Advances in Urological Diagnosis and Imaging - AUDI (Vol. 4 - n. 2 - 2021)

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ISSN 2612-7601

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

OFFICIAL JOURNAL of

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Italian Society of Integrated Diagnostic in Urology, Andrology, Nephrology

Vol. 4 - n. 2 - 2021


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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)

ASSISTANT EDITOR JUNIOR Carlo Giulioni, 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, 2

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

General Information

Contents

AIMS and SCOPE

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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.

Andrea B. Galosi, Daniele Castellani, Gianluca Giannarini

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Endocrinology and andrology in the era of COVID-19 Emanuele Baldassarre, Antonio Ciccarelli, Alessandra Fraioli, Ilaria Prosperi Porta

AUDI is Open Access at www.issuu.com Why Open Access? Because it shares science at your finger tips with no payment. It is a new approach to medical literature, offering accessible information to all readers, becoming a fundamental tool, improving innovation, efficiency and interaction among scientists.

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COPYRIGHT

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Papers are accepted for publication with the understanding that no substantial part has been, or will be published elsewhere. By submitting a manuscript, the authors agree that the copyright is transferred to the publisher if and when the article is accepted for publication. The copyright covers the exclusive rights to reproduce and distribute the article, including reprints, photographic reproduction and translation. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior written permission of the Publisher.

Identifying the ideal patient with localized prostate cancer candidate to Focal Therapy

Penile perfusion index (PPI) for the non-invasive evaluation of the vascularization of the penis

Marco Grasso, Salvatore Ivano Blanco, Caterina Lania, Emanuele Grasso,Vittorio Segramora

The effect of COVID-19 on the male genitourinary system Carlo Giulioni,Vito Lacetera

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Disfunzione erettile, diritto alla salute sessuale maschile e livelli essenziali di assistenza (LEA) Enrico Caraceni, Angelo Marronaro, Edoardo Pescatori, Andrea B. Galosi

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Advances in Urological Diagnosis and Imaging - 2021; 4, 2


EDITORIAL

Identifying the ideal patient with localized prostate cancer candidate to Focal Therapy Andrea Benedetto Galosi 1, Daniele Castellani 1, Gianluca Giannarini

2

1

Division of Urology, University Hospital “Ospedali Riuniti”, School of Medicine, Department of Clinical, Special and Dental Sciences, Marche Polytechnic University, Ancona; 2 Urology Unit, Santa Maria della Misericordia University Hospital, Udine, Italy. This editorial summarizes the discussion that took place in a round table on primary Focal Therapy (FT) for prostate cancer (PCa) held at the XXI Annual virtual Congress of the Associazione Urologi Italiani (AURO.IT) in May 2021. The round table aimed at addressing the question: “which are the best criteria to identify the ideal candidate to primary focal therapy?”. The aim of FT for clinically localized PCa is to “selectively ablate known disease and preserve existing functions, with the overall objective of minimizing lifetime morbidity without compromising life expectancy” (1). Professor Caroline Moore from the UCLH (UK), one of the most renowned international experts in FT, gave an extensive and updated lecture on the topic, followed by a panel discussion. Leading centers in FT have overcome several limitations in pre-operative staging and grading using standardized imaging, such as the multiparametric MRI, and biopsy (TRUS/MRI fusion biopsy). However, there remains uncertainty regarding the natural history of untreated, clinically insignificant, cancer foci, which should be carefully monitored after treatment.The strongest message from the discussion was the desperate need for good quality data on oncological and functional outcomes, as well as on quality of life after FT compared to standard whole-gland treatments. Early clinical experiences with a variety of FT modalities evaluated at a short-to-medium-term follow-up are encouraging, but hampered by limitations in study design and small sample size. According to experts’ opinions, FT should be delivered within clinical trials to assess outcomes and complications, since long-term oncological data on management of local recurrence progression and functional outcomes of salvage radical treatments after FT are still missing or based on a limited number of cases with short follow-up. The panel suggested that the ideal candidate to FT should have a unifocal and unilateral index lesion that is MR-visible and contains high-grade disease (ISUP grade grouping 2 or 3) verified by targeted biopsy, plus or minus other low-risk non-index lesions (Table 1) (2). Ideally, prostate volume should be in the range of 2060 ml in absence of median lobe or obstructive lower urinary tract symptoms. Ideal anatomical locations of the index lesion are (3):

- the peripheral zone in the mid and base gland using the transrectal approach (HIFU) (4), - the anterior gland zone especially in the mid and base gland using transperineal approach (Cryoablation), - the apex: brachytherapy. Although FT refers to any form of subtotal prostate ablation, the ideal treatment should have a 5mm safety margin of normal tissue surrounding the MRI index lesion. The most commonly used and reliable treatment strategy is Hemi-ablation. However, true target ablation or threequarters ablation (one side and a portion of the contralateral, also called hokey stick ablation) can also be performed in selected cases (Table 2). The panel was in agreement that an accurate definition of biochemical failure after FT cannot be presently defined because of insufficient data. Finally, there was a consensus that it is essential to measure PSA and to perform periodic biopsies during follow-up. Post-treatment PSA measurement should be performed at 3-mo intervals during the first year, every 6 months in the second year, and annually in the third year. Thereafter, the frequency of checking PSA is at the discretion of the investigators (5). The panel was also in agreement that the optimal biopsy strategy includes TRUS-guided systematic sampling as well as additional targeted biopsies to be taken in the treated area after 6 to 12 months after FT, and in case of new MRI-visible lesions.

REFERENCES 1. Postema AW, De Reijke TM, Ukimura O, et al. Standardization of definitions in focal therapy of prostate cancer: report from a Delphi consensus project. World J Urol. 2016; 34:1373-82. 2. Ahmed HU. The index lesion and the origin of prostate cancer. N. Engl J Med. 2009; 361:1704-1706. 3. Sivaraman A, Barret E. Focal therapy for prostate cancer: an ‘à la Carte’ approach. Eur Urol. 2016; 69:973-975. 4. Huber PM, Afzal N, Arya M, et al. Focal HIFU therapy for anterior compared to posterior prostate cancer lesions. World J Urol. 2021; 39:1115-1119. 5. Muller BG, van den Bos W, Brausi M, et al. Follow-up modalities in focal therapy for prostate cancer: results from a Delphi consensus project. World J Urol. 2015; 33:1503-1509. Advances in Urological Diagnosis and Imaging - 2021; 4,2

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A.B. Galosi, D. Castellani, G. Giannarini Table 1. Criteria to select the ideal candidate for primary Focal Therapy.

IDEAL inclusion criteria Clinical stage

T1 or T2a

Radiological stage

T2 (intracapsular) and N0 (without pelvis lymph nodes enlargement >10mm)

Radiologic imaging

MRI concordant with biopsy, only one index lesion MR visible as PI-RADS score 3, 4 or 5

Pre-treatment Biopsy

target fusion biopsy (3 cores) + extended mapping

Pathology

unilateral target biopsy showing Gleason score 3 + 4 or 4+3, or high volume 3+3 (+/- perineural invasion)

Tumor locations

Anterior gland using needle-based transperineal therapies (Cryotherapy, Electroporation, or Photodynamic therapy) Posterior gland using a High-Intensity Focused Ultrasound Apex: brachytherapy

Prostate volume

<40ml in the candidate for High-Intensity Focused Ultrasound

Life expectancy

>10 years

Serum PSA

PSA <10 ng/ml, even if a strict cut-off does not exist

Exclusion criteria Active urinary tract infection Bladder Outlet Obstruction, voiding symptoms Pathology

- non-adenocarcinoma variant - Bilateral tumor (grade group >1 or high volume grade group 1)

Radiological stage mpMR

T3 or N+

Criteria that should be counseled carefully before FT enrollment Radiologic imaging

mpMR negative imaging more than one lesion with PI-RADS 4-5

Pathology

bilateral lesion intraductal carcinoma or cribriform pattern low volume 3+3 in target biopsy (active surveillance)

Prostate size

median lobe >14mm (grade III Intravescical Prostatic Protrusion) Gland larger >40ml can be treated using needle approach

Tumor locations

Extreme base may be difficult Proximity to apex assessed carefully

Radiological stage

T3a with limited capsular involvement counseled carefully

Age

< 10 years of life expectancy

Table 2. Proposed checklist to select the ideal candidate to FT 1. Tumor ablation margin at least 5 mm 2. Informed consent a. to accept uncertainty on outcomes of salvage treatments of FT failure b. about missing data on long-term outcome 3. The index lesion should be MRI visible 4. Aim of FT: Treatment of clinically significant cancer 5. Patients should be highly motivated to preserve sexual and urinary functions 6. Availability to a long-term follow-up (repeat MRI and biopsy)

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Advances in Urological Diagnosis and Imaging - 2021; 4,2

CORRESPONDENCE Daniele Castellani Department of Urology, University Hospital “Ospedali Riuniti”, Marche Polytechnic University. 71 Conca Street, 60126 Torrette, Ancona - Italy. E-mail: castellanidaniele@gmail.com


LETTER TO THE EDITOR

Endocrinology and andrology in the era of COVID-19

Emanuele Baldassarre 1, Antonio Ciccarelli 2, Alessandra Fraioli 3, Ilaria Prosperi Porta 4. 1 2 3 4

Department Department Department Department

of of of of

Urology and Andrology, Umberto Parini Hospital, Aosta; Medicine – Endocrinology Diabetology and Dietology Unit, Umberto Parini Hospital, Aosta; IVF, Umberto Parini Hospital, Aosta; Emergency Medicine, Umberto Parini Hospital, Aosta.

