Sepsis associated with urinary tract infection. Antibiotic treatment with piperacillin.

Urosepsis is mostly induced by nosocomial gram-negative organisms. It is an infection that is difficult to treat and has high mortality, especially when associated with septic shock. For obstructive urosepsis, which occurs mostly after an acute stone occlusion of the upper urinary tract in pyelonephritis, intensive systemic medical therapy and drainage (and sometimes removal) of the septic kidney are necessary. For non-obstructive urosepsis, which is mostly an iatrogenic complication of diagnostic or therapeutic procedures on the genito-urinary tract, the same intensive medical care and urinary drainage are adequate. Systemic therapy in the treatment of urosepsis encompasses several disorders. Specific pathogenic mechanisms of shock, including failure of the microcirculation, hemostatic disorders, and microbiological problems, have to be considered in the systemic treatment of urosepsis. Appropriate antibiotic therapy may triple chances of survival. In this connection, piperacillin was successfully used in 30 patients with urosepsis treated at our institution.

Management of benign prostatic hyperplasia with particular emphasis on aromatase inhibitors.

The pathogenesis of human benign prostatic hyperplasia (BPH) has not been fully elucidated. There is, however, evidence that estrogens--besides other factors--might play an important role for the growth of the prostate. Consequently, estrogen deprivation might be a new, useful principle for a conservative treatment of BPH. Atamestane, a new, highly selective steroidal aromatase inhibitor has been proven to be successful in antagonizing experimentally-induced estrogen-related stromal overgrowth of the prostate in dogs and monkeys. Double-blind placebo controlled studies are now underway in Europe and the U.S.A. It is anticipated that these studies will give us a definite answer of the clinical validity of this concept in BPH patients in the near future. However, it is very important to take into consideration that for an effective treatment of BPH, a reduction of both the glandular and stromal elements has to be achieved. In other words, both androgens and estrogens seem to be involved in the regulation of (over)growth of the prostate. Therefore, a combination of an androgen and estrogen deprivation might be a more promising approach than any single treatment.

Effects of estrogen deprivation on human benign prostatic hyperplasia.

Sex steroids are thought to play an essential role in the pathogenesis of human benign prostatic hyperplasia (BPH). Since recent studies in animal models and in men have shown that estrogens might be causally linked to the onset and maintenance of BPH, we examined the effect of 1-methyl-androsta-1,4-diene-3,17-dione (Atamestane), a newly developed aromatase inhibitor, in men with BPH. In an open multicenter study 49 men (mean age 70.1 years, range 55 to 84) with obstructive BPH were treated with atamestane (3 x 200 mg/day) for 3 months. Of the 49 patients 44 completed the treatment period; the other patients discontinued the study for reasons unrelated to treatment. With treatment BPH-related symptoms such as daytime voiding frequency, nycturia, peak flow and residual urine improved considerably; however, these parameters did not reach statistical significance. The mean prostatic volume decreased significantly from 74.2 +/- 31.7 to 64.0 +/- 31 ml (mean +/- SD). Serum estrogen levels decreased markedly during treatment. In addition intraprostatic estrogen concentration decreased with treatment as compared to estrogen levels in hyperplastic prostates from untreated patients. The following conclusions can be drawn from this study: first, estrogens appear to have an important supportive role in established BPH, and second, estrogen deprivation improved BPH-related symptoms and reduced significantly prostatic volume.

Effects of the aromatase inhibitor testolactone on human benign prostatic hyperplasia.

UNLABELLED: The aromatase inhibitor testolactone was used for endocrine treatment of benign prostatic hyperplasia (BPH). Thirteen patients (mean age 79 years) with complete urinary retention (BPH stage IV) without improvement after 4 weeks of bladder drainage by suprapubic catheter were treated with testolactone 100 mg, b.i.d., for 6 months. Nine men (mean age 80 years) with identical conditions who did not receive hormonal therapy served as controls. Results, treatment group: In 7 patients spontaneous micturation reoccurred after an average treatment period of 8 weeks (group A); 6 patients continued to need the catheter (group B). Prostatic volume decreased in all patients, and an average volume reduction of 26% was found in group A, whereas in group B the decrease averaged 15%. Finally, the testosterone/estradiol ratio significantly increased in all patients during treatment. CONTROL GROUP: Prostatic volume did not change nor did spontaneous micturation occur during the whole observation period.

[Prostatic cancer. Staging via transrectal prostatic sonography and computed tomography with histopathological correlation]. / Prostatakarzinom. Stadieneinteilung durch transrektale Prostatasonographie und Computertomographie mit histopathologischer Korrelation.

