Male infertility and urological tumors: Pathogenesis and therapeutical implications.

Most genitourinary tract cancers have a negative impact on male fertility. Although testicular cancers have the worst impact, other tumors such as prostate, bladder, and penis are diagnosed early and treated in relatively younger patients in which couple fertility can be an important concern. The purpose of this review is to highlight both the pathogenetic mechanisms of damage to male fertility in the context of the main urological cancers and the methods of preserving male fertility in an oncological setting, in light of the most recent scientific evidence. A systematic review of available literature was carried out on the main scientific search engines, such as PubMed, Clinicaltrials.Gov, and Google scholar. Three hundred twenty-five relevant articles on this subject were identified, 98 of which were selected being the most relevant to the purpose of this review. There is a strong evidence in literature that all of the genitourinary oncological therapies have a deep negative impact on male fertility: orchiectomy, partial orchiectomy, retroperitoneal lymphadenectomy (RPLND), radical cystectomy, prostatectomy, penectomy, as well as radiotherapy, chemotherapy, and hormonal androgen suppression. Preservation of fertility is possible and includes cryopreservation, hormonal manipulation with GnRH analogs before chemotherapy, androgen replacement. Germ cell auto transplantation is an intriguing strategy with future perspectives. Careful evaluation of male fertility must be a key point before treating genitourinary tumors, taking into account patients' age and couples' perspectives. Informed consent should provide adequate information to the patient about the current state of his fertility and about the balance between risks and benefits in oncological terms. Standard approaches to genitourinary tumors should include a multidisciplinary team with urologists, oncologists, radiotherapists, psycho-sexologists, andrologists, gynecologists, and reproductive endocrinologists.

The clinical use of statistical permutation test methodology: a tool for identifying predictive variables of outcome.

OBJECTIVES: To identify the predictive variables affecting the outcome after radical surgery for bladder cancer by a newer statistical methodology, i.e. nonparametric combination (NPC). METHODS: A multicenter study enrolled 1,312 patients who had undergone radical cystectomy for bladder cancer in 11 Italian oncological centers from January 1982 to December 2002. A statistical analysis of their medical history and diagnostic, pathological and postoperative variables was performed using a NPC test. The patients were included in a comprehensive database with medical history and clinical and pathological data. Five-year survival was used as the dependent variable, and p values were corrected for multiplicity using a closed testing procedure. The newer nonparametric approach was used to evaluate the prognostic importance of the variables. All of the analyses were performed using routines developed in MATLAB© and the significance level was set at α = 0.05. RESULTS: A significant prognostic predictive value (p < 0.01) for tumor clinical staging, hydronephrosis, tumor pathological staging, grading, presence of concomitant carcinoma in situ, regional lymph node involvement, corpora cavernosa invasion, microvascular invasion, lymphatic invasion and prostatic stroma involvement was found. CONCLUSIONS: The NPC test could handle any type of variable (categorical and quantitative) and take into account the multivariate relation among variables. This newer methodology offers a significant contribution in biomedical studies with several endpoints and is recommended in presence of non-normal data and missing values, as well as solving high-dimensional data and problems relating to small sample sizes.

Size of bladder cancers: correlation among different types of measurement.

OBJECTIVE: It was the aim of this study to evaluate the accuracy of the measurement of tumor size comparing the objective size with that measured by preoperative cystoscopy, by preoperative ultrasound (US) and with the diameter described by the operator before the transurethral resection. PATIENTS AND METHODS: This study included 100 patients with bladder papillary endoscopic features of single or multiple neoplasms who were candidates for transurethral resection. The sizes of the same neoplasms measured during preoperative cystoscopy, preoperative US and described by the operator before the transurethral resection were evaluated. A statistical analysis of the errors of measurement was performed if compared with an objective measurement done with an ureteral catheter. RESULTS: The statistical analysis of the data shows that there are no substantial differences between the objective and subjective measurement, and therefore, the measurements reported by individual operators are reliable. On the contrary, the diameters given by preoperative cystoscopy and US differ significantly from the objective measurement. CONCLUSIONS: This study shows that the most reliable measurement is the subjective measurement made directly by the urologist in the operating room.

Thermochemotherapy for non-muscle-invasive bladder cancer: is there a chance to avoid early cystectomy?.

