Pharmacodynamic effects of aripiprazole and ziprasidone with respect to p-glycoprotein substrate properties.

INTRODUCTION: Aripiprazole, an atypical antipsychotic drug with mixed antagonism and agonism on dopamine D2 and serotonin receptors, is a substrate of the efflux transporter P-glycoprotein (P-gp). Here we tested the pharmacodynamic consequences of these properties in a P-gp deficient mouse model by studying the effects of aripiprazole and of ziprasidone on motor coordination. METHODS: The motor behaviour of wild-type (WT) and P-gp deficient [abcb1ab(-/-)] mice was investigated on a RotaRod. Mice received acute injections of either aripirazole or ziprasidone. For comparison, the dopamine receptor antagonist haloperidol and serotonin receptor ligands buspirone and ketanserin were also applied. RESULTS: Pharmacokinetic analyses revealed P-gp activity for aripiprazole and ziprasidone. This was indicated by 3.1- and 1.9-fold higher ratios of brain to plasma concentrations of drugs in knock-out to WT animals. Acute doses of ariprazole or ziprasidone impaired motor behaviour on the RotaRod. Effects were similar after injection of haloperidol, whereas the serotonin receptor ligands buspirone and ketanserin enhanced RotaRod performance. Genotype dependent differences of motor performance were found for aripiprazole but not for ziprasidone. DISCUSSION: Evidence was given that P-gp substrate properties have pharmacodynamic consequences for aripiprazole but not for ziprasidone and thus affect dopamine receptor related motor behaviour.

Spatial learning and expression patterns of PP1 mRNA in mouse hippocampus.

BACKGROUND: Synaptic plasticity is believed to be the major cellular basis for learning and memory. Protein phosphorylation is a key process involved in changes in the efficacy of neurotransmission. In long-term changes synaptic plasticity is followed by structural plasticity and protein de novo synthesis. Such mechanisms are believed to build the basis of hippocampal learning and memory investigated in the Morris water maze (MWM) task. To examine the role of dephosphorylation during that model for spatial learning, we analyzed protein phosphatase 1 (PP1) expression in the hippocampus of mice at various stages of the task and in two groups with different learning abilities. METHODS: Mice were trained for 4 days with four trials each day in the MWM. For gene expression hippocampi were prepared 1, 6 and 24 h after the last trial of each day. PP1 and brain-derived neurotrophic factor (BDNF) mRNA levels were determined by quantitative real-time PCR. RESULTS: The task requirements themselves affected expression levels of both PP1 and BDNF. In contrast to BDNF, PP1 was differentially expressed during learning. Poorly and well performing mice differed significantly. When performance was poor the expression level of PP1 was higher. CONCLUSION: Present results add further in vivo evidence that not only phosphorylation but also dephosphorylation is a major mechanism involved in learning and memory. Therefore, inhibition of hippocampal phosphatase activity might improve learning and memory.

Solubilization of nuclear steroid 5 alpha-reductase from rat ventral prostate.

delta 4-Steroid-5 alpha-reductase (3-oxo-5 alpha-steroid:NADP+ delta 4-oxidoreductase, EC 1.3.1.22), is a membrane-bound enzyme. In the ventral prostate of the rat, its activity is found within the nuclear envelope. Solubilization of this enzyme can only be achieved in the presence of detergents. We studied the inhibitory effect of various detergents on 5 alpha-reductase activity as a function of detergent concentration, of pH, of incubation time, of salt concentration and of additives to the buffer system. Four detergents (Lubrol WX, CHAPS, L-alpha-lysophosphatidylcholine and octyl D-glucopyranoside) were selected for subsequent solubilization studies. The overall recovery of solubilized enzyme activity was about 30% when compared to 100% of 5 alpha-reductase activity found in freshly prepared nuclei. Up to 20-30% of the nuclear proteins were extracted during the solubilization procedure. Among the various treatments tested, a concentration of 3 mg/ml L-alpha-lysophosphatidylcholine per 10 mg/ml of nuclear protein in the presence of 5 mM MgCl2, 0.1 M KCl, 0.1 M sodium citrate and 5 mM NADPH yielded the maximal enzymic activity of 56%, 15% of the nuclear proteins being solubilized in an active and stable form. The activity in these extracts could be kept stable for 2 days at 4 degrees C with a recovery of 75% of enzymic activity. A 3-fold increase of specific 5 alpha-reductase activity was obtained during solubilization under optimal conditions.

Tissue-Specific and Development-Dependent Accumulation of Phenylpropanoids in Larch Mycorrhizas.

The tissue-specific and development-dependent accumulation of secondary products in roots and mycorrhizas of larch (Larix decidua Mill.; Pinaceae) was studied using high-performance liquid chromatography and histochemical methods. The compounds identified were soluble catechin, epicatechin, quercetin 3-O-[alpha]-rhamnoside, cyanidin- and peonidin 3-O-[beta]-glucoside, 4-O-[beta]-hydroxybenzoyl-O-[beta]-glucose, 4-hydroxybenzoate 4-O-[beta]-glucoside, maltol 3-O-[beta]-glucoside, and the wall-bound 4-hydroxybenzaldehyde, vanillin, and ferulate. In addition, we partially identified a tetrahydroxystilbene monoglycoside, a quercetin glycoside, and eight oligomeric proanthocyanidins. Comparison between the compounds accumulating in the apical tissue of fine roots, long roots, and in vitro grown mycorrhizas (L. decidua-Suillus tridentinus) showed elevated levels of the major compounds catechin and epicatechin as well as the minor compound 4-hydroxybenzoate 4-O-[beta]-glucoside specifically in the root apex of young mycorrhizas. The amounts of wall-bound 4-hydroxybenzaldehyde and vanillin were increased in all of the mycorrhizal sections examined. During the early stages of mycorrhization the concentrations of these compounds increased rapidly, perhaps induced by the mycorrhizal fungus. In addition, studies of L. decidua-Boletinus cavipes mycorrhizas from a natural stand showed that the central part of the subapical cortex tissue and the endodermis both accumulate massive concentrations of catechin, epicatechin, and wall-bound ferulate compared with the outer part of the cortex, where the Hartig net is being formed.

A novel fibrinogen γ chain frameshift deletion (c.637delT) in a patient with hypodysfibrinogenemia associated with thrombosis.

UNLABELLED: Inherited fibrinogen (FG) disorders are rare and result in quantitative or/and qualitative FG deficiency. While the majority of patients with clinically relevant FG deficiencies demonstrate a bleeding phenotype, a subset of patients are at increased risk of thrombosis. PATIENTS AND METHODