Injectables in the prostate

PURPOSE OF REVIEW: Benign prostatic hyperplasia with associated symptoms and morbidity is increasingly common among aging men. Medical treatment of lower urinary tract symptoms is the mainstay of therapy with progressive disease requiring more invasive intervention. Transurethral resection of the prostate remains a widely applied gold standard therapy. Numerous minimally invasive surgical therapy options have arisen and subsequently faded over recent years. Those remaining in use are largely positioned between pharmacological treatment and transurethral resection of the prostate. Intraprostatic injection therapy, the oldest minimally invasive surgical therapy, has been investigated for over 100 years with renewed interest recently. This review will provide some history of intraprostatic injection for benign prostatic hyperplasia including the most recent reports using transperineal, transrectal and transurethral routes with different injectables. RECENT FINDINGS: For benign prostatic hyperplasia, transperineal and transurethral injection routes have received the most systematic evaluation. Intraprostatic injection of botulinum toxin type A has received much recent attention with regards to mechanism of action and efficacy. Anhydrous ethanol remains the most extensively studied injectable to date. SUMMARY: Injection therapy remains a very promising minimally invasive surgical therapy for benign prostatic hyperplasia with increased attention from the urologic community in recent years. Further experience both with systematic laboratory and clinical trials investigation will be necessary before widespread clinical adoption.     

Treatment of outflow tract obstruction due to benign prostatic hyperplasia with the pollen extract, cernilton. A double-blind, placebo-controlled study.

Whilst prostatectomy remains the "gold standard" for the treatment of outflow tract obstruction due to benign prostatic hyperplasia, medical treatment--if only for symptomatic relief--appears to be an attractive alternative. Most of the pharmacological agents in use block the hormonal or the sympathetic neurological pathways that influence prostate growth and function. All of these drugs are known to have side effects. Sixty patients with outflow obstruction due to benign prostatic hyperplasia (BPH) were entered into a double-blind, placebo-controlled study to evaluate the effect of a 6-month course of the pollen extract, Cernilton. There was a statistically significant subjective improvement with Cernilton (69% of the patients) compared with placebo (30%). There was a significant decrease in residual urine in the patients treated with Cernilton and in the antero-posterior (A-P) diameter of the prostate on ultrasound. However, differences in respect of flow rate and voided volume were not statistically significant. It is concluded that Cernilton has a beneficial effect in BPH and may have a place in the treatment of patients with mild or moderate symptoms of outflow obstruction.     

Ethanol injection for the treatment of benign prostatic hyperplasia

Recent studies examining the benefit of prostatic ethanol injection for symptomatic benign prostatic hyperplasia (BPH) have demonstrated significant postsurgical improvements (after 1 to 3 months) in BPH parameters such as symptom score, flow rate, and postvoid residual. Transperineal and transurethral injection routes have been reported to be safe and well-tolerated in men. Animal and human studies demonstrate that this treatment has a direct necrotic effect on prostatic tissue with negligible systemic absorption. Although this technique demonstrates promise as a minimally invasive treatment for BPH, further study of a large series of men is clearly required to define its benefit.     

A study of the radiologic predictors of curve flexibility in adolescent idiopathic scoliosis

STUDY DESIGN: A study of flexibility of 101 idiopathic scoliosis antero-posterior radiographs. OBJECTIVE: To discover if there are any parameters on plain antero-posterior radiographs that can predict the flexibility of scoliosis curves. SUMMARY OF BACKGROUND DATA: Previously the flexibility index, generated from fulcrum bending x-rays, has been shown to be an accurate measure of curve stiffness. METHODS: Five postulated predictors of flexibility, measured on 101 immediate preoperative scoliosis radiographs, were compared with the flexibility index generated from fulcrum bending radiographs. Correlation between the 5 parameters and flexibility index was studied. Further analysis was performed to assess the significance of curve location in prediction of flexibility. Linear regression analysis was used. RESULTS: Linear regression including all 5 predictors showed Cobb angle and age to be the only significant predictors of flexibility. When Cobb angle and age were analyzed with location (thoracic, thoracolumbar) this was also found to be a significant factor. CONCLUSIONS: Cobb angle, age, and curve location are useful predictors of flexibility on antero-posterior radiographs. This may aid preoperative planning in the out-patients department.     