OBJECTIVES: Non-muscle-invasive bladder cancer is characterized by a high recurrence rate after primary transurethral resection. In case of bacillus Calmette-Guérin-refractory neoplasms, cystectomy is the gold standard. In this study the effects of thermochemotherapy with mitomycin C were evaluated in high-risk bladder cancer nonresponders to previous therapy. PATIENTS AND METHODS: Between January 2006 and December 2009, 30 patients were enrolled with recurrent stage carcinoma in situ, Ta and T1, grade G1 to G3 non-muscle-invasive bladder cancer refractory to chemotherapy or immunotherapy and so becoming suitable for radical cystectomy. All patients underwent endovesical thermochemotherapy: 16 patients underwent a prophylactic scheme and 14 patients underwent an ablative scheme. RESULTS: All the patients completed the study. The mean follow-up for all the patients enrolled was 14 months. Thirteen of 30 patients (43.30%) were disease free and 17 patients (56.70%) had recurrence. In the prophylactic group, 7 of 16 patients (43.75%) were disease free and 9 patients (46.25%) had tumor recurrence; no progression was observed. In the ablative group, 3 patients (17, 64%) had progression to muscle-invasive disease. Side effects were generally mild. CONCLUSIONS: Thermochemotherapy could be considered an additional tool in patients refractory to intravesical therapies before considering early cystectomy.

Value of current chemotherapy and surgery in advanced and metastatic bladder cancer.

The aim of the present paper was to review findings from the most relevant studies and to evaluate the value of current chemotherapy and surgery in advanced unresectable and metastatic bladder cancer. Studies were identified by searching the MEDLINE® and PubMed® databases up to 2011 using both medical subject heading (Mesh) and a free text strategy with the name of the known individual chemotherapeutic drug and the following key words: 'muscle-invasive bladder cancer', 'chemotherapeutics agents', and 'surgery in advanced bladder cancer'. At the end of our literature research we selected 141 articles complying with the aim of the review. The results showed that it has been many years since the MVAC (methotrexate, vinblastine, adriamycin, cisplatin) regimen was first developed. The use of cisplatin-based combination chemotherapy is associated with significant toxicity and produces long-term survival in only approximately 15-20% of patients. Gemcitabine + cisplatin represents the gold standard in the treatment of metastatic bladder cancer. In conclusion, the optimal approach in the management of advanced urothelial cancer continues to evolve. Further progress relies on the expansion of research into tumor biology and an understanding of the underlying molecular 'fingerprints' that can be used to enhance diagnostic and therapeutic strategies. Cisplatin-based therapy has had the best track record thus far.

Paclitaxel-hyaluronic acid for intravesical therapy of bacillus Calmette-Guérin refractory carcinoma in situ of the bladder: results of a phase I study.

PURPOSE: Carcinoma in situ represents high grade anaplasia of the bladder mucosa. Intravesical immunotherapy with bacillus Calmette-Guérin is the gold standard treatment for patients with carcinoma in situ. Patients with carcinoma in situ refractory to bacillus Calmette-Guérin are candidates for major surgery such as radical cystectomy. We identified the maximum tolerated dose and the recommended dose, and evaluated the safety profile of paclitaxel-hyaluronic acid bioconjugate given by intravesical instillation to patients with carcinoma in situ refractory to bacillus Calmette-Guérin. MATERIALS AND METHODS: A total of 16 patients with carcinoma in situ refractory to bacillus Calmette-Guérin were enrolled in a phase I, open label, single institution study. A minimum of 3 eligible patients were included per dose level. Paclitaxel-hyaluronic acid solution (ONCOFID-P-B™) was administered for 6 consecutive weeks. The primary objective was to identify the maximum tolerated dose and the recommended dose. As secondary objectives the safety profile of ONCOFID-P-B, the pharmacokinetic profile after each instillation and the tumor response were also evaluated. RESULTS: No dose limiting toxicity occurred at any drug level evaluated. The plasma levels of the study drug were always below the lower limit of quantification at all tested doses after each instillation. A total of 11 adverse events were reported by 7 patients and 9 (60%) showed complete treatment response. CONCLUSIONS: Intravesical instillation of ONCOFID-P-B for carcinoma in situ refractory to bacillus Calmette-Guérin showed minimal toxicity and no systemic absorption in the first human intravesical clinical trial to our knowledge. Finally, satisfactory response rates were observed.