Pre-operative staging, using transrectal prostatic sonography and CT, was carried out in 30 patients with cytologically confirmed carcinomas of the prostate and the results compared with the clinical findings. All patients underwent radical prostatectomy and the pre-operative findings could be verified histologically. Transrectal prostatic sonography is better than CT or clinical examination for determining local tumour spread or penetration of the capsule. A high proportion of enlarged pelvic lymph-nodes shown by CT had non-specific changes; failure to demonstrate enlarged nodes excludes lymph node metastases with considerable certainty. Transrectal prostatic sonography provides a higher degree of information regarding local tumour spread, whereas CT indicates the presence or absence of lymph node metastases.

Pyelocalyceal diverticula.

The aim of the present paper is to report on the frequency of pyelocalyceal diverticula and the relation to other renal abnormalities in 5000 routine IVPs. Pyelocalyceal diverticula are mostly occasional findings and they usually cause symptoms when complicated by inflammation or stones. These complications will characterize the symptoms. There is an indication for surgical treatment when the diverticula are complicated by stones or inflammation which fail to respond to simple antibiotic treatment. According to our experience, the removal of the diverticulum bearing renal segment is a safe procedure with good postoperative results.

[Endocrinologic factors in the development of benign prostatic hyperplasia]. / Endokrinologische Faktoren für die Entstehung der benignen Prostatahyperplasie.

The development of benign prostatic hyperplasia is determined by aging and a functioning testis. This concept of the pathogenesis is supported by studies showing that regression of the enlarged prostate can be achieved by means of drugs that interfere with either the synthesis or the action of testosterone. Since both these therapeutic principles lead to symptoms of hypogonadism their therapeutic value is limited. Recent observations, however, indicate the feasibility of developing agents that will relieve the obstruction of urinary outflow and cause shrinkage of the enlarged prostate without impairing the action of androgen in other tissues.

Testosterone recovery in the off-treatment time in prostate cancer patients undergoing intermittent androgen deprivation therapy.

BACKGROUND: Intermittent androgen deprivation (IAD) for prostate cancer was studied with the objective of reducing the side effects of treatment and potentially delaying the development of hormone resistance. There also appears to be a quality of life benefit during off-treatment intervals owing to the recovery of serum testosterone levels. METHODS: In this multicentre European prospective randomised phase III trial EC507, testosterone serum concentrations were analysed in prostate cancer patients with PSA progression after radical prostatectomy. Patients were randomised to a continuous androgen deprivation (CAD) and IAD therapy using a 3-month depot with 11.25 mg leuprorelin acetate as microcapsule formulation. A complete IAD cycle comprises both a 6-month androgen deprivation therapy plus the off-treatment time (OTT). RESULTS: Serum testosterone recovery was recorded in 109 patients during OTT in the IAD group. Testosterone recovery to baseline values was achieved in 79.3% during the first and in 64.9% during the second IAD cycle, respectively. Median time to testosterone normalisation was 100 days in the first and 115 days in the second cycle, respectively. No significant difference was observed up to 1000 days between IAD and CAD with regard to time to androgen-independent progression. This is the first prospective study of leuprorelin acetate 11.25mg demonstrating normalisation of testosterone levels in the off-treatment period in patients undergoing IAD. CONCLUSIONS: The prerequisite of an IAD treatment is the testosterone recovery during off-treatment periods. In this study, in patients with PSA relapse after radical prostatectomy, a real achievement of intermittent castration with normalisation of testosterone levels during off-treatment periods could be confirmed.

Safety and clinical efficacy of a new 6-month depot formulation of leuprorelin acetate in patients with prostate cancer in Europe.

This multicentre European study compared the safety and tolerability of the existing 11.25 mg 3-month depot of leuprorelin acetate with a new 30 mg 6-month depot in men with newly diagnosed prostate cancer or prostate-specific antigen relapse after radiotherapy or prostatectomy. The primary end points were safety and tolerability and secondary end points were clinical response based on European Organization for Research and Treatment of Cancer (EORTC) criteria and response rate by time point for testosterone suppression (castrate level

Neo-adjuvant hormonal therapy of prostate cancer.

