AUTHOR INFORMATION

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Authored by Eli Lizza, MD, Clinical Associate Professor, Department of Surgery, Section of Urology, University of Medicine and Dentistry of New Jersey

Coauthored by James J Bruno II, MD, Staff Physician, Department of Surgery, Division of Urology, Lenox Hill Hospital

Eli Lizza, MD, is a member of the following medical societies: American Medical Association, American Society for Reproductive Medicine, American Urological Association, and International Society for Sexual Medicine

Edited by Leonard Gabriel Gomella, MD, FACS, Director of Urologic Oncology, Bernard W Godwin Associate Professor of Prostate Cancer, Department of Urology, Kimmel Cancer Center, Thomas Jefferson University; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Allen Frank Morey, MD, Chief, Urology Service, Brooke Army Medical Center; Clinical Assistant Professor, Department of Surgery, Uniformed Services University of the Health Sciences; J Stuart Wolf, Jr, MD, FACS, David A Bloom Professor of Urology, Director, Division of Minimally Invasive Urology, Department of Urology, University of Michigan Medical Center; and Stephen W Leslie, MD, FACS, Founder and Medical Director, Lorain Kidney Stone Research Center; Clinical Assistant Professor, Department of Urology, Medical College of Ohio; Chief Editor - eMedicine Urology

Author's Email:	Eli Lizza, MD
Editor's Email:	Leonard Gabriel Gomella, MD, FACS

eMedicine Journal, February 12 2007, VOLUME 8, Number 2

INTRODUCTION

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François Gigot de Peyronie is widely credited for first describing penile curvature, now known as Peyronie disease (PD), in 1743. However, the precise etiology of this condition remains unclear. It is characterized by curvature in the penile shaft that is often preceded by painful erections and accompanied by an area of fibrosis (see Image 1). The characteristic angulation is frequently associated with erectile dysfunction (ED), either as a result of buckling of the penile shaft with intromission or because of a lack of rigidity distal to the area of associated fibrosis. This lack of rigidity seems to be the result of compromise to the distal penile blood supply. Over the years, various medical and surgical therapies have been used to treat this condition. The number and variety of these attempts at treatment stands as a testament to their relative lack of effectiveness.

This article defines the problem of PD, outlines a reasonable evaluation of patients with PD, reviews the medical therapies that have been used, and presents the surgical options that are currently available. The indications for treatment are discussed, as are the expected outcomes. The goal is to impart a practical approach to the diagnosis and treatment of PD in the clinical setting. Also included is recently published information from evidence-based research. Other important information has been included only after noting the limitations of the associated study.

Problem: PD is a curvature of the penis, particularly during erections, that is usually associated with a palpable area of fibrosis in the tunica albuginea. It is often preceded by painful erections and may be associated with ED. The curvature is usually obvious when the penis is erect but occasionally may be noted even when the penis is flaccid. The fibrotic area, known as a plaque, can vary in firmness and sometimes becomes calcified. Although PD implies that this condition is a disease, this is a misnomer. The condition of PD is not associated with an infecting organism and cannot be transmitted from one person to another.

Schwarzer et al reported on a large population-based self-report survey to identify the prevalence of this condition. A questionnaire was sent to 8000 men, and 4432 (55.4%) responded. The authors found a prevalence of 3.2% for the new appearance of a palpable plaque. The prevalence by age was 1.5% for men aged 30-39 years, 3% for men aged 40-49 years, 3% for men aged 50-59 years, 4% for men aged 60-69 years, and 6.5% for men aged 70 or older. Associated with the plaque, 84% reported penile angulation, 47% reported painful erections, 32% noted the triad of plaque, angulation, and pain, and 41% also reported ED.

Frequency: The PD rate is reported to be 0.39-3%. However, this is probably an underestimation because of the embarrassment most men feel about having this condition. Underreporting may also result from the lack of men seeking assistance when their symptoms are mild or nondebilitating. Although this condition usually affects men aged 40-70 years, according to Gelbard et al, Carson, and Lindsay et al, it can also occur in younger individuals.

Etiology: The etiology of PD remains enigmatic. It has been associated with deficiency in vitamin E, ingestion of beta-blocking agents, and elevations of serotonin levels. PD is associated with Dupuytren contractures and with HLA-B7, implying a genetic link to its etiology.

More recently, PD has been thought to result from vascular trauma or injury to the penis. The injury may be trivial or involve only microscopic vessels and tissues. This triggers the release of cytokines that activate fibroblast proliferation and produce collagen, the main matrix component of a Peyronie plaque, within the tunica albuginea.

Usta et al investigated the relationship between comorbid conditions and the severity and degree of penile curvature in men with PD. These authors found that the presence of diabetes, hyperlipidemia, hypercholesteremia, or hypertension was not statistically related to the severity of penile curvature in men with PD. The number of comorbidities also did not affect the degree of curvature. The rates of hypertension, hypercholesterolemia, diabetes, hyperlipidemia, and heart disease were significantly higher in men with PD and ED compared with those with PD alone. The authors believed that this relationship was more likely related to the ED rather than the PD.

In order to evaluate the association between PD and ED, El-Sakka (2006) studied the prevalence of PD in a population of men known to have ED. In this prospective study, 1440 men with ED were assessed with IIEF and categorized as having mild (12%), moderate (38%) or severe (50%) ED. Eight percent were found to have PD primarily on the basis of the presence of a penile plaque. An analysis of socio-demographic factors also identified significant associations between PD and the following risk factors for ED: age, obesity, smoking (duration and # of cigarettes smoked/day), longer duration and increased severity of ED, DM, dyslipidemia and psychological disorders. No significant association was found between PD and HTN or IHD in this study. It remains unclear as to how much these risk factors contribute to the development of PD and as to how ED and PD influence each other.

Bjekic et al. (2006) examined the risk factors for PD in a case controlled study. Eighty-two men with PD diagnosed by history along with the presence of a well-defined palpable penile plaque were matched against 264 men who had neither a history nor signs of PD. The following risk factors were identified: genetic predisposition in association with a family history of Dupuytren’s contracture; minor vascular penile trauma, either accidental or iatrogenic from cystoscopy or TURP; systemic vascular diseases including DM, HTN, and hyperlipidemia: smoking and alcohol consumption. The use for propranolol and a history of non-gonococcal urethritis were also found to be risk factors foe PD. How these risk factors contribute to the initiation of PD remains elusive.

Pathophysiology: During normal erectile function, neural stimulation results in relaxation of the cavernosal smooth muscle tissue and the cavernosal arteries, bringing blood into the penis and the trabecular spaces within the corporeal bodies. This state initially results in both increased blood flow into the corporeal bodies and pooling of more blood within these organs. As a result, they expand and stretch the surrounding tunica albuginea. This thick expansile layer is composed of collagen and elastic fibers in an irregular framework. It normally stretches in length and width to its maximum size, at which point further stretching does not occur.

Expansion results in stretching, compression, and closure, of the subtunical venules that perforate the tunica and drain blood from the corpora. Consequently, blood cannot drain easily from the penis, which results in an increase in intracorporeal hydrostatic pressure. This increased pressure allows the penis to become rigid once the tunica has reached its maximum length and width. The process is similar to overinflating a car tire. Once the maximum length of the steel belts in the tire is reached, further inflation only makes the tire harder and more rigid.

In PD, the initial inflammatory response is characterized by chronic lymphocytic and plasmacytic infiltration of the tunica albuginea. This may be the result of minor penile trauma as can happen unnoticed during intercourse. Devine et al believe that such trauma can result in a dorsal and ventral delamination injury to the tunica albuginea, causing inflammation, induration, and fibrin deposition between the tunical layers. If scar tissue formation and extracellular matrix deposition exceed collagen and matrix degradation, as Levine et al postulate, then increased collagen is deposited in the tunica albuginea, resulting in fibrosis and plaque formation.

Luangkhot et al reported that men with PD have more type III collagen than type I collagen in their tunica albuginea. Chiang et al also found increased type III collagen in the adjacent penile tissue in men with PD and in the tunica in men with corporeal veno-occlusive dysfunction (venous leak syndrome). This may indicate that a more generalized penile abnormality is involved in PD.

Transforming growth factor-beta is a cytokine involved in tissue repair and scar formation. El-Sakka et al showed its production to be up-regulated in men with PD and that it may be responsible for the increase in collagen deposition associated with this condition.

Clinical: The natural history of PD is variable. Progression can occur over several years. If the fibrosis becomes calcified, the angulation becomes quite stable. Earlier studies described PD as being a self-limited condition, with spontaneous resolution in most cases. However, this does not appear to be accurate. In 1990, Gelbard et al found that the plaque completely resolved without treatment in only 13% of men, while 40% described their condition as progressive and 47% noted no change. Because spontaneous resolution is unlikely in most men, most investigators recommend intervention if and when the condition impacts significantly upon sexual function. Devine et al proposed that the earlier that medical intervention is initiated, the more likely it is to be successful.

Men with PD may present with any combination of (1) penile pain, which is more pronounced during erections; (2) penile angulation, which may be apparent only with an erection or may be noted in a flaccid penis; (3) a plaque that is usually palpable at the site of and on the acute side of the angulation; and (4) decreased erectile function, either from loss of rigidity or from penile buckling caused by the angulation. The symptoms often follow the usual progression of PD; progressive angulation can approach a maximum angle of 90°, thus complicating intromission. Penile pain per se almost always resolves without therapy, and this has led to controversy in assessing therapeutic outcomes. Alternatively, some patients note pain in the penis that may subside before the appearance of a palpable plaque or of penile angulation. A less common manifestation is a palpable plaque with no associated pain or angulation.

For practical purposes, PD can be divided into acute and chronic phases. The acute phase usually lasts for the first 18-24 months and is characterized by a changing inflammatory pattern that may include penile pain, some curvature, and a penile nodule. The chronic phase is characterized by a stable plaque, often with calcification, and penile angulation. Loss of erectile ability is associated more often with the chronic phase.

INDICATIONS

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If the diagnosis of PD is made early in the course (ie, within the first 6 mo of the onset of any symptoms), attempt nonsurgical therapy. If not successful, maintain such therapy for a reasonable time, at least 6 months, before considering more invasive measures.

Before surgical intervention is contemplated, certain criteria should be met.

• A sufficient duration should elapse since the inception of symptoms to ensure that the condition is stable and to be certain that spontaneous resolution will not occur. This duration is governed by the severity and debilitating effects of the symptoms. It should be in the range of 1-2 years. During this time, nonsurgical treatments can be applied. A significant end point in the observation period is the presence of calcification in the plaque. This usually indicates a stable plaque, and no further angulation or resolution can be anticipated at this point.

• If possible, the patient should attempt nonsurgical therapy first. If this therapy fails, consider proceeding to more invasive measures.

• The condition should be debilitating, prohibiting satisfactory intercourse. The authors do not believe that operating to correct small curvatures simply for cosmetic reasons is reasonable. Usually, some degree of curvature remains afterwards, either from residual disease or from resultant scar tissue. These patients are not usually satisfied with the results.

• The associated finding of ED that is not responsive to medication therapy is an indication to use surgical approaches that treat both the curvature and the ED.

RELEVANT ANATOMY AND CONTRAINDICATIONS

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Relevant Anatomy: The penile shaft is made up of 3 erectile bodies, the 2 corpora cavernosa dorsally and the corpus spongiosum containing the urethra ventrally. They are surrounded by vessels, fascia, and skin. The corpora cavernosa are on adjacent sides of the median raphe. This fenestrated midline structure acts as a buttress to the shaft, connecting to the tunica albuginea dorsally and ventrally. It is composed of the same elastic fibers as the tunica albuginea and it allows free communication between the 2 corpora cavernosa. The corpora are composed of erectile tissue that surrounds the cavernosal artery located within each corpus. This tissue is spongelike, being composed of many vascular spaces capable of expanding and filling with blood after adequate smooth muscle relaxation from proper neural stimulation.

A tough fibrous layer, the tunica albuginea, surrounds the corpora cavernosa. This is composed of 2 layers of elastic tissue and collagen. This layer gives the penis rigidity as the intracorporeal pressure increases. The plaque of PD develops in this layer, although the plaque can also extend into the surrounding corporeal tissue. The deep dorsal vein lies in the dorsal sulcus between the 2 corpora. It is flanked by a dorsal artery and a dorsal nerve bundle. The latter can either be in the form of a large visible nerve running lateral to each artery, or it can be fanned out into several fine nerve strands that progress distally along the dorsolateral aspect of the penile shaft. This second scenario can complicate reconstructive surgery because of the heightened chance of injuring one or more of these strands, resulting in anesthesia of some of the penile skin.

Lying in the ventral sulcus is the third erectile body, the corpus spongiosum. This envelops the urethra and is continuous distally with the glans penis. The corpus spongiosum is encased in the Buck fascia, a tough elastic layer that continues dorsally to also enclose the corpora cavernosa, superficial to the tunica albuginea, the deep dorsal vein, and the dorsal arteries and nerves. The next superficial layer is the Dartos fascia. This is composed of loose areolar tissue that allows free and easy movement of the skin over the penile shaft. Within this layer are contained the superficial veins of the penis. A prominent vein in this layer is the superficial dorsal vein, which is often visible through the penile skin. The outermost layer is composed of penile skin that folds back upon itself distally to form the prepuce.

Contraindications: In general, contraindications to treatment of PD are based on the severity of symptoms. If little or no loss of penile rigidity is present and if the curvature is minimal and does not compromise function, then intervention is contraindicated. In this setting, intervention is not likely to enhance function or appearance, although it will expose the patient to potential adverse effects, including a worsening of the symptoms.

Topical and/or oral treatments are contraindicated in any person who has a known hypersensitivity to any specific agent. Injectable agents are generally tolerated well and appear to have little if any systemic effects due to the small amounts injected. As with topical and oral agents, they should not be used in any person who has demonstrated an allergic reaction to the particular medication contemplated.

Surgical treatment is contraindicated in men who have minimal symptoms. In addition, surgery should not be used when the extent of the disease is not yet stable. If plaque excision is performed before the process of fibrosis is complete, the procedure is doomed to fail because further plaque and subsequent curvature will develop.

Implantation of a penile prosthesis is contraindicated in any person with an ongoing infection anywhere in the body. In addition to the contraindications mentioned above, an inflatable prosthesis is contraindicated in a patient who lacks the manual dexterity to operate the prosthesis.

WORKUP

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Lab Studies:

• No specific blood test is available for PD. Although an association exists between PD and HLA-B7 surface antigen, it is not a specific marker for this disease. Also, identifying this marker in order to diagnose PD is not practical because the diagnosis should be obvious based on the history and physical examination findings.

Imaging Studies:

• The main objective of imaging studies in a patient with PD is to identify calcification of the plaque because this end point usually signifies maturity of the plaque, and, when it is present, further angulation should not occur. This can be accomplished in a variety of ways.


• • A simple x-ray film of the penis can often help identify calcification within the plaque.
  
  
  
  • Alternatively, penile ultrasound can be used to help delineate the plaque and to place the calcification within it by the characteristic echogenic shadowing.
  
  
  
  • Corpus cavernosography can be used to help delineate the plaque and any compression of the cavernosal space. This test is usually not necessary because the findings typically do not alter the course of treatment.
  
  
  
  • MRI of the penis has recently been used to image the plaque while it is still composed of fibrous tissue (see Images 2-4). Although this is not the preferred imaging technique because of cost and availability, it may prove helpful in questionable cases.
  
  
  
  • Recently, investigators have used imaging studies to attempt to distinguish unstable, evolving PD from stable PD. Erdogru et al used penile scintigraphy with technetium Tc 99m human immunoglobulin G in a prospective study. These authors found ^99mTc human immunoglobulin G at the plaque site in 10 of 11 patients with unstable plaques, compared with only 2 of 14 patients with stable plaques and 0 of 7 control patients. Although this technique requires some refinement and the data must be confirmed, it nevertheless presents a measurable parameter to help distinguish unstable PD, which is best treated medically, from stable PD, which may require surgical intervention.
  
  
  

Other Tests:

• If ED is associated with the PD, then duplex ultrasound with intracavernous injections of a vasoactive agent, such as alprostadil, and/or dynamic infusion cavernosometry and cavernosography may be indicated to help identify associated arteriogenic ED or corporeal veno-occlusive dysfunction. These tests should be used only when the results will potentially alter the therapeutic plan. If, for example, the patient and the physician have already decided to treat PD and ED concurrently with the implantation of a penile prosthesis, then these tests would not be necessary.

TREATMENT

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Medical therapy: The optimum medical therapy for PD has not yet been identified. If the pain and/or curvature are minimal and do not preclude normal sexual function, refraining from medical treatment and observing the patient are reasonable. This observation can be continued as long as the symptoms remain stable. When evaluating a specific therapy, it is important to consider the placebo effect. This is especially germaine to PD since some of the symptoms of PD can spontaneously improve without therapy in a significant number of men. To quantify the level of spontaneous improvement that can be expected, Mulhall, Schiff and Guhring (Mulhall 2006)published a prospective analysis of 246 men with PD. These men were originally seen within 6 months of onset of symptoms and were followed without treatment for at least 12 months from onset of symptoms. The patients presented with a mean baseline penile curvature of 42 degrees. Twelve percent improved (mean change of 15 degrees), 40% remained unchanged and 48% worsened (mean change
of 22 degrees). All patients who initially demonstrated penile pain reported improvement while 89% noted complete resolution of the pain, again without any treatment. Mean flaccid penile length decreased during observation from 12.2 cm to 11.4 cm, which was not statistically significant. One must keep these results in mind while evaluating interventions which may expose the patient to untoward side effects or complications with little improvement in results over what can be expected from observation alone.

Oral preparations

When therapy is used, initiate medical treatment first. Several oral preparations have been used with varying degrees of effectiveness. The antioxidant vitamin E has been used since 1948 because of its low incidence of adverse effects and low cost. The effectiveness of vitamin E that was initially reported has not been confirmed by subsequent investigators. At the US National Institutes of Health conference on PD in 1993, Devine and Snow reported on 105 patients treated with oral vitamin E. These patients reported a 99% reduction in pain and a 13% reduction in penile curvature, even though 70% of the patients were found to have no objective change in their symptoms. This speaks to the need for properly validated studies with placebo-controlled groups and well-defined, measurable end points of treatment.

Another oral agent that has had varied success in treating this affliction is potassium aminobenzoate ([PABA] Potaba). This compound is considered to be a member of the vitamin B complex. The antifibrotic action of PABA may be due to its production of increased oxygen uptake at the tissue level, which enhances oxygen-dependent monoamine oxidase activity, which, in turn, prevents or causes regression of tissue fibrosis.

Zarafonetis and Horrax first reported on the use of PABA to treat PD. All 21 men studied reported a reduction in pain, 82% noted an improvement in penile curvature, and 76% experienced a decrease in plaque size.

In a retrospective study, Carson found a decrease in penile plaque size in 18 of 32 patients and a resolution of penile angulation in 18 of 31 patients treated with 12 g of PABA daily for at least 3 months. Of 31 patients, 8 also reported complete resolution of angulation. Carson recommended that a prospective, double-blinded, multicenter, well-controlled study using objective criteria be performed to confirm his findings.

This has been the medical treatment used most frequently by the authors as first-line therapy. Unfortunately, therapy requires an excessive amount of PABA to be taken each day for a usual 6-month course. Most patients find the adverse gastrointestinal effects to be intolerable. In the continued absence of a well-controlled prospective study, it is difficult to recommend this therapy.

Colletta et al reported that the nonsteroidal antiestrogen tamoxifen facilitates the release of transforming growth factor-beta from human fibroblasts in vitro, which can result in inhibition of the inflammatory response and a decrease in fibroblast production. Ralph et al reported on 36 men receiving 20 mg of tamoxifen twice daily for 3 months. Sixteen of 20 patients reported improvement in penile pain, 11 of 31 had improved penile curvature, and 12 of 35 were noted to have a reduction in the size of their penile plaque.

However, in a more recent prospective, randomized, placebo-controlled study, Teloken et al found no significant improvement in pain, penile curvature, or plaque size in 25 patients with PD who were treated with tamoxifen. These patients received either 20 mg of tamoxifen twice daily for 3 months or a placebo for the same time period. Evaluations were performed before treatment and 4 months after treatment. In view of this last report, tamoxifen does not appear to be of value in treating PD.

The anti-inflammatory agent colchicine has been shown by Fell et al and by Harris and Krane to decrease collagen formation and to stimulate collagenase activity by interfering with the transcellular movement of collagen and by decreasing collagen-processing enzyme activity. In a noncontrolled study, Akkus et al reported on 24 men who used colchicine for 3-5 months. A slight decrease in curvature was noted by 11% of patients, a marked decrease was reported by 26%, and a decrease in plaque size occurred in 50%. Levine noted that most patients have poor tolerance of colchicine and frequently report gastrointestinal disturbances.

Prieto Castro et al reported on the results of a prospective, single-blinded, randomized study comparing vitamin E at 400 mg/d and colchicine at 1 mg every 12 hours together (N = 23) with ibuprofen at 400 mg/d as a control (N = 22) for 6 months. The men treated in this study were all in the early stages of the disease and had their symptoms for 6 months or less. They also had to be free from associated ED, have a curvature of not more than 30°, and have no calcification in their plaques. No significant difference in pain response was noted between the 2 groups. Plaque size increased in the group receiving ibuprofen, while it decreased in the vitamin E/colchicine group; the difference was significant. The change in penile curvature was also significant. Adverse effects included temporary diarrhea in 4 of 23 men taking colchicine.

The limitations of this study include the small sample size and the single-blinded study design. In spite of these limitations, this study indicates that the combination of vitamin E and colchicine may be an effective oral therapy for early, mild cases of PD. Larger, double-blinded studies are necessary to confirm these findings.

Safarinejad reported the results of a randomized double-blinded, placebo-controlled study comparing the effects of colchicine to placebo in 78 men. Although pain resolved in 60% of patients treated with 0.5-2.5 mg/d of colchicine orally for 4 months, it also resolved in 63.6% of those treated with placebo. Similarly, no differences in the reduction of penile deformity or decrease in plaque size was noted between the 2 groups. Safarinejad found no substantial differences between colchicine therapy and placebo. Furthermore, significant drug-related adverse effects were reported in the colchicine group, and these effects required cessation of therapy in 2 patients.

Injection therapy

An alternative approach was taken by Culha et al, who treated 38 patients with both PD and ED. These patients received a combination of oral colchicine and vitamin E along with intracavernous injection therapy using prostaglandin E1 (PGE1). The authors used a questionnaire to assess patient quality of life before treatment and 10 months after treatment and found improvement in all parameters. Symptoms were reported to diminish in 24 men. The authors recognize and report that none of these men started the study with severe curvature of the penis or intolerable pain while erect. Nevertheless, this combination therapy may be beneficial in selected men with PD and ED whose symptoms are not severe.

Intralesional injection of various substances has been used for decades in an attempt to dissolve the plaques of PD. Winter and Khanna reported decreased plaque size and penile pain after injection of dexamethasone. Williams and Green found marked improvement in symptoms after injection of triamcinolone hexacetonide every 6 weeks for 36 weeks. These investigators concluded that men with small, firm, discrete nodules were most likely to respond. Both studies noted the presence of marked local adverse effects from the intralesional injections, which could complicate subsequent surgery.

More recently, Cipollone et al addressed the use of intralesional injection with betamethasone in a prospective, randomized, placebo-controlled study of 30 men. At 12-month follow-up, no significant differences were noted between the placebo group and the steroid group with respect to the disappearance of pain, a decrease of plaque volume, or a decrease of penile curvature. Interestingly, at 12 months, figures for all 3 parameters had decreased, noting a disappearance of pain with erection in 66.6% of the treated group versus 53.3% of the control group, a decrease in plaque volume in 40% of the treated group versus 40% of the control patients, and a diminishment of curvature in 20% of the treated patients versus 26.6% of the control patients.

The authors concluded that the effect was likely due to a mechanical effect of the injected volume rather than the specific agent used. However, this also might represent the natural progression of the disease and may not be related to this treatment. This study also points to the need to use prospective, randomized, placebo-controlled studies before drawing conclusions regarding the efficacy of any therapeutic intervention.

In another study, Lamprakopoulos et al treated 112 men with intralesional betamethasone and hyaluronidase injections. Each received 12 injections. The authors reported that 31% of patients were cured and that another 55% were improved. However, they stressed that the treatment appeared most efficacious in men with smaller lesions (<20 mm) that were of recent onset ( <12 mo). This study was neither randomized nor placebo-controlled. In view of the previous study, these results appear less dramatic.

Verapamil is a calcium channel blocker that has gained attention for the treatment of PD since Lee and Ping found that it induced increased collagenase activity. Levine et al first published results of the use of intralesional verapamil for PD in an uncontrolled study in 1994. These authors reported reduced pain in 93% of men treated with 10 mg of verapamil injected intralesionally. They also noted 100% subjective improvement in hourglass deformity, 42% objective improvement in curvature, and 58% improvement in ED.

More recently, Lasser et al and Rehman et al addressed this approach. The first of these studies used a nonrandomized constant dose of verapamil in 11 men. Of these men, 9 also received concurrent therapy with either testosterone or PABA. The authors reported that plaque size decreased significantly in 7 (55%) of 11 patients, softening was noted in 6 (55%) patients, curvature decreased in 4 (50%) of 8 men, and pain resolved in 4 (100%) of 4 men. Rehman et al, in the second single-blinded study, noted benefit in using verapamil in men with noncalcified plaques and penile angulation of less than 30°. Collectively, these studies reported minimal complications and no arrhythmias or hypotensive episodes.

Although these studies appear to demonstrate a benefit from intralesional verapamil, drawing a definitive conclusion on the efficacy of this treatment remains difficult without a well-constructed, double-blinded, placebo-controlled study. In lieu of such data, a larger cohort from a multicenter collaborative study would be more beneficial.

Electromotive administration

Another approach to the delivery of medication to a Peyronie plaque is the use of electromotive drug administration (EMDA), also known as iontophoresis. In this approach, the electrokinetic transport of charged molecules is used to enhance the transdermal application of a drug. Riedl et al reported on 100 patients treated in an uncontrolled, prospective study. They used a mixture of dexamethasone, lidocaine, and verapamil in a self-adhesive receptacle, which was placed over the plaque, along with an electrical current of 5 mA. These authors reported resolution of pain in 96%, diminution of plaque in 53%, improvement of penile deviation in 37%, and improvement of ED in 44%.

Montorsi et al treated 40 men with PD by EMDA with orgotein, dexamethasone, and lidocaine in a double-blinded, placebo-controlled, partial crossover study. They also reported on another 25 men who were treated in an uncontrolled study with verapamil and dexamethasone. Sessions used 3 mA of current for 20 minutes 3 times a week, with assessment at 1 and 3 months after the initiation of therapy. The authors reported disappearance of penile pain in 100% of men, significant improvement or disappearance of penile plaque in 90% (2 drug) and 79% (3 drug), improvement in penile deformity in 88% (2 drug) and 62% (3 drug), and improved penile rigidity in more than 80% in both groups.

The benefit of this therapy appears to be more pronounced in patients with a short history of debilitation, ie, in men in the initial stages of their condition. The main advantage of this treatment is that this administration is painless. Neither group reported adverse effects.

Martin et al investigated the use of transdermal verapamil without EMDA to see if the substance would be absorbed through the skin. A commercially available preparation of verapamil gel (0.5 mL, 40 mg/mL) was applied to the penises of men scheduled for penile implantation on the night before and the morning of their surgery. The level of verapamil was measured in the urine and the tunica. No adverse effects were noted. Although small levels of verapamil were identified in the urine (signifying a low level of systemic absorption), none was identified in the tunical tissue. These authors concluded that no rationale supports the topical use of verapamil for PD. This finding may not apply to other topical verapamil preparations; however, the authors make a strong case against the use of topically applied verapamil without EMDA.

In 2003, Levine et al reported on the use of EMDA to transport verapamil into the tunica albuginea. This noncontrolled, nonrandomized, single-blinded study used either verapamil at 10 mg alone or verapamil with epinephrine for 20 minutes in men with PD who then immediately underwent plaque excision. The levels of verapamil in the excised tunica were compared with levels in the tunica from men who either had no treatment or who had intralesional injection of verapamil. These authors found detectable levels of verapamil in 10 (71.5%) of 14 men treated with topical verapamil with EMDA. They found EMDA to be a safe technique that is capable of transporting verapamil into the tunica. Epinephrine, which was used to decrease vascular dispersion, did not increase tunical concentrations. This study did not address the question of whether the verapamil helps the PD at these levels.

In 2003, Di Stasi reported results from their prospective, nonblinded study of 49 men. The study involved treatments with verapamil at 5 mg and dexamethasone at 8 mg with EMDA 4 times a week for 6 consecutive weeks. Pain resolved in 88%, curvature disappeared in 10% and improved greater than 50% in 35%, plaque disappeared in 8% and was noted to be greater than 50% less in another 14%, ED was completely resolved in 42% and improved in another 17%, and vaginal penetration was possible after treatment in 68% and improved in another 5%. The authors found that results were better in men with smaller, noncalcified plaques. The small sample and the nonblinded study design retract from the significance of this study, although it does meet the stated criteria for evidence-based research.

In 2004, Di Stasi et al reported on the results of a prospective, randomized, controlled, double-blinded study of 73 men who were treated with either verapamil at 5 mg and dexamethasone at 8 mg diluted to 5 mL (study group) or 5 mL of lidocaine 2% (control group) with EMDA. Each participant received 4 sessions per week, each lasting 20 minutes, for 6 consecutive weeks.

These authors found a significant decrease in plaque volume, a significant improvement in penile deviation, and significant relief of erectile pain in the study group compared with the control group. Indeed, while no patient in the control group exhibited complete resolution of either the plaque or the penile deviation, the plaque resolved completely in 5 (14%) of the study patients. Penile deviation also completely resolved in 5 (14%) of study patients. Erectile activity was regained in 11% of the control group compared with 51% in the study group. Although transient erythema was reported at the sites of the electrodes in all patients, no other adverse effects were reported.

In a 2004 editorial, Wessels stated that this study does not comment on the men who dropped out, nor does it demonstrate that the mechanism of PD falls under the regulation of one or both of these drugs. In spite of these drawbacks, the power of the study design is significant as evidence-based research, and the results are compelling.

Extracorporeal shockwave therapy

An alternative approach has been to try to disrupt the plaque by means of mechanical force using extracorporeal shockwave therapy (ESWT). Mirone et al reported on the use of ESWT in 130 men in a prospective trial. The authors used a Minilith SL1 lithotriptor (Storz Medical AG, Kreuzlingen, Switzerland), which is commonly used to treat salivary stones. They divided their patients into 3 groups. The first group of 21 men received only ESWT for 3 sessions of 20 minutes each. The second group of 36 patients underwent similar treatment, followed by a cycle of 12 perilesional injections of 10 mg of verapamil every 2 weeks. They compared the results in these groups with their 73 previously treated men who had received only the verapamil injections. They noted reduction of plaque in 11 of 12 men in the first group and in 7 of 36 men in the second group. The treatment was well tolerated.

Husain et al treated 37 men with a minimum of 3 treatments at 3-week intervals. They noted a 47% improvement in angulation, and 60% reported relief of penile pain. Both studies reported minimal penile bruising as the only adverse effect. However, many investigators are concerned that ESWT will induce more inflammation to the tunica than it will eradicate.

In January 2004, Hauck et al reported on a prospective study of 114 patients who were treated with ESWT during one session consisting of 4000 shock waves. The study was initiated as case-controlled, but because the response to medical treatment was so poor and because so many patients desired ESWT, it was converted to a prospective study. Patients were accepted with and without calcification of the plaques and regardless of whether they were in the active or stable stage of their disease.

No significant change was noted in plaque size, penile curvature, or sexual function after ESWT. Penile pain was relieved in 76% of treated patients. The authors found that in the subgroup of patients with penile curvature of 31-60°, ESWT seemed to have a significant effect on decreasing penile curvature. They also noted that penile pain appeared to resolve more rapidly after ESWT than during the natural course of the disease. In spite of these findings, the authors concluded that on the basis of their findings, "ESWT should not be recommended as a standard procedure for Peyronie’s disease."

In February 2004, Hauck et al completed an exploratory meta-analysis of treatment outcomes from 17 study groups compared with natural history outcomes and with control groups from 2 of the studies. The authors found that ESWT seemed to help resolve penile pain faster and seemed to help ED but had a questionable effect on penile plaque and curvature. They concluded that based on the available literature and because of the lack of controlled studies, ESWT is not an effective evidence-based therapy at the time of their review.

Interferon alfa-2b

Interferon alfa-2b (IFN a-2b) has been found by Duncan et al to affect the production of collagen in human fibroblasts derived from Peyronie plaques by inhibiting fibroblast proliferation and stimulating collagenase activity. This naturally occurring, low molecular weight protein is part of the immune system, interfering with viruses and causing antiproliferative and antitumorigenic effects. Wegner et al were the first to report the use of intralesional IFN a-2b to treat PD in 1995. These authors demonstrated decreased penile pain, decreased penile curvature, and diminished plaque size. However, these same authors reported 2 years later on the results of 90 treatments in 30 men with early PD. They found the treatment to be unsuccessful. The disease continued to progress in 25% of their patients, and the adverse effects were intolerable. Myalgia and fever were noted with 74 of 90 treatments.

Other authors have noted more encouraging results. Judge and Wisniewski reported improvements in penile pain, curvature, plaque hardness, and plaque size compared with controls in a study of 13 men with PD. Ahuja et al reported resolution of penile pain in 90% of men with PD, significant improvement in curvature in 65%, and objective decrease in plaque size in 85%. Astorga et al reported on 34 patients treated with intralesional IFN a-2b(10 million IU) twice weekly for 14 weeks. These authors reported that ED disappeared in 79.2% of patients, palpable lesions resolved in 62%, curvature resolved in 47%, and a complete clinical response was noted in 16 (47%) of 34 men, including 5 men in whom other treatments had failed.

Brake et al noted poor results after a 3-week course of injections of 2 million IU of IFN a-2b three times per week in 23 patients. Although 13 of 19 patients with pretreatment pain were rendered pain free, no significant change was noted in penile deviation or plaque size in any of the patients and only 7 (30%) described an improvement in sexual function. Overall, only 26% of patients were satisfied with their outcome.

All of these studies describe significant rates of adverse effects with interferon alfa-2b therapy, most commonly flulike symptoms and fever, but also hematomas, penile edema, penile cysts requiring surgical excision, and the development of venous leak.

In 2006, Hellstrom et al. (Hellstrom 2006)reported on a simgle blind, multi center, placebo controlled, prospective, parallel study which examined the safety and efficacy of intralesional IFN a-2b as a minimally invasive treatment for PD. Fifty five men received IFN a-2b at a dose of 5 million IU dissolved in 10 ml NS biweekly for 12 weeks using the multi-puncture technique. Sixty two men received 10 ml NS only. The authors report significantly greater improvement in penile curvature, penile plaque size and density, and resolution of penile pain in the treated group compared to the placebo group. Teh flu-like side effects did not contribure to drop-out. This is a well done study and the findings are significant. However, they must be tempered by the fact that the mean penile curvature changed in the treatment group from 50 degrees to 36 degrees. This is not straight and so it reflects a partial response to the treatment. Further, there was also a significant improvement in the placebo group which received only NS. This implies a theraputic hydrostatic effect from the injection procedure.

Also in 2006, Inal et al. (Inal 2006) presented a randomized, prospective study or 30 patients which compared treatment with oral vitamine E alone, intralesional IFN a-2b alone and a combination of both simultaneously. The authors found no statistically significant changes in plaque size or penile curvature within each group or among the three groups. They also found no difference in the quality of intercourse or in the presence of penile pain among the groups. This was a realtively small study with only 10 patients randomized to each group. The authors concluded that "intralesional IFN a-2b therapy either alone or in combination with vitamin E is invasive and expensive and has limited effects on early stage PD with significant side effects."

This therapy continues to require further prospective, placebo-controlled, double-blinded, multi-institutional studies with long-term follow-up before it can be recommended for use in treating PD.

External vacuum devices

External vacuum devices have been used to attempt to stretch the scarred areas through mechanical means. The patient is instructed to apply the vacuum cylinder and inflate it to maximal tolerable pressure for 10-15 minutes. No tension ring or band is applied. This procedure is repeated once or twice a day for several months. In a small series of 12 patients, 4 patients noted significant curvature improvement, 2 reported slight improvement, and the rest showed no clear benefit, although none demonstrated progression of the curvature. Leslie has suggested that this mechanical approach might work better if supplemented with colchicine or other medical antifibrotic therapies.

Low-dose radiation therapy

Another nonsurgical approach to treating PD is the use of low-dose radiation therapy. Incrocci et al reported the results of a retrospective analysis, by mailed questionnaire, of 197 patients who received this treatment from 1982-1997. They had 106 respondents. However, their mean follow-up period was only 3 months. Penile pain was reported to be diminished or absent in 83% of men, and 23% reported decreased penile deformity. The authors also noted that almost half the men were impotent after treatment, and 29% had undergone surgery to correct their penile curvature. The etiology of the ED remains unclear in these patients.

In 2003, Mulhall et al reported on the irradiation of cultured cells from Peyronie plaques and from neonatal foreskin. These authors found that all plaque-derived fibroblasts that were irradiated with 5 Gy demonstrated significant elevations in basic fibroblast growth factor and platelet-derived growth factor-AB compared with the nonirradiated cultures. The neonatal foreskin cultures did not demonstrate this finding. The authors concluded that their data suggest irradiation may promote fibrosis in persons with PD by possibly increasing the production of fibrogenic cytokines.

Prospective multicenter studies with longer follow-up care are necessary to identify the potential efficacy and long-term adverse effects of this treatment before it can be recommended.

Summary of nonsurgical therapy

In general, the therapies reviewed are best suited to early PD, before the development of a stable or calcified plaque. Because the extent of the fibrosis is still evolving during this phase, assessing the therapeutic response to these interventions is difficult without placebo-controlled studies. The oral and topical methods are likely to be of value with less chance for adverse effects, while the intralesional techniques have the disadvantage of requiring recurrent penile injections. These can be painful and are also associated with local adverse effects. The transdermal methods appear to offer the best of both worlds in that they allow for greater delivery of the agent directly to the site, while eliminating the trauma of injection. Whether or not these methods will allow enough agent to penetrate the plaque to make a significant difference when compared with a blinded placebo control remains unclear.

When these therapies fail or when the plaque becomes calcified, surgical intervention usually becomes necessary for those patients who are sexually debilitated by PD.

Surgical therapy: Before the clinician considers surgical intervention for PD, the patient should meet all of the surgical criteria. The type of surgery chosen, to a large extent, depends on whether the PD is associated with ED. It also depends on the particular characteristics of the individual plaque.

If the plaque is located distally and the angulation is not very severe, a plication procedure can be offered. This operation, usually performed through a circumcising incision, is best suited for a man with a large penis. The ease of the operation and its large chance of being successful must be weighed against the almost universal resulting loss of some penile length. The amount of loss is usually approximately 1 cm.

Greenfield et al (2006) performed a retrospective analysis of 102 out of 154 men treated with penile plication for penile curvature. Patients were contacted by questionnaire for follow-up. Mean duration of follow-up was 29 months. Ninety-nine percent of men reported a straight penis after surgery. The mean loss of penile length was 0.36 + 0.5 cm with a range of 0 to 2.5 cm. The authors identified three factors that were associated with greater postoperative loss of penile length: larger pre operative penile length; greater pre operative curvature; ventrally placed curvature.

When the penile length or the patient's preference precludes the use of the Nesbit plication and if the patient retains erectile ability, then an incision or excision of the plaque can be considered with grafting to reconstruct the tunica albuginea. Although this operation has the advantage of allowing good reconstruction of the penis, potential problems exist. If the plaque is under the dorsal neurovascular bundles, penile anesthesia can result after dissection. Mobilization of the neurovascular complex is often technically difficult in the event of dorsal fibrosis.

The ideal graft material, which should be durable while elastic and tough but flexible, has not yet been identified. Lue et al have used venous patches fashioned from the deep dorsal and the saphenous veins. El-Sakka et al reported on the results of their technique in 113 patients observed postoperatively for as long as 18 months. In 96% of the men, the penis became straight; in 94%, no penile narrowing occurred; and in 83%, penile length was believed to be the same or longer after the operation. Of those men who were potent before surgery, 83% noted the same or better function after the operation. A lasting change in penile sensation was noted by 10%, but 92% were satisfied overall.

Recently, several other novel "off-the-shelf" substances have been used for patches (eg, dermis, tunica vaginalis, temporalis fascia, foreskin, silastic material, Gore-Tex, Dacron). The results have not been as impressive as those reported by Devine and Horton, Treiber and Gilbert, Fournier et al, Ganabathi et al, Krishnamurti, and Yachia et al. Other investigators have reported results using saphenous grafts, and these results were not as good. Montorsi et al reported on 50 men who were observed for a mean of 32 months. Complete penile straightening was reported in 80%, and penile shortening was noted in 40%. Kadioglu et al found the technique to be successful for straightening the penis in 15 of 20 men with a mean follow-up period of 13 months. However, these investigators incised the plaque without complete excision.

It appears that incision of the plaque without excision has become the preferred method. Arena et al used a combination of plaque incision and contralateral tunical plication in 24 men. After a mean follow-up period of 24 months, 1 man had persistent curvature. Significantly, 12 (50%) of 24 men reported penile shortening after surgery. Lue and El-Sakka have reported on a technique to lengthen a shortened penis caused by PD by means of circular venous grafting combined with daily penile stretching by means of a vacuum erection device in 4 men. Although results with this technique are interesting, further testing with a larger cohort is necessary before it can be recommended.

In a critical review of the surgical treatment of PD, Kadioglu et al. (2006) also addressed penile straightening procedures. These authors stressed that indications for surgical intervention should include: symptoms present for at least 12 months and stable for three or more months; a degree of curvature and/or narrowing that interferes with sexual penetration; an assessment of concurrent ED and of preoperative penile length; and a realistic discussion of patient expectations and likely results. The last should address the fact that the patient’s penis will not return to exactly the way it was before the onset of his symptoms, no matter what intervention is taken.

The authors presented their algorithm for surgical treatment. They recommend a tunical shortening procedure (e.g. Nesbitt) when there is good erectile function, a simple curvature of 60 degrees or less and no significant hourglass or hinge type deformity. If the patient retains erectile capability but has a complex curvature or one that is > 60 degrees, or if there is erectile instability due to an hourglass or hinge deformity, then a tunical lengthening procedure (e.g. incision with graft) should be considered. IF the patient is found to have both ED and PD, then implantation of a penile prosthesis with penile remodeling/reconstruction appears to be best. The authors present a review of the results of various plication techniques and appear to favor the technique of plication without incision into the tunica (Essed and Schrader, 1985) and the 16-dot method of Gholami and Lue (2002). These techniques are easy to perform, employ minimal dissection, require less experience and have very good satisfaction rates for achieving a straight penis (up to 93%). The main drawbacks include penile shortening in > 40% of men and recurrence of curvature in 15%.

When a lengthening procedure is indicated, Kadioglu et al. agree that plaque incision (Lue 1998) is the preferred method rather than excision. If the curvature is dorsal, they prefer to expose the plaque through the bed of the excised (and preserved) deep dorsal vein. Dissection of the NVB is done from medial to lateral. In this way, the plaque can be exposed and the length of the NVB can be restored with less chance of injury to these structures. They contrast the “H” incision with the tripod-shaped incision proposed by Ejydio (2004). The authors also discuss the optimal graft material. The vein patch is the most common and has distinct advantages, such as: inexpensive cost, no foreign body risk, good elasticity and a thin wall allowing for revascularization and minimizing the chance of graft contraction or ischemia. The vein is also conducive to reformation of the tunica albuginea over the vein patch site. Drawbacks in using a vein patch, which is usually harvested from the saphenous vein, include theneed for a second incision to harvest the vein. This will obviously lengthen the operative time. As with other grafting procedures, problems with bulging at the graft site, hourglass deformity, pain or numbness can occur.

While short-term straightening rates are satisfactory, longer term results diminish with five year satisfactory rates reported to be around 60% (Montorsi et al. 2004). One must keep in mind that this procedure is indicated in men with significant curvature and/or deformity and that it offers the chance to restore some of a patient’s lost penile length.

Among the alternatives to vein grafts, allograft tissue appears to be superior to synthetic material at present. The latter can stimulate significant postoperative inflammatory responses and increase the chances for recurrent curvature. The alloplastic tissues most commonly used include cadaveric or bovine pericardium or cadaveric fascia lata. These tissues are treated to create an acellular matrix that retains tensile strength while minimizing the chance of immune reaction, antigen exposure or host infection. The matrix allows host tissue to grow in and subsequently replace the graft. Kadioglu et al. noted that use of an allograft for lateral curvature was more likely to be associated with residual curvature postoperatively.

Kalsi et al. (2006) reported on the use of human treated fascia lata in a small group of men with an average deformity of 67 degrees (20 – 90 degrees). In this prospective study, a transverse “I” incision was employed. The resultant defect is narrower than the typical “H” incision and 1-3 grafts are required per patient. The authors report excellent or satisfactory results in 13/14 men at a mean of 31 months (17-37 months) postoperatively. The penis was completely straight in 11/14; there was no penile shortening in 10/14 while 4/14 had >1cm shortening and one patient developed ED after surgery. These authors noted results similar to saphenous vein grafting without the extra operative time, morbidity and second incision that are required for vein harvesting.

