1 L’esperienza italiana su… Casa di Cura Villa Montallegro - GenovaPERISCOPIO L’esperienza italiana su… Shock waves e DE Antonio Casarico Polo Urologico Ist. Cl. Pavia e Vigevano – Ist. Cl. Beato Matteo -Vigevano Casa di Cura Villa Montallegro - Genova

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4 Antonio Casarico e Paolo PuppoLong Term Efficacy of Low Intensity Linear Focused Shockwave Therapy for Vascular Erectile Dysfunction Patients: 20 months follow-up Antonio Casarico e Paolo Puppo Villa Montallegro - Genova Urologia 2 - Ist. Clin. Beato Matteo - Vigevano

5 La Rivoluzione delle Onde d’Urto2015

6 14 pts evaluable at LONG TERM F-USafety and Efficacy Associated with Treating ED Patients with Low Intensity Shockwaves by Renova 20 MONTHS FOLLOW-UP SUCCESS at 6 months F-U = 19 pts 14 pts evaluable at LONG TERM F-U (15-21 months; mean 19.8 months) Mean age 63,42 (47-75) Mean ED duration 4,71 (1-20) years PDE5i NON-RESPONDERS 2 = 14,2% PDE5i RESPONDERS = 85,7%

7 14 pts evaluable at LONG TERM F-USafety and Efficacy Associated with Treating ED Patients with Low Intensity Shockwaves by Renova 20 MONTHS FOLLOW-UP 14 pts evaluable at LONG TERM F-U (15-21 months; mean 19.8 months) Smokers /14= 64% Diabetes /14= 21,4% Dyslipidemia 3/14= 21,4% CV disease 4/14= 28,5% Hypertension 7/14= 50% 2 o more /14= 21,4% PDE5i RESPONDERS = 14,2% PDE5i NON-RESPONDERS 12 = 85,7%

8 Success to ALL Primary and Secondary Efficacy ObjectivesSafety and Efficacy Associated with Treating ED Patients with Low Intensity Shockwaves by Renova 20 MONTHS FOLLOW-UP Success maintained IIEF IIEF6= / +5 IIEF6= / +2 SEP 2-3 GAQ 1-2 EHS Success to ALL Primary and Secondary Efficacy Objectives 11=78,5%

9 Success to ALL Primary and Secondary Efficacy ObjectivesSafety and Efficacy Associated with Treating ED Patients with Low Intensity Shockwaves by Renova 20 MONTHS FOLLOW-UP Success Maintained PDE5i NON RESPONDERS 2/2 =100% PDE5i RESPONDERS 9/12 =75% Success to ALL Primary and Secondary Efficacy Objectives

10 SUCCESS MAINTAINED 2/2 ptsSafety and Efficacy Associated with Treating ED Patients with Low Intensity Shockwaves by Renova 20 MONTHS FOLLOW-UP IIEF6 PDE5i NON RESPONDERS SUCCESS MAINTAINED 2/2 pts 1ST pt 19 (+1) 2nd pt 23 (-2)

11 IIEF6 SUCCESS MAINTAINED 9/12 pts PDE5i RESPONDERSSafety and Efficacy Associated with Treating ED Patients with Low Intensity Shockwaves by Renova 20 MONTHS FOLLOW-UP IIEF6 PDE5i RESPONDERS SUCCESS MAINTAINED 9/12 pts IIEF6 (23-29) mean 26,44 LOST 4 points overall - IIEF6 unchanged = 5 pts lost 2 points each = 2 pts (29>27 // 25>23) - NO PDE5i lost 1 point = 1 pt (27>26) - sometimes PDE5i gained 1 point = 1 pt (26>27)

12 SUCCESS MAINTAINED 9 ptsSafety and Efficacy Associated with Treating ED Patients with Low Intensity Shockwaves by Renova 20 MONTHS FOLLOW-UP EHS 4 PDE5i RESPONDERS SUCCESS MAINTAINED 9 pts 6 MONTHS F-U = 5 pt 20 MONTHS F-U = 4 pts

13 SUCCESS MAINTAINED 9 ptsSafety and Efficacy Associated with Treating ED Patients with Low Intensity Shockwaves by Renova 20 MONTHS FOLLOW-UP STOP PDE5i PDE5i RESPONDERS SUCCESS MAINTAINED 9 pts STOP PDE5i = 5 (55,5%)

14 Shockwave Therapy Applications1000 Urology Orthopedics Shock Wave Pressure Level (bar) 500 Tripter X-1 ~ 450 Bar StoneFragmentation ED Renova ~80 bar Angiogenesis Orthima ~ 200 bar Anti Inflammatory 100 Clinical Field 80’s 90’s 2000+

15 Carry energy - able to propagate through a medium.SHOCKWAVES Carry energy - able to propagate through a medium. sequence of single sonic pulses fast pressure rise (<10 nanoseconds) high-pressure peak (100 MPa), short lifecycle (10 microseconds)

16 tissue is first compressed due to the positive pressure SHOCKWAVES tissue is first compressed due to the positive pressure then expands due to the tensile properties of the tissue phenomenon: CAVITATION (resembled a micrometer-sized violent collapse of bubbles) SW induces a SHEAR STRESS on endothelial cell membranes

17 Low Intensity ShockwavesClinical Background Low Intensity Shockwaves induce ANGIOGENESIS

18 Angiogenesis process of sprouting new blood vessels from pre-existing vessels. major cells involved in this process are the endothelial cells, which line the blood vessels and constitute capillaries.