At present, only locally confined carcinoma of the prostate can be cured if all of the tumor tissue can be removed by surgery [36]. Early detection strategies using serum prostate-specific antigen (PSA), digital rectal examination (DRE) and transrectal ultrasound (TRUS) have been increasingly used. However, exact clinical determination of the local tumor extension is only possible to a limited extent [4, 13, 28, 34]. Up to 60% of clinical locally confined tumors are understaged after histopathological examination of the radical prostatectomy specimen. Furthermore a high incidence of positive margins of up to 60% has been reported [7, 21]. Although a clear surgical margin does not exclude local or distant disease recurrence, it is regarded as a good prognostic factor [3, 25]. Androgen withdrawal prior to radical prostatectomy is an attractive theoretical option to decrease the risk of disease recurrence, since tumor regression can be induced by any procedure that reduces the intracellular concentration of dihydrotesterone by more than 80%. The benefit of preoperative medical androgen deprivation is controversial [6-8, 13, 15-17, 20, 23, 35, 37]. A priori a benefit would not be expected in any case if androgen withdrawal had no effect on the tumor. We therefore investigated the effects of a neo-adjuvant androgen-ablative therapy (NAT) in a large population of 375 patients who underwent radical retropubic prostatectomy (RRP) after NAT. We report in particular the effects of NAT on prostate volume measured by TRUS, PSA, clinical stage and tumor morphology including positive surgical margins. Furthermore the recently reported first results of prospective randomized trials comparing RRP alone versus NAT plus RRP are discussed to analyze the possible impact of NAT.

Intermittent endocrine therapy of prostate cancer.

INTRODUCTION: Permanent androgen suppression is the therapy of choice in the treatment of advanced prostate cancer. Intermittent androgen deprivation (IAD) through reversible medical castration results, hypothetically, in androgen-induced differentiation of tumor stem cells with recovery of the apoptotic potential. The cycle of periods with and without androgen withdrawal should delay androgen-independent tumor progression. RESULTS: In initial pilot studies, the IAD concept proved less successful in patients with a high tumor burden than in those with locally advanced prostatic cancer. In our own pilot study, patients with a low tumor burden could be successfully treated with IAD. CONCLUSION: Until further studies have been completed, the therapeutic concept with IAD should be regarded as experimental. Only further prospective randomized phase III studies will be able to establish whether survival and quality of life of patients with prostatic cancer can be considerably improved by IAD.

Intermittent androgen blockade in prostate cancer: rationale and clinical experience.

Cancer of the prostate continues to be one of the most common malignancies in men in Europe, with a large number of patients presenting with advanced disease. The current standard treatment for metastatic cancer of the prostate, permanent androgen withdrawal, is palliative. Patients treated with permanent androgen blockade usually relapse and die secondary to prostate cancer's ability to progress to an androgen-independent state of growth. Based on experimental and preclinical studies, intermittent androgen blockade appears to be a potential alternative to permanent androgen blockade. Through the cycling of reversible androgen suppression, there appears to be recovery of apoptosis and subsequent slower progression to an androgen-independent state. In this paper experimental and preclinical studies concerning intermittent androgen blockade are reviewed. At present several prospective randomized trials are under way to test intermittent androgen blockade as an alternative treatment in various stages of cancer of the prostate. However, until the results of these trials are available, this approach remains experimental.

Effects of androgen deprivation prior to radical prostatectomy in 375 patients.

The effects of pharmacotherapeutic complete androgen deprivation treatment for 2 months before radical retropubic prostatectomy (RRP) were investigated in an open study in 375 patients. Prostate volume, tumor staging and prostatespecific antigen (PSA) were investigated as clinical parameters. The RRP specimens were analyzed particularly in terms of tumor cell regressions, pathological tumor staging and grading. Before neoadjuvant therapy (NAT) the 375 patients were classified according to stage: 36 (9.6%) were T1B; 137 (46.1%) were T2, and 166 (44.3%) were T3 stage. After NAT, the clinical investigation (digital rectal examination + transrectal ultrasonography) gave an impression of a T0 stage in 11% of the T2 patients, and a T2 tumor stage in 39% of the T3 patients. The histopathological analysis of the initial T1B and T2 cases did not reveal any tumor in the RRP specimen in 11 (3.8%) cases, a pT2 tumor in 153 (73%) cases, and a pT3 tumor in 48 (23.5%) cases. In the patients initially classified as T3, a tumor was no longer found in 1 (0.6%) case, and a pT2 tumor was found in 48 (29.3%) cases and a pT3 tumor in 113 (67.7%) cases. Under NAT, the prostate volume fell by 34% in T3 tumors and by 24% in T2 tumors. The fall in PSA averaged 85% without significant differences in the individual tumor stages. A statistically significant correlation could not be demonstrated between the fall of PSA and the definitive pathological tumor stage. Tumor cell regressions were found in all preparations. The degree of regression was predominantly RII. These results document the direct effect on tumor cells of an inductive androgen-ablative pharmacotherapy. Regression and volume reduction of the tumor might lead to an improvement of the local surgical control. A final clinical evaluation of NAT will only be possible after long-term analysis of ongoing prospective, randomized studies.