When ED that is not amenable to medical intervention accompanies penile curvature, counsel the patient for implantation of a penile prosthesis at the time of correction of the angulation. Either a semirigid or an inflatable prosthesis can be used. The use of a semirigid prosthesis usually allows for reasonable straightening of the shaft, but it has a poor cosmetic result. The erect penis is sometimes difficult to conceal. Most men desire an inflatable prosthesis for a better cosmetic result. If the prosthesis alone is not enough to straighten the penis, then penile remodeling can be attempted as described by Wilson and Delk. This involves manual and forcible bending of the shaft in the direction opposite to the curvature with the prosthesis inflated. Before this is performed, the tubing from the cylinders must be clamped with a rubber-shod clamp to protect the pumping mechanism of the prosthesis. A characteristic crackling or snapping sound is usually heard with successful attempts.

When remodeling is unsuccessful, the tunica can be incised through the plaque with one or more small incisions. If the penis is still angled, then it will likely be necessary to excise the area of plaque and replace it with a graft. Hellstrom and Reddy reported on the use of processed cadaveric pericardial tissue to accomplish this in 11 men. Of these, 8 men were treated with excision of plaque and placement of pericardial graft, while the other 3 men also received a penile prosthesis. These authors reported resolution of penile curvature in all patients with a mean follow-up period of 14 months.

The choice of prosthesis can make a difference in the ultimate outcome. The American Medical Systems (AMS) Ultrex cylinders should not be used because these rely on an intact tunica albuginea for their rigidity. The Mentor Alpha 1 cylinders are more rigid and can be used for remodeling and for reconstruction but will herniate through a large defect in the tunica. The AMS CX cylinders are best suited for reconstruction in this population because they only expand to a predetermined width, regardless of whether they are surrounded by an intact tunica. They allow remodeling of the penile shaft and/or tunical incision with or without grafting in most cases.

Preoperative details: When evaluating a patient for surgical intervention for PD, the patient must meet all the surgical criteria. Further, a detailed discussion of the procedure that includes a description of the procedure proposed, the ultimate goal of the procedure, the risks of the procedure, the chances for success, and the alternative methods of treatment that are available is needed. If possible, include the patient's partner in this discussion.

When counseling a patient for any of the surgical interventions, advising him that his penis will not look exactly as it did prior to the development of PD is important. Some residual angling may remain, it may look wider, and it will probably be somewhat shorter than before his symptoms started. This conversation is essential so that the patient will have a realistic expectation of the anticipated results. The time spent on this issue before surgery may save considerably more time and frustration on the part of both the doctor and the patient postoperatively.

The anticipated use of perioperative graft material should also be addressed. The best plan is to decide before surgery whether a prosthesis will be used, rather than waiting to make that decision intraoperatively. Many surgeons use a duplex ultrasound evaluation of the penile vasculature before surgery; however, this scan is not used universally. Many surgeons ask the patient to shower with an antibacterial soap for 1 or more days prior to surgery, especially if prosthesis placement is anticipated. Systemic broad-spectrum antibiotics are initiated in the immediate preoperative period and continued for 72-120 hours after the operation.

Intraoperative details: The details of surgery vary because the plaque can manifest in different areas of the shaft. Which particular procedure or combination of procedures will be used is another factor to be considered.

Nesbit excision/plication

When an excision or plication procedure is selected, it is typically performed through a circumcising incision. The subcutaneous tissue and the Buck fascia are dissected and retracted proximally to expose the tunica albuginea with the overlying neurovascular bundles. The patient is given an artificial erection by placing a tourniquet around the base of the penis and injecting saline into the penis through a 25-gauge butterfly needle. Alternatively, an intracorporeal injection of PGE1 may be used just prior to the scrub at the onset of the procedure.

When a full erection is achieved, tissue directly opposite the area of greatest curvature can either be excised or plicated. Excision is performed by removing an ellipse of tunical tissue and suturing the defect in a circumferential manner with interrupted, nonabsorbable sutures while carefully avoiding the underlying corporeal tissue and the overlying neurovascular tissue. Plication is performed by placing several parallel rows of 2-0 silk suture through the tunica in a line extending perpendicular to the shaft. The sutures are placed in and out, in and out to plicate, or bunch up, the tunica. Each is placed approximately 5 mm apart. Take care to avoid injury to the neurovascular bundles dorsally and the corpus spongiosum ventrally. When the sutures are tied, the penis should become straighter. If necessary, another row of sutures is placed parallel to the first row. The wound is irrigated and closed without a drain. A Coban dressing can be applied for 4-6 hours to minimize postoperative bleeding.

Ralph (2006) discussed the variations of penile straightening procedures such as the Nesbitt operation and contrasted this to the recent modification of penile plication without incision as popularized by Essed and Schrader (1985) and Ebbehoj and Mets (1985). Although the plication alone is easier and requires less dissection, it has a higher rate of recurrence of the deformity. Ralph believes that this is due to reliance on the strength of the suture alone for the repair to be successful. In spite of this problem, the plication technique appears to be well suited to dorsal and ventral curvatures since it requires minimal dissection of the dorsal NVB or the corpus spongiosum.

In 2003, van der Horst et al described a modification of this plication that includes the use of parallel incisions in the tunica albuginea, perpendicular to the shaft and at the point opposite the greatest curvature (Figures 5,6,7,8). These authors then used an inverted stitch technique to minimize pain from the sutures. They found that polytetrafluoroethylene sutures were associated with less discomfort and were less likely to be felt by the patient than polypropylene sutures. In 55 patients who started out with greater than 20° curvature and who did not have ED all had anatomical straightening postoperatively, and 90% were able to achieve intercourse, compared with 62% preoperatively; 74% noted some degree of penile shortening. In a 2004 follow up study, van der Horst et al reported that from a quality-of-life standpoint, 88% of patients and 78%of their partners were satisfied with the operative outcome.

Plaque incision/excision and graft placement

If plaque incision/excision and graft placement are planned, the dissection becomes a little more difficult. If the plaque and curvature are located distally in the shaft, a circumcising incision can be used. After exposing the shaft, proceed with the dissection of the plaque to incise or remove all affected tissue.

If a synthetic graft is to be used, it is made ready. If the deep dorsal and saphenous veins are to be used, these are harvested and prepared for insertion. All extraneous tissue is removed from the venous graft, and the typical long, narrow piece of tissue is cut carefully into shorter strips, which are sutured together to fashion a suitable patch. Then, this is sutured into place using 4-0 or 5-0 nonabsorbable sutures. Importantly, remember that the graft will appear larger before it is sewn compared with afterwards.

If the plaque is located in the proximal shaft, then a penoscrotal incision is preferred. This incision starts at the base of the penis and continues proximally along the median raphe for approximately 2 inches. It allows excellent access to the proximal penile shaft and is best suited for ventrally located plaques. If necessary, the shaft can be degloved by stripping the skin off the penile shaft superficial to the Buck fascia in a distal fashion and leaving it attached at the level of the corona. This approach is also useful if more than 1 plaque is present. An alternative approach, when multiple plaques are present, is to use more than 1 incision to achieve access to all plaques. In choosing the correct approach, remember that the goal of surgery is to leave the patient with a straight penis while preserving the maximum amount of normal sensation and erectile function.

After access has been obtained by one of these approaches and the Buck fascia has been dissected clear, care must be taken to preserve the neurovascular bundles in dorsal dissection and the urethra and corpus spongiosum in ventral dissections.

In cases in which exposing the entire penile shaft is necessary, Devine et al reported in 1992 on the use of a 2-incision method to deglove the shaft. One incision is made lateral to the base of the penis and extended down to the scrotum. The second is a circumcising incision through the scar of a previous circumcision. The skin can be dissected free from the shaft, and the penis can be retracted free from the skin, to be replaced at the end of the dissection.

Whenever dissection is anticipated in the region of the urethra or if a prosthesis is used, place a Foley catheter and keep it in the sterile field by clamping the end. This can be removed the following morning if the dissection proceeds without complications.

In 2002, Hauck et al attempted a novel approach to remove the plaque, using a dental drill and carbide bur. These authors attempted to thin the tunica at the plaque site with the bur. They then made a small transverse incision in the plaque and placed a graft fashioned from autologous deep dorsal vein. They treated 13 men with severe curvature (mean preoperative curvature of 73°) and were able to achieve a straight penis intraoperatively in all patients. However, their postoperative results were disappointing. The curvature recurred in 8 of 13 men, penile shortening (mean 3.3 cm shorter) occurred in 7 of 13 men, and decreased rigidity during intercourse was reported in 4 of 13 men after the procedure. These results caused the authors to abandon this procedure.

Hatzichristou et al combined a Nesbit placation with a corporoplasty. A standard Nesbit placation was used at the point opposite to maximal curvature. The resulting ellipse of tunica albuginea was then used as a free graft and sutured to the defect created by excision of the plaque on the opposite side of the shaft. With this method, penile shortening could be minimized and the ideal reconstructive tissue could be used, autologous tunica albuginea. The authors reported on 17 men so treated with mean follow-up of 39.5 months (range 18-62 mo). All patients reported successful penile straightening and maintenance of their preoperative erectile function. Forty-seven percent had objective penile shortening, although only 11% considered this significant. Larger studies on this interesting combined treatment are needed.