Botulinum toxin A treatment for lower urinary tract symptoms/benign prostatic hyperplasia

Botulinum toxin A (BoNT-A) has been widely used in the treatment of overactive bladder and neurogenic detrusor overactivity. Recently, prostatic injection of BoNT-A had been tried to reduce the prostate volume and relieve lower urinary tract symptoms (LUTS) in patients with benign prostatic enlargement (BPE) due to benign prostatic hyperplasia (BPH). However, the efficacy of BoNT-A on BPE is still controversial. Traditionally, male LUTS have been considered as synonym of BPE because most male LUTS developed in aging men. Recent investigations have revealed that bladder dysfunction and bladder outlet dysfunction other than BPE contribute equally in male LUTS. Injecting BoNT-A into the prostatic urethra and bladder neck yielded improvement of LUTS, but not reduction of the prostatic volume, especially in men with small prostatic volume. The therapeutic effects of BoNT-A on LUTS might not be due to prostatic volume reduction, but through inhibiting the adrenergic hyperactivity in men with LUTS/BPH. This article discusses the current consensus and controversy of BoNT-A treatment on LUTS/BPH.     

Assessment of voiding disorders and conservative pharmacological treatment of benign prostatic hypertrophy

The symptoms of benign prostatic hypertrophy consist of two major groups, obstructive symptoms and irritative symptoms. Uroflowmetry is a safe, easy and accurate method to assess the obstructive symptoms. Furthermore, electromyography of abdominal wall and the monitoring of rectal pressure is helpful to know involvement of abdominal straining. Cystometry provides us objective findings of bladder irritability in bladder outlet obstruction. Detrusor hyperreflexia was revealed in 55%, and uninhibited detrusor contraction was revealed in 22.5% of the patients with benign prostatic hypertrophy. The most sophisticated technique to estimate the volume of prostatic adenoma is transrectal ultrasonotomography. The value, cranio-caudal X left-right X antero-posterior axis length, has been proved to closey correlate to the resected volume of the prostatic adenoma. However there was no correlation between the estimated prostatic volume and the severity of dysuria. The comparison of the uroflow rates before and after loading phentolamine is a helpful method to determine the sympathetic influence to lower urinary tract obstructions. This test differentiates functional obstruction from organic obstruction. Conservative pharmacological therapy on the patients with benign prostatic hypertrophy were also studied. The value of efficacy of prazocine hydrochloride (0.5-6.0 mg/day), Eviprostat (6Tab/day), Prostetin (200-400 mg/day), Hachimi-Jiogan (5 g and 7.5 g/day) on subjective symptoms were 47.8 86.2, 58.5, 52.9 and 66.7% respectively. Ninety-one of the 141 patients with benign prostatic hypertrophy who visited the out-patient clinic in 1983 were given pharmacological treatment initially.     

Correlation of embryonic development and adult neoplastic changes of human prostate

We have studied embryonic and fetal differentiation of the human prostate in relation to androgen-producing Leydig cell differentiation. We have studied the differentiation of human prostatic glands and the synthesis of acid phosphatase in vivo and in vitro. These studies have shown that the mesenchyme at the level of the openings of the para- and mesonephric ducts to the urethra was the local initiator of prostatic differentiation. All prostatic acini developed by epithelial outgrowths from the urethral epithelium. None of them grew from para- or mesonephric ducts. However, the epithelium on the colliculus seminalis differed from the rest of the urethral epithelium morphologically and in acid phosphatase content. Androgens accelerated differentiation in vitro and acid phosphatase activity was shown to be present in prostatic urethral epithelium and prostatic acini both in vivo and in vitro. According to these studies embryonic differentiation gives no direct answer to the localisation of adult neoplastic changes in different parts of the prostate, although in the posterior part there might be a mixture of cells from ductal and urethral epithelium. Secretion of acid phosphatase seems to be a constitutional phenomenon of this part of epithelium and is partly regulated by androgens. Epitheliomesenchymal interaction is important in differentiation and the role of this interaction in adult diseases might be valuable to be studied.     

Prostatic ultrasonography: a useful technique?

Two hundred and forty-four transrectal prostatic ultrasonograms have been reviewed and the findings compared with the final pathological or clinical diagnosis. A high degree of accuracy was achieved in diagnosing benign prostatic hyperplasia. Ultrasonography proved invaluable in staging proven prostatic carcinomas but it was disappointing as a primary diagnostic tool for cancer, with false positive and negatives rates of 12 and 31% respectively. These findings are discussed in the light of other workers' results. Further applications for prostatic ultrasonography are outlined.     