[Prostatitis syndromes and sporting activities]. / Sindromi prostatiche e sport.

INTRODUCTION: Prostatitis-like syndromes are high prevalent health problems and frequently considered by patients and physicians as strictly correlated to sports causing perineal compression. These syndromes and their relationships with sporting activities have been discussed in this report. METHODS: We reviewed peer-reviewed scientific articles published by May 2009 and searched according to the following term selection: prostatitis, pudendal nerve, sport, cycling. RESULTS: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a major healthcare burden heavily affecting patients' Quality of Life. No clear evidence of any direct etiologic relationship has been found in literature between prostatitis, either bacterial or non-bacterial, and sports activities. On the other hand, some types of sport causing perineal compression, such as cycling, can exacerbate symptoms of acute and chronic prostatitis; a temporary sport discontinuation is justified in these patients. CP/CPPS may be often caused by pudendal nerve entrapment (PNE). Prostatitis-like urogenital neuropathic pain together with voiding and sexual dysfunctions are the hallmark of PNE. A common feature is that flexion activities of the hip, such as climbing, squatting, cycling provoke or worsen urogenital pain or pelvic pain. Many of the patients with PNE are cyclists, played American football, lifted weights, or wrestled as teenagers and young adults. PNE represents the most common bicycling associated urogenital problems. CONCLUSIONS: Overall, studies show that no causal relationship has been demonstrated between prostatitis and sporting activities. Conversely, urologists should be aware that sports involving vigorous hip flexion activities or prolonged perineal compression are a potential and not an infrequent cause of uroandrological symptoms caused by pudendal nerve entrapment.

[Sports and genitourinary traumas]. / Sport e traumi genitourinari.

INTRODUCTION: Statistical data referring to sports-related traumas of the urinary tract are quite scarce; nevertheless, it is possible to draw general data on the relationship between sports and urological traumas. METHODS: Literature review of peer-reviewed articles published by May 2009. RESULTS: Urological traumas account for about 10% of all traumas, and about 13% of them is sports-related. Genitourinary traumas are among the most common cause of abdominal injuries in sports. Blunt injuries are more common than penetrating ones and renal injuries are by far the most common, followed by testicular injuries; ureters, bladder and penis injuries are much more infrequent. Considering chronic microtraumas, injuries of bulbar urethra are also common in sports that involve riding. Overall, the incidence of genitourinary trauma due to sports is low. Renal traumas in sports injuries usually consist of grade I-II lesions and usually do not require surgical treatment. Cycling is the sporting activity most commonly associated with genitourinary injuries, followed by winter sports, horse riding and contact/collision sports. Literature data suggest that significant injuries are rare also in athletes with only one testicle or kidney. General preventive measures against sport-related injuries, along with the use of protective cups for male external genitalia, are generally sufficient to reduce the incidence of urogenital trauma. CONCLUSIONS: Overall, studies show that urogenital injuries are uncommon in team and individual sports, and that most of them are low-grade injuries. Participation in sports that involve the potential for contact or collision needs to be carefully assessed in the athletes with only one testicle or kidney, even though urogenital injuries should not preclude sports participation to an appropriately informed and counseled patient. Further research is needed to acquire more knowledge on genitourinary injuries according to age, sports type and technical skill.

[Doping and urologic tumors]. / Doping e neoplasie urologiche.

Several substances such as growth hormone (GH), erythropoietin (Epo), and anabolic steroids (AS) are improperly utilized to increase the performance of athletes. Evaluating the potential cancer risk associated with doping agents is difficult since these drugs are often used at very high doses and in combination with other licit or illicit drugs. The GH, via its mediator, the insulin-like growth factor 1 (IGF-1), is involved in the development and progression of cancer. Animal studies suggested that high levels of GH/IGF-1 increase progression of androgen-independent prostate cancer. Clinical data regarding prostate cancer are mostly based on epidemiological studies or indirect data such as IGF-1 high levels in patients with prostate cancer. Even if experimental studies showed a correlation between Epo and cancer, no clinical data are currently available on cancer development related to Epo as a doping agent. Androgens are involved in prostate carcinogenesis modulating genes that regulate cell proliferation, apoptosis and angiogenesis. Most information on AS is anecdotal (case reports on prostate, kidney and testicular cancers). Prospective epidemiologic studies failed to support the hypothesis that circulating androgens are positively associated with prostate cancer risk. Currently, clinical and epidemiological studies supporting association between doping and urological neoplasias are not available. Nowadays, exposure to doping agents starts more prematurely with a consequent longer exposition period; drugs are often used at very high doses and in combination with other licit or illicit drugs. Due to all these elements it is impossible to predict all the side effects, including cancer; more detailed studies are therefore necessary.