19 Angiogenesis Angiogenesis

20 2017 ?

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22 ANIMAL STUDIES

23 Low Energy Shock Waves Induce AngiogenesisShear stress Intracellular & extracellular responses Stimulates endothelial Nitric Oxide Synthase (Enos) Release of Vascular Endothelial Growth Factors (VEGF) Proliferating Cell Nuclear Antigen (PCNA) production Neovascularization

24 Clinical Background Conclusions:Extracorporeal Cardiac Shock Wave Therapy Markedly Ameliorate Ischemia - Induced Myocardial Dysfunction in Pigs in Vivo Nishida T, Shimokawa H et al. Department of Cardiovascular Surgery, Cardiovascular Medicine, Kyushu University, Fukuoka, Japan Circulation. 2004; 110: Conclusions: Extracorporeal cardiac SW therapy is an effective and noninvasive therapeutic strategy for ischemic heart disease.

25 Low Intensity Shockwaves Induce AngiogenesisExtracorporeal Cardiac Shockwave Therapy Markedly Ameliorate Ischemia - Induced Myocardial Dysfunction in Pigs in Vivo

26 Increase in the Number of CapillariesFactor VIII Staining Number of Capillaries (/mm2) Endocardium (n=6) Epicardium (n=6) Control P< 0.05 P< 0.05 1000 1400 400 1200 800 200 1000 1400 400 1200 800 200 SW Control SW Control SW 20 μm

27 Clinical Background Shockwaves Induce AngiogenesisShock wave therapy induces neovascularization at the tendon–bone junction: A study in rabbits CJWang et al. Journal of Orthopaedic Research 21 (2003) 984–989 SWT induces in-growth of neovascularization associated with early release of angiogenesis related markers at the Achilles tendon–bone junction in rabbits. neovascularization …to improve blood supply and tissue regeneration at the tendon–bone junction

28 The effects of LISW on vEGF and eNOS are maintained for several weeks following even a single shock wave application of 500 shocks

29 Clinical Background Shockwaves Induce AngiogenesisExtracorporeal shock wave therapy ameliorates hind limb ischemia in rabbits Keiji Oi, Y Fukumoto et al. Dept Cardiovasc Medicine, Kyushu Univers Grad School of Med Sciences. Tohoku J Exp Med Feb ;214 (2):151-8 Surgical excision of the entire unilateral rabbit femoral artery 0.09 mJ/mm², 30 spots, 200 shots/spot

30 Development of Collateral Arteries following Low Intensity ShockwaveA much larger quantity of collateral arteries develop in the group treated with shock wave Pre treatment Day 7 Post treatment Day 28

31 Increase of Capillaries

32 300 shocks at an energy level of 0.1mJ/mm2Effects of low-energy shockwave therapy on the erectile function and tissue of a diabetic rat model Qiu X, Lin G, Xin Z, Ferretti L, Zhang H, Lue TF, Lin CS. UCSF J Sex Med 2013;10:738–746 300 shocks at an energy level of 0.1mJ/mm2 restored EF to levels similar to normal control ….regeneration of nNOS-positive nerves, endothelium, and smooth muscle…. mediated by recruitment of endogenous MSCs … resembled previous human clinical trials

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34 nNOS Intracavernous Pressure

35 Arterial endoltheliumSinusoidal endothelium Arterial endolthelium Smooth muscle

36 reduced neuronal loss in damaged neural tissue Low-energy extracorporeal shock wave therapy promotes vascular endothelial growth factor expression and improves locomotor recovery after spinal cord injury Yamaya S. et al (Sendai, Japan) J Neurosurg 2014; 121: 6, low-energy ESWT significantly increased expressions of VEGF and Flt-1 in the spinal cord reduced neuronal loss in damaged neural tissue improved locomotor function after SCI. enhances the neuroprotective effect of VEGF in reducing secondary injury and leads to better locomotor recovery following SCI.