Dear Editor, in this particular period we faced a complete overwhelming of our routine activity and a dismantling of working life, with profound logistical changes within hospitals. We would stimulate the andrologists to a careful reflection on what is happening, reporting our experience. Unlike the endocrinological-andrologist, with an internistic background more suitable for “front-line” activity, the urological-andrologist has been catapulted into COVID-19 ward. In our Center in Northern Italy, hit hard by the pandemic, with the highest Italian incidence of confirmed cases of SARS-CoV-2 (about 850 cases / 100,000 inhabitants), all the medical doctors, included andrologists, were actively involved in new Covid wards. From the debut of March 2020, all our outpatient activities, both public and private practice, have been abruptly interrupted. Practically we had to think “more urgent things”, inventing skills and activities that we had never done before, like for example the non invasive ventilation. The time for us suddenly took on a different dimension between the shifts in Covid and the much material to study at home, continuously updated. Our goal was to guarantee to everyone a correct communication and update information. The Italian Society of Andrology (SIA) immediately recognized the need to maintain the relationships between us and organized periodic webcalls on the various andrological topics. Some surveys were also proposed for us and for patients on the quality of sexual life during the quarantine in order to optimize for the next future the data (1). The most complex aspect remains the management of patients, in a period where the outpatients, diagnostic tests and ordinary surgical activity were suspended. In particular in our region we have an outpatient dedicated to Andrology twice a week, with a space dedicated to erection rehabilitation therapies, Doppler Ultrasonography and male infertility. The personal relationship with many patients, also due to

our rather small reality (about 130,000 inhabitants) and family members, however, continued through the telephone and email. I realized that the patient generally looked for a moment to exchange confidences with a trusted doctor, rather than having clarifications on a clinical problem. Very few patients have expressed to us a worsening of erectile deficit or premature ejaculation, but we noticed many cases of symptoms of suspected exacerbated prostatitis or orchiepididymitis, although in the past scientific literature the SARS-Cov was not isolated in the testicular tissue (2). We generally managed with therapies already known to the patient or with simple hygiene-dietary advice. In the pediatric andrology field, despite the low prevalence of the virus in children, our activity has completely stopped, limiting itself only to emergencies. About the world of infertility, which remained “freezed” in a sort of limbo, with many psychological strains on couples. The surgical activity at the moment has been completely stopped, with many psychological implications, especially in patients waiting for TESE (testicular sperm extraction) or microTESE and who had already undergone a hormone therapy course. Anyway, as suggested by Simoni M et al. (3) some interventions cannot be postponed also in during the limitations of COVID-19, like semen cryopreservation before cancer therapy. Beyond the ethical implications, which will be assessed over time, with the scope to give an immediate response, our Region and other private structures have offered a free psychological counseling service which has proved very useful in these cases. We realized that telemedicine could be the future in the world of IVF, also in consideration of the distances between the patient's home and the center to which they rely. In the world of infertility there is not only an email or a sharing of screenshots of blood analysis by mobile but above all there is a close relationship with a multidisciplinary team in which the visual element creates a fundamental empathy for a good final result. Advances in Urological Diagnosis and Imaging - 2021; 4,2

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E. Baldassarre, A. Ciccarelli, A. Fraioli, I. Prosperi Porta

Anyway It is very complex to imagine the andrological repercussions of this pandemic be and perhaps there has not been enough time to ask this to date. We believe that a gradual resumption of normal clinical activity will be increasingly integrated by the figure of the sex therapist for the individual and couples, who in a first “psychological” phase will be able to help the patient to recompose the puzzle pieces of an interrupted continuum and in a second “sexuological” phase he will be able to devote himself more specifically to the andrological disorder in itself.

References 1. Baldassarre E. An andrologist in the front line Covid-19 team. Int J Impot Res. 2020; 32(5):558-559. 2. Xu J, Qi L, Chi X, et al. Orchitis: A Complication of Severe Acute Respiratory Syndrome (SARS). Biology of reproduction. 2006; 74(2):410-416. 3. Simoni M, Hofman MC. Striving for the best: Complying with the quality criteria required by ANDROLOGY is not optional. Andrology. 2021; 9(1):5

CORRESPONDENCE Emanuele Baldassarre, MD Umberto Parini Hospital, Department of Urology and Andrology Viale Ginevra 3 11100 Aosta - Italy e-mail: ebaldas75@gmail.com Phone: +393932611979 +390165543272

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Advances in Urological Diagnosis and Imaging - 2021; 4,2


ORIGINAL

PAPER

Penile perfusion index (PPI) for the non-invasive evaluation of the vascularization of the penis Marco Grasso 1, Salvatore Ivano Blanco 1, Caterina Lania 2, Emanuele Grasso 3, Vittorio Segramora 3. 1 2 3

Dept of Urology, San Gerardo Hospital Monza (MB), Italy; Dept of Urology, San Raffaele Institute, Milano, Italy; Dept of Vascular Surgery, San Gerardo Hospital Monza (MB), Italy.

Objectives. The aim of the study is to define if PPI can be considered a sensitive, noninvasive parameter to predict the effectiveness of therapy. Material and Methods. From June 2003 to September 2016 we evaluated 422 patients for ED. We performed vascular penile evaluation with a non invasive method. In basal condition we considered the ratio between penile and humeral pressure and the response to PDE5in during follow-up. The values of PPI were compared to the recovery of erection. Results. the results show that the recovery of valid erections both after taking the drug and spontaneously occurs mainly with PPI higher than 0.8. Conclusion. A PPI value > of 0.8 proved to be an effective “predictor” of a valid response to phosphodiesterase inhibitors and therefore an indicator of correct vascularization. A value of IPP <0.8 should lead to a complete cardio-vascular study. We believe that it is no longer motivated to submit the patient to the risks of color Doppler with FIC, not producing any further diagnostic element useful to the patient.

SUMMARY

KEY WORDS: Penile, ED, PDE5in, Doppler.

INTRODUCTION The spread of phosphodiesterase inhibitors (PDE5in) has completely changed the approach strategies to erectile dysfunction (ED). It is still considered important in the first approach to the patient to rule out hormonal or metabolic problems and evaluate the vascularization of the penis. In the diagnosis of ED, Doppler ultrasound with drug induced erection is now performed all over the world. We believe that this examination can be replaced by a less invasive test which is the evaluation of the PPI (Penile Perfusion Index). Since the early 1980s, the evaluation of the vascularization of the penis using Doppler technology has entered in the common practice for diagnosing erectile dysfunction (1). At the beginning, simple velocimeters with pencil probes were used. Subsequently, with the development of an increasingly advanced technology designed for other districts in which lumen diameter and flow velocity are essential parameters, we switched to the use of eco-color / power doppler instrumentation. With these more modern tools, the evidence of morphological parameters (patency and diameter) as well as

dynamics (flow velocity) have been used in the evaluation of the single dorsal and cavernous arteries. This method, however, involves the use of drugs injected into the corpora cavernosa to induce a pharmacological erection, without which these evaluations are not possible in the penile area where, in conditions of rest, the vessels are small. The development of increasingly valid drugs for the treatment of erectile dysfunction (we refer to phosphodiesterase inhibitor drugs) has in fact remodeled the therapeutic approach to ED that today benefits from the use of these drugs, also tailoring the choice according to the patient`s performance requests. We have wondered whether it is still appropriate to submit patients to an examination that requires time, highly qualified personnel and high-tech and cost-effective tools, but above all, that requires mandatory invasive intracavernous injection of prostaglandins. This procedure, besides being painful, can lead to local complications, especially the fearful post-injection priapism. For this purpose, expert staff must be available for 24 hours after the exam. In the early 1980s we started using a new parameter which is the relationship between humeral pressure and cavernous pressure. We have Advances in Urological Diagnosis and Imaging - 2021; 4,2

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M. Grasso, S.I. Blanco, C. Lania, E. Grasso, V. Segramora.

defined this parameter as the penile perfusion index (2). We have, after having performed hundreds of tests and compared the results with parameters of healthy volunteers, defined as normal a PPI equal to or greater than 0.8. This parameter is easily detected by bilaterally measuring the cavernous pressure at the balanus preputial sulcus. This test can be easily performed either with a pencil probe (velocimeter) or, with higher technical difficulties, with a small linear probe. In both cases, it is not necessary to induce an erection pharmacologically. The aim of the work is to define whether PPI can be considered a valid predictive test that therefore makes a more invasive and dangerous examination useless. We then evaluated the response to phosphodiesterase inhibitors in patients with PPI lower or higher than 0.8.