[Sport, infertility and erectile dysfunction]. / Sport, sterilità e disfunzione erettile.

In the last decades a growing interest has been dedicated to prevention, diagnosis and therapy of male genital pathologies, such as varicocele, infertility and erectile dysfunction in the population involved in sport activities. High incidence (up to 30%) of varicocele has been reported in a population of athletes and up to 60-80% in the subgroup of body-builders. The incidence of varicocele specifically increases with hours of training, in a linear model. Controversial data come from literature about the effects of physical activity on fertility, with prevalence of trials demonstrating worsening of seminal parameters. Furthermore, it has been demonstrated that physical stress in healthy male athletes can interfere with LH levels. Bicycling is one of the major risk factors for erectile dysfunction, with incidence of 13-24%. This is due to the prolonged compression of perineal arteries leading to reduced chronic penile perfusion. Bioengineering studies have been the basis for industry to produce specifically shaped saddles that significantly reduce and minimize compressive effects. Finally, high frequency of lower urinary tract symptoms (LUTS) in cyclists has been related to increased incidence of erectile dysfunction in comparison with normal population.

[Androgen-deprivation therapy in prostate cancer: clinical evidence and future perspectives]. / La deprivazione androgenica nel carcinoma prostatico: evidenze cliniche e prospettive future.

Androgens are involved in the development and progression of prostate cancer even if the mechanism is not well-recognized. For this reason androgen-deprivation therapy remains a milestone for the treatment of patients with advanced and metastatic disease and, in the last years, in conjunction with radiotherapy and surgery in locally advanced tumors. Alternative options, such as intermittent deprivation suppression, seem to be promising in terms of clinical benefits and toxicity profile. However, current therapies present side effects, such as testosterone surge with consequent clinical flare-up, metabolic syndrome and hormone-resistance, which develops after a variable number of years. Novel therapies such as LH-RH antagonists and prolonged depot LH-RH analogues have been developed in order to avoid clinical flare-up and testosterone microsurges. Novel androgen synthesis inhibitors, such as abiraterone acetate and MDV3100, have been recently discovered and tested as promising hormonal second-line agents in patients with castration-resistant prostate cancer. Finally, long-term side effects from androgen deprivation, such as osteoporosis, sarcopenic obesity and cardiovascular morbidity should be carefully monitored and properly treated.

Mitomycin C for the treatment of bladder cancer.

Bladder cancer is a heterogeneous disease: approximately 75% of its forms are non muscle invasive neoplasms. Standard treatment for non muscle invasive bladder cancer (NMIBC) consists of complete transurethral resection (TURB) of all visible lesions. Recurrence rates following TURB and intravesical chemoprophylaxis seem to decrease to 25-50% in 2 years of follow-up. The aim of the present paper is to review findings from the most relevant studies and evaluate the potentials of mitomycin C (MMC) in the treatment of non muscle invasive bladder cancer. Studies were identified by searching MEDLINE(R) and Pubmed(R) databases up to 2010 using both medical subject heading (Mesh) and a free text strategy with the name of known individual chemotherapeutic drug and the following key words: "non muscle-invasive bladder cancer", "intravesical therapy", "Mitomycin C", "Device Therapy". At the end of our research in literature we selected 66 articles. From literature is clear that in case of low or intermediate risk superficial bladder cancer, MMC is one of the most used agents with limited side effects. In fact MMC has a high molecular weight and is relatively hydrophobic, resulting in less sistemic absorption. Regimens are based on weekly instillations but despite many studies there is not universal consensus on timing and duration of therapy. MMC early istillation seems effective in preventing tumour recurrence in low risk non muscle invasive neoplasms. MMC maintenance chemotherapy continue to be considered effective in reducing tumour recurrence rate in low and intermediate risk tumours. It is known in literature that the lack of response to intravesical chemotherapy in patients with non muscle invasive bladder cancer is due to two factors: lack of sensitivity of the neoplasm to intravesical chemotherapy and inadequate drug delivery to the tumour. In order to resolve these limitations in the last years MMC, in many centers, is used with device assisted therapies or with new administration scheme.