37 AUA 2016 San Diego May 6-10 MP86-06: Combination therapy using human adipose-derived stem cells on the cavernous nerve and low-energy shockwaves on the corpus cavernosum in a rat model of postprostatectomy erectile dysfunction Ohseong Kwon*, Jin Bong Choi, Yong Hyun Park, Woong Jin Bae, Hyuk Jin Cho, U-Syn Ha, Sung Hoo Hong, Se Woong Kim, Ji Youl Lee, Seoul, Korea, Republic of. Rats were randomly divided into five groups: Control, BCNI (bilateral cavernous nerve injury), ADSC (BCNI group with h-ADSCs on the cavernous nerve), SWT (BCNI group with low-energy SWT on the corpus cavernosum), and ADSC/SWT (BCNI group with a combination of h-ADSCs and low-energy SWT). After four weeks, erectile function was assessed using intracavernosal pressure (ICP). The cavernous nerves and penile tissue were evaluated through immunostaining, western blotting and a cyclic guanosine monophosphate (cGMP) assay. ADSC/SWT significantly improved ICP. ADSC had significantly increased ?-III tubulin expression of cavernous nerve, and SWT had markedly enhanced vascular endothelial growth factor (VEGF) expression in corpus cavernosum. ADSC/SWT group had a significantly increased in alpha smooth muscle content (P <.05), neural nitric oxide synthase (nNOS) of the dorsal penile nerve (P <.05), endothelial nitric oxide synthase (eNOS) protein expression (P <.05), and cGMP level (P <.05), reduces the apoptotic index in corpus cavernosum.

38 Low-energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model Huixi Li,1,2 et al. and Tom F. Lue1 1 Knuppe Molec Urol Lab, Dept of Urol, Sch of Medic, Univ of California, San Francisco, CA,USA; 2 Dept of Urol, Peking Univers First Hospit and the Instit of Urol, Peking Univers, Beijing, P.R. China; 3 Diabetes Center, Univers of California, San Francisco, CA, USA; 4 Dept of Urol, Kaohsiung Med Univers Hospit, Dept of Uro, Faculty of Medic, Kaohsiung Med Univers, Kaohsiung, Taiwan J Sex Med 2016;13:22e32 Methods: 32 male Sprague-Dawley rats.…into 4 groups: sham surgery (Sham), pelvic neurovascular injury (PVNI) :bilateral cavernous nerve injury and internal pudendal bundle injury PVNI treated with LESW at Low energy: 0.06 mJ/mm2, 300 pulses 3 Hz PVNI treated with LESW at High energy: mJ/mm2, 1000 pulses at 3Hz Main Outcome: The intracavernous pressure (ICP), histological examination, and Western blot (WB), Cell cycle, Schwann cell activation.

39 INTRACAVERNOUS PRESSURE (ICP)Low-energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model Huixi Li,1,2 et al. and Tom F. Lue1 - J Sex Med 2016;13:22e32 INTRACAVERNOUS PRESSURE (ICP)

40 RECRUITING OF ENDOGENOUS PROGENITOR CELLS IN VIVOLow-energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model Huixi Li,1,2 et al. and Tom F. Lue1 - J Sex Med 2016;13:22e32 RECRUITING OF ENDOGENOUS PROGENITOR CELLS IN VIVO

41 NEUROVASCULAR CHANGES IN PENILE TISSUELow-energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model Huixi Li,1,2 et al. and Tom F. Lue1 - J Sex Med 2016;13:22e32 NEUROVASCULAR CHANGES IN PENILE TISSUE

42 REGENERATION OF nNOS POSITIVE CAVERNOUS NERVESLow-energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model Huixi Li,1,2 et al. and Tom F. Lue1 - J Sex Med 2016;13:22e32 REGENERATION OF nNOS POSITIVE CAVERNOUS NERVES

43 ACTIVATION OF SCHWANN CELLS IN VIVOLow-energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model Huixi Li,1,2 et al. and Tom F. Lue1 - J Sex Med 2016;13:22e32 ACTIVATION OF SCHWANN CELLS IN VIVO

44 ACTIVATION OF SCHWANN CELLS IN VIVOLow-energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model Huixi Li,1,2 et al. and Tom F. Lue1 - J Sex Med 2016;13:22e32 ACTIVATION OF SCHWANN CELLS IN VIVO

45 nerve generation with more progenitor cells Low-energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model Huixi Li,1,2 et al. and Tom F. Lue1 J Sex Med 2016;13:22e32 LESW treatment improves erectile function in a rat model of pelvic neurovascular injury by angiogenesis, tissue restoration nerve generation with more progenitor cells activation of Schwann cells (in vitro direct effect on Schwann cell proliferation). more complete re-innervation of penile tissue with regeneration of neuronal nitric oxide synthase (nNOS)-positive nerves.

46 2016 Sep;196(3):950-6 Low Intensity Extracorporeal Shock Wave Therapy Improves Erectile Function in a Model of Type II Diabetes Independently of NO/cGMP Pathway R Assaly-Kaddoum, F Giuliano, M Laurin, D Gorny, M Kergoat, J Bernabé, Y Vardi, L Alexandre, D Behr-Roussel LISWT twice weekly for 3 weeks. repeated after a 3-week no-treatment interval. (0.09 mJ/mm2).. Low intensity extracorporeal shock wave therapy significantly improved erectile function in GK rats to the same extent as sildenafil. Treatment effects were potentiated when combined with sildenafil. Shock wave effects were not associated with improved cavernous endothelium dependent or independent, or nitrergic reactivity. not mediated by a nitric oxide/cyclic guanosine monophosphate dependent mechanism.

