Stesura Seveso Archivio Italiano di Urologia e Andrologia 2024; 96(4):12956 1 CASE SERIES inevitably causes various types of penile deformation. Its prevalence ranges from 3.2% to 13.1% and is less common in Asian countries (0.6-5.0%) and among populations of black African descent (0.1-3.5%) (1-8). PD typically affects middle-aged men, but cases have increased among younger patients in recent years. In 2001, two authors reported the prevalence of PD in young people under the age of 40 as 1.5% and 4.8% (2, 9). Some authors have noted an increase in the incidence of PD in younger patients, with their study showing an 18.6% incidence in individuals under 40 compared with the 24.2% incidence found in our most recent study (10, 11). PD symptoms include penile deformity (in more than 90% of cases), penile pain (in between 20% and 70% of cases), erectile dysfunction (in over 30% of cases), and psychological distress, such as anx- iety and depression (in approximately 48% of cases) (12, 13). Penile deformities can manifest as curvature, shorten- ing, twisting, indentations, hourglass deformities, and in more severe cases, "flail penis". Traumatic theory appears to be the most widely accepted of the several etiopathogenetic hypotheses. According to this theory, the local accumulation of fibrin resulting from trauma (whether micro- or macro-trauma) is believed to initiate the disease process by triggering the production of free radicals (oxidative stress) and fibrogenic cytokines, leading to excessive collagen production and deposition (plaque) (14-22). The disease progresses in two phases: The inflammatory ("active") phase comes first, lasting for approximately 12-18 months, during which plaque for- mation and remodeling occur (23-30). Conservative med- ical therapy is recommended during this first phase. The second phase is the "stabilization" stage, wherein the dis- ease stops progressing, the plaque stops growing, and any pain usually subsides. Surgical treatment is recommended during this second phase if there is a severe penile defor- mity that hinders sexual intercourse or if severe erectile dysfunction is present (23, 24, 26, 27,30-34). The conservative medical treatment in the first phase of PD includes oral therapies, penile infiltrations, including vitamin E, colchicine, potaba, tamoxifen, pentoxifylline (PTX), bioactive food extracts with an antioxidant action (L-arginine, carnitine, propolis, bilberry, coenzyme Q10, etc.), non-steroidal anti-inflammatory drugs (NSAIDs), phos- phodiesterase 5 (PDE-5) inhibitors, penile infiltrations (ver- apamil, corticosteroids, interferon-α2b (IFNa2b), pentoxi- Introduction: Peyronie’s disease (PD) is char- acterized by fibrosis of the penile tunica albuginea. Conservative treatment options may involve oral and/or injectable medications. Materials and methods: This case series includes four patients with PD in the first phase. The diagnosis of PD included a med- ical history; penile palpation; a physical examination of the penis, documenting penile deformity (Kelâmi method); penile dynamic Doppler ultrasound (PDDU) + elastography, measur- ing the plaque and calculating its volume (cm3), and the defor- mation index (strain ratio); and the completion of the following questionnaires: IIEF to assess erectile function, VAS to assess pain, and Peyronie's Disease Questionnaire (PDQ) symptom bother to evaluate the psychosexual impact of the disease. Diagnostic follow-up evaluations were conducted before and every 6-12 months throughout the conservative treatment. The four patients were treated at our andrology clinic between January 2019 and November 2023. Our treatment included the following: bilberry, propolis, ginkgo biloba, silymarin, L-carni- tine, coenzime Q-10, Boswellia, superoxide dismutase, vitamin E, vitamin C, topical diclofenac gel, propolis cream, and peri- lesional penile injections with pentoxifylline for cases involving penile plaques with volumes of > 0.100 cm3. Results: Complete resorption of the PD plaque after treatment occurred in all cases. The disappearance of Peyronie's plaque occurred over a period ranging from 18 to 36 months, in rela- tion to the volume of the plaque. Conclusions: Despite the limited sample size in our study, these patients verifiably achieved the complete resorption of the affected disease area. Our results will provide useful insights for uroandrological clinical practice. Nevertheless, randomized con- trolled trials with a larger number of PD patients are needed to demonstrate the effectiveness of multimodal antioxidant treat- ment. KEY WORDS: Peyronie’s disease; Oxidative stress; Antioxidants; Pentoxifylline. Submitted 26 August 2024; Accepted 2 September 2024 INTRODUCTION PD is a genetically based chronic inflammatory condition that affects the tunica albuginea of the penile corpora cav- ernosa in genetically predisposed males, leading to the for- mation of an inelastic and fibrous penile plaque that Healing of Peyronie's disease after multimodal antioxidant treatment. A case series Gianni Paulis 1, Giovanni De Giorgio 2, Andrea Paulis 3 1 Department of Urology and Andrology, Peyronie’s Care Center, Castelfidardo Clinical Analysis Center, Rome, Italy; 2 Department of Urology and Andrology, Section of Ultrasound Diagnostics, Castelfidardo Clinical Analysis Center, Rome, Italy; 3 Bambino Gesù Children’s Hospital, IRCCS (Istituti di Ricovero e Cura a Carattere Scientifico), Rome, Italy. DOI: 10.4081/aiua.2024.12956 Summary Archivio Italiano di Urologia e Andrologia 2024; 96(4):12956 G. Paulis, G. De Giorgio, A. Paulis 2 fylline (PTX), hyaluronic acid, and clostridium histolyticum collagenase (CCH) (26, 33, 35-40). The physical treatment in the first phase of PD includes extracorporeal shock wave therapy (ESWT), iontophoresis, and penile traction and vacuum devices (26, 33, 59, 60). Surgical treatments for PD are targeted to each patient's specific needs and may include corporoplasty, with or without grafts, and the possible insertion of a penile pros- thesis (28, 31, 32, 34, 36, 41). PD diagnostics involves penile palpations, photographic documentation of the deformation (according to the Kelâmi guidelines), penile dynamic Doppler ultrasound (PDDU), and the completion of questionnaires for pain (VAS), erectile function (IIEF), and psychometric evaluations like the Peyronie's Disease Questionnaire (PDQ) (10, 42-47). The scientific literature reports eleven human patients with PD who have recovered following medical treatment with antioxidants (48-51). Cases of PD resolution have been published before, but only in experimental studies in rats (52-54). The scientific literature has always reported the possibility of the spontaneous resolution of PD (31, 55-57). However, some studies do not agree with this pos- sibility (58-59). We believe that treating oxidative stress (a key mechanism of inflammation) with antioxidants is the best therapeutic approach to treat PD (35, 60-62). Multimodal treatment aims to achieve superior outcomes compared with using a single substance or therapy alone. All the antioxidants we use have anti-inflammatory and antifibrotic properties by blocking the activity of the NF-kB factor. In our multimodal treatment, we have also used NSAID (diclofenac), although administered locally to avoid possible long-term toxic effects due to oral administration (63, 64). This case report aimed to present four cases of patients with PD who experienced plaque regression following “multimodal” antioxidant therapy (with oral antioxidants, topical diclofenac gel, and penile perilesional injections with 60 mg of pentoxifylline). Our recent four articles have shown that the duration of multimodal treatment needed to regress Peyronie's plaque directly depends on the plaque's size (48-51). Therefore, larger plaques require a relatively longer time to completely regress. In our recent case report, a patient with PD achieved complete plaque regression in just four months of combined antioxidant therapy, as his plaque was small (51). METHODS This case series includes four cases of patients with PD in the first phase who experienced the plaque's disappear- ance following "multimodal" antioxidant therapy includ- ing various oral antioxidants, topical diclofenac gel and propolis cream, and penile perilesional injections with a potent antioxidant and antifibrotic substance, pentoxi- fylline, specifically for cases involving penile plaques with volumes of > 0.100 cm3. The complete list of antioxidant substances used is shown in the following tables 1, 2, 3, and 4. The diagnosis of PD included a detailed medical history; penile palpation; a physical examination of the penis, documenting penile deformity using the Kelâmi method and measuring the angulation; penile dynamic Doppler ultrasound (PDDU) + elastography, measuring the plaque in three dimensions and calculating its volume (cm3) using the ellipsoid for- mula (volume = 0.524 × length × width × thickness) and the deformation index (strain ratio); and the completion of the following questionnaires: IIEF to assess erectile function, VAS to assess pain, and the Questionnaire (PDQ symptom bother) to evaluate the psychosexual impact of the disease (10, 42-47, 65, 66). The strain ratio (or deformation index), indicating the plaque's stiffness was detected via echo-elastography. The strain ratio, expressed as a number, represents the ratio between the stiffness of the pathological tissue (plaque) and that of the adjacent normal tissue. The four patients were treated at our andrology clinic between January 2019 and November 2023. All patients signed an informed consent form for the multimodal treatment. During the consent process, patients were informed that the treatment for PD would be lengthy due to the chronic nature of the disease. The patients also agreed to the publication of their clinical data, provided that they be published anonymously. All these patients did not consent to the publication of photos of their penises, even though they would have been pub- lished anonymously. A single andrologist operator performed and assessed PDDU with elastography on all patients in a single session. We used the Philips HD 15 machine (Washington, United States) that was later upgraded to a Philips Affinity 70 G (Washington, United States). In each of the 4 cases described, we reported the type of ultrasound machine used. Diagnostic follow-up evaluations were conducted before and approximately every 6-12 months throughout the conservative treatment. RESULTS Case series presentation In each case presented, several treatment cycles combined with antioxidants were necessary before reaching com- plete plaque reabsorption. We describe the four individ- ual cases in detail, with their personal clinical character- istics present before and at the end of treatment when the therapeutic goal was achieved. A table listing the individ- ual variations obtained after each treatment cycle is included for each clinical case presentation. Case 1 Case 1 was a 57-year-old Caucasian man, a non-smoker, suffering from chronic prostatitis, with the presence at the origin of a congenital penile curvature (dorsal of 25 degrees, left lateral of 5 degrees, and right lateral of 5 degrees), before the appearance of PD. The patient did not report any trau- matic events involving his penis in the previous 6-12 months. He reported that he had started to notice a penile curvature, different from usual, approximately 6-8 months earlier. At the time of our visit, the patient did not report any penile pain (VAS score = 0) nor complained of erectile dys- function. The IIEF score was 26. The PDQ symptom both- er score was 11. In our observations, the penile deformation presented as a multiplanar curve, with a significantly reduced penile diameter in its distal third. The goniometric Archivio Italiano di Urologia e Andrologia 2024; 96(4):12956 3 Multimodal antioxidant treatment of Peyronie's disease Table 1. Case 1: clinical data collected before, during, and after antioxidant treatment. Ultrasound measurements Plaque strain ratio Dorsal curve of 41 degrees VAS IIEF PDQ bother a right lateral curve score score score of 