Methodology of superficial bladder cancer trials: objective evaluation of treatment - the need for standardization.

The formulation of proper evaluation criteria after superficial bladder cancer therapy poses several methodological problems that are often peculiar to the disease. The Achilles' heel of many trials is possibly found in the criteria used in the evaluation of the trial's outcome. As a consequence, total agreement regarding the criteria for response and the evaluation of response is needed. The adoption of standard response criteria should be given high priority. Uniform criteria of response should be chosen because they meet standards of reliability and statistical validity. Thus, the criteria must be reproducible and correlate with some measures of patient benefit such as quantity and quality of survival. A proposal for standardization in superficial bladder cancer clinical trials is presented based upon the current knowledge of methodology used for conducting clinical trials and upon the experience coming from clinical research groups.

[Integrated treatment with hyperthermia and chemotherapy for non-muscle invasive bladder cancer].

Oncology-applied hyperthermia is a very old form of therapy. In recent years hyperthermia has been investigated with the aim of improving the treatment for non-muscle invasive bladder cancer to prevent relapse and disease progression, in association with mitomycin-C, a well-known chemotherapeutic agent, to enhance its effect. Target patients are those with non-muscle invasive transitional cell carcinoma, showing medium (Ta-T1, G1-2, multifocal, diameter >3 cm) or high (T1, G3, multifocal or rapidly relapsing, CIS) risk for recurrence or progression. The treatment may be prophylactic following tumor eradication, or ablative when tumor cannot be otherwise eradicated. Several studies have shown the benefits of thermochemotherapy with lower risk for relapse than other treatment options, and 66-80% complete responses following ablative treatment. This association of treatments has a synergic therapeutic effect, higher than administering hyperthermia and drug therapy as single treatment.

[Contrast media in urogenital radiology].

BACKGROUND. Contrast media are widely used in urogenital radiology. The ideal contrast agent should be totally inert, causing no interactions with organism, and with a rapid and complete excretion. Adverse reactions could occur after using any type of contrast media. Contrast enhanced procedures are performed with increasing frequency and the patients population is progressively older and with multiple co-morbid conditions, thus contrast media toxicity is becoming a serious problem. Contrast media-induced nephropathy (CIN) is considered an important cause of hospital-acquired renal failure. The administration of gadolinium-based contrast agents has been recently associated with the development of a serious adverse reaction, potentially lethal in patients with renal insufficiency, named nephrogenic systemic fibrosis (NSF). METHODS. Literature review on contrast media in urogenital radiology, CIN, NSF. CONCLUSIONS. Since 1996, the Contrast Media Safety Committee of the European Society of Urogenital Radiology (ESUR) has released its guidelines regarding safety about the use of contrast media. CIN, and the emerging NSF, are topics of increasing interest for urologists, radiologists, nephrologists, dermatologists and all the clinicians. Contrast media have progressively become safer in the last years. Even if rare, some adverse reactions still occurr up to now. CIN and its prevention remain an issue under debate. In the past, whenever a patient required a contrast-enhanced imaging study, the trend was to select magnetic resonance imaging with gadolinium-based contrast agents in order to avoid the well-known CIN of iodinated-based contrast agents. The awareness of NFS is changing the contrast-enhanced imaging in patients with renal failure. At present we have to investigate NSF etiopathogenesis, in order to prevent and eventually to cure it. The understanding of the risk factors for both CIN and NSF is an emerging need, the adoption of all preventive measures to reduce the risks remain a mandatory issue.

Benign prostatic hyperplasia as a progressive disease: a guide to the risk factors and options for medical management.