47 RATTO UGUALI? UOMO

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49 Clinical History - Enhancement of Coronary CollateralsControl Group SW Group 4 weeks post AC implantation 4 weeks post treatment

50 Improved LV ejection fraction and strokevolume Double-blind and placebo-controlled study of the effectiveness and safety of extracorporeal cardiac shock wave therapy for severe angina pectoris. Kikuchi Y et al. Circ J Mar;74(3): LI-ESWT Improved LV ejection fraction and strokevolume Significantly ameliorated severity of the chest pain after a 6-minute walk.

51 Wang YCardiovasc Ultrasound. 2012 Aug 17;10:35.Initial clinical experience with extracorporeal shock wave therapy in treatment of ischemic heart failure. Vasyuk YA et al. Congest Heart Fail Sep-Oct;16(5): A modified regimen of extracorporeal cardiac shock wave therapy for treatment of coronary artery disease. Wang YCardiovasc Ultrasound Aug 17;10:35. Randomized and double-blind controlled clinical trial of extracorporeal cardiac shock wave therapy for coronary heart disease. Yang P et al. Heart Vessels May;28(3): LI-ESWT ameliorated the severity of angina pectoris and ischemic heart failure

52 ERECTILE DYSFUNCTION HUMAN STUDIES

53 Conclusions: Clinical HistoryCan Low-Intensity Extracorporeal Shockwave Therapy Improve Erectile Function? A 6-Month Follow-up Pilot Study in Patients with Organic Erectile Dysfunction Vardi Y, Appel B, Jacob G, Massrwi O, Gruenwald I Eur Urol 58: 243–248, 2010 Conclusions: first study that assessed the efficacy of LI-ESWT for ED…. tolerable and effective, suggesting a physiologic impact on Cavernosal hemodynamics. potential to improve erectile function and to contribute to penile rehabilitation without pharmacotherapy. ….short-term results are promising

54 ERECTILE DYSFUNCTION HUMAN STUDIES (only randomized controlled)

55 Gruenwald I, Appel B, Vardi Y. J Sex Med 9: 259–264, 2012Clinical History Low-intensity extracorporeal shock wave therapy- a novel effective treatment for erectile dysfunction in severe ED patients who respond poorly to PDE5 inhibitor therapy. Gruenwald I, Appel B, Vardi Y. J Sex Med 9: 259–264, 2012 CONCLUSIONS: LI-ESWT ……potential to treat a subgroup of severe ED patients. …need to be reconfirmed by multicenter sham control studies in a larger group of ED patients.

56 Vardi Y, Appel B, Kilchevsky A, Gruenwald IClinical History Does low intensity extracorporeal shock wave therapy have a physiological effect on erectile function? Short-term results of a randomized, double-blind, sham controlled study. Vardi Y, Appel B, Kilchevsky A, Gruenwald I J. Urol. May;187(5): , 2012 Conclusions: first randomized, double-blind, sham controlled study shows positive short-term clinical and physiological effect on the erectile function of men who respond to oral phosphodiesterase type 5 inhibitor therapy…feasibility and tolerability potential rehabilitative characteristics

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58 Low-Intensity Linear Shockwave Therapy for ED by RenovaSummary of Presented Clinical Trials

59 Improvement in IIEF-EFCongress: SLAMS, August 2013 Principal Investigator: Y. Reisman Protocol: 3600 shocks/session 52 patients, mean age: 57.2 years 79% Success % Success P value Improvement in IIEF-EF Baseline IIEF-EF Age 78.8% <0.0001 6.8 14.7 ± 4.9 57.2 ± 10.1

60 Congress: MESSM, November 2013 Protocol: 3600 shocks/session Principal Investigator: Y. Reisman Protocol: 3600 shocks/session 57 patients, mean age: 56.9 years 82% Success GAQ 2 GAQ 1 SEP 3 SEP 2 IIEF-6 - 26% 60% 14.7 Baseline 65% 74% 86% 21.6 1 Month FU

61 Congress: CUS, November 2013 Protocol: 3600 shocks/session Principal Investigator: Igor Motil Protocol: 3600 shocks/session 14 patients, mean age: 55.5 years 1 Month FU Baseline IIEF-5 19.85 14.54 1 month follow-up: GAQ: 85.7% SEP 2: 78.5% SEP 3: 71.4% EHS: improvement of 1 point or more in 78.5%

62 Congress: SMU, November 2013 Princip Investig: M. Pelayo-Nieto Centro Médico Nacional 20 de Noviembre, ISSSTE, México, Protocol: 5000 shocks/session 15 patients, mean age: 59.6 years 80% Success GAQ 2 GAQ 1 EHS SEP 3 SEP 2 IIEF-Q15 IIEF-5 - 2.47 33.3% 46.7% 2.8 14.53 Baseline 80.0% 3.2 3.4 19.6 1 Month FU

