[Economic aspects of evidence-based metaphylaxis]. / Okonomische Aspekte der evidenzbasierten Harnsteinmetaphylaxe.

The calculation model which we developed for the cost of stone therapy and metaphylaxis in Germany some years ago with a social health insurance company is based on estimates of stone incidence, types and recurrence rates, actual costs for stone removal, and metaphylaxis (based on data from a district of the social health care system). There are 200,000 stone recurrences per year in Germany. Costs for treatment of these stones amount to $687,000,000. Stone metaphylaxis reduces the recurrence rate by some 40%. The annual cost for stone removal could be lowered by $275,300,000. Metabolic evaluation/metaphylaxis amount to $70,100,000 per year, resulting in a net saving of $205,200,000. In 1997, there were 96 days off work per stone patient resulting in 5,800,000 days off work in Germany per year. Metaphylaxis is not only medically effective in stone formers but also can lower health care cost significantly. Although health care conditions may vary from country to country, in principle this calculation model is applicable also to other countries.

Reduction of high-energy shock-wave-induced renal tubular injury by selenium.

In shock-wave-induced renal injury cavitation-generated free radicals play an important role. Using an in vitro model with Madin-Darby canine kidney (MDCK) cells, we investigated the influence of selenium, a free radical scavenger, in shock-wave-induced tubular cell injury. Suspensions of MDCK cells (33 x 10(6) cells/ml) were placed in small containers (volume 1.1 ml) for shock wave exposure. Two groups of 12 containers each were examined: (1) control (no medication), (2) selenium (0.4 microg/ml nutrient medium). Six containers in each group were exposed to shock waves (impulse rate 256, frequency 60 Hz, generator voltage 18 kV), while the other six containers in each group served as a control. After shock wave exposure, the concentration of cellular enzymes such as lactate dehydrogenase (LDH), N-acetyl-beta-glucosaminidase (NAG), glutamate oxaloacetate transaminase (GOT) and glutamate lactate dehydrogenase (GLDH) in the nutrient medium was examined. Following shock wave exposure there was a significant rise in LDH, NAG, GOT and GLDH concentrations. Selenium reduced this enzyme leakage significantly. Thus we conclude that selenium protects renal tubular cells against shock-wave-induced injury. Since selenium is an essential part of glutathione peroxidase, this effect seems to be mediated by a reduction in reactive oxygen species.

Limitation of shock-wave-induced renal tubular dysfunction by nifedipine.

In a prospective randomized study, the effects of the calcium entry blocker nifedipine on shock-wave-induced tubular impairment were studied. 24 patients with renal pelvic or calyceal stones undergoing anesthesia-free extra-corporeal shock wave lithotripsy (ESWL) without ancillary measures were randomly assigned to the nifedipine group (n = 12) or the control group (n = 12). Four doses of nifedipine (10 mg t.i.d.) were given orally, starting the night before ESWL. Controls received no medication. To assess renal tubular function, the urinary excretion of alpha 1-microglobulin (A1M), N-acetyl-beta-glucosaminidase (NAG) and Tamm-Horsfall protein (THP) were measured before, immediately, 12 and 24 h after ESWL. After lithotripsy, there was a rise in urinary A1M and NAG which was significantly higher in the control than in the nifedipine group. THP, a glycoprotein synthesized by distal tubular cells, fell significantly less in the nifedipine group compared to the controls. Our results indicate that nifedipine exhibits a protective effect on shock-wave-induced tubular damage similar to verapamil. The underlying mechanisms are not clarified yet, direct actions on tubular cells and interference with renal hemodynamics have to be discussed.

Influence of transrectal hyperthermia on prostate-specific antigen in prostatic cancer and benign prostatic hyperplasia.