The significance of serum levels of insulin-like growth factor-1 in patients with prostate cancer.

OBJECTIVES: To compare the serum levels of insulin-like growth factor-1 (IGF-1) in patients with prostate cancer and in control patients with no malignancy, and to evaluate any possible influence of testicular androgen withdrawal on the level of IGF-1 in patients with prostate cancer. PATIENTS AND METHODS: IGF-1 was measured in serum samples from 238 patients using both a chemiluminescence method and a radio-immunoassay. From a subgroup of 19 patients presenting with newly diagnosed carcinoma of the prostate, IGF-1 and testosterone values were measured before and during the course of testicular androgen withdrawal, achieved by the administration of luteinizing hormone-releasing hormone (LHRH) analogues combined with anti-androgens. RESULTS: There were no significant differences in the mean serum levels of IGF-1 patients with and without prostate cancer (158.6 and 159.1 ng/mL, respectively). There were no significant differences in mean IGF-1 levels before and after antiandrogen therapy; the mean (median, SD, range) levels of testosterone (microg/L) and IGF-1 (ng/mL) before androgen withdrawal were 4.81 (4.84, 1.26, 3.11-6.93) and 157.1 (152.5, 26.7, 122.8-195. 1). After androgen withdrawal the corresponding values were 0.303 (0. 218, 0.24, 0.13-0.81) and 169.7 (31.7, 168.6, 124.9-227.6). A linear regression analysis (P = 0.76) and Spearman rank order correlation test (correlation coefficient -0.0613, P = 0.64) showed no association between levels of testosterone and IGF-1. Freeze and thaw cycles applied to the samples had no effect on the IGF-1 values measured. CONCLUSIONS: There was no significant association between IGF-1 serum levels and prostate cancer. Short-term androgen withdrawal using LHRH analogues combined with anti-androgens had no effect on the levels of IGF-1.

Placebo controlled double-blind study to test the efficacy of the aromatase inhibitor atamestane in patients with benign prostatic hyperplasia not requiring operation. The Schering 90.062 Study Group.

PURPOSE: We tested the theoretical concept that a selective decrease in estrogens has a beneficial therapeutic effect on established benign prostatic hyperplasia. MATERIALS AND METHODS: In a double-blind study 160 patients from 14 centers were randomized between 2 groups to receive either placebo or the aromatase inhibitor atamestane (1-methyl-androsin-1,4 diene-3 17-dione, 400 mg. daily for 48 weeks). RESULTS: The aromatase inhibitor decreased the mean estradiol level by approximately 40% and estrone by 60%. The testosterone concentration increased by more than 40% and dihydrotestosterone increased to 30%. Analysis of clinical parameters showed no difference between placebo and atamestane. CONCLUSIONS: The counter regulatory increase in androgens may counterbalance any positive effect of the decrease in estrogens to preserve intraprostatic homeostasis.

Intermittent complete androgen blockade in PSA relapse after radical prostatectomy and incidental prostate cancer.

OBJECTIVES: To determine the efficacy, safety and feasibility of intermittent androgen deprivation (IAD) in patients with prostate-specific antigen (PSA) relapse after radical prostatectomy or with an incidental prostate cancer (pT1B) after transurethral resection of the prostate (TURP). METHODS: Open, nonrandomized, prospective pilot study using the luteinizing hormone-releasing hormone analogue (LH-RHa), leuprorelin acetate (1-month depot) and cyproterone acetate. RESULTS: Forty-four patients have been enrolled. After a 30-64 months' follow-up no progression to androgen-independent status has been observed. Of the entire observation period, 26.6 months (44-58%) remained treatment-free. During the treatment-free periods, normal testosterone levels were obtained, resulting in a cessation of the symptoms of androgen suppression and an improvement in quality of life. CONCLUSIONS: These results indicate that IAD is an effective and feasible therapy in patients with early stages of prostate cancer. Larger trials are necessary to confirm these encouraging results. Therefore, a European prospective, randomized, multicenter study (RELAPSE study) has been started to compare IAD with continuous androgen blockade in terms of time to tumor progression, safety and quality of life in patients with PSA relapse after radical prostatectomy.

Effects of the antioestrogen tamoxifen on steroid induced morphological and biochemical changes in the castrated dog prostate.