17 degrees, and a left lateral curve of 17 degrees Basal plaque: Basal plaque = 1.8 0 26 11 12.1 × 10.4 × 4.23 mm (volume = 0.279 cm3 Distal plaque: Distal plaque = 2.53 24.0 × 29.3 × 4.35 mm with two internal calcifications measuring 5.2 × 9.3 mm and 5.0 × 8.0 mm (volume = 1.60 cm3) Total volume of the two plaques = 1.879 cm3 First cycle Orally: L-carnitine 1000 mg + Propolis 700 mg + Ginkgo biloba 240 mg of multimodal treatment with antioxidants + Bilberry 180 mg + Coenzyme Q-10 100 mg + Silymarin 400 mg (6 months) + Boswellia 200 mg + Vitamin C 50 mg + Vitamin E 48 mg + Superoxide dismutase 11000 IU/g 10 mg/daily/for 6 months; + Topically: Propolis cream/2 x daily + Diclofenac gel 4%/daily/for 6 months; + Peri-lesional penile injections: Pentoxifylline 60 mg (with 30 G needle) every 2 weeks for 6 months. Ultrasound measurements Plaque strain ratio Dorsal curve of 33 degrees VAS IIEF PDQ bother a right lateral curve score score score of 17 degrees, and a left lateral curve of 17 degrees Basal plaque: Basal plaque = 1.6 0 26 8 8.72 × 6.85 × 2.80 mm (volume = 0.087 cm3) Distal plaque: Distal plaque = 2.21 17.6 × 17.1 × 2.91 mm with internal calcification measuring 3.3 x 2.4 mm (volume = 0.458 cm3) The other internal calcification was no longer detectable The total volume of the two plaques = 0.545 cm3 After the first treatment cycle, the total volume of the two plaques decreased by 70.9% compared with the initial situation Second cycle Orally: L-carnitine 1000 mg + Propolis 700 mg + Ginkgo biloba 240 mg of multimodal treatment with antioxidants + Bilberry 180 mg + Coenzyme Q-10 100 mg + Silymarin 400 mg (12 months) + Boswellia 200 mg + Vitamin C 50 mg + Vitamin E 48 mg + Superoxide dismutase 11000 IU/g 10 mg/daily/for 12 months; + Topically: Propolis cream/2 x daily + Diclofenac gel 4%/daily/for 12 months; + Peri-lesional penile injections: Pentoxifylline 60 mg (with 30 G needle) every month for 12 months. Ultrasound measurements Plaque strain ratio Dorsal curve of 33 degrees, VAS IIEF PDQ bother a right lateral curve score score score of 7 degrees, and a left lateral curve of 7 degrees Basal plaque: Basal plaque = 1.2 0 27 4 4.4 × 4.52 × 2.13 mm (volume = 0.022 cm3) Distal plaque: Distal plaque = 1.53 9.91 × 8.5 × 2.14 mm with internal calcification measuring 2.8 x 1.6 mm (volume = 0.094 cm3) Total volume of the two plaques = 0.116 cm3 After the second treatment cycle, the total volume of the two plaques decreased by 93.8% compared with the initial situation Third cycle Orally: L-Carnitine 1000 mg + Propolis 700 mg + Ginkgo biloba 240 mg of multimodal treatment with antioxidants + Bilberry 180 mg + Coenzyme Q-10 100 mg + Silymarin 400 mg (18 months) + Boswellia 200 mg + Vitamin-C 50 mg + Vitamin-E 48 mg + Superoxide dismutase 11000 IU/g 10 mg/daily/for 6 months; + Topically: Propolis cream/2 x daily + Diclofenac gel 4%/daily/for 18 months; + Peri-lesional penile injections: Pentoxifylline 60 mg (with 30 G needle), 1 penile injection every 2 months for 12 months Penile plaques were no longer detectable Absence of non-elastic After the regression Total therapy duration until plaque’s disappearance = 30 months penile areas of the plaques, the same penile congenital condition that preceded PD was present, with a dorsal curve of 10 degrees VAS = visual analog scale, a pain measurement questionnaire (score range: 0-10) (45); IIEF = International Index of Erectile Function, a questionnaire for assessing erectile function with a score range of 0-30, indicating different ED severity levels (no ED, score range: 26-30) (46); PDQ symptom bother = PD Questionnaire symptom bother for evaluating the psychosexual impact, with a score range of 0-30 (10, 47, 66). The strain ratio (deformation index), detected via echo-elastography, indicates the plaque's stiffness (65). It is expressed as a number, representing the ratio between the stiffness of the pathological tissue (plaque) and that of the adjacent normal tissue. When elastography does not detect any anelastic area (plaque), the strain ratio index corresponds to 1. In this case, the image displayed on the ultrasound machine screen does not show any index. Archivio Italiano di Urologia e Andrologia 2024; 96(4):12956 G. Paulis, G. De Giorgio, A. Paulis 4 measurements showed a dorsal curve of 41 degrees, a right lateral curve of 17 degrees, and a left lateral curve of 17 degrees. Upon palpation, two basal and distal penile plaques of approximately 10 mm and 20 mm in length were detected, respectively, both with a fibrous consistency. Two plaques were present in the penile eco-elastography exami- nation. The first penile plaque was located in the basal third and measured 12.1 × 10.4 × 4.23 mm (volume = 0.279 cm3), while the second plaque was located in the distal third and measured 24.0 × 29.3 × 4.35 mm (volume = 1.60 cm3). Two calcifications in the second plaque measured 5.2 × 9.3 mm and 5.0 × 8.0 mm. The total volume of the two plaques was 1.879 cm3. The ultrasound appearance of the basal plaque was iso-hyperechoic, and that of the distal plaque was iso-hyperechoic-calcific. The strain ratios of the two basal and distal penile plaques were 1.8 and 2.53, respectively. The cavernous arteries showed a normal arterial flow and end-diastolic velocity in the PDDU examination (with a penile injection of 10 mcg of alprostadil). The patient then underwent multimodal therapy with antioxidants. The complete list of antioxidant substances in the multimodal treatment administered to the patient, alongside the pre-treatment clinical data and those related to each subsequent follow-up after the three treatment cycles, is shown in Table 1. After completing the third cycle of six perilesional penile injections with 60 mg of pentoxifylline (every 2 months), the patient delayed the scheduled follow-up after 12 months and continued oral and local home therapy for an additional 6 months. The follow-up was then performed 18 months after the last check-up. Images of the ultrasound examination before, during, and after treatment are pre- sented in Figure 1. After three treatment