63 SEP 3 SEP 2 IIEF-6 24% 57% 12 Baseline 76% 84% 23.5 1 Month FUCongress: ESSM, January 2014 Principal Investigator: Fabrizio Iacono Centro Urolab, Naples, Italy Protocol: 3600 shocks/session 42 patients, mean age: 59.2 years SEP 3 SEP 2 IIEF-6 24% 57% 12 Baseline 76% 84% 23.5 1 Month FU

64 Congress: SLAMS, August 2014Principal Investigator: Hisasue, S shockwaves generator (ED1000, MEDISPEC, MD, USA); Protocol: 300 shocks/session X 12 sessions 56 patients, mean age: 64 years In the multivariate analysis, age and concomitant comorbidities number were the statistically significant predictors for the efficacy of LI-SWT. Older ED patients with several comorbidities should be informed about the less responsiveness to LI-SWT

65 LIWST significant in the subgroup with severe erectile dysfunctionInt J Urol Oct;21(10):1041-5 Extracorporeal shockwave therapy in the treatment of erectile dysfunction: a prospective, randomized, double-blinded, placebo controlled study. Yee CH1, Chan ES, Hou SS, Ng CF. 58 patients - 28 patients randomized into the sham -30 patients randomized into the LISWT LIWST significant in the subgroup with severe erectile dysfunction LISWT IIEF improvement: 10.1 ± 4.1 Vs sham IIEF improvement: 3.2 ± 3.3; P = 0.003

66 LIWST could add a new advanced treatment for EDInt J Impot Res Dec 4 Initial experience with linear focused shockwave treatment for erectile dysfunction: a 6-month follow-up pilot study. Reisman Y, Hind A, Varaneckas A, Motil I. single-arm pilot study to assess safety and efficacy of Renova® on vasculogenic ED 58 pts (mild/severe ED) – FU 1,3, 6 months LIWST could add a new advanced treatment for ED IIEF: baseline months FU 47 pts (81%) had a successful treatment

67 16th World Meeting on Sexual MedicineOctober 11th 2014, Sao Paulo, Brazil Safety and Efficient Duration of Linear Focused Shockwave Treatment for Erectile Dysfunction – A 12 months Follow-up Pilot Study Reisman Y 20 pts Vasculogenic ED - IIEF-EF 12.35±3.16 (Range 7-18) 6 mths FU, 18/20 (90%) success 15/18 (83.3% ) positive outcome longer than 12 months 4 pts (20%) PDE5i-non responders became responsive 2 patients (10%) stopped using PDE5i.

68 Organic ED (PDE5 Resp/NonResp)Can low-intensity extracorporeal shockwave therapy improve erectile dysfunction? A prospective, randomized, double-blind, placebocontrolled study A Olsen, M Persiani, S Boie, M Hanna and Lars Lund Scand J Urol Dec 3:1-5. 105 pts – median age 60y (37-80) Organic ED (PDE5 Resp/NonResp) Random>LISWT/PLACEBO>5 weeks>PLACEBO>LISWT Duolith SD1® (Storz) mJ/mm2, 5 Hz six positions (distal, centre and proximal part) 5 sessions x 5 weeks = total 3000 SW

69 Can low-intensity extracorporeal shockwave therapy improve erectile dysfunction? A prospective, randomized, double-blind, placebocontrolled study A Olsen, M Persiani, S Boie, M Hanna and Lars Lund Scand J Urol Dec 3:1-5. 5 WEEKS FU

70 A Olsen, M Persiani, S Boie, M Hanna and Lars LundCan low-intensity extracorporeal shockwave therapy improve erectile dysfunction? A prospective, randomized, double-blind, placebo controlled study A Olsen, M Persiani, S Boie, M Hanna and Lars Lund Scand J Urol Dec 3:1-5. FU after treatment

71 eaumadrid2015 Hatzichristou D.G. Erectile dysfunction shock wave therapy (EDSWT) improves hemodynamic parameters in patients with vasculogenic erectile dysfunction (ED): A triplex-based sham-controlled trial Chang T-J. Molecular signaling mechanisms of low-intensity extracorporeal shockwave (LI-ESW) on penile erection in rat model

72 AMERICAN UROLOGIC ASSOCIATION 2015Monday, May 18, :00 PM-3:00 PM PD45-10: The Safety and Efficacy of Li-ESWT in 604 patients for Erectile Dysfunction: Summary of Current and Evolving Evidence R Feldman*, Middlebury CT, B Denes, Laguna Beach, CA, B Appel, Haifa, Israel, SS Vasan, Bangalore, India, T Shultz, Gaithersburg, MD, A Burnett, Baltimore, MD POOLED DATA from 5 randomized, placebo-controlled studies (USA, Israel, Greece and India) 3 single-arm open label studies (Israel, Japan). N=604 men

73 AMERICAN UROLOGIC ASSOCIATION 2015Monday, May 18, :00 PM-3:00 PM PD45-10: The Safety and Efficacy of Li-ESWT in 604 patients for Erectile Dysfunction: Summary of Current and Evolving Evidence R Feldman*, Middlebury CT, B Denes, Laguna Beach, CA, B Appel, Haifa, Israel, SS Vasan, Bangalore, India, T Shultz, Gaithersburg, MD, A Burnett, Baltimore, MD Li-ESWT-ED1000® Medispec applicator; Active Rx N=440; Sham Rx N=164).; 2X weekly for 3 weeks and repeated after 3 week total of 12 Rx sessions.

