileo segment and bilateral ureterocutaneostomy was then performed. 7 years after, ureterocutaneostomy was converted into an ileal conduit, with subsequent improvement in quality of life. Nowadays the patient is living and disease-free.

Surgery still represents the mainstay of therapy for UrC. Radical cystectomy proved to be a safe and effective alternative to partial cystectomy in advanced-stage UrC.

SUMMARY

KEY WORDS: Urachus, urachal carcinoma, radical cystectomy, partial cystectomy, cancer diagnosis, cancer treatment.

INTRODUCTION The urachus is a tubular structure that connects the fetal bladder to the allantois. During the fourth and fifth month in embryonic life, the urachus gradually degenerates into a rudimentary fibromuscular closed canal, which is known as the median umbilical ligament (1). The urachus comprises 3 distinct tissue layers: an epithelial canal lined by urothelium, submucosal connective tissues, and an outer layer of smooth muscle. Urachal neoplasms can arise in any of these layers and can be epithelial or mesenchymal. Like urothelium at other sites, the epithelium often demonstrates focal glandular metaplasia, and this provides a morphologic basis for the development of intestinal-type tumors. Urachal carcinoma (UrC) is rare and comprises 0.35% to 0.7% of all bladder cancers and 22% to 35% of vesical adenocarcinomas (1). The median age at diagnosis of UrC is 51 years, and the prognosis is relatively poor with a 5-year survival of 37 % and a 10-year survival of 17 %. Although hematuria is the most common symptom, the disease is usually advanced when this symptom appears.

The common metastatic sites include lymph nodes, peritoneum and lung (1). Diagnosis is based on CT imaging with evidence of a cystic or solid structure in the bladder dome or in the bladder midline. Several criteria have been proposed to help in UrC diagnosis: location in the dome of the bladder, absence of cystitis cystica or cystitis glandularis, predominant involvement of the muscularis rather

than the submucosa, demonstration of an urachal remnant connected to the neoplasm and the presence of a suprapubic mass (2). Several staging classifications have been developed through years, but the most commonly adopted is the Sheldon-Mayo staging system (Supplementary Table 1) (1). Its nature of a well-differentiated tumour with a theorical good prognosis is contrasted by the rarity of symptoms in the earlier stages. This often led to a late presentation of the UrC at advanced stage and frequently because of adjacent organs invasion and/or distant metastasis. The mainstay of treatment for these tumors is partial cystectomy with en bloc resection of the median umbilical ligament up to the umbilicus (3). Leaving the umbilicus in place provides inadequate control and has been associated with a higher risk of relapse. In our case the disease involved an ileal tract and the bladder wall at the time of diagnosis, so we decided to perform radical cystectomy with ileal segment resection. Despite the high recurrence rate of UrC, the radical treatment we adopted in this context led to a long-term disease-free survival. According to literature, tumor stage and surgical margin status are the strongest predictors of survival (3). Radical treatment reduces the positive surgical margins rate, and help avoiding recurrences, associated to a poor prognosis, as adjuvant or salvage chemotherapies benefits are still a matter of debate. This is probably related to the very advanced stage at presentation of the disease (3). Partial cystectomy has been proposed in a limited amount of low stage disAdvances in Urological Diagnosis and Imaging - 2021; 4,1

19

A. Bertaccini, U. Barbaresi, A. Colella, F. Manferrari, R. Schiavina Table 1. Sheldon and Mayo staging system for urachal cancer.

Sheldon staging Stage I

Urachal cancer confined to urachal mucosa (no invasion beyond urachal mucosa)

Stage II

Urachal cancer with invasion confined to urachus itself

Stage IIIA

Local urachal cancer extension to bladder

Stage IIIB

Local urachal cancer extension to abdominal wall

Stage IIIC

Local urachal cancer extension to peritoneum

Stage IIID

Local urachal cancer extension to viscera other than bladder

Stage IVA

Metastatic to regional lumph node

Stage IVB

Metastatic urachal cancer to distant sites

Mayo staging Stage I

Tumor confined to urachus and/or bladder

Stage II

Tumor extending beyond the muscular layer of urachus and/or the bladder

Stage III

Tumor infiltrating the regional lymph node

Stage IV

Tumor infiltrating non-regional lymph nodes or other distant sites

eases to reduce the adverse features of a surgical treatment, but its adoption in clinical practice is limited by the high risk of seeding and of a non-complete tumor resection (2).