The prostate-specific antigen (PSA) is a glycoprotein synthesized exclusively by the prostate. Since manipulations on the prostate can increase PSA serum levels, we investigated the effects of transrectal hyperthermia on PSA levels in prostate cancer (PC) and benign prostatic hyperplasia (BPH). Patients and treatments were the following: group 1a, PC St.D (n = 12): 8 hyperthermia sessions (twice a week) and LHRH-agonists plus flutamide; group 1b, PC St.D (hormone resistant; n = 10): 8 hyperthermia sessions (once a week) and epirubicin (50 mg intravenously, once a week); group 1c, PC St.C (n = 5): 6 hyperthermia sessions (once a week) and radiotherapy (60 Gy); group 2, BPH (n = 10): 8 sessions (twice a week). PSA levels were determined before, during (immediately before each hyperthermia session) and 1 week after therapy. Apart from hormone-/hyperthermia-treated patients, who showed a continuous decrease in PSA during therapy, all the other groups revealed a transient increase in PSA during the hyperthermia treatment. This effect is attributed to manipulations on the prostate and hyperthermia-specific effects on prostatic cells. The decrease in PSA on hormone/hyperthermia therapy can be explained by the tremendous effect of androgen deprivation on PSA levels overshadowing the hyperthermia effect.

[Local hyperthermia in prostate cancer]. / Lokale Hyperthermie beim Prostatakarzinom.

We conducted a clinical trial evaluating the effects of hyperthermia in patients with carcinoma of the prostate, treating 20 patients with newly diagnosed carcinoma of the prostate with local microwave hyperthermia (915 MHz). Histological examination revealed hypoeremic effects and diffuse oedema with interstitial lymphoplasmatic cellular infiltration. However, necrotic tumour cells were not found in any of specimens. A second series consisted of 10 patients with metastasizing carcinoma of the prostate (n = 4 untreated; n = 6 hormone-resistant). For 8 weeks, epirubicin was administered once weekly, followed each time by local microwave hyperthermia 1 h later. The efficacy was evaluated according to the EORTC criteria. In 4 patients with untreated carcinoma no change was found in the size of the prostate or metastases. In 3 of the 6 patients with hormone-resistant carcinoma progressive disease was found, while the other 3 had stable disease. Only in 2 of the 10 patients did the grading of tumour regression reveal any improvement. Cytophotometric studies showed no change of DNA ploidy. Currently we consider hyperthermia unsuitable as monotherapy for carcinoma of the prostate, and the combination of epirubicin and hyperthermia is no more favourable than monotherapy with epirubicin alone. Further studies are necessary to evaluate other cytotoxic regimens and various patterns of application for hyperthermia.

[Local hyperthermia in benign prostatic hyperplasia]. / Lokale Hyperthermie bei benigner Prostatahyperplasie.

In recent years, hyperthermia has been used for the treatment of benign prostatic hyperplasia (BPH). The preliminary results reported were promising. Except for patients with total urinary retention, however, objective voiding parameters have not been reported in detail for patients with "prostatism". In a phase II study we treated 30 patients with BPH by local microwave hyperthermia (915 MHz). The prostate was heated transrectally to 42-43 degrees C in eight sessions of 60 min each. The sessions were given twice a week. To assess the results of the treatment the following parameters were determined before and 4 weeks after hyperthermia therapy: transrectal ultrasound of the prostate with volumetry, urinary flow rate, and residual volume. In all, 28 patients were evaluatable. Only 2/28 showed clinical improvement. Neither the voiding parameters nor the size of the prostate were significantly changed by hyperthermia. The success rate of 7.1% is even lower than the spontaneous temporary regression rate of BPH. Thus, to our mind, hyperthermia cannot be regarded an effective treatment comparable to TUR for BPH.

Histological effects of local microwave hyperthermia in prostatic cancer.