MATERIALS

AND METHODS

From June 2003 to September 2016 we evaluated 422 patients for ED excluding those with diabetes, known arterial disease or endocrinopathy. All patients underwent: 1. Dosage of: LH, Testosterone, Prolactin, TSH, CBC, Glycemia, Creatinine. 2. Evaluation of the arteries of the penis using either a Doppler velocimeter with a pencil probe or an Echocolordoppler with a linear probe (Figure 1, 2).

Figure 1. Linear probe

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Advances in Urological Diagnosis and Imaging - 2021; 4,2

With both methods, the two dorsal and cavernous arteries were identified and recorded in basal conditions. The systolic pressure of the cavernous arteries identified in the balano-preputial sulcus was measured using an inflatable neonatal sphinx-manometer positioned at the base of the penis. The systolic pressure of the humeral artery was then recorded. PPI is determined by the ratio of cavernous systolic pressure to systolic brachial pressure. Patients included in the study were treated with PDES inhibitors (sildenafil 25/50 mg, tadalafil 5/20 mg, vardenafil 10/20 mg) in accordance with the standard schedules of administration of these drugs. In all cases the lowest effective dose was used. In order to make the clinical response data simple and reproducible, we used the Sexual Encounter Profile SEP which uses a series of questions regarding sexual intercourse. We considered SEP Q2 that quantifies the penetration “Have you ever been able to insert the penis into your partner's vagina?”, and SEP Q3 which gives the real measure of therapeutic success “Did your erection last long enough to define intercourse satisfactory?”.

RESULTS The patients were all reviewed within one year after the start of therapy. We evaluated the obtaining of a positive response, that is appropriate for a satisfactory sexual inter-

Figure 2. Pencil probe


PPI for the non-invasive penile evaluation

course (SEP-Q3) regardless of continuous or sporadic use. The correlation between PPI and response rate (SEP Q3 valid erection) for the various blood pressure ranges was as follows: - PPI > 0.8 = 75% (315pts, 308pts responders), - PPI > 0.7 and < 0.8 = 20% (86pts; 44pts responders), - PPI < 0.7 = 5% (21pts; 2pts responders). In the group of patients with PPI ≥ 0.8, 46% recovered adequate natural intercourse without further taking the drug after a treatment period of 3 to 6 months. In the group with PPI < 0.8 only 8% of patients had occasionally intercourse without using drugs. There were no significant differences between the three groups of drugs used.

DISCUSSION We have to thank Christian Andreas Doppler (Salzburg, Austria, November 29, 1803 / Venice, Italy, March 17, 1853) for his pioneering studies: “Changes in the frequency of transmitted waves when relative motion exists between the source of the wave and the observer”. In medicine, by exploiting the application of this effect to ultrasound, it is possible to study the functionality of blood vessels. The first medical applications of the Doppler effect date back to the mid-60s of the twentieth century, with the creation of a small instrument (the Flowmeter Doppler) for percutaneous measurement of blood flow. With the development of ultrasound, the combination of Flowmeter Doppler and ultrasound probe takes place in a single instrument, thus creating the Duplex Doppler technique which allows the operator to more easily identify the target point to be measured (3). In the Diagnostic evaluation of ED patients CDDU (Dynamic color duplex doppler ultrasound) is not considered mandatory in all cases. After having collected a detailed medical and sexual history of patient and having

Figure 3. Portable Doppler Velocimeter

made a careful physical examination, the Dynamic duplex ultrasound of the penis, even if a second-level diagnostic test, is still today considered a decisive examination in the differential diagnosis between ED due to vascular cause (vasculogenic) or non-vascular (neurogenic, anatomical, hormonal, druginduced and / or psychogenic). It is well known to all that the objective interpretation of the examination results is very difficult due to the existing differences in the execution of the procedure between centers /hospitals due to the lack of standardization (4). CDDU is used for a morphological study of the penis (anatomy and echotexture) and vascular, usually using a 7.5-12MHz linear array U / S probe for small parts in Bmode, doppler mode should be set with an angle of 60° e 4. The target arteries of the vascular study are the intracavernosal, these are sampled before and after pharmacologically induced erection, with ICI of PGE1 at the initial dosage of 10 µg. Normally the following data are recorded: PSV (Peak sysolic velocity), EDV (End-diastolic velocity), RI (Resistive index). A PSV after ICI between 25 and 30 cm / sec is considered normal, EDV> 6cm / sec and RI <0.6 are indicative of the presence of a normal venous leak (5-6). In view of the considerable invasiveness of ICI and the reticence of many patients to this type of procedure, several authors have explored alternative evaluations. Color Duplex Doppler ultrasound without ICI can be a valid alternative, a cutoff PSV value of 10 cm / second in the flaccid state could be considered accurate in predicting arterial insufficiency (7). The cavernous arteries of the penis, if sampled at the distal end of the corpus cavernosum, are easily identifiable with a small Doppler flowmeter, even without the aid of ultrasound detection. In order to perform a simple, repeatable, fast and non-invasive evaluation of the arterial vascularization of the penis, flowmeter Doppler can be considered a valid and current technique, sufficient to diagnose ED caused by arterial disease. The method we have described and used for years is of simple execution, feasible even with a “low cost” instrument, such as the Doppler velocimeter (Figure 3). Being achieved without induced erection it practically eliminates local complications and the risk of prolonged erection. A PPI value > of 0.8 proved to be an effective “predictor” of a valid response to phosphodiesterase inhibitors and therefore an indicator of correct vascularization. A value of IPP <0.8 should lead to a complete cardio-vascular study. We believe that it is no longer motivated to submit the patient to the risks of color Doppler with FIC, not producing any further diagnostic element useful to the patient.

CONCLUSIONS It is advisable to consider what is the sense of carrying out an invasive study of the vascularity of the penis since the therapy that can be proposed in any case includes the use of phosphodiesterase inhibitors. The baseline study with evaluation of the PPI is sufficient to determine the efficiency of the arterial system and, consequently, the possibility of a pharmacological response. Advances in Urological Diagnosis and Imaging - 2021; 4,2

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M. Grasso, S.I. Blanco, C. Lania, E. Grasso, V. Segramora.

REFERENCES 1. Annoni F, Lania C, Grasso M, et al. Evaluation of penile circulation with the Doppler Technique. J. of Andrology. 1984; 5:131-134. 2. Grasso M, Lania C, Blanco S, Castelli M. Penile Perfusion Index (PPI) is an effective marker of efficacy for PDE5 inhibitors. J Urol Vol. 2012; 187,e465. 3. Dev Maulik. Doppler Ultrasound in Obstetrics and Gynaecology, Springer, 2005. 4. Sikka SC, et al. Standardization of vascular assessment of erectile dysfunction: standard operating procedures for duplex ultrasound. J Sex Med. 2013; 10:120-129.

5. Lue TF, Hricak H, Marich KW, Tanagho EA. Vasculogenic impotence evaluated by high-resolution ultrasonography and pulsed Doppler spectrum analysis. Radiology. 1985; 155(3):777-81. 6. Lee B, Sikka SC, Randrup ER, et al. Standardization of penile blood flow parameters in normal men using intracavernous prostaglandin E1 and visual sexual stimulation. J Urol. 1993; 149(1):49-52. 7. Roy C, Saussine C, Tuchmann C, et al. Duplex Doppler sonography of the flaccid penis: potential role in the evaluation of impotence. Clin Ultrasound. 2000; 28(6):290-4.