cycles, totaling 36 months of multimodal antioxidant therapy, the patient underwent a complete follow-up, and no penile nodules were palpable. No plaque was detected in the ultrasound exam- ination. The patient did not report any penile pain (VAS score = 0) nor complained of erectile dysfunction. The IIEF score was 27. The PDQ symptom bother score was four. The patient had an excellent psychological state, and the penis's appearance was compa- rable to the condition before PD (congenital curvature of the penis), The patient expressed satisfaction with the excellent results achieved at the end of our treatment. Case 2 A 48-year-old Caucasian man, a non-smok- er, reported that he had suffered from pro- statitis in the past but had no related symp- toms at the time of the visit. The patient reported that he already had a congenital penile curvature before the onset of PD. The congenital penile deformity consisted of a mild dorsal curvature of 10 degrees. The patient did not report any traumatic events involving his penis in the previous 6- 12 months. He reported that he had started to notice a penile curvature, different from usual, approximately 9 months earlier. The patient did not report any penile pain (VAS score = 0) nor complained of erectile dys- function at the time of our visit. The IIEF score was 27. The PDQ symptom bother score was 10. In our observation, the penile deformation presented with a dorsal curve of 45 degrees. Upon palpation, two plaques were detected at the basal third level and the distal level of the penis, approximately 10 Figure 1. Images of the ultrasound exam (longitudinal and transverse scan) are shown before (A), during (B) and (C), and after multimodal treatment (D). Archivio Italiano di Urologia e Andrologia 2024; 96(4):12956 5 Multimodal antioxidant treatment of Peyronie's disease mm and 15 mm in length, respectively. Both plaques had a fibrous consistency. Two plaques were present in the penile eco-elastography examination. The first penile plaque was located at the basal third and measured 9.28 × 10.9 × 3.99 mm (volume = 0.212 cm3), while the second plaque was located in the distal third and measured 14.3 × 11.7 × 2.86 mm (volume = 0.252 cm3). The total volume of the two plaques was 0.464 cm3. The ultrasound appearance of the two plaques was iso-hyperechoic. The strain ratios of the two basal and distal penile plaques were 2.1 and 1.89, respectively. The cavernous arteries exhibited a normal arterial flow and end-diastolic velocity in the PDDU exam- ination (a penile injection of 10 mcg of alprostadil). The patient then underwent multimodal therapy with antioxi- dants. However, the patient did not consent to the publi- cation of photos of his penis, even if published anony- mously. Table 2 displays the full list of antioxidant substances Table 2. Case 2: clinical data collected before, during, and after antioxidant treatment. Ultrasound measurements Plaque strain ratio Dorsal curve of VAS IIEF PDQ bother 45 degrees score score score Basal plaque: Basal plaque = 2.1 0 27 10 9.28 × 10.9 × 3.99 mm (volume = 0.212 cm3) Distal plaque: Distal plaque = 1.89 14.3 × 11.7 × 2.86 mm (volume = 0.252 cm3) Total volume of the two plaques = 0.464 cm3 First cycle Orally: L-carnitine 1000 mg + Propolis 700 mg + Ginkgo biloba 240 mg of multimodal treatment with antioxidants + Bilberry 180 mg + Coenzyme Q-10 100 mg + Silymarin 400 mg (6 months) + Boswellia 200 mg + Vitamin C 50 mg + Vitamin E 48 mg + Superoxide dismutase 11000 IU/g 10 mg/daily/for 6 months; + Topically: Propolis cream/2 x daily + Diclofenac gel 4%/daily/for 6 months; + Peri-lesional penile injections: Pentoxifylline 60 mg (with 30 G needle) every 2 weeks for 6 months. Ultrasound measurements Plaque strain ratio Dorsal curve of VAS IIEF PDQ bother 42 degrees score score score Basal plaque: Basal plaque = 1.87 0 27 6 5.54 × 7.65 × 3.24 mm (volume = 0.072 cm3) Distal plaque: Distal plaque = 1.69 7.9 × 6.14 × 2.65 mm (volume = 0.067cm3) Total volume of the two plaques = 0.139 cm3 After the first treatment cycle, the total volume of the two plaques decreased by 70% compared with the initial situation Second cycle Orally: L-carnitine 1000 mg + Propolis 700 mg + Ginkgo biloba 240 mg of multimodal treatment with antioxidants + Bilberry 180 mg + Coenzyme Q-10 100 mg + Silymarin 400 mg (12 months) + Boswellia 200 mg + Vitamin C 50 mg + Vitamin E 48 mg + Superoxide dismutase 11000 IU/g 10 mg/daily/for 12 months; + Topically: Propolis cream/2 x daily + Diclofenac gel 4%/daily/for 12 months; + Peri-lesional penile injections: Pentoxifylline 60 mg (with 30 G needle) every month for 12 months. Ultrasound measurements Plaque strain ratio Dorsal curve of VAS IIEF PDQ bother 42 degrees score score score Basal plaque: Basal plaque = 1.62 0 27 4 2.89 × 3.34 × 1.88 mm (volume = 0.010 cm3) Distal plaque: Distal plaque = 1.26 3.2 × 3.14 × 2.7 mm (volume = 0.014 cm3) Total volume of the two plaques = 0.024 cm3 After the second treatment cycle, the total volume of the two plaques decreased by 94.8% compared with the initial situation Third cycle Orally: L-Carnitine 1000 mg + Propolis 700 mg + Ginkgo biloba 240 mg of multimodal treatment with antioxidants + Bilberry 180 mg + Coenzyme Q-10 100 mg + Silymarin 400 mg (12 months) + Boswellia 200 mg + Vitamin-C 50 mg + Vitamin-E 48 mg + Superoxide dismutase 11000 IU/g 10 mg/daily/for 6 months; + Topically: Propolis cream/2 x daily + Diclofenac gel 4%/daily/for 12 months. Penile plaques were no longer detectable Absence of non-elastic After the regression Total therapy duration until plaque’s disappearance = 30 months penile areas of the plaques, the same penile congenital condition that preceded PD was present, with a dorsal curve of 10 degrees VAS = visual analog scale, a pain measurement questionnaire (score range: 0-10) (45); IIEF = International Index of Erectile Function, a questionnaire for assessing erectile function with a score range of 0-30, indicating different ED severity levels (no ED, score range: 26-30) (46); PDQ symptom bother = PD Questionnaire symptom bother for evaluating the