Adeniyi et al reported results with the Lue procedure of plaque excision and grafting with saphenous vein in 51 patients with a mean follow-up of 16 months. Ninety-two percent reported a satisfactory functional outcome, and 82% had complete straightening of their penises. However, 35% reported penile shortening, 12% had difficulty with intercourse, and 8% developed ED after surgery.

In an innovative approach, Bella et al. (2006) reported on a minimally invasive, intracorporal incision of the Peyronie’s plaque using a 5 mm triangular blade that is introduced under the tunica albuginea. The technique was ewmployed on 23 men with a median deformity of 60 degrees (30-90 degrees), a palpable plaque < 2cm long and a stable, painless curvature for at least 12 months. Significantly, 21/23 had a dorsal curvature, 19/23 had normal preoperative erectile function. The main advantage of this technique is that it can be performed through one or two 1cm lateral corporotomy incisions and requires minimal mobilization of the NVB over the plaque – a distinct advantage in treating dorsal plaques. However, 12/17 men with preoperative curvature > 60 degrees required ventral plication sutures to achieve full straightness. The presence of plaque calcification is reported not to prevent successful release of curvature. Initially, 21/23 men were found to have successful correction of penile curvature, defined as < 10 degrees of residual curvature. A telephone survey of 20 available patients at a mean of 25 months after surgery found 11 (55%) men able to achieve rigidity sufficient for intercourse without additional therapy. Another 5 (25%) men required Sildenafil citrate or prostaglandin E1 to achieve satisfactory function. Seventeen (85%) men reported penile shortening which did not adversely affect erectile function and one reported partial glans hypoesthesia.
While this technique is easier than incision and grafting, it is more difficult than plication alone and reports similar results. Nevertheless, this approach may be beneficial in men with significant dorsal curvature. We await further long term follow up with a larger patient population.

Placement of a penile prosthesis

In patients with both PD and ED, the physician should consider treatment that addresses both of these problems simultaneously, such as the placement of an inflatable penile prosthesis. The patient should have a stable plaque, poor sexual function, and associated ED with poor response to oral agents such as sildenafil. This alternative offers the patient the ability to achieve and maintain rigidity while straightening the penis. It minimizes penile shortening.

When the decision has been made to use a prosthesis, either with or without a graft, the preferred approach is the penoscrotal incision. This allows easy access to the corpora cavernosa. It also allows access to the scrotum for placement of the prosthetic pump and to the retroperitoneum through the inguinal canal for placement of the reservoir.

The penis can be degloved to allow incision/excision of a plaque, with or without grafting. The alternative approach is the infrapubic incision. While this allows for direct placement of the reservoir, it does not allow comparable access to the corpora cavernosa. As a result, cavernosal dilatation may be difficult, especially in men with corporeal fibrosis from PD. In either of these approaches, additional circumferential incisions or a circumcising incision can be added to improve access to a particular plaque.

If a penile prosthesis is used, one can attempt to remodel the penis over the inflated prosthesis. After the cylinders are placed within the corporeal bodies, they are fully inflated. The tubing that connects each cylinder to the pump is then clamped with rubber-shod clamps. This protects the pump mechanism from damage. Next, the penile shaft is bent forcibly in the direction opposite to the point of maximum curvature. As the shaft is deformed, a cracking sound may be heard, which represents disruption of the fibrous plaque. After this procedure, inflate the cylinders further and assess the straightness of the penis. The remodeling can be attempted more than once, but take care to not place an excessive amount of pressure on the distal tips of the corpora with the distal tips of the prosthesis because this may predispose the patient to extrusion of one or both cylinders through the corporeal tip and out the urethra.

If remodeling is not successful, then mark the area of plaque and/or curvature with an intraoperative marker. If a Mentor prosthesis is being used, it must be removed from the corporeal space before incision or excision of the plaque is attempted. If an AMS CX prosthesis is used, the surgeon can allow the cylinder to remain inside the corporeal body as long as cautery and not a scalpel is used on the plaque. The AMS silicone prosthesis will not conduct the cautery electric current, while the Mentor isomer prosthesis will conduct the current and will be damaged or destroyed during plaque removal.

If the plaque(s) is small, then incision may be sufficient. This is performed by making circumferential incisions in the tunica albuginea at the level of each plaque. If these are small, placing a graft or closing the resultant defects is not necessary. They may be left open and covered with the Buck fascia during closure. On the other hand, if the plaque is large, a large H-shaped incision can be used to open up the plaque. This incision is made directly over the plaque and is extended until the penile shaft is straight. Such an incision usually requires placement of a graft to close the tunica albuginea. This will guard against aneurysm of the tunica and/or extrusion of the prosthesis.

If the plaque is located dorsally, elevating each neurovascular bundle off the tunica albuginea may be necessary to allow access to the plaque. This can be accomplished by dissection parallel to the penile shaft while elevating each neurovascular bundle. One must be careful in this area because damage to these structures results in loss of penile sensation. On the other hand, if the plaque resides ventrally, the operator may have to separate the corpus spongiosum from the tunica albuginea before attempting to remove the plaque. This dissection can be tedious and can lead to an increased possibility of urethral injury.

If the patient has not been previously circumcised and a circumferential incision is selected, performing a circumcision after reconstruction is prudent in order to prevent ischemic skin damage secondary to mobilization. These dissections can be tedious because the plaque can extend into the cavernosal tissue.

In 2001, Montorsi et al reported on 10 men with severe penile curvature, fibrosis, and shortening due to PD. They were treated with several cavernosal relaxing incisions and insertion of an inflatable prosthesis. Average penile length increased by 2.3 cm in the flaccid penis and 3 cm in the erect penis at 6 months after surgery. Nine of 10 men reported successful intercourse with better erections and straight penises.

In 2004, Mulhall et al reported on the treatment of 36 men for combined PD and ED with a penile prosthesis and assessed the need for intraoperative adjuvant maneuvers. The authors found that in all men with preoperative curvature of less than 30°, placement of a prosthesis and full inflation of it was sufficient to result in a straight penis. In men with a curve greater than 45°, 86% required plaque incision to achieve a straight penis. Only 5.5% required a graft, and these men had curvature of greater than 60°. These authors used the Mentor Alpha 1 prosthesis in all men.

Kadioglu et al. (2006)found that a penile prosthesis alone or with penile modeling could result in a straight penis in up to 75-85% of men. An inflatable prosthesis, such as the AMS-CX or the Mentor Alpha 1, is preferred over a semi-rigid prosthesis or a tunica expanding prosthesis, such as the Mentor Ultrex model. When penile deformity persists, simple incision of the plaque without grafting can increase the success rate to 95%. Incision of the plaque with grafting over a prosthesis is usually reserved for men with >60 degree curvature or a dorsal plaque that is > 4 cm long.

Postoperative details: At the end of the procedure, the penis is usually wrapped with Coban dressing over gauze. Remove this dressing after 4-6 hours and replace it with a sterile, nonconstricting dressing. The Foley catheter is removed on the following morning, and the patient is sent home with a prescription for oral antibiotics. He is seen for follow-up care in 1 week.

Lue and El-Sakka institute daily use of a vacuum erection device for 6 months starting 1 month after reconstruction of foreshortened penises. This technique can also be used in men who undergo plaque incision or excision without prosthesis implantation.

Encourage men who have the concurrent placement of a prosthesis to inflate the prosthesis daily as soon as this is tolerable. It usually takes 4-6 weeks for the pain and edema to subside enough to allow the prosthesis to be inflated.

Follow-up care: Follow-up care varies depending on the type of treatment used. When a specific medical treatment is used, plan follow-up care for regular intervals after the intervention is completed to evaluate the results and to check for progression of symptoms. A reasonable routine is every 3 months until the patient stabilizes.

Surgical intervention requires closer follow-up care initially to ensure that the patient heals well from the surgery. Normal surgical practice should guide follow-up care during this phase. Afterward, the patient should continue to be observed regularly to assess the results of the surgery and to identify any recurrence of symptoms. This can be performed at 3-month intervals for the first year and yearly after that. These guidelines may have to be altered markedly in any individual situation based on the result of the intervention, any progression of the PD, and the level of anxiety and frustration of the patient.

For excellent patient education resources, visit eMedicine's Erectile Dysfunction Center. Also, see eMedicine's patient education articles Impotence/Erectile Dysfunction, Erectile Dysfunction FAQs, and Nonsurgical Treatment of Erectile Dysfunction.

COMPLICATIONS

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Complications from the treatment of PD depend on the particular treatment used.

Oral therapy has little chance of resulting in complications. Medications that are injected into the plaque can result in edema or scarring at the site of injection. This can lead to worsening of the curvature and/or penile shortening. Intraplaque injection may rarely result in ulcer formation.

Surgical intervention carries the risks associated with any operation, ie, the risk of infection, bleeding, or an anesthesia complication. Incision or excision of a scar may lead to scar reformation with return of the curvature. It may also lead to increased penile foreshortening.