In this study we report the management, surgical treatment and subsequent longterm follow up of a patient affected by advanced stage UrC.

CASE

REPORT

In February 2010, a 57-year-old patient presenting with hematuria was submitted to abdominal ultrasonography (US), which revealed the presence of a 5 cm expansive esophytic neoformation of the bladder, in contact with direct contiguity to the overlying ileal loop. A computerized tomography with urographic phase (Uro-CT) was then performed and it reported the presence of a voluminous expansive process >8cm, extensively infiltrating the posterior bladder wall and expanding cranially, with the presence of a gaseous component, suggesting

Figure 1. Pre-operative CT scan showing a voluminous solid tumor infiltrating the bladder bottom, and expanding upwards into the abdominal cavity, with gaseous component in the cranial portion.

20

Advances in Urological Diagnosis and Imaging - 2021; 4,1

Surgical treatment of locally advanced urachal cancer: A single case with a long-term follow up and literature review

ileal deep involvement (Figure 1). The patient was then submitted to cystoscopy and resection of the tumor (TURB-T). Pathological examination described an adenocarcinoma with intestinal differentiation, morphologically consistent with UrC. In order to complete the clinical staging, a bone scan was performed and resulted negative for bone metastasis. In March 2010, a radical cystectomy with nerve-sparing technique, resection of the involved ileo segment and bilateral ureterocutaneostomy with single outlet was performed. The hospital stay was 9 days. At discharge, the patient was in good clinical status, Hb was 9.5 mg/dl, and serum creatinine 1.25 mg/dL. Pathological examination revealed moderately differentiated adenocarcinoma, G2, intestinal type, compatible with UrC, infiltrating the bladder wall, the fat and the ileal loop. 6 months after surgery the patient was submitted to a chestabdomen CT scan, with no signs of recurrence. From 2011 to 2015 US and Uro-CT were alternatively performed every 6 months and resulted negative for relapse or metastasis. From 2016 to 2019 Uro-CT was annually performed and reported negative for recurrences and metastasis. In 2017, 7 years after the UrC removal, the patient underwent surgery to convert the ureterocutaneostomy into an ileal conduit (uretero-ileo-cutaneosto-

my), which led to an improvement in quality of life and reduced infection risks related to ureteral stenting.

Nowadays the patient is disease-free, and the ileal conduit allows him to lead an active and sporting life.

CONCLUSIONS UrC is an aggressive neoplasm with surgery still representing the mainstay of therapy. Radical cystectomy proved to be a safe alternative to partial cystectomy in advancedstage UrC, reducing recurrence risk factors and providing an acceptable long-term quality of life.

REFERENCES 1. Szarvas T, Modos O, Niedworok C, et al. Clinical, prognostic, and therapeutic aspects of urachal carcinoma-A comprehensive review with meta-analysis of 1,010 cases. Urol Oncol. 2016; 34(9):388-398.

2. Tomita K, Tobisu KI, Kume H, et al. Long survival with extended surgery for urachal carcinoma involving adjacent organs. J Urol. 1998; 159(4):1298.

3. Herr HW, Bochner BH, Sharp D, et al. Urachal carcinoma: contemporary surgical outcomes. J Urol. 2007; 178(1):74-78; discussion 78.

CORRESPONDENCE Umberto Barbaresi, MD Department of Urology, S.Orsola Malpighi University Hospital Via Palagi, 9 – 40138 Bologna Phone: 0512142942 e-mail: ubarbaresi@libero.it

Advances in Urological Diagnosis and Imaging - 2021; 4,1

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Instructions to Authors AIMS AND SCOPE

Advances in Urological Diagnosis and Imaging is a free open access journal. The Journal has the purpose of promote, spread and favorite the scientific knowledge and research in diagnosis and imaging in Urology, Andrology and Nephrology.

Advances in Urological Diagnosis and Imaging publishes every 4 months original articles, reviews, case reports, position papers, guidelines, editorials, abstracts and congress proceedings.

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PRESENTANO

124 autori 592 pagine + di 1500 immagini ecografiche 61 video Hardcover Cofanetto

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