psychosexual impact, with a score range of 0-30 (10, 47, 66). The strain ratio (deformation index), detected via echo-elastography, indicates the plaque's stiffness (65). It is expressed as a number, representing the ratio between the stiffness of the pathological tissue (plaque) and that of the adjacent normal tissue. When elastography does not detect any anelastic area (plaque), the strain ratio index corresponds to 1. In this case, the image displayed on the ultrasound machine screen does not show any index. Archivio Italiano di Urologia e Andrologia 2024; 96(4):12956 G. Paulis, G. De Giorgio, A. Paulis 6 included in the multimodal treatment given to the patient, alongside the clinical data before treatment and at each fol- low-up after the treatment cycles. The images from the ultrasound examination before, dur- ing, and after treatment are presented in Figure 2. After undergoing three cycles of treatment, which lasted a total of 30 months, the patient had a comprehensive fol- low-up assessment that revealed no palpable penile nod- ules. The ultrasound examination did not detect any plaque. The patient did not report any penile pain (VAS score = 0) nor complained of erectile dysfunction, the IIEF score was 27. The PDQ symptom bother score was four. The patient's psychological well-being was excellent, and the penis's appearance was similar to its pre-PD state (a congenital dorsal curvature of the penis of 10 degrees). The patient expressed satisfaction with the outstanding results obtained after completing our antioxidant treatment. Case 3 A 42-year-old Caucasian man, a non-smoker, reported having fibromyalgia. The patient mentioned experiencing a traumatic event to his penis during sexual intercourse approximately 4 months before. He noticed a slight dorsal curvature of the penis under the glans, at the distal third of the penis, approximately 2 months ago. He also report- ed feeling pain in the penis during erection and sometimes at rest for the past 2 months. During the visit, the patient reported penile pain during erection (VAS score = 5) but did not mention erectile dysfunction. His IIEF score was 26, and the PDQ symptom bother score was 14. The penile deformity observed was a 20-degree sub-glandular dorsal curve. No penile plaque was detected upon palpa- tion. A plaque was detected in the penile echo- elastography examination. The plaque was located in the distal third of the penis and measured 6.49 × 4.52 × 2.79 mm (volume = 0.043 cm3). The ultrasound appearance of the plaque was isoechoic with mild hypere- chogenicity in its distal portion. The plaque strain ratio was 1.8. The cavernous arteries showed normal arterial flows and end-dias- tolic velocities during the PDDU examina- tion (a penile injection of 10 mcg of alprostadil). The patient underwent multi- modal therapy with antioxidants but with- out penile injections of pentoxifylline due to the plaque's small size. Table 3 shows the complete list of antioxidant substances included in the multimodal treatment administered to the patient, alongside the clinical data before treatment and at each fol- low-up after the treatment cycles. The images from the ultrasound examina- tion before, during, and after treatment are presented in Figure 3. After undergoing three cycles of treatment, which lasted a total of 18 months, the patient had a comprehensive follow-up assessment that revealed no palpable penile nodules. The ultrasound examination did not detect any plaque, the patient did not complain of penile pain (VAS score = 0), and the IIEF score was 27. The PDQ symptom bother score was four. The patient's psycho- logical state was excellent, and no curvature of the penis was noticeable during the erec- tile phase. The patient expressed satisfaction with the outstanding results obtained after completing the antioxidant treatment. Figure 2. The images from the ultrasound examination (longitudinal and transverse scans) are shown in sequence: before (A), during (B) and (C), and after (D) the multimodal treatment. Archivio Italiano di Urologia e Andrologia 2024; 96(4):12956 7 Multimodal antioxidant treatment of Peyronie's disease Figure 3. The images from the ultrasound examination (longitudinal and transverse scans) are shown in sequence: before (A), during (B) and (C), and after (D) the multimodal treatment. Table 3. Case 3: clinical data collected before, during, and after antioxidant treatment. Distal plaque ultrasound measurements: Plaque strain ratio Dorsal curve VAS IIEF PDQ bother 6.49 × 4.52 × 2.79 mm (volume = 0.043 cm3) score score score 1.8 20 degree 5 26 14 First cycle Orally: L-carnitine 1000 mg + propolis 700 mg + Ginkgo biloba 240 mg of multimodal treatment with antioxidants + bilberry 180 mg + coenzyme Q-10 100 mg + silymarin 400 mg (6 months) + Boswellia 200 mg + vitamin C 50 mg + vitamin E 48 mg + superoxide dismutase 11000 IU/g 10 mg/daily/for 6 months; + topically: propolis cream/2 x daily + diclofenac gel 4%/daily/for 6 months; Distal plaque ultrasound measurements: Plaque strain ratio Dorsal curve VAS IIEF PDQ bother 5.14 × 3.8 × 2.01 mm (volume = 0.021 cm3) score score score 1.62 8 degree 3 27 10 After the first treatment cycle, the total volume of the two plaques decreased by 51.1% compared with the initial situation Second cycle Orally: L-carnitine 1000 mg + propolis 700 mg + Ginkgo biloba 240 mg of multimodal treatment with antioxidants + bilberry 180 mg + coenzyme Q-10 100 mg + silymarin 400 mg (12 months) + Boswellia 200 mg + vitamin C 50 mg + vitamin E 48 mg + superoxide dismutase 11000 IU/g 10 mg/daily/for 6 months; + topically: propolis cream/2 x daily + diclofenac gel 4%/daily/for 6 months Distal plaque ultrasound measurements: Plaque strain ratio Dorsal curve VAS IIEF PDQ bother 3.41 × 3.41 × 1.84 mm (volume = 0.011 cm3) score score score 1.2 5 degree 0 27 4 After the first treatment cycle, the total volume of the two plaques decreased by 74.4% compared with the initial situation Third cycle orally: L-Carnitine 1000 mg + Propolis 700 mg + Ginkgo biloba 240 mg of multimodal treatment with antioxidants + Bilberry 