CORRESPONDENCE Marco Grasso Dept of Urology, San Gerardo Hospital Monza (MB), Italy E-mail: m.grasso@asst-monza.it Phone. + 39 3386356677

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REVIEW

The effect of COVID-19 on the male genitourinary system Carlo Giulioni 1, Vito Lacetera 1 2

2

Università Politecnica delle Marche-Azienda Ospedaliera Ospedali Riuniti Torrette di Ancona; Azienda Ospedaliera Ospedali Riuniti Marche Nord, Division of Urology, Pesaro.

SUMMARY

Objective. To discuss the impact of COVID-19 and anti-SARS-CoV-2 vaccination on the genitourinary system. Material and methods. A literature search was performed through MEDLINE via PubMed and

Web of Science. Results. SARS-CoV-2 induces cytokine storm in kidney and testis, due to their expression of ACE2 and TMPRSS2. Acute renal failure is a real concern for patients with COVID-19 and the monitoring of its function is mandatory. Even male fertility seems to be affected through sperm cells damage and hormonal profile alteration, although further studies are necessary to ascertain it. Patients treated with intravescical instillation of Bacillus Calmette-Guerin have the same incidence of being affected by COVID-19 and should be strictly monitored due to increased risk of severe complications. COVID-19 vaccination implies rare side effects related to the genitourinary system and lymph node enlargement. To avoid tumor overstaging, diagnostic imaging is not recommended soon after its administration. Conclusions. Kidney and testis are susceptible to SARS-CoV-2 infection. Urologists should be updated on COVID-19 implications on urogenital organs.

KEY WORDS: COVID-19; Urology; Acute kidney injury; Male infertility; SARS-CoV-2..

INTRODUCTION Since Coronavirus disease 2019 (COVID-19) was declared a global public health emergency on 30 January 2020, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has had a noteworthy impact on the global health care industry. As of July 24, 2021, over 192 million confirmed cases of COVID-19 and over 4 million were reported on World Health Organization (WHO) website (1). It is already known that COVID-19 affects the respiratory system in the first instance, causing severe respiratory illness up to acute respiratory distress syndrome (ARDS) (2). SARS-CoV-2 penetrates the cell through its affinity for Angiotensin I converting enzyme 2 (ACE2) receptor and the activation of its S protein via serine protease TMPRSS2 (3). These two proteins are mainly present in alveolar cells, although they may occur in other types of endothelial cells, determining several extrapulmonary dysfunctions. Indeed, sequencing Single-cell RNA, SARS-CoV2 was

reported from several organs, including the heart, ileum, esophagus, bladder, and kidney (4). Besides, Fan et al. demonstrated the high expression of ACE2 in kidney and testis (5). Virus infection and male genitourinary tract involvement have only partially been addressed by current literature. Andrologists and Urologists must be updated on evidence based on the latest research. Therefore, the literature was screened and the main results were summarized in a narrative review.

METHODS Our objective was to perform a narrative review to assess the effect of COVID-19 on the urogenital system. A comprehensive literature search was performed on July 24, 2021, through MEDLINE via PubMed and Web of Science, finding the most discussed topic. The following Medical Subject Headings were used: COVID-19, SARS-COV-2, genitourinary system, acute kidney injury, male infertility, bacillus Calmette-Guérin, and anti-COVID-19 vaccination. Advances in Urological Diagnosis and Imaging - 2021; 4,2

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RESULTS ACUTE

Figure 1. The pathogenesis of acute kidney injury related to COVID-19.

KIDNEY INJURY

Acute kidney injury (AKI) affects 6.7% of patients with SARS-CoV-2 (6) and it is the most frequent extrapulmonary manifestation associated with ARDS (7). Nephron damage is attributable to primary infection and secondary causes (Figure 1): 1. Virus damage on endothelial cells and glomerular basement membrane: the virus may directly induce interleukin cascade generating complement activation (8). Under electron microscopy, glomerular endothelial cells are swollen with vacuolar degeneration inside, thrombus may be seen in the capillaries, and protein casts and pigment casts are visible in the lumen (9). Moreover, glomerular diseases may indirectly occur in patients with SARS-CoV-2: collapsing glomerulopathy is the most frequent, especially in individuals of African descent with high-risk APOL1 genotypes, but antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, anti-glomerular basement membrane disease and immunoglobulin A vasculitis have been reported (10). 2. Virus damage on renal bloodstream: thrombotic microangiopathy (and consequent cortical necrosis) and endothelial dysfunction (with cell apoptosis) are consequences of Disseminated intravascular coagulation (DIC), secondary to SARS-CoV2 infection (11). 3. COVID-19 complications affecting renal function: - renal hypoperfusion (hypovolemia related to fluid loss: fever, vomit, or diarrhea) - renal hypoperfusion related to septic shock - tubular damage related to organ cross-talk between myocardial and kidney, defined as Cardiorenal Syndrome (12). According to Cheruiyot et al., AKI is associated with SARS-CoV-2 severity (OR= 18.5; 95% CI 8.9938.08) and mortality (OR= 23.9; 95% CI 18.8430.31). In multivariate analysis, these relationships are not affected by patient’s comorbidities (as cardiovascular disease, hypertension, or diabetes) (13). Anyway, history of diabetes (p=0.02), hypertension (p<0.01), and baseline serum creatinine levels (p=0.04) were positively related to AKI incidence (14). Regard the management of these patients, volume overload, metabolic acidosis, and hyperkalemia should be corrected as in AKI with septic shock (11). If it is not possible to achieve values within threshold ones, dialysis may be necessary. To summarizing, the incidence of acute renal failure is greater in overall patients with SARS-CoV2 infection, especially in severe ones, and it increases mortality. Therefore, monitoring the glomerular filtration rate during the hospital stay is recommended.

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Figure 2. The pathogenesis of male infertility related to COVID-19. HPG: Hypothalamic-Pituitary-Gonadal.


The effect of COVID-19 on the male genitourinary system

MALE

INFERTILITY

Examining the pathological modifications in the testis of six patients deceased of COVID-19, Xu et al. reported a significant widespread germ cells damage, few or absent spermatozoa in the seminiferous tubules and inflammatory infiltrate composed of T lymphocytes and histiocytes (15). As showed in Figure 2 the pathogenesis of male fertility impairment may be related to two targets: germ cells damage and Leydig cells damage, which affects the Hypothalamic‐Pituitary‐Gonadal Axis. We suggest that SARS-Cov-2 may overcome the blood-testis-barrier (BTB), which controls the passage of molecules only suitable for spermatogenesis. Although it is formed by several structures (tight junctions, ectoplasmic specializations, desmosomes, and gap junctions), more than 30 different types of viruses entry the seminiferous tubules, triggering the inflammation process and altering semen quality (16). Once the virus passed the BTB, serine protease TMPRSS2 and ACE2 receptor let the virus infect testis cells. Stanley et al. showed that TMPRSS2 is expressed in spermatogonia and elongated spermatids (19). A recent study reported the expression of ACE2 receptor by spermatogenic stem cells (17), other than Sertoli and Leydig cells (18). This study showed that overexpression of ACE2 in germ cells was positively associated with male infertility. ACE2 receptor activates 5‐Hydroxytryptamine Receptor 3A (HTR3A), which triggers apoptosis indirectly via TNF‐α production (17). We do not know if SARS-CoV-2 infection of the testis is correlated to detectable virus presence in the semen. Only two studies investigated this possible association. SARS‐CoV‐2 was found in 2/23 (8.3%) cured patients and 4/15 (26.7%) patients in the acute phase (20). The other study did not confirm previous authors’ results: SARSCoV-2 was not identified in the- semen samples of 34 patients in acute phase of COVID-19 (21). Even in 6 patients with scrotal discomfort, suggesting viral orchitis, SARS-CoV-2 was not found (21). Although the mechanisms of virus diffusion into the semen may be related also to prostatic involvement, the temporary inflammatory obstruction of seminal pathways could explain this phenomenon. The second source of male infertility is related to hormonal profile, which in turn depends on two factors. As previously described, the inflammation involves also Leydig cells, where ACE2 and angiotensin 1–7-Mas receptor, fundamental for testosterone (TT) synthesis, are pronounced (22). Therefore, these receptors, allow the virus to enter and, subsequently, stop the TT production. As a matter of fact, in 81 reproductive-aged men with SARS-CoV-2 infection, the ratio of testosterone (TT) to luteinizing hormone (LH) was lower and serum LH was significantly higher than in the control group (23). Even Cinislioglu et al. investigated serum TT levels and discovered that it was significantly lower in patients with COVID-19 than in healthy men (p< 0.001) and that blood concentration was decreased in severe and dead patients than, respectively, in moderate (p<0.001) and survivors (p<0.001) ones (24). Moreover, psychological disorders play a key role in poor male fertility: stress may affect semen quality (especially in terms of total sperm count, sperm concentration, and semen vol-