When dissection is necessary under either the dorsal neurovascular bundles or the corpus spongiosum, the chance is always present that these structures might be injured. Damage to the neurovascular bundle can result in permanent anesthesia in the glans and/or portions of the shaft. It can also lead to loss of erections by compromising the corporeal veno-occlusive mechanism. Damage to the dorsal arteries is unlikely to affect penile erections unless it is proximal, at or above the level of the origin of the cavernosal artery. Injury to the corpus spongiosum can usually be repaired with fine absorbable sutures, but take care to not injure the urethra, which it covers. If symptoms persist after a grafting procedure, prosthesis placement is normally not substantially complicated from the prior surgery.

If a prosthesis is implanted, then the patient is subject to all the potential complications associated with this device. Notably, infection can occur, especially because these procedures usually require longer operative times because of their complexity. Perioperative antibiotic therapy is a necessity. Prosthesis malfunction or poor prosthetic fit can also arise, but these should occur with no greater frequency than when a prosthesis is used to treat ED alone.

OUTCOME AND PROGNOSIS

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In general, the outcome of treatment can be judged in 2 ways, (1) by the degree of improvement in penile curvature and plaque and (2) by the return to satisfactory sexual functioning. These are mutually exclusive end points. Either may be the primary goal of an individual patient. The most satisfying results are obtained when the primary goal of the patient is identified early in the course of treatment. The prognosis for achieving these goals is very good if all of the potential interventions listed are included.

The most recent available data have identified some new trends in the treatment of PD, as follows:

• Oral treatments should use a combination of colchicine and vitamin E because this combination is most likely to be successful.

• Topical verapamil alone does not seem to be as effective as when it is used with EMDA to transport it into the tunica.

Some tenets of treatment remain, as follows:

• Many cases, especially the mild ones, spontaneously resolve and require little more than reassurance.

• Pain usually resolves with or without treatment and is not a good predictor of successful therapy.

• Oral therapy should be initiated first, especially in men with unstable plaque.

• Indications for surgical intervention should include: symptoms present for at least 12 months and stable for three or more months; a degree of curvature and/or narrowing that interferes with sexual penetration; an assessment of concurrent ED and of preoperative penile length; and a realistic discussion of patient expectations and likely results. The last should address the fact that the patient’s penis will not return to exactly the way it was before the onset of his symptoms, no matter what intervention is taken.

• Consider penile plication when there is good erectile function, a simple curvature of 60 degrees or less and no significant hourglass or hinge type deformity. Simple plication of the tunica without excision or plication after linear incision appear to maximize results with minimal side effects. Some loss of penile length can be anticipated. Proper patient selection and counseling are necessary to maximize postoperative satisfaction.

• If the patient retains erectile capability but has a complex curvature or one that is > 60 degrees, or if there is erectile instability due to an hourglass or hinge deformity, then plaque incision with graft placement should be considered.

• When PD and ED are both present, the best therapy appears to be implantation of a penile prosthesis with modeling or, in men with extreme curvature, plaque incision with or without graft placement.

FUTURE AND CONTROVERSIES

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In 2000, Anderson et al developed an in vitro tissue model with fibroblasts cultured from Peyronie plaque tissue along with fibroblasts from normal tunica and foreskin as controls. The authors investigated the effects of the addition of various agents, including PGE1, colchicine, or verapamil at various concentrations, on the inhibition of fibroblast proliferation. In this pilot study, they found inhibition to occur at high levels of each of the agents tested. However, they also found no statistically significant proliferation rates between the plaque and the normal tunical cells, suggesting that the effect may not be selective to PD. It may be the result of the high concentrations used in the study. Nevertheless, this model holds promise as a means to develop and test new pharmacological regimens for treating PD.

TEST QUESTIONS

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CME Question 1: The indications for surgical intervention for Peyronie disease include which of the following?

A: Symptoms should be present for at least 1 year and/or calcification of the plaque with stabilization of the curvature should be present.
B: The condition should be debilitating and prohibit satisfactory sexual intercourse.
C: The patient's desire for his penis to be perfect again should factor heavily into the decision to proceed with surgery.
D: Both A and C
E: Both A and B

The correct answer is E: Before treating Peyronie disease with surgical intervention, the physician should confirm that the symptoms have been present for at least 1 year or that the plaque is calcified and stable. Surgery should only be offered to men in whom the plaque and/or curvature cause debilitating symptoms, such as loss of ability to perform satisfactory sexual intercourse.

CME Question 2: Which of the following statements about Peyronie disease is true?

A: Because the Peyronie plaque is fibrotic in nature, no chance of spontaneous resolution exists and medical therapy rarely helps.
B: Before surgical treatment is considered, giving the patient’s condition a chance to resolve either spontaneously or with less invasive medical therapy is wise.
C: Surgical therapy is best if initiated early, before the plaque has a chance to spread.
D: Medical therapy works best when initiated early, before the plaque becomes calcified.
E: Both B and D

The correct answer is E: Because some patients with Peyronie disease improve spontaneously and others respond to less invasive treatments, each patient should be given a trial of observation or medical intervention before he is subjected to a surgical procedure. Usually, when the plaque is calcified, no response to either observation or medical therapy occurs.

Pearl Question 1 (T/F): Discussing expectations for the result of treatment with the patient before initiating therapy for Peyronie disease is wise to ensure that the patient and his partner have a realistic expectation of the anticipated outcome.

The correct answer is True: A detailed discussion of the procedure with the patient is necessary. This discussion should include a description of the procedure proposed, the ultimate goal of the procedure, the risks of the procedure, the chances for success, and the alternative methods of treatment available. If possible, the patient`s partner should be included in this discussion. When counseling a patient for any of the surgical interventions, advising him that his penis will not look exactly as it did prior to the development of Peyronie disease is important. Some residual angling may remain, it may look wider, and it will probably be somewhat shorter than before his symptoms started. This conversation is essential so that the patient will have a realistic expectation of the anticipated results. The time spent on this issue before surgery may save considerably more time and frustration on the part of both the doctor and the patient postoperatively.

Pearl Question 2 (T/F): The calcium channel blocker verapamil has gained attention in the treatment of Peyronie disease because it was found to increase vasodilatation in the scar.

The correct answer is False: Verapamil was found to increase collagenase activity, not vasodilatation.

Pearl Question 3 (T/F): Potassium aminobenzoate should be the first line of treatment for Peyronie disease because it is easy to administer, one pill a day, and has an excellent chance of being successful.

The correct answer is False: Although potassium aminobenzoate can be used as a first line of therapy, it is not well tolerated because it requires taking 24 pills (12 g) daily and is associated with indigestion. The chance of success with this treatment varies greatly. Most investigators find 25-50% subjective improvement.

Pearl Question 4 (T/F): When a patient has both Peyronie disease and erectile dysfunction, the most prudent course of therapy is implantation of a penile prosthesis after a trial of medical therapy.

The correct answer is True: When erectile dysfunction accompanies penile curvature, the patient should be counseled for implantation of a penile prosthesis at the time of correction of the angulation. Either a semirigid or an inflatable prosthesis can be used.

PICTURES

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Caption: Picture 1. Penile angulation indicative of Peyronie disease. Courtesy of Allen Seftel, MD.
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Caption: Picture 2. MRI of the penis in the axial plane (T1-weighted image). The penis is in the erect position with the corpus spongiosum located ventrally (upper part of the frame). The tunica albuginea can be seen as the dark band outlining the corpora cavernosa. The tunica albuginea appears irregular and heterogeneous dorsally, which is consistent with the presence of a fibrous plaque. The image on the left is without annotation. The image on the right is identical but with annotation. Courtesy of Evan H. Dillon, MD
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Caption: Picture 3. Precontrast MRI of the penis in the axial plane (T1-weighted image with fat saturation). Preaxial image demonstrates lack of definition of the tunica albuginea in the dorsal aspect of the penis. The image on the left is without annotation. The image on the right is identical but with annotation. Courtesy of Evan H. Dillon, MD.
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Caption: Picture 4. Postcontrast MRI of the penis in the axial plane (T1-weighted image with fat saturation). Image obtained after the injection of gadolinium demonstrates enhancement of the tunica albuginea in the dorsal aspect of the penis. Enhancement reflects the presence of active inflammation in the region of the plaque. The image on the left is without annotation. The image on the right is identical but with annotation. Courtesy of Evan H. Dillon, MD.
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Caption: Picture 5. Skin is incised through previous circumcision and retracted. Artificial erectin is achieved with injection of NS via butterfly with tourniquet at base of penis. This demonstrates 45 degree curvature of the penile shaft to patient's left.
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Caption: Picture 6. Buck's fascia has been incised along the convex, right side of the penile shaft to expose the tunica albuginea. The right dorsal neurovascular bundle has been dissected from the tunica albuginea (left side of figure). Parallel incisions have been made through the tunica albuginea to allow plication of the convex side of the shaft.
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Caption: Picture 7. The isthmus of tunical tissue has been buried by suturing the proximal side of the proximal incision to the distal side of the distal incision. Another set of incisions were placed distal to the original set for further correction of the curvature. These were then sutured in a similar fashion. The second suture line can be seen closer to the corona.
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Caption: Picture 8. Buck's fascia and the skin layer have each been reapproximated. A repeat artificial erection demonstrates correction of the curvature. Teh penis is then dressed with xeroform gauze and Coban dressing.
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BIBLIOGRAPHY

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