180 mg + Coenzyme Q-10 100 mg + Silymarin 400 mg (6 months) + Boswellia 200 mg + Vitamin-C 50 mg + Vitamin-E 48 mg + superoxide dismutase 11000 IU/g 10 mg/daily/for 6 months; + topically: Propolis cream/2 x daily + Diclofenac gel 4%/daily/for 6 months Penile plaques was no longer detectable Absence of non-elastic Absence of VAS IIEF PDQ bother Total therapy duration until plaque’s disappearance = 18 months penile areas penile curvature score score score 0 27 4 VAS = visual analog scale, a pain measurement questionnaire (score range: 0-10) (45); IIEF = International Index of Erectile Function, a questionnaire for assessing erectile function with a score range of 0-30, indicating different ED severity levels (no ED, score range: 26-30) (46); PDQ symptom bother = PD Questionnaire symptom bother for evaluating the psychosexual impact, with a score range of 0-30 (10, 47, 66). The strain ratio (deformation index), detected via echo-elastography, indicates the plaque's stiffness (65). It is expressed as a number, representing the ratio between the stiffness of the pathological tissue (plaque) and that of the adjacent normal tissue. When elastography does not detect any anelastic area (plaque), the strain ratio index corresponds to 1. In this case, the image displayed on the ultrasound machine screen does not show any index. Archivio Italiano di Urologia e Andrologia 2024; 96(4):12956 G. Paulis, G. De Giorgio, A. Paulis 8 Case 4 A 47-year-old Caucasian man, a non-smoker, reported having irritable bowel syndrome. He reported that he had been suffering from erectile dysfunction for approximate- ly 10 years. The patient had been taking a 10 mg tadalafil tablet before sexual intercourse for this disorder for sev- eral years. The patient did not remember any traumatic event involv- ing his penis. He reported noticing the appearance of penile deformity and penile pain during erection for approximately 9 months. Upon penile examination, a 15 mm long nodule with a fibrous consistency was palpable. The VAS score was three. The patient’s IIEF score was 20, and the PDQ symptom bother score was 15. The penile deformity observed consisted of a 30-degree dorsal curva- ture of the penis associated with another curvature to the left of the same degree. The middle third level of the penile shaft had an “hourglass” appearance. A plaque was detect- ed in the penile echo-elastography examination in the middle third of the penis and measured 18.8 × 15.8 × 3.42 mm (volume = 0.532 cm3). The ultrasound appearance of the plaque was iso-hyperechoic. The plaque strain ratio was 2.3. In the PDDU examination (a penile injection of 10 mcg of alprostadil), the cavernous arteries showed nor- mal arterial flows, while the end-diastolic speeds were high (12.2 cm/s on the right; 10.6 cm/s on the left), indi- cating veno-occlusive insufficiency. The patient underwent multimodal therapy with antioxidants, including periodic perilesional penile injections with 60 mg of pentoxifylline. However, we allowed the patient to continue taking one 10 mg tadalafil tablet before sexual intercourse. Table 4 shows the complete list of antioxidant substances included in the multimodal treatment administered to the patient, alongside the clinical data before treatment and at each follow-up after the treatment cycles. The images from the ultrasound examination before, dur- ing, and after treatment are presented in Figure 4. After completing three treatment cycles over 30 months, the patient underwent a thorough follow-up evaluation that showed no palpable penile nodules. An ultrasound examination also did not find any plaque. During the PDDU examination (a penile injection of 10 mcg of alprostadil), the cavernous arteries showed normal arterial flows, while the end-diastolic velocities remained elevated Table 4. Case 4: clinical data collected before, during, and after antioxidant treatment. Plaque on the penile mid-shaft Plaque strain ratio A dorsal curve of 30 degrees VAS IIEF PDQ bother Ultrasound measurements: and a left lateral curve score score score 18.8 × 15.8 × 3.42 mm (volume = 0.532 cm3) 2.3 of 30 degrees 3 20 15 First cycle Orally: L-carnitine 1000 mg + Propolis 700 mg + Ginkgo biloba 240 mg of multimodal treatment with antioxidants + Bilberry 180 mg + Coenzyme Q-10 100 mg + Silymarin 400 mg (6 months) + Boswellia 200 mg + Vitamin C 50 mg + Vitamin E 48 mg + Superoxide dismutase 11000 IU/g 10 mg/daily/for 6 months; + Topically: Propolis cream/2 x daily + Diclofenac gel 4%/daily/for 6 months; + Peri-lesional penile injections: Pentoxifylline 60 mg (with 30 G needle) every 2 weeks for 6 months Plaque on the penile mid-shaft Plaque strain ratio A dorsal curve of 20 degrees VAS IIEF PDQ bother Ultrasound measurements: and a left lateral curve score score score 8.89 × 6.97 × 3.28 mm (volume = 0.106 cm3) 1.7 of 20 degrees 1 22 12 After the first treatment cycle, the total volume of the two plaques decreased by 80.0% compared with the initial situation Second cycle Orally: L-carnitine 1000 mg + Propolis 700 mg + Ginkgo biloba 240 mg of multimodal treatment with antioxidants + Bilberry 180 mg + Coenzyme Q-10 100 mg + Silymarin 400 mg (12 months) + Boswellia 200 mg + Vitamin C 50 mg + Vitamin E 48 mg + Superoxide dismutase 11000 IU/g 10 mg/daily/for 12 months; + Topically: Propolis cream/2 x daily + Diclofenac gel 4%/daily/for 12 months + Peri-lesional penile injections: Pentoxifylline 60 mg (with 30 G needle) every 2 weeks for 12 months Plaque on the penile mid-shaft Plaque strain ratio A dorsal curve of 12 degrees VAS IIEF PDQ bother Ultrasound measurements: and a left lateral curve score score score 4.31 × 3.27 × 2.42 mm (volume = 0.018 cm3) 1.1 of 10 degrees 0 22 8 After the first treatment cycle, the total volume of the two plaques decreased by 96.6% compared with the initial situation Third cycle Orally: L-Carnitine 1000 mg + Propolis 700 mg + Ginkgo biloba 240 mg of multimodal treatment with antioxidants + Bilberry 180 mg + Coenzyme Q-10 100 mg + Silymarin 400 mg (12 months) + Boswellia 200 mg + Vitamin-C 50 mg + Vitamin-E 48 mg + Superoxide dismutase 