ume) and sperm DNA fragmentation (25). Testosterone replacement is the suggested therapy: the decay in hypogonadism may be resolved and metabolic and cardiovascular diseases secondary to COVID-19 could benefit (26). Another noteworthy element is the hormonal profile after recovery from COVID-19. Currently, only one study was published, reporting no relationship between low serum testosterone and post-acute COVID-19 syndrome in 41 patients (27). Therefore, further prospective studies, with a control group and a bigger sample size are required to achieve more robust data. In summary, the virus seems to induce sexual dysfunction in several pathways. Although no evidence emerged in the literature, the follow-up of serum Testosterone level may be suggested. In young men, a consultation regarding their fertility may be necessary.

INTRAVESCICAL INSTILLATION OF BACILLUS CALMETTE-GUÉRIN IN COVID-19 ERA

Bacillus Calmette-Guerin (BCG) vaccine derives from Mycobacterium bovis and it was used against tuberculosis for several decades. According to the European Association of Urology (EAU), BCG treatment is recommended for intermediate- and high-risk Non-muscle-invasive Bladder Cancer (NMIBC) (28). BCG enhances the immunity system conferring non-specific protection against respiratory infections. The etiology seems to be linked to “trained immunity” of memory B and T cells that recognizes these mycobacterium antigens and, due to molecular similarity, viral ones (29). Therefore, it was supposed a protective role of the BCG vaccine against SARS-CoV-2 (30). However, de Chaisemartin rejected this hypothesis affirming that it implies no effect on COVID-19 (31). Even in retrospective studies on patients treated with BCG, no relationship was noted. Karabay et al. reported no significant difference between the BCG case and control group in terms of COVID-19 diagnosis (p> 0,05) and PCR test positivity (p non-available) (32). In the paper with the biggest cohort (2803 cases), no evidence of a protective role was showed (33). Furthermore, Fedeli et al. stated that risks of infection, hospitalization, and adverse outcomes is greater [as also confirmed by a systematic review, especially regarding ARDS (34)] with risks of untreated bladder cancer. Only Gallegos et al. reported that the mortality rate was lower in patients between 70 and 79 years, although similar COVID-19 incidence was observed (35). Briefly, scientific research reported that not only does the intravescical instillation of BCG has not a protective role against SARS-CoV-2, but also it increases the incidence of complications related to hypersensitivity and cytokine storm.

ANTI-SARS-COV-2 VACCINATION

The last hint is dedicated to the COVID-19 vaccination. The frequency of side effects related to the urologic system is under 1% of cases, which consist of urinary infections, lower urinary tract symptoms, and, less frequently, hematuria (36). Anyway, after administration of the first or second dosage of vaccine ipsilateral lymphadenopathy (LAP) may occur. In a literature search, recruiting 19 studies, 68 cases of LAP were reported, especially after PfizerBioNTech® and Moderna® types (37). This has to be Advances in Urological Diagnosis and Imaging - 2021; 4,2

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encountered in oncologic patients, due to the risk of overstaging with diagnostic imaging. Indeed, Özütemiz et al. reported that vaccination mimicked metastasis in five cases and the biopsies in two of them confirmed reactive LAP (38).

CONCLUSIONS In conclusion, all findings seem to suggest a relationship between COVID-19 and acute kidney injury and seminal impairment. We have dealt with the mechanisms underlying the damage of the urogenital system. We hope that this review will lay the groundwork for further studies. Moreover, patients with bladder cancer and treated with BCG should be strictly monitored due to adverse outcomes overlapped. Therefore, although COVID-19 manifestation predominantly affects the respiratory system, urogenital previous disease and complications should be contemplated during the patient’s management, considering the transition from pandemic to endemic by SARSCoV-2.

REFERENCES

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1. World Health Organization Coronavirus disease (COVID-19) pandemic. Available at: https://covid19.who.int/

20. Li D, Jin M, Bao P, et al. Clinical Characteristics and Results of Semen Tests Among Men With Coronavirus Disease 2019. JAMA Netw Open. 2020; 3(5):e208292. Erratum in: JAMA Netw Open. 2020; 3(6):e2010845.

2. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395(10223):497-506.

21. Pan F, Xiao X, Guo J, et al. No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019. Fertil Steril. 2020; 113(6):1135-1139.

3. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020; 181(2):271-280.e8.

22. Simões e Silva AC, Silveira KD, Ferreira AJ, Teixeira MM. ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis. Br J Pharmacol. 2013; 169(3):477-92.

4. Zou X, Chen K, Zou J, et al. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med. 2020; 14(2):185-192.

23. Ma L, Xie W, Li D, et al. Effect of SARS-CoV-2 infection upon male gonadal function: A single center-based study. MedRxiv 2020.

5. Fan C, Lu W, Li K, et al. ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Infection in COVID-19 Patients. Front Med (Lausanne). 2021; 7:563893. 6. Chu KH, Tsang WK, Tang CS, et al. Acute renal impairment in coronavirus-associated severe acute respiratory syndrome. Kidney Int. 2005; 67:698-705. 7. Nimkar A, Naaraayan A, Hasan A, et al. Incidence and Risk Factors for Acute Kidney Injury and Its Effect on Mortality in Patients Hospitalized From COVID-19. Mayo Clin Proc Innov Qual Outcomes. 2020; 4(6):687-695. 8. Chen X, Zhao B, Qu Y, et al. Detectable Serum Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load (RNAemia) Is Closely Correlated With Drastically Elevated Interleukin 6 Level in Critically Ill Patients With Coronavirus Disease 2019. Clin Infect Dis. 2020; 71(8):1937-1942. 9. Yao XH, Li TY, He ZC, et al. A pathological report of three COVID19 cases by minimal invasive autopsies. Zhonghua Bing Li Xue Za Zhi. 2020; 49(5):411-417. 10. Ng JH, Bijol V, Sparks MA, Sise ME, Izzedine H, Jhaveri KD. Pathophysiology and Pathology of Acute Kidney Injury in Patients With COVID-19. Adv Chronic Kidney Dis. 2020; 27(5):365-376. 11. Henry BM, Benoit SW, de Oliveira MHS, et al. ADAMTS13 activity to von Willebrand factor antigen ratio predicts acute kidney injury in patients with COVID-19: Evidence of SARS-CoV-2 induced secondary thrombotic microangiopathy. Int J Lab Hematol. 2021; 43 Suppl 1:129-136.

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12. Apetrii M, Enache S, Siriopol D, et al. A brand-new cardiorenal syndrome in the COVID-19 setting. Clin Kidney J. 2020; 13(3):291-296.

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24. Cinislioglu AE, Cinislioglu N, Demirdogen SO, et al. The relationship of serum testosterone levels with the clinical course and prognosis of COVID-19 disease in male patients: a prospective study. Andrology. 2021. 25. Li R, Yin T, Fang F, et al. Potential risks of SARS-CoV-2 infection on reproductive health. Reprod Biomed Online. 2020; 41(1):89-95. 26. Cannarella R, Calogero AE, Condorelli RA, et al. Systemic effects of the hormonal treatment of male hypogonadism with preliminary indications for the management of COVID-19 patients. Ther Adv Endocrinol Metab. 2020; 11:2042018820966438. 27. Moreno-Perez O, Merino E, Alfayate R, COVID19-ALC Research group et al. Male pituitary-gonadal axis dysfunction in post-acute COVID-19 syndrome-Prevalence and associated factors: A Mediterranean case series. Clin Endocrinol (Oxf). 2021. 28. EAU Guidelines. Edn. presented at the EAU Annual Congress Milan 2021. ISBN 978-94-92671-13-4. 29. Redelman-Sidi G. Could BCG be used to protect against COVID19? Nat Rev Urol. 2020; 17(6):316-7. 30. Desouky E. BCG versus COVID-19: impact on urology. World J Urol. 2021; 39(3):823-827. 31. de Chaisemartin C, de Chaisemartin L. Bacille Calmette-Guérin Vaccination in Infancy Does Not Protect Against Coronavirus Disease 2019 (COVID-19): Evidence From a Natural Experiment in Sweden. Clin Infect Dis. 2021; 72(10):e501-e505. 32. Karabay O, Köse O, Tocoglu A, et al. Investigation of the frequency of COVID-19 in patients treated with intravesical BCG. Rev Assoc Med Bras (1992). 2020; 66Suppl 2(Suppl 2):91-95.