The effect of the antioestrogen tamoxifen (TA) was investigated in different types of steroid-induced benign prostatic hyperplasia (BPH) in the castrated dog by histological, histochemical and biochemical analysis. A 6 months treatment with oestradiol-17 beta (E2) alone resulted in cystic and stromal hyperplasia and squamous epithelial metaplasia with a striking prostatic weight increase DNA and RNA content of the total glands increased significantly. The histochemical results and zinc values indicated the loss of normal epithelial function due to metaplatic transformation. The E2 induced cystic and metaplastic hyperplasia was prevented by TA while the stromal proliferation was significantly decreased but not abolished. Biochemical determinations revealed an effect similar to castration. After combined treatment with E2 and 3 alpha-androstanediol (3 alpha-diol) TA completely suppressed squamous metaplasia. A 3 alpha-diol induced glandular proliferation, monitored by a positive histochemical reaction, and significantly elevated zinc, DNA and RNA contents prevailed. A partial stromal stimulation indicates stimulating effects of 3 alpha-diol too on the stroma. The antioestrogenic effects of tamoxifen on experimentally induced BPH mainly manifest at the E2 induced epithelial alterations. The abolishing effects at the stromal level are distinct but not so impressive.

Transdifferentiation of distal but not proximal tubular epithelial cells from human kidney in culture.

Human renal proximal and distal (thick ascending limb and early distal convoluted tubule) epithelial cells have been isolated according to their specific antigen expression. The cells were well characterized by flow cytometry, enzyme cytochemistry and electron microscopy and cultured for up to 3 months. Cultured tubular cells coexpressed cytokeratin and vimentin as intermediate filament proteins. While primary isolated cells, proximal as well as distal, revealed the phenotypic characteristics of their nephron origin, cultured distal cells showed the tendency to dedifferentiate/transdifferentiate. Distal cells lost their characteristic expression of Tamm-Horsfall glycoprotein and started de novo expression of the proximal marker proteins aminopeptidase M, gamma-glutamyl transferase and dipeptidyl peptidase IV. The expression of these antigens by distal cells could be shown by flow-cytometric analysis and fluorescence microscopy. Enzyme activity assays revealed the activity of aminopeptidase M, gamma-glutamyl transferase and dipeptidyl peptidase IV, but not of the proximal marker enzyme alkaline phosphatase. This antigenic shift could not be prevented in different culture media, and the original phenotype could not be restored. Cultured cells displayed characteristic hormonal stimulation patterns indicative of their proximal and distal origins, as shown by activation of adenylate cyclase by different peptide hormones. These results indicate that distal tubular cells possibly transdifferentiate to a more proximal phenotype in view of loss of the distal marker enzyme Tamm-Horsfall protein and de novo expression of proximal marker enzymes like dipeptidyl peptidase IV and aminopeptidase M.

Comparison of LH-RH analogue 1-month depot and 3-month depot by their hormone levels and pharmacokinetic profile in patients with advanced prostate cancer.

In an open, randomized phase II pharmacokinetic study conducted in Germany and Italy, a total of 42 patients with advanced or metastatic prostate cancer (PCa) were treated for 9 months with the luteinizing hormone-releasing hormone analogue (LH-RH-a) leuprorelin acetate depot in two different formulations. Fifteen patients received the 1-month depot and 27 patients received the newly developed 3-month depot, containing 3.75 mg and 11.25 mg, respectively. In both groups, subcutaneous injections of leuprorelin acetate injected monthly or at 3-month intervals produced a complete down-regulation of the pituitary and led to persistent suppression of testosterone and dihydrotestosterone to the castrate range (< or = 50 ng/dl for testosterone) within the first month of treatment, which thereafter could be maintained over the entire observation period of 9 months. In 10 patients, pretreatment with an antiandrogen for the prevention of clinical flare-up resulted in a slightly more profound and earlier drop in serum testosterone. The 3-month depot showed a higher median peak serum concentration (Cmax) of leuprorelin at 20.8 ng/ml than the 1-month depot at 10.7 ng/ml but, conversely, this did not influence the rise in serum testosterone levels. Cmax occurred at 3 h for the 3-month and at 1 h for the 1-month depot formulation. During the steady state, constant release could be detected, starting on day 3 and day 7 for the 1-month and 3-month depot, respectively. A marked decrease in median prostate-specific antigen levels of 97.8% (1-month depot) and 96.6% (3-month depot) compared with baseline was observed, indicating an objective clinical response for more than 80% of all patients in both arms. Based on European Organization for Research and Treatment of Cancer criteria, the best response in terms of complete/partial remissions and stabilization was comparable in the two arms at 86.7% (1-month depot) and 85.2% (3-month depot). 6.7% in the 1-month group and 3% in the 3-month depot group showed progression of the disease. The most common side effects in both treatment groups were related to hormone deprivation. Both formulations of the potent LH-RH-a leuprorelin acetate were highly effective in the treatment of advanced PCa and led to comparable endocrine and clinical effects.