11000 IU/g 10 mg/daily/for 6 months; + Topically: Propolis cream/2 x daily + Diclofenac gel 4%/daily/for 18 months Penile plaques was no longer detectable Absence of non-elastic A dorsal curve of 10 degrees VAS IIEF PDQ bother Total therapy duration until plaque’s disappearance = 30 months penile areas and a left lateral curve score score score of 5 degrees 0 22 6 VAS = visual analog scale, a pain measurement questionnaire (score range: 0-10) (45)); IIEF = International Index of Erectile Function, a questionnaire for assessing erectile function with a score range of 0-30, indicating different ED severity levels (no ED, score range: 26-30) (46); PDQ symptom bother = PD Questionnaire symptom bother for evaluating the psychosexual impact, with a score range of 0-30 (10, 47, 66). The strain ratio (deformation index), detected via echo-elastography, indicates the plaque's stiffness (65). It is expressed as a number, representing the ratio between the stiffness of the pathological tissue (plaque) and that of the adjacent normal tissue. When elastography does not detect any anelastic area (plaque), the strain ratio index corresponds to 1. In this case, the image displayed on the ultrasound machine screen does not show any index. Archivio Italiano di Urologia e Andrologia 2024; 96(4):12956 9 Multimodal antioxidant treatment of Peyronie's disease (8.8 cm/s on the right; 8.6 cm/s on the left), indicating per- sistent occlusive insufficiency, albeit modestly improved after our treatments. The IIEF score was 22, while it was 20 before our treatment. Erectile dysfunction was moderately improved because, initially, the plaque likely deprived the penis of a portion of functioning erectile tissue. The patient did not report any penile pain (VAS score = 0). After the plaque completely regressed, we observed a residual penile deformity characterized by a dorsal curve of 10 degrees and a left lateral curve of 5 degrees. Before our treatment, the initial penile deformity consisted of a dorsal curve of 30 degrees and a left lateral curve of 30 degrees. The PDQ symptom bother score was four. The patient's psychological state had certainly improved com- pared with pre-treatment; however, the erectile dysfunc- tion still caused some concern for the patient. The patient reported that the slight residual penile deformation no longer worried him. The patient was pleased with the good results achieved after finishing the antioxidant treat- ment. Complete resorption of the PD plaque after treatment occurred in all cases. The disappearance of Peyronie's plaque occurred over a period ranging from 18 to 36 months, in relation to the volume of the plaque. DISCUSSION The scientific literature has documented eleven PD human patients who have recovered following medical treatment with bioactive food extracts with antioxidant properties (48-51). All 11 cases already published that had achieved complete plaque reabsorption after antioxi- dant treatment involved men in the first phase of PD. Before these experiences, cases of PD healing had been published, but these were experimental studies on rats in which PD-like plaques were induced with solutions of human fibrin and thrombin or with transforming growth factor-b1 (52-54). Before these healing experiences, the scientific literature had always reported the possible spontaneous resolution of the disease in 3.2-13% of cases, as expression of the natural history of PD (31, 55-57). However, some of these studies were not based on instrumental exams but on patient self-reports via questionnaires. Like other authors with extensive experience in this disease, we believe PD cannot resolve spontaneously (58, 59). In a study pub- lished in 2013, we demonstrated that penile curvature can improve without the disease regressing. Without treatment, Peyronie's plaque in its progression can extend to the contralateral side of the curve and cause a reduc- tion in the elasticity of the cavernous tissue, resulting in a paradoxical improvement of the penile curvature (29). Numerous articles in the scientific literature on PD con- sider surgical treatment the "gold standard" and the ideal and definitive therapeutic option. Unfortunately, these considerations have led most uroandrologists to believe that PD is an incurable disease, resulting in a widespread pessimistic attitude and resistance to medical therapy for PD. On the contrary, we have always believed that since PD is related to chronic inflammation, the best treatment would be to treat this disease like any other chronic inflammatory disease. Long-term treatment of PD patients with NSAIDs, corti- costeroids, or other drugs can lead to chronic damage or toxicity in organs such as the liver, kidneys, immune sys- tem, and gastrointestinal system. Therefore, we have Figure 4. The images of the ultrasound examination (longitudinal and transverse scans) are shown in sequence: before (A), during (B) and (C), and after (D) the multimodal treatment. Archivio Italiano di Urologia e Andrologia 2024; 96(4):12956 G. Paulis, G. De Giorgio, A. Paulis 10 always believed that targeting oxidative stress, a key mechanism in inflammation, with antioxidants is the best therapeutic approach for interrupting the inflammatory process of this disease (35, 60-62). Although antioxidants are not included in the current EAU European Association of Urology (EAU) and American Urological Association (AUA) guidelines for treating PD, three randomized stud- ies in the literature have discussed the use of antioxidant substances in PD patients (31, 32, 68-70). Additionally, several controlled studies have shown positive outcomes when antioxidants have been used in combination (61, 62, 67). The EAU and AUA guidelines strongly recom- mend infiltrative therapy with collagenase clostridium his- tolyticum (CCH) or interferon alpha-2b (31, 32, 39). However, we did not employ CCH in treatment as it is indicated for PD in the "stabilization phase". On the con- trary, our PD patients were all in the active phase of the disease. Furthermore, in Italy, the drug Xiapex (CCH) has been