The effect of COVID-19 on the male genitourinary system 33. Fedeli U, Porreca A, Colicchia M, et al. Intravescical instillation of Calmette-Guérin bacillus and COVID-19 risk. Hum Vaccin Immunother. 2021; 17(2):416-417. 34. Leeson CE, Ismail A, Hashad MM, et al. Systematic Review: Safety of Intravesical Therapy for Bladder Cancer in the Era of COVID-19. SN Compr Clin Med. 2020; 1-5. 35. Gallegos H, Rojas PA, Sepúlveda F, et al. Protective role of intravesical BCG in COVID-19 severity. BMC Urol. 2021; 21(1):50.

36. Mjaess G, Lilly E, Mansour R, et al. COVID-19 and BCG: where’s the challenge? World J Urol. 2021; 2:1-3. 37. Zhao H, Souders C, Carmel M, Anger JT. Low Rates of Urologic Side Effects Following Coronavirus Disease Vaccination: An Analysis of the Food and Drug Administration Vaccine Adverse Event Reporting System. Urology. 2021; 153:11-13. 38. Özütemiz C, Krystosek LA, Church AL, et al. Lymphadenopathy in COVID-19 Vaccine Recipients: Diagnostic Dilemma in Oncologic Patients. Radiology. 2021; 300(1):E296-E300.

CORRESPONDENCE Carlo Giulioni Department of Urology, University Hospital “Ospedali Riuniti”. 71 Conca Street, 60126, Ancona – Italy Email: carlo.giulioni9@gmail.com Phone: +39 320/7011978 ORCID: 0000-0001-9934-4011

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EDITORIALE

Disfunzione erettile, diritto alla salute sessuale maschile e livelli essenziali di assistenza (LEA) Enrico Caraceni 1, Angelo Marronaro 1, Edoardo Pescatori 2, Andrea Benedetto Galosi 3. 1 2 3

U.O.C. Urologia, Asur Area Vasta 3 PO, - Civitanova Marche; Andrologist, Hesperia Hospital Modena; Division of Urology, University Hospital “Ospedali Riuniti”, School of Medicine, Department of Clinical, Special and Dental Sciences, Marche Polytechnic University, Ancona;

SUMMARY

Erectile dysfunction, human right to male sexual health and essentials level of assistance (LEA)

The essential levels of assistance (LEA) are the performances and services that the Italian National Health Service (SSN) is required to provide to all citizens, free of charge or upon payment of a participation fee (ticket), with the public resources collected through the general taxation (taxes). They are established by a law every several years according to financial and national health programming. The last version was enacted on the 18 of March, 2017, the Decree of the President of the Council of Ministers (DPCM) of January 12, 2017 with the new essential levels of assistance was published in the Official Gazette (Ordinary Supplement No. 15) Previous decree was enacted the November 29 of 2001. LEA is mandatory for the regions in order to ensure a homogeneous provision of health services in the different regions. The individual regions are required to provide only the services expressly mentioned in this law. The LEA application regarding male sexual health and penile prosthesis implantation generates in Italy some paradoxical situations. Number 1: too low number of penile implant cases. Number 2: important territorial inhomogeneity in the number of prosthetic implants. Number 3: recognition of the right to sexual health as an exclusive prerogative of the female gender. Number 4: Penile prosthetic devices too expensive in Italy versus Europe and USA. In conclusions the treatment of impotence in Italy is not an available possibility for all the Italian Citizen and this represents, especially for cancer patients but not only, a very heavy burning. In Italy it is necessary and urgent to update the LEA so that this inequality is overcome.

KEY WORDS: Penile prosthesis, erectile disfunction,male sexual health,LEA, essentials level of assistance, IPP, impotence.

INTRODUZIONE Si intende per disfunzione erettile (DE) l’incapacità ad ottenere e/o mantenere una erezione sufficiente al completamento di un rapporto sessuale penetrativo. Il sinto-

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mo è molto frequente soprattutto dopo i 60 anni e arriva in alcune fasce di età ad interessare 1 italiano su 3 (Parazzini et al.) (1). La disfunzione erettile non è considerata in senso stretto una malattia essendo di per sé espressione di numerose


Disfunzione erettile, diritto alla salute sessuale maschile e livelli essenziali di assistenza (LEA)

malattie come diabete, ipertensione, malattie neurologiche, pene curvo acquisito (Induratio Penis Plastica), posttrapianto renale, traumi anche della strada, ed esito chirurgico/radioterapico di trattamento di neoplasie maligne di prostata, vescica, retto.Tuttavia esiste ormai una letteratura molta ampia che dimostra come tale disfunzione sia a sua volta causa di emarginazione sociale, di importanti problematiche familiari e in ultima analisi di depressione (2). Quest’ultima è una vera malattia che può portare a comportamenti abnormi con esito talvolta anche infausto. Le protesi peniene sono da tempo ampiamente utilizzate nella terapia della disfunzione erettile sia in Italia che nel resto del mondo industrializzato. Lo scopo è quello di superare l’handicap legato alla disfunzione erettile non altrimenti trattabile recuperando la funzione erettiva perduta e ripristinando così l’attività sessuale penetrativa. Non si tratta certo di un approccio sperimentale ma di una terapia prevista da tutte le linee guida internazionali quando altre misure terapeutiche disponibili falliscono. Esistono diverse tipologie di protesi peniene ed oggi le più utilizzate sono le protesi idrauliche tricomponenti perché consentono di avere la possibilità di alternare l’erezione con la flaccidità del pene riproducendo il più fedelmente possibile la fisiologia umana. Inoltre l’erezione ottenuta è generalmente più rigida e più simile a quella naturale rispetto ad altre protesi peniene più economiche (3, 4).

REALTÀ

ITALIANA

In Italia esiste una realtà che alimenta diverse situazioni che possiamo e forse dobbiamo considerare paradossali e che richiedono interventi urgenti da parte delle autorità preposte per addivenire a provvedimenti adeguati poiché tali paradossi creano conseguenze severe e diseguaglianze gravi nel trattamento dei cittadini. È assolutamente importante e nostro imprescindibile compito riferire tutto questo a chi di competenza non per polemizzare, ma al fine di consentire la adozione dei provvedimenti del caso.

PARADOSSO NUMERO 1:

SI IMPIANTA TROPPO POCO

L’Italia è tra i paesi che effettuano meno impianti di protesi peniene in Europa e nel mondo civilizzato. La domanda di trattamento da parte della popolazione secondo i dati di Parazzini dell’Istituto Mario Negri di Milano è stimata intorno ai 2880 casi/anno (1). Probabilmente il dato epidemiologico è sottostimato: a riprova e a titolo meramente esemplificativo, secondo i dati AGENAS in Italia nel 2016 sono stati effettuati non meno di 12.000 ricoveri per tumori maligni della prostata trattati con prostatectomia radicale. Sappiamo bene che questo intervento comporta DE severa in almeno il 50% dei casi e che quindi potrebbe da solo causare una prevalenza di DE generalmente severa in 6000 casi/anno che ovviamente si accumulano negli anni. Tra l’altro il numero degli interventi di prostatectomia radicale, secondo la stessa fonte, è in lento ma progressivo aumento. Gli impianti di protesi peniena effettivamente realizzati in

Italia invece non superano i 500/anno ed il dato è sostanzialmente stabile da molti anni. La ragione di questa negazione di risposta pubblica in termini di salute non è chiara; quello che è evidente invece è che in questo modo si viene a creare un primo paradosso: nonostante esista una soluzione eccellente per il problema, la maggior parte dei candidati non ha accesso alle cure e persino i pazienti oncologici, una volta estirpato in qualche modo il tumore, vengono troppo spesso abbandonati al loro destino soli di fronte alla propria erezione perduta.