Recent investigations have shown that hyperthermia can reduce the volume of the prostate and improve local symptoms in patients with carcinoma of the prostate. Histological examinations of the effect of hyperthermia on prostatic cancer tissue, however, have not been performed systematically until now. Thus, we initiated a study to investigate the effects of heat on prostatic cancer as a prerequisite for further clinical trials on hyperthermia as treatment for prostatic cancer. Twenty patients with untreated prostatic cancer underwent local hyperthermia (915 MHz), each receiving four sessions of 60 min each. The intraprostatic temperature was 42-43 degrees C. Histological specimens of the prostate were taken before the treatment and 1-2 weeks after the last hyperthermia session. Hyperthermia produced hyperaemic alterations of the prostatic stroma and a diffuse oedema with interstitial lymphoplasmacellular infiltration. Definite signs of tumour cell necrosis, however, could not be seen in any of the patients. Hence the shrinkage of prostatic tumours described earlier cannot be explained by histologically proven tumour cell destruction. Thus hyperthermia is not adequate as a single treatment for prostatic cancer. Hyperthermia may, however, be useful as part of integrated therapy regimens together with cytostatic or hormonal agents and radiotherapy because of hyperaemic, chemo- and radiosensitizing effects.

Local microwave hyperthermia of benign prostatic hyperplasia.

Recently, hyperthermia has been used for treatment of benign prostatic hyperplasia. The preliminary results reported were promising. However, apart from patients with total urinary retention, objective voiding parameters have not been reported in detail for patients with prostatism. In a phase II study we treated 30 patients with benign prostatic hyperplasia by local microwave hyperthermia (915 MHz.). The prostate was heated transrectally to 42 to 43C, with the treatment consisting of 8 sessions of 60 minutes each given twice a week. To assess the results of treatment several parameters were determined before and 4 weeks after hyperthermia therapy, including transrectal ultrasound of the prostate with volumetry, urinary flow rate and residual volume. Of the patients 28 could be evaluated and only 2 showed a relevant improvement. Neither the voiding parameters nor the size of the prostate could be changed significantly by hyperthermia. The success rate of 7.1% is even lower than the spontaneous temporary regression rate of benign prostatic hyperplasia. Thus, we believe that hyperthermia cannot be regarded as an effective treatment for benign prostatic hyperplasia comparable to transurethral resection.

Combination of hyperthermia and cytostatics in the treatment of bladder cancer.

The intravenous administration of cytostatics in cases of locally extended carcinomas of the bladder seems to promise success. As concomitant disadvantage however we have to mention that the drugs in high concentrations needed for this treatment give rise to systemic toxic effects limiting the rational use of the drug. A further rise of cytostatic tissue concentration seems possible by performing a synchronous tumor injection of cytostatics and microspheres. An additional anticancer effect and the synergistic activation of cytostatic effectivity must be assumed by a following local transurethral high-frequency hyperthermia of the bladder. Our first urological experiences with this integrated therapy in six locoregional (T3-4N0M0) and six advanced metastasizing (T3-4N1M0-1) bladder cancers are presented consisting of a combined intraarterial cytostatic microspheres carcinoma infusion (CMCI) and scheduled adjunctive transurethral high-frequency hyperthermia (TUHH). In the case of locoregional tumor the aim was cancer destruction or debulking and in the case of metastasizing tumor palliation of local disease. Mechanisms of action, methodical procedures, indications, results as well as side effects of the intraarterial CMCI and TUHH treatment as developed by our department are presented and discussed.

[Effect of calcium antagonists (nifedipine) on nephrocalcinosis and calcium excretion in the rat]. / Zur Wirkung von Kalziumantagonisten (Nifedipin) auf die Nephrokalzinose und Kalziumausscheidung der Ratte.

An animal model was established to test the effect of a calcium antagonist on nephrocalcinosis, which was induced by an atherogenous diet, and its effect on the excretion of calcium and other parameters relevant for stone formation. With the administration of nifedipine (Adalat), the grade of nephrocalcinosis could be significantly reduced. Furthermore, with nifedipine the excretion of calcium and sodium in the urine was raised, while phosphate and potassium levels were lowered. The excretion of magnesium and citrate, reduced by an atherogenous diet, could be raised significantly with the administration of nifedipine. The pathophysiological mechanisms underlying the effect of nifedipine on nephrocalcinosis and on the excretion of the urine parameters are discussed. Apparently hypercalciuria is the result of a reduced reabsorption of calcium in the tubulus. The inhibitory effect on the genesis of nephrocalcinosis is possibly due to the lower calcium influx into the tubular cells.