Tissue culture in the investigation of prostatic cancer

Conclusions Tissue culture has a great potential value in the investigation of prostatic cancer but the technique has not yet been exploited fully. This is due mainly to inherent practical problems, particularly the fact that very few (if any) prostatic tumours can be established in culture as cell lines and the fact that normal human prostatic epithelium is very rarely available for culture. Nevertheless the method can be used to give information on hormone and drug metabolism by the tissue. Further technical developments should allow us eventually to establish cell lines for study from surgically removed tissue but the problem of providing normal control tissue for comparison is likely to remain.This paper was presented at the International Conference on Prostatic Cancer, Leeds, July 6th–9th, 1976     

Secretion of prostate-specific antigen-suppressing activity by two human prostate carcinoma cell lines

The well-differentiated human prostatic carcinoma cell line LNCaP has often been used as a model to study the modulation of prostate-specific antigen (PSA) expression. In this study, we examined the effect of conditioned medium from two androgen-unresponsive, PSA-negative human prostatic carcinoma cell lines, PC-3 and DU-145, on PSA expression by the LNCaP cells. Our results show, for the first time, that the undifferentiated PC-3 and DU-145 cells secrete a factor that lowers PSA mRNA and protein levels in LNCaP cells. Further characterization of the PSA-suppressing activity indicated that it was trypsin as well as acid sensitive, heat-stable, and ammonium sulfate precipitable. The activity was present in the 30-100-kd fraction of PC-3 and DU-145 conditioned media. This PSA-suppression factor could act in an autocrine manner to render undifferentiated prostatic carcinoma cells PSA negative. It may also be responsible for the lack of increase in serum PSA levels observed in a subset of patients with hormone-resistant prostatic carcinoma.     

Treatment of benign prostatic hypertrophy by a long-acting gonadotropin-releasing hormone analogue: 1-year experience.

Benign prostatic hypertrophy, a common ailment among elderly men, usually is treated by surgery. Since androgens enhance prostatic hypertrophy, their withdrawal seems a logical way to treat this condition. Recently gonadotropin-releasing hormone analogues, known to produce "chemical castration," have been tried in cases of benign prostatic hypertrophy. We report our experience with 20 men treated by a monthly injection of gonadotropin-releasing hormone for prolonged periods. In 17 men treated for 6 months the prostatic volume decreased to an average of 63% of the initial volume; however, this did not correlate with clinical objective improvement. Only 6 men attained normal flow rates. Residual urine volume remained unaltered. Ten patients experienced subjective amelioration, while only 7 (40%) reported objective and subjective improvement. Maximal decrease in prostatic volumes was reached at 9 months of treatment and further treatment did not cause additional shrinkage. At 3 months after discontinuation of treatment prostatic volumes returned to 95 +/- 10.5% of pre-treatment values. A similar decrease in flow rates also was noted. Symptoms remained improved for longer periods. We conclude that this mode of treatment offers little to the majority of men with benign prostatic hypertrophy. Proper patient selection, based perhaps on serum prostate specific antigen, might augment positive results. This therapy should be restricted to patients considered high risk for any surgical and anesthetic intervention, and then it will have to be continued indefinitely.     

Botulinum toxin as a new therapy option for voiding disorders: current state of the art

Botulinum toxin is a presynaptic neuromuscular blocking agent inducing selective and reversible muscle weakness up to several months when injected intramuscularly in minute quantities. Different medical disciplines have discovered the toxin to treat mainly muscular hypercontraction. In urology, indications for botulinum-A toxin have been neurogenic detrusor overactivity, detrusor-sphincter dyssynergia, motor and sensory urge and, more recently, chronic prostatic pain. The available literature was reviewed using Medline Services. The keywords "botulinum-A toxin", "detrusor-sphincter dyssynergia", "neurogenic bladder", "spinal cord injury", "denervation", "chronic prostatic pain", "chronic urinary retention" were used to obtain references. A toxin injection is effective to treat detrusor-sphincter dyssynergia when injected either transurethrally or transperineally. After treatment, external urethral sphincter pressure, voiding pressure and post-void residual volume decreased. The effect lasts between 2 to 9 months depending on the number of injections. Best indications seem to be multiple sclerosis and incomplete spinal cord injury patients suffering from neurogenic detrusor overactivity and detrusor-sphincter dyssynergia. According to the previous results, the use of botulinum-A toxin injections into the external urethral sphincter has been extended to a variety of bladder obstructions and to decrease outlet resistance in patients with acontractile detrusor. In cases of successful treatment, spontaneous voiding re-occurs and catheterization can be resumed. Injections of the toxin into the external urethral sphincter also seem to have a beneficial effect on chronic prostatic pain, presumably by reducing hypertonicity and hyperactivity of the external urethral sphincter. Injections of botulinum-A toxin into the detrusor muscle has first been tested to treat neurogenic detrusor activity in spinal cord injured patients and in myelomeningocele children. Long lasting (mean 9 months) detrusor relaxation occurs after injection of usually 300 units of Botox). Continence is restored in about 95% of the patients and anticholinergic drugs can be markedly reduced or even stopped. Excellent results of botulinum-A toxin injections into the detrusor in neurogenic detrusor overactivity have lead to an expansion of this treatment to incontinence due to idiopathic detrusor overactivity. Although preliminary results are promising, adequate dosage of the toxin required for this indication is not yet known. In conclusion, it appears that botulinum toxin injection into either the external urethral sphincter or the detrusor offers new promising treatment options for many different urological dysfunctions. However, large controlled trials are absolutely required to establish the role of botulinum-A toxin injections in the fields of urology and neurourology on evidence based medicine.     