PARADOSSO NUMERO 2:

DIRITTO ALLA SALUTE SESSUALE MASCHILE E IMPLANTOLOGIA PENIENA ESCLUSI DAI LEA. DISOMOGENEITÀ TERRITORIALE DELLA EROGAZIONE DELLE PRESTAZIONI. CAUSA – EFFETTO?

In Italia la erogazione dell’assistenza sanitaria è una competenza regionale. I livelli essenziali di assistenza (LEA), introdotti nel 2001, per evitare che il regime di aziendalizzazione del sistema sanitario nazionale introdotto con la legge 502 del 1992 e l’affidamento della assistenza sanitaria alle regioni potessero creare disomogeneità e quindi sperequazione nella erogazione dei servizi. I LEA hanno subito diversi adeguamenti, l’ultimo con Decreto del Presidente del Consiglio dei Ministri (DPCM) del 12 gennaio 2017. Il nuovo Decreto sostituisce integralmente il DPCM 29 novembre 2001. Gli adeguamenti si sono resi necessari per la verificata disomogeneità dei livelli prestazionali a tutti nota sul territorio nazionale creando realtà sanitarie con più servizi e realtà meno attente con i flussi migratori di popolazione che tutti conosciamo e per introdurre nuove prestazioni ingiustamente escluse dai LEA. La possibilità di accedere all’impianto di protesi peniene oltre ad essere sottodimensionata rispetto alla richiesta del territorio come precisato nel paragrafo precedente, è tutt’altro che omogeneamente erogata sul territorio nazionale (5). I dati del Registro nazionale SIA di implantologia protesica peniena dimostrano che i chirurghi che erogano questa prestazione sono poco più di 30 in Italia, il numero complessivo di prestazioni erogate è basso, meno di 400/anno registrate, con liste di attesa generalmente lunghe e comprese tra 1 e 2 anni. Inoltre la distribuzione sul territorio di queste prestazioni è tutt’altro che omogenea: oltre il 75% delle prestazioni è erogato tra nord e centro in modo abbastanza equivalente, mentre solo il 25% dei pazienti è trattato nel sud. Come se non bastasse dalla stessa fonte risulta anche che non tutte le regioni erogano tale prestazione: nel nord sono apparentemente senza impianti la Liguria, la Valle D’Aosta e il Trentino, nel centro l’Umbria e nel sud Abruzzo, Molise, Calabria, Basilicata e Sardegna: ben 5 regioni non sembrano erogare tale prestazione. In sintesi, complessivamente 11 regioni - di cui 5 nel sud - non erogano la prestazione. Inoltre anche all’interno del gruppo delle regioni che erogano la prestazione il numero di Advances in Urological Diagnosis and Imaging - 2021; 4,2

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E. Caraceni, A. Marronaro, E. Pescatori, A.B. Galosi

impianti effettuato mostra grande variabilità, oscillando notevolmente da 2 ad oltre 60 casi da regione a regione. Ci troviamo di fronte ad un quadro nazionale a macchia di leopardo con regioni che realizzano un guadagno risparmiando a scapito di altre più virtuose che si vedono caricato un DRG penalizzante a causa della mobilità attiva a cui sono costretti i pazienti. Diventa cioè conveniente per alcune regioni inviare furi regione in mobilità passiva una prestazione che costa più di quanto frutti: un atteggiamento che dimostra di non saper interpretare il proprio ruolo (rispondere alla domanda di salute del territorio regionale). Questo senza considerare il disagio che i cittadini e le loro famiglie sono costretti ad affrontare: lunghi e dispendiosi viaggi, con liste di attesa lunghissime, a volte senza riuscire comunque ad ottenere la prestazione. È abbastanza paradossale che i LEA, nati per tutelare la uniformità della erogazione delle prestazioni sul territorio nazionale, non tengano affatto conto della implantologia protesica peniena cosi come di tutta la implantologia urologica che comprende anche le protesi per la incontinenza urinaria. Le regioni hanno infatti l’obbligo di erogare tutto quanto incluso nei LEA ma sono tenute ad erogare solo quanto espressamente elencato. Nessun obbligo esiste qualora la prestazione non è inclusa nella legge. Gli elenchi delle prestazioni incluse sono contenuti negli allegati del DPCM in particolare nei primi 3 e non contemplano purtroppo le protesi urogenitali. A poco o nulla vale l'osservazione che ,in ambito LEA in regime di assistenza ospedaliera, è lo specialista che deve indicare le necessità cliniche del paziente. Se la salute sessuale maschie non viene riconosciuta come una priorità da tutelare. Questo demotiva la implantologia e porta i gestori delle aziende sanitarie a non finanziare questa tipologia di attività.

PARADOSSO NUMERO 3:

TUTELA DELLA SALUTE SESSUALE FEMMINILE E MANCATA TUTELA DEL DIRITTO ALLA SALUTE SESSUALE MASCHILE

Il diritto alla salute sessuale maschile non solo rientra nel più generale diritto alla salute garantito dalla Costituzione Italiana all’Articolo 32 a tutti i cittadini ma è riconosciuto anche da numerosi organismi internazionali attenti ai diritti civili come l’OMS, la conferenza internazionale delle Nazioni Unite del 1968, la conferenza internazionale delle donne del 1974 e dalla conferenza internazionale del Cairo del 1994 e tanti altri. Non solo ma vi sono anche diverse sentenze della Corte di Cassazione e della Corte Costituzionale che hanno riconosciuto inequivocabilmente tale diritto. Inoltre il diritto alla salute sessuale in tutte le enunciazioni esistenti è previsto per entrambi i generi per i quali è sempre prevista la parità. Ovvero entrambi i generi maschile e femminile, hanno entrambi diritto al benessere sessuale e riproduttivo. Sembra pertanto quanto meno singolare che i LEA enuncino il diritto alla salute delle donne e prevedano in caso di mastectomia per neoplasia l’impiego delle protesi mammarie mentre omettano il genere maschile che, in assenza di esplicita enunciazione almeno al diritto alla

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Advances in Urological Diagnosis and Imaging - 2021; 4,2

salute sessuale , viene implicitamente mutilato di analogo diritto.

PARADOSSO NUMERO 4:

DIFFERENZE RILEVANTI NEI COSTI DEL DEVICE

È verosimile che il costo delle protesi peniene presenti una grande variabilità in Europa e nel mondo. Anche all’interno del mercato comune la variabilità è elevata. L’Italia è il paese dove le protesi idrauliche tricomponenti, cioè i modelli più utilizzati nel mondo, presentano i costi tra i più alti. Le protesi idrauliche tricomponenti oscillano nel nostro paese come costo tra 6500 e 9000 €, IVA esclusa. Il rimborso invece, laddove previsto, vale 2300 € in ricovero ordinario: DRG 341. ll fatto che il mercato italiano sia di dimensioni inferiori rispetto agli altri giustifica almeno in parte questa situazione. Un maggiore impiego delle protesi comporterebbe una vendita maggiore che potrebbe portare ad una riduzione dei costi per le ditte importatrici e quindi ad un prezzo di vendita più competitivo. Il mercato comune europeo di per sé non ha risolto il problema.

PRECISAZIONI

IMPORTANTI:

1) Si potrebbe pensare di primo acchitto che la incapacità ad avere rapporti sessuali sia di per sé cosa marginale rispetto al pericolo di vita che può essere legato ad alcune malattie come ad esempio quelle oncologiche. È ormai dimostrato che la disfunzione erettile vada ad aggravare altre malattie di cui è sintomo come il diabete, la ipertensione, le comorbosità dei trapiantati renali, i traumi del piccolo bacino e dell’apparato urogenitale, le malattie oncologiche, le neurolesioni. L’aggravamento consiste nel peggiorare queste patologie con la comparsa della depressione legata alla disfunzione erettiva e alla distorsione della immagine di sé che questa comporta con la relativa proiezione sociale del problema. In altre parole il paziente deve sommare al burning legato alla sua malattia di base, sia essa oncologica, metabolica o altro, anche il danno della sua vita di tutti i giorni legato al fatto di non riuscire più ad avere rapporti sessuali normali e soddisfacenti. La depressione generata da questa situazione che diventa un vero handicap può essere molto grave e può mettere a rischio anche la vita stessa oltre alla qualità di vita del paziente. 2) L’asportazione di una neoplasia con un intervento chirurgico può guarire il paziente dal punto di vista oncologico, ma il medico e con esso il sistema di assistenza sanitaria non possono e non devono trascurare sintomi come l’impotenza e la incontinenza urinaria. Quando presenti il paziente e la partner non devono essere abbandonati a sé stessi perché tali disturbi condizionano pesantemente la qualità di vita sia del paziente che della partner al punto da vanificare quasi completamente il risultato oncologico ottenuto con l’intervento chirurgico ai fini della qualità di vita residua. Anche in questi casi come nelle donne dopo mastectomia è necessario riconoscere la disfunzione e farsene