74 AMERICAN UROLOGIC ASSOCIATION 2015Monday, May 18, :00 PM-3:00 PM PD45-10: The Safety and Efficacy of Li-ESWT in 604 patients for Erectile Dysfunction: Summary of Current and Evolving Evidence R Feldman*, Middlebury CT, B Denes, Laguna Beach, CA, B Appel, Haifa, Israel, SS Vasan, Bangalore, India, T Shultz, Gaithersburg, MD, A Burnett, Baltimore, MD POOLED DATA IIEF Mean change F1 F2 F3 F4 5 6.8 6.2 7

75 AMERICAN UROLOGIC ASSOCIATION 2015Country USA Greece Israel RCT RCT1 †Group D ††RCT2 Response to PDE5i prior to Li-ESWT Responders Poor responders ‡MCID II-EF EF domain 62% vs. 37.5% in treatment vs. placebo group, p=0.025 58.6% vs.12.5% in treatment vs. placebo group, p=0.003 49.3% vs. 9.1% in treatment vs. placebo group, p<0.01 45.8% vs. 12.5% in treatment vs. placebo group, p=0.021 40.5% vs. 0% in treatment vs. placebo group, p=0.001 IIEF-EF mean change from baseline 6.1 vs.2.5 points in treatment vs. placebo group, p=0.02 4.6 vs.1.4 points in treatment vs. placebo group, p<0.001 5.3 vs. 0.2 in treatment vs. placebo group, p<0.001 5.5 vs points in treatment vs. placebo group, p<0.001 5.4 vs. 0.1 points in treatment vs. placebo group, p<0.001 US Doppler NA PSV increased by 4.5 vs. 0.6 cm/sec in treatment vs. placebo, p<0.001 FMD Flow mediated dilation Mean AUC difference, treatment vs. placebo, p=0.002 Mean AUC difference, treatment vs. placebo, p=0.002 Mean AUC difference, treatment vs. placebo, p=0.001 NPT Mean difference treatment vs. placebo, p=0.016 Population 103 pt. (treatment-84, placebo-40) 46 pt. (treatment-31, placebo-15) 89 pt. (treatment-59, placebo-30) 24 pt. 55 pt. (treatment- 37, placebo-18)

76 double-blind, placebo-controlled study,Low intensity extracorporeal shockwave therapy for erectile dysfunction: a study in an Indian population. Srini VS1, Reddy RK, Shultz T, Denes B. Can J Urol Feb;22(1): double-blind, placebo-controlled study, organic ED who responded to PDE5i. randomized to receive either 12 sessions of LI-ESWT (n = 95) or placebo/sham therapy (n = 40). Outcomes assessed at 1, 3, 6, 9 and 12 months post-treatment. significant increase in the EHS and IIEF-EF Domain scores from visit 1 to follow up 5 (12 months) By 1 month after treatment highly significant differences between the LI-ESWT and placebo groups (p < ). Out of 60 men in the LI-ESWT group, 47 (78%) men at FU1 and 43 (71%) at FU5 were able to achieve spontaneous erections hard enough for penetration (EHS ≥ 3) compared to none in the placebo group.

77 18th ESSM Congress 2016- MadridPS ASSESSMENT OF THE TREATMENT EFFICACY OF THE LOW-ENERGY SHOCK WAVE THERAPY IN PATIENTS WITH VASCULAR ERECTILE DYSFUNCTION Aksonov, P.1; Gorpynchenko, I.1; Romaniuk, M.2 - Kiev, Ukraine 105 men with moderate to severe ED, randomized 52men (16 arter., 28 venous , 8 A-V ED) >> LESWT 53 men (17 arter., 25 venous, 11 A-V ED)>> LESWT + SILD (50 mg e.o.d. 8 w) treatment protocol one LESWT session/week during 8 weeks intensity was 0.09 mJ/mm2, a total of 5000 pulses on four segments.

78 18th ESSM Congress 2016- MadridPS ASSESSMENT OF THE TREATMENT EFFICACY OF THE LOW-ENERGY SHOCK WAVE THERAPY IN PATIENTS WITH VASCULAR ERECTILE DYSFUNCTION Aksonov, P.1; Gorpynchenko, I.1; Romaniuk, M.2 - Kiev, Ukraine arterial and A-V ED showed biggest changes of the IIEF and peak systolic velocity with combination therapy Arterial ED demonstrated more noticeable effect IIEF score improved by 62.58% (p=0.022) at the end of treatment , at 6 months by 38.61% (p=0.042),at 12 months by 29 96%(p=0.026), peak systolic velocity increased by % at the end of treatment (p= 0.022), after 6 months by 66.35%(p=0.037)). In the monotherapy group, changes were significant only in patients with arterial and arteriovenous ED only after 6 months of treatment