Human prostatic lymphoscintigraphy. A preliminary report.

A simple method for demonstrating prostatic lymphatic drainage by transrectal injection of 99mTc labelled antimony sulphide colloid into the prostatic capsule has been developed. This technique may be readily applied in clinical practice with obvious potential in the assessment and follow-up of patients with carcinoma of the prostate.     

Clinical studies on endocrine therapy of prostatic carcinoma (1): Multivariate analyses of prognostic factors in patients with prostatic carcinoma given endocrine therapy

The general trend on the treatment for prostatic carcinoma has been changing from endocrine therapy alone to an alternative type according to stage. We evaluated clinically the favorable and unfavorable outcome of endocrine therapy in Japan, so that others will be appropriately evaluated. In a cooperative study made by members of five universities, 572 patients with clinically or histologically reconfirmed prostatic carcinoma were entered in this retrospective study. We studied the true influence of prognostic factors on the prognosis of 497 patients with prostatic carcinoma who had received endocrine therapy, employing multivariate analyses, such as quantification method II, multiple regression analysis and Cox's proportional hazard model. Twelve factors were considered in the study; "age", "stage", "histological findings (structural atypism = SAT, nuclear anaplasia = NAN, Gleason's primary and secondary pattern)", "pretreatment level of total acid (ACP) and of alkaline phosphatase (ALP)", "castration performed or not performed", "doses of estrogen", "type of response of local prostatic tumor and of ACP to endocrine therapy". Analysis of the "importance" of a prognostic factor by a partial correlation determined by quantification method II, revealed "stage" to have the greatest "importance" on prognosis throughout the entire period. "Response of local prostatic tumor", "response of ACP" and "Gleason's primary pattern" tended to be important factors for prognosis, in particular, in the first half period, and "age" and "Gleason's secondary pattern" were important in the latter half. Multiple regression analysis revealed the "stage", once again to be the most influential factor on the prognosis for the entire observation period. Also "response of local prostatic tumor", "SAT" and "Gleason's primary pattern" affected the patients' prognosis in the first half of the observation period. In the latter half, "age" became more of an influential factor than "histological findings". Analysis with Cox's proportional hazard model revealed that "response of ACP", "stage", "age", "Gleason's primary and secondary pattern", and "response of local prostatic tumor" were definitely the more influential prognostic factors, of which chi-square values (or t values) were statistically significant. Comparison of the significant factors in each multivariate analysis revealed that common influential prognostic factors, such as "age", "stage", "histological findings (mainly Gleason's primary and secondary pattern)", "response of local prostatic tumor" and "response of ACP" were coincident to the clinical impression. The clarification of these factors would be clinically beneficial when treating patients with endocrine therapy.     

中药鸦胆子油乳治疗中、晚期前列腺癌

本文报道33例中、晚期前列腺癌采用中药鸦胆子油乳(以下称鸦油乳)注射疗法,对14例C期用鸦油乳腺体内注射+去势术(含2例未去势术)治疗,对19例D期采用鸦油乳腺体内注射和静肪内滴注+去势术(含4例未去势术)治疗后,近期疗效满意。C期14例达CR,D期3例达CR和16例达PR效果。与既往常用之单纯去势、内分泌治疗和放疗相比3年生存率高且无副作用。     

Prostatic Intraepithelial Neoplasia: Influence of Clinical and Pathological Data on the Detection of Prostate Cancer

Purpose

We attempted to characterize patients diagnosed with prostatic intraepithelial neoplasia without concurrent cancer on biopsy who had prostate cancer on subsequent biopsy.