Disfunzione erettile, diritto alla salute sessuale maschile e livelli essenziali di assistenza (LEA)

carico affrontandola e risolvendola, anche con l’impianto di protesi, se necessario. 3) Sta emergendo in maniera sempre più evidente in letteratura la indicazione a trattare con impianto protesico precoce i pazienti affetti da priapismo a basso flusso resistente alla terapia. Si tratta spesso di giovani altrimenti destinati alla perdita irreversibile e definitiva della funzione erettiva che hanno il diritto a ricevere un impianto protesico. 4) Un discorso a parte meritano i mielolesi, spesso anch’essi giovani, a cui non può essere evidentemente negato il diritto alla sessualità.

gati dei LEA ed anche le protesi necessarie per il trattamento della incontinenza urinaria. Potrebbe essere altrettanto utile centralizzare a livello nazionale più che regionale la determinazione del volume annuale in funzione della domanda esistente e prevedibile e del prezzo di questi presidi ad alto costo in modo da ottenere un livellamento in basso del prezzo e un adeguamento con le altre nazioni Europee dei costi di acquisizione.

CONCLUSIONI

2. Jannini EA, McCabe MP, Salonia A, et al. Controversies in Sexual Medicine: organic vs. psychogenic? The Manichean diagnosis in sexual medicine. J Sex Med. 2010; 7:1726-33.

Al fine di ridurre la sperequazione di cui il cittadino italiano di sesso maschile oggi è oggetto non abbiamo soluzioni miracolistiche da offrire al decisore. Anche l’ampliamento dei LEA, rispettati solo da 8 regioni in Italia, potrebbe essere una misura insufficiente. Tuttavia crediamo che se fosse introdotto il diritto alla salute sessuale maschile insieme a quella femminile ciò rappresenterebbe un segno di rispetto e di civiltà oltreché uno stimolo per le Regioni a fare meglio e di più in questa direzione. Questo provvedimento dovrebbe essere completato dalla introduzione esplicita delle protesi peniene tutte negli alle-

BIBLIOGRAFIA 1. Parazzini F, Menchini F, Bortolotti A, et al. Frequency and determinants of erectile dysfunction in Italy. Eur Urol. 2000; 37: 43-9.

3. Laurence A Levine, Edgardo F Becher, Anthony J Bella, et al. Penile Prosthesis Surgery: Current Recommendations From the International Consultation on Sexual Medicine. J Sex Med. 2016; 13(7):1145. 4. Natali A, Olianas R, Fisch M. Penile implantation in Europe: successes and complications with 253 implants in Italy and Germany. J Sex Med. 2008; 5:1503-1512. 5. Pescatori E, et al. INSIST-ED Italian Society of andrology registry on penile prosthesis surgery. First data analysis . Archivio Italiano di Andrologia 2016; 88,2.

CORRISPONDENZA Enrico Caraceni U.O.C. Urologia, Asur Area Vasta 3 PO, Civitanova Marche e-mail: ecarace1@gmail.com

Advances in Urological Diagnosis and Imaging - 2021; 4,2

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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. To publish in Advances in Urological Diagnosis and Imaging is free. The official language of the journal is English. For papers with national interest, because of local contents, in the ”Italian Corner” it’s accepted their publication in Italian and the abstract must be in English. The editing of these papers follows the Instructions below described. All accepted paper will be published after a peer reviewed process.

AUTHORS’

RESPONSIBILITIES - Manuscripts are accepted with the understanding that they have not been published or submitted for publication in any other journal. Authors must submit the results of clinical and experimental studies conducted according to the Helsinki Declaration on clinical research and to the Ethical Code on animal research set forth by WHO (WHO Chronicle 1985; 39:51). The Authors must obtain permission to reproduce figures, tables and text from previously published material. Written permission must be obtained from the original copyright holder (generally the Publisher). Manuscripts must be written in English language in accordance with the “Uniform Requirements for Manuscripts submitted to biomedical journals” defined by The International Committee of Medical Journal Editors (http://www.ICMJE.org). Manuscripts in Italian language can be published only after translation (expenses will be charged to the Authors). Manuscripts should be typed double spaced with wide margins. They must be subdivided into the following sections: Title page - It must contain: a) title; b) a short (no more than 40 characters) running head title; c) first, middle and last name of each Author without abbreviations; d) University or Hospital, and Department of each Author; e) last name, address and e-mail of all the Authors; f) corresponding Author; g) phone and/or fax number to facilitate communication; h) acknowledgement of financial support; i) list of abbreviations.

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

TEXT - For original articles concerning experimental or clinical studies, the fol-

lowing standard scheme must be followed: Summary - Key Words Introduction - Material and Methods - Results - Discussion - Conclusions References - Tables - Legends - Figures. Case Report should be divided into: Summary - Introduction (optional) - Case report(s) - Conclusions - References (Discussion and Supplementary Figures,Tables and References can be submitted for publication in Supplementary Materials).

SIZE

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

REFERENCES - References must be sorted in order of quotation and num-

bered with arabic digits between parentheses. Only the references quoted in the text can be listed. Journal titles must be abbreviated as in the Index Medicus. Only studies published on easily retrieved sources can be quoted. Unpublished studies cannot be quoted, however articles “in press” can be listed with the proper indication of the journal title, year and possibly volume. References must be listed as follows:

• Journal articles All Authors if there are six or fewer, otherwise the first three, followed by “et al.”. Complete names for Work Groups or Committees. Complete title in the original language. Title of the journal following Index Medicus rules. Year of publication; Volume number: First page. Example: Starzl T, Iwatsuki S, Shaw BW, et al. Left hepatic trisegmentectomy. Surg Gynecol Obstet. 1982; 155:21. • Books Authors - Complete title in the original language. Edition number (if later than the first). City of publication: Publisher, Year of publication. Example: Bergel DIA. Cardiovascular dynamics. 2nd ed. London: Academic Press Inc., 1974. • Book chapters Authors of the chapters - Complete chapter title. In: Book Editor, complete Book Title, Edition number. City of publication: Publisher, Publication year: first page of chapter in the book. Example: Sagawa K.The use of central theory and system analysis. In: Bergel DH (Ed), Cardiovascular dynamics. 2nd ed. London: Academic Press Inc., 1964; 115.

TABLES - Tables must be aimed to make comprehension of the written text

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

FIGURES - Figures are also graphics, algorithms, photographs, drawings. Figures

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

MANUSCRIPT REVIEW - Only manuscript written according to the above

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

MANUSCRIPT PRESENTATION - Authors must submit their manuscripts

(MAC and WINDOWS Microsoft Word are accepted) to the Assistant Editor (dellatti@hotmail.com).

PROOFS - Authors are responsible for ensuring that all manuscripts are accu-

rately typed before final submission. Galley proofs will be sent to the Corresponding Author. Proofs should be returned within seven days from receipt.

IMPORTANT TO KNOW - PAPERS ON: MEDICAL AND SURGICAL DEVICES, DIAGNOSTIC INSTRUMENTS, REGISTERED DRUGS, DIET SUPPLEMENTS, NUTRACEUTICALS

S.I.E.U.N. guarantees the Authors the publication of the article for scientific purposes completely free of charge. Each of the Authors is required to declare at the bottom of their article if they have received funding or grants from Sponsors for publication / study. Papers that contain references to devices (medical and surgical), diagnostic instruments, registered drugs, diet supplements, nutraceuticals must not be used for commercial purposes without the authorization of Edizioni Scripta Manent. The Authors are required to declare in the Copyright Assignment Form which possible Sponsors could be interested in a commercial use of the reprints. Sponsor are requested to buy a minimum amount of 100 reprints at a cost of € 1.500 (1 to 4 pages) or € 2.000 (5 to 8 pages). Prices for the purchase of number of reprints greater than 100 can be negotiated with Edizioni Scripta Manent. Edizioni Scripta Manent retains copyright for republishing and the distribution rights for commercial purpose.

TRANSLATION - Translation of manuscripts in Italian language is offered on

payment. Translation and reprints can be requested to Edizioni Scripta Manent by e-mail to info@edizioniscriptamanent.eu


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