79 prospective, randomized, double-blind, sham controlled studyMay 2016, 195: 5, 1550–1555 Penile Low Intensity Shock Wave Treatment is Able to Shift PDE5i Nonresponders to Responders: A Double-Blind, Sham Controlled Study ND. Kitrey,  I Gruenwald∗, B Appel‡, A Shechter∗, O Massarwa∗, Yoram Vardi‡                           prospective, randomized, double-blind, sham controlled study vasculogenic erectile dysfunction who stopped using PDE5i due to no efficacy. All patients had an erection hardness score of 2 or less with PDE5i. 58 patients were randomized, 37 treated with LISW (12 sessions of 1,500 pulses of 0.09 mJ/mm2 at 120 shock waves per minute) 18 treated with a sham probe (16 pts underwent LISWT 1 month after sham treatment). All patients evaluated using the flow mediated dilatation technique for penile endothelial function.

80 EHS ≥3 54,1% 0% 56,3%* IIEF efficacy 40,5%May 2016, 195: 5, 1550–1555 Penile Low Intensity Shock Wave Treatment is Able to Shift PDE5i Nonresponders to Responders: A Double-Blind, Sham Controlled Study ND. Kitrey,  I Gruenwald∗, B Appel‡, A Shechter∗, O Massarwa∗, Yoram Vardi‡                           LISWT SHAM LISWT AFTER SHAM EHS ≥3 54,1% 0% 56,3%* p<0,0001 *P <0,005 IIEF efficacy 40,5%

81 1115: Low-intensity extracorporeal shock wave therapy for severe erectile dysfunction in poor responders to phosphodiesterase type-5 inhibitors: A short-term prospective study Zewin T., El-Assmy A., Harraz A., Elsherbini A., Musa Z., Bayoumi A., Al-Kenawy M., Sheir K., Shokeir A.

82 18th ESSM Congress 2016- MadridHP PENILE LOW-INTENSITY SHOCK WAVE THERAPY FOR ERECTILE DYSFUNCTION: PERSONAL EXPERIENCE Alei, G. ; Letizia, P. ; Rossi, A. ; De Marco, F. Rome, Italy 46 men, mean age 54 years, with mild to moderate vasculogenic ED who responded well to the use of PDE5i. treatment protocol: one treatment sessions per week for 6 weeks, a 6 -weeks no-treatment interval. Each session 3000 shock waves (energy intensity of 4 mJ/mm3) to each penile shaft and 1000 shock waves for each crura. 6 weeks after treatment, erectile function improved in the 85% of the case, good result in 10% and no results in 5% of the patients. average increase in the IIEF-EF domain score was 8.8 points NPT parameters and Penile blood flow improved significantly

83 (only systematic review or metanalysis)ERECTILE DYSFUNCTION HUMAN STUDIES (only systematic review or metanalysis)

84 Trattamento: < 6 sett-9 sett.14 studi paz. ( ) Inclusi solo 7 CRT DE vascolare, neurogena, DE+Peyronie, DE+dolore pelvico cronico Energia: mJ/mm2 SW/trattamento: Trattamento: < 6 sett-9 sett.

85 migliora IIEF (mean diff: 2.00 p<0.0001) Low-intensity Extracorporeal Shock Wave Treatment Improves Erectile Function: A Systematic Review and Meta-analysis Z Lu, G Lina, Reed-Maldonadoa, C Wangb, Y Leec and Tom F. Lue European Urology, published on line 2016 migliora IIEF (mean diff: p<0.0001) migliora EHS (risk differ: p=0.01) efficacia almeno 3 mesi DE lieve-moderata ha maggior beneficio

86 Escludendo ED+Peyronie (energia>0Escludendo ED+Peyronie (energia>0.2 mJ/mm2) IIEF migliore con energia 0.09mJ/mm2 vs 0.1–0.2mJ/mm2

87 migliore incremento IIEFMaggiore n° SW (MD: 2.86; p<0.0001) Trattam. <6 sett. (MD:2.11;p=0.0003) migliore incremento IIEF

88

89 7 CRT (SHAM) - 602 paz. (solo DE vascolare pura) >> LE 1aetà media 60,7 anni IIEF-EF basale 9,2 F-U 19,8 settimane (range 13-56) Vardi Y et al. J Urol 2012;187:1769– 75 Srini VS et alCan J Urol 2015;22:7614–22 Yee CH, et al. Int J Urol 2014;21:1041 Kitrey ND et al. J Urol 2016;195: Feldman R et al. J Urol 2015;193: Fojecki GT et al. Post. ESSM. December 2015; København Hatzichristou DG et al. Abst124 EAU, March 2015Madrid,

90 IIEF: Obiettivo primario SHOCK WAVES CRT 0,9 mJ/mm CRT IIEF: Obiettivo primario Omnispec ED1000 (Medispec Ltd, Yehud, Israele) 6 CRT Richard Wolf GmbH (Knittlingen, Germania) CRT Uno CRT che utilizzò Duolith SD1, (Storz, Switzerland) non venne incluso perchè non segnalato IIEF (richiesto agli autori) Olsen AB et al. Scand J Urol 2015;49:329–33