Benign prostatic hyperplasia (BPH) is a complex disease that is progressive in many men. BPH is commonly associated with bothersome lower urinary tract symptoms; progressive disease can also result in complications such as acute urinary retention (AUR) and BPH-related surgery. It is therefore important to identify men at increased risk of BPH progression to optimise therapy. Several factors are associated with progression, including age and prostate volume (PV). Serum prostate-specific antigen level is closely correlated with PV, making it useful for determining the risk of BPH progression. Medical therapy is the most frequently used treatment for BPH. 5-alpha-reductase inhibitors impact the underlying disease and decrease PV; this results in improved symptoms, urinary flow and quality of life, and a reduced risk of AUR and BPH-related surgery. Alpha-blockers achieve rapid symptom relief but do not reduce the overall risk of AUR or BPH-related surgery, presumably because they have no effect on PV. Combination therapy provides greater and more durable benefits than either monotherapy and is a recommended option in treatment guidelines. The Combination of Avodart and Tamsulosin (CombAT) study is currently evaluating the combination of dutasteride with tamsulosin over 4 years in a population of men at increased risk of BPH progression. A preplanned 2-year analysis has shown sustained symptom improvement with combination therapy, significantly greater than with either monotherapy. CombAT is also the first study to show benefit in improving BPH symptoms for combination therapy over the alpha-blocker, tamsulosin, from 9 months of treatment.

[Therapeutic education in urology: a fundamental resource for the sick and the health carers].

Therapeutic Education (TE) means to build a partnership between doctors and patients comparing knowledge and therapeutic procedures to manage the disease and its treatment. Patients cannot be a mere passive beneficiary of therapeutic services, but they must play an active role, be conscious and participate in charging proper and community health. Patient TE is a pathway characterized by an "educational diagnosis" including identification of patient demands about pathology; an "educational-therapeutic policy" based on assignment of tasks and rules to manage every aspect of pathology; and the "evaluation" of results of patients' educational process. The aim of TE is to allow the patients to know their pathology, to properly perform therapeutic procedures, to self-manage and prevent complications and to adopt a correct lifestyle. It can be useful to organize theoretical and practical lessons reserved to groups of patients. TE can be applied to urologic pathologies. These pathologies are often chronic diseases and affect elderly patients, who are organically and psychologically fragile. Urologic patients must often manage urostomies, urinary drains, complex follow-up plans. The patients' learning about procedures and disease management represents a professional duty of the urologic team: bladder and prostate cancer, urinary drains management are fields where we can apply a TE plan to support and safeguard the patients' health.

[Phytotherapy in urology].

Complementary and alternative medicine (CAM) includes various practices, measures and products which are not presently considered as part of the conventional (mainstream) medicine. Herbal products, vitamins, minerals and amino acids are increasingly popular as dietary supplements for the treatment, improvement and prophylaxis of urological diseases, and as therapeutic options to improve general health and well-being. As these products are available for free without prescription, conventional healthcare providers are often unaware that their patients are using CAM. A particular attention is paid to herbal products by the public. For this reason it is essential to know that some herbal supplements may act in the same way as chemical drugs, and that the fact that they originate 'from nature' does not mean that they are safe and/or with no potential harmful effects and/or toxicity. The possible interactions with conventional medications and contamination with prescription drugs and metals have been reported. The active components of many phytotherapeutic preparations and their mechanism(s) of action are still being determined and evaluated. There is scientific evidence for the effectiveness of some treatments, but for most of them, many important key questions still need to be answered through basic research and well-designed studies, according to established guidelines. Because of the increasing popularity and use of Phytotherapy, urologists should not ignore it, and be well informed about its benefits and potential risks.

[Botulinum toxin in the treatment of overactive bladder].

Clinical effectiveness of botulinum toxin (BTX) in the treatment of both neurogenic and idiopathic detrusor overactivity has been demonstrated in several studies. However, different protocols and techniques have been used by authors. METHODS. Literature review on intradetrusor injection of BTX for detrusor overactivity. RESULTS. The greatest clinical experience reports the use of 200 and 300 U Botox®. Available data suggest that clinical efficacy, duration, and the side effect profile is similar at these doses. Very few data, on the other hand, are available regarding the clinical outcomes using the Dysport® preparation; isolated reports support that efficacy is similar when using a dosing range of 500 to 1000 SU with increased risk of systemic side effects using 1000 SU. A variety of injection volumes was used, demonstrating similar efficacy and tolerability profile. Clinical effect duration extends six to ten months in the majority of studies. Data suggest that a repeated injection scheme proves successful in the vast majority of initial responders. CONCLUSIONS. Safety, effectiveness, specificity and reversibility make BTX a new attractive treatment modality for overactive bladder syndrome. However, more experience is needed to standardize the injection protocol with respect to therapeutic outcomes and adverse effects.