Materials and Methods

The records of 93 patients with low and high grade prostatic intraepithelial neoplasia without concurrent cancer on initial biopsy were analyzed. The relationships among prostatic intraepithelial neoplasia grades, patient age, digital rectal examination, serum prostate specific antigen (PSA), transrectal ultrasound appearance and final pathological results were investigated.

Results

Subsequent carcinoma was found on repeat biopsy in 13.3 percent of patients with low grade and 47.9 percent with high grade prostatic intraepithelial neoplasia (p less than 0.001). In the former group digital rectal examination, patient age, serum PSA and transrectal ultrasound were not predictive of cancer. Transrectal ultrasound appearance, digital rectal examination and serum PSA were statistically different between high grade prostatic intraepithelial neoplasia with and without subsequent cancer (p less than 0.001, p = 0.008 and p = 0.016, respectively, univariate analysis). On multivariate analysis of patients with high grade prostatic intraepithelial neoplasia only digital rectal examination and PSA were predictive of subsequent carcinoma.

Conclusions

High grade prostatic intraepithelial neoplasia is a strong predictor of subsequent cancer, especially in men with abnormal digital rectal examination and elevated serum PSA. Patients with high grade prostatic intraepithelial neoplasia should undergo repeat biopsy to exclude cancer. Further investigations are needed to optimize the treatment of patients with low grade prostatic intraepithelial neoplasia.     

Genito-urinary malacoplakia. Report of 10 cases and review of the literature

The malakoplakia is a rare and benign disease. Its urinary localisation is commonly known. It has no clinical particularity. The diagnosis is histological. The physiopathology is infectious associated with a local macrophage function failure. The treatment associates antibiotic and colinergic drugs. Surgical removal is necessary only when the organ is destroyed. We report 10 cases of urinary malakoplakia with 4 renal localisation's causing pyonephrosis in the majority of cases, 3 prostatic localisation's that were wrongly considered as prostatic adénocarcinoma after a rectal examination and finally 3 testicular localisation's causing a necrotic destruction of the testis. The urinalysis was positive in 4 cases. We did 4 kidney removals, 3 endoscopic prostatic resections and 3 testis removals. The diagnosis was made by the histological examination of the surgical products.     

Testicular blood flow and vasomotion can be maintained by testosterone in Leydig cell-depleted rats

The effect of testosterone supplementation on testicular blood flow, testicular vasomotion, the number of polymorphonuclear leucocytes (PMN's) in testicular blood vessels and prostatic blood flow were studied in rats in which the Leydig cell had been destroyed specifically by a single injection of ethane dimethylsulfonate (EDS). Other rats were supplemented with testosterone by subcutaneous injection of 25 mg testosterone propionate on days 1, 3 and 6. In some experiments, the effect of a single injection of 25 or 125 mg testosterone was studied. Testicular and prostatic blood flow and the number of PMN's in testicular blood vessels decreased, and vasomotion disappeared in Leydig cell-depleted rats, but testosterone supplementation restored all parameters to normal values. Moreover, a single injection of testosterone was able to restore testicular and prostatic blood flow to normal levels but had an inconsistent effect on vasomotion. These results suggest that testosterone may play a role in the physiological control of the testicular microcirculation.     

Characterisation of human prostatic adrenoceptors using pharmacology receptor binding and localisation

Benign prostatic enlargement is a common cause of bladder outlet obstruction. Recent work has demonstrated the important role played by the sympathetic nervous system in the control of prostatic muscle tone. Although isometric muscle strip studies and clinical trials have highlighted the influence of alpha-1 adrenoceptors, radioisotope ligand binding studies have demonstrated a relatively increased density of alpha-2 adrenoceptors in the muscle within prostatic tissue, the significance of which is as yet unexplained. Forty patients entered a study using pharmacological muscle strip experiments, radioligand binding assays and receptor autoradiography. Pharmacological data from these studies confirmed that contraction of prostatic muscle is mediated predominantly by alpha-1 adrenoceptor stimulation, with no evidence of significant alpha-2 adrenoceptor or cholinergic mediated effects. Radioligand binding studies confirmed that there is a higher concentration of alpha-1 binding sites as contrasted to alpha-2 within normal prostate, but that this relationship approaches equity in adenomatous prostate. Autoradiographic localisation demonstrated that alpha-1 adrenoceptor binding is predominant within prostatic stroma with only a small component of alpha-2 adrenoceptors in this compartment. This comprehensive study supports the suggestion that prostatic muscular contraction is controlled by the influence of the sympathetic nervous system acting via alpha-1 adrenoceptors. These findings support the therapeutic use of specific alpha-1 adrenoceptor blockade in the management of benign prostatic hyperplasia.