91

92 Forest plot of change in IIEF score

93 Subanalysis by total treatment shocks

94 Risultato della MetanalisiIIEF +6.40; (p<0.0001) SHAM punti; (p<0.0001) DIFF. TRA GRUPPI (p<0.0001) (trattamento attivo meno gruppo di controllo ) > 4 punti, (minima differenza clinicamente significativa) Rosen RC . Eur Urol 2011;60:

95 Uno dei sette CRT dimostrò un effetto positivo nettamente maggiore(paz. selezionati con Ecocolordoppler >> sicuramente affetti da DE vasculogenica) Srini VS. et al. Can J Urol 2015;22:7614–22

96 EAU GUIDELINES ON MALE SEXUAL DYSFUNCTIONK. Hatzimouratidis (Chair), F. Giuliano, I. Moncada, A. Muneer, A. Salonia (Vice-chair), P. Verze Guideline Associates: A. Parnham, E.C. Serefoglu (Limited text update March 2017) First line therapy Shockwave therapy The use of low-intensity extracorporeal shockwave therapy (LI-SWT) was proposed as a novel treatment for ED [ ]. …the number of studies of LI-SWT for ED has increased dramatically ……most of these studies reported encouraging results, regardless of variation in LI-SWT set-up parameters or treatment protocols. As a whole these studies suggest that LI-SWT could significantly improve the IIEF and Erection Hardness Score of ED pts[193]. The publication of robust evidence from additional RCTs and longer-term follow-up would provide more confidence regarding use of LI-SWT for ED patients. Therefore clear recommendations cannot be given.

97 CHE MACCHINE ABBIAMO?

98 LINEAR LISWT

99 AGADA’ MEDICAL TECHNOLOGIESMEDISPEC ED1000 AGADA’ MEDICAL TECHNOLOGIES FOCUSED LISWT DORNIER – ARIES ED STORZ MEDICAL DUOLITH® SD1 T-TOP

100 12 CENTRI ATTIVI IN ITALIA

101 The first “lithotripsy type” technologyfocalized at one point

102

103 What makes this system so unique?

104 Electrohydraulic Technology Electromagnetic TechnologyFocal Zone ESWL vs. ED Tripter Compact X-1 Stone Fragmentation 13 mm Electrohydraulic Technology Renova On the bottom of each diagram (under the numbers) please write Axial distance (cm). Under the top light blue box and on the right side of the light blue box, write 0,1,2,3,4,5,6,7, (spread out from each other). Under and on the side of the light blue box on bottom, write 0,1,2,3,4 (spread out from each other. LSWT ED Therapy Treatment area 70 mm Electromagnetic Technology

105 Second Generation: Line Focused Shockwave TherapyRenova is the first SW therapy device developed especially for ED treatment

106 LOW-INTENSITY SHOCKWAVES showesCONCLUSIONS LOW-INTENSITY SHOCKWAVES showes EFFICACY in pts with multiple co-morbidities, different degrees of response to PDE5i and wide range of ED severities NO SIDE EFFECTS NO ADVERSE EVENTS LONG TERM EFFICACY RECOVERY OF SEVERE ED possible alternative treatment for some of the PDE5i Non-responders EFFECTIVE HEALING OF ED eliminating the need for PDE5 inhibitors

107 DE vasculogenica – (neurogenica??)LISWT - INDICAZIONI DE vasculogenica – (neurogenica??) PREVENZIONE: segni iniziali di DE: per evitare il peggioramento o la necessità di assumere farmaci TERAPIA: DE responsiva ai PDE5I: per guarire o migliorare la disfunzione erettile TERAPIA: assunzione dei PDE5i impossibile: per effetti collaterali o per controindicazioni TERAPIA: DE non responsiva ai PDE5i e/o a farmaci per iniezione intracavernosa: per migliorare la disfunzione erettile e acquisire la risposta ai farmaci RIABILITAZIONE: dopo interventi di chirurgia pelvica: per minimizzare i danni vascolari verificatisi nella fase intraoperatoria o evitarne la comparsa nella fase postoperatoria e per stimolare la rigenerazione neuronale

108 NEED FOR FURTHER RESEARCHDISCUSSION NEED FOR FURTHER RESEARCH LISWT Linear vs Focused

109 NEED FOR FURTHER RESEARCHSW: number per session SW: number to crura/corpora SW: total number Schedule of treatment Frequence of session Additional treatment Repeated treatment

110 NEED FOR FURTHER RESEARCHmore successful results positive effect last longer useful for unsuccessfull pts useful for pts who lost successfull result ED following radical pelvic surgery Penile implant surgery (complementary erection)

111 “ Ad Esculapio e alla salute dedica Lucio Claudio Ermippo, che visse centoquindici anni e cinque giorni grazie al respiro di giovani donne, fra la sorpresa dei medici. Segua la tua vita l’esempio della sua”

112 GRAZIE PER L’ATTENZIONE