withdrawn from the market by the Italian Medicines Agency (AIFA) as of January 1, 2020. Additionally, we did not utilize interferon alpha-2b due to its high cost and potential side effects, including fever and flu-like symp- toms, fatigue, nausea, diarrhea, vomiting, and dizziness. The positive response to our treatments is attributed to the antioxidant properties of the substances used, which can interrupt inflammation and negatively interfere with oxidative stress, a key factor in fibrogenesis (19, 20). Figure 5 shows the interfering activities of antioxidants on the various pathogenetic mechanisms involved in PD. Propolis, bilberry, silymarin, boswellia, coenzyme Q-10, carnitine, and Ginkgo biloba exhibit antioxidant and antifibrotic activity, inhibit pro-inflammatory cytokines, metalloproteins with anti-elastic properties, the COX-2 enzyme, and NF-kappa-B factor (22). Coenzyme Q-10 also protects cellular membranes from lipid peroxidation caused by reactive species, and regenerates vitamin E to its natural and non-oxidized state after it has oxidized from exerting its antioxidant action (22). Carnitine also reduces the production of inducible nitric oxide synthase (iNOS), inhibits fibroblast proliferation and their differ- entiation into osteoblasts, and induces vasodilation through an endothelial mechanism that utilizes the nitric oxide pathway (22). Superoxide dismutase (SOD) protects the human body from tissue damage caused by ROS by removing superoxide anion. SOD has anti-inflammatory action and inhibits fibroblast proliferation (22, 71). Vitamin C acts as a scav- enger against reactive species and inhibits pro-inflammato- ry cytokines, and fibroblast proliferation (22). Vitamin E is a ROS scavenger and inhibits NF-kB factor, COX-2, pro- inflammatory cytokines, PDGF, and fibroblast proliferation (22, 35). Pentoxifylline (PTX) inhibits ROS, myofibroblastic differentiation, collagen deposition, NF-kB factor, pro- inflammatory cytokines, TGF-beta-1, COX-2, iNOS pro- tein expression, and PAI-1 and stimulates fibroblast apop- tosis. In our multimodal treatment, we also used diclofenac (an NSAID) administered locally to avoid potential organ damage associated with long-term oral therapy (29, 30). Diclofenac also has antioxidant properties and has been demonstrated to penetrate tissues deeply (63, 64). The multimodal antioxidant treatment for PD described in this article is the same as described in our recent arti- cles and differs only in the dose of PTX used for penile injections, which is 60 mg instead of 100 mg. We noticed that by reducing the dose of PTX, we achieved the same results as in the past with higher doses of PTX. The treatment lasted for an extended period in three of the four cases described here (30-36 months). A pro- Figure 5. Inhibitory action of antioxidant agents on the main pathogenetic mechanisms of Peyronie's disease. Archivio Italiano di Urologia e Andrologia 2024; 96(4):12956 11 Multimodal antioxidant treatment of Peyronie's disease longed treatment duration is essential due to the chronic inflammatory nature of PD, which requires time for com- plete plaque resorption. The treatment duration may also be affected by the size of the PD plaque. The excellent result obtained in the third case, with a shorter treatment time (a year and six months) compared with the other three cases, is likely because of the early diagnosis (four months after the penile trauma). In this case, we were able to provide the patient with a shorter course of treat- ment without periodic penile injections, as the plaque was small (0.043 cm3) because the PD was in an early stage. In our treatment plan involving penile injections, we progressively extended the time between each pentox- ifylline injection throughout the treatment process. This approach was based on the understanding that even minor peri-lesional injections can cause trauma, which is a known trigger for developing PD. We preferred increas- ing the intervals between injections (every 2 weeks > every month > every 2 months) whenever regression of the disease was observed during scheduled follow-ups to minimize the risk of new traumas. It has been reported in the literature that ultrasound eval- uation of the penis in PD cannot provide adequate plaque measurements. We believe, however, that an accurate plaque size can be obtained if a highly sensitive and up- to-date ultrasound machine with an elastographic mod- ule is used and, above all, if an expert clinician with great experience in this disease performs the evaluation (31, 65, 72, 73). Therefore, we believe that our findings resulted from both the treatment substances and the specific ultrasound eval- uation method we employed. This method enabled us to accurately diagnose the affected area (plaque) and closely monitor its progression during scheduled follow-ups. CONCLUSIONS Despite the small sample size in this case report, our mul- timodal antioxidant treatment yielded highly satisfactory outcomes, allowing for the complete disappearance of the penile plaques in the disease area. We believe that the excellent responses to our therapy were due to the appro- priate use of antioxidant substances, as well as the use of a very sensitive and up-to-date ultrasound machine capa- ble of recognizing the plaques and providing their loca- tions and precise dimensions. Additionally, having a cli- nician with great experience in PD conduct the echoelas- tography examinations contributed to the positive out- comes. 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Correspondence Gianni Paulis, MD paulisg@libero.it Department of Urology and Andrology, Peyronie’s Care Center, Castelfidardo Clinical Analysis Center, 00185 Rome, Italy Giovanni De Giorgio, MD Department of Urology and Andrology, Section of Ultrasound Diagnostics, Castelfidardo Clinical Analysis Center, 00185 Rome, Italy Andrea Paulis andrea.fx.94@gmail.com Bambino Gesù Children’s Hospital, IRCCS (Istituti di Ricovero e Cura a Carattere Scientifico), Rome, Italy Conflict of interest: The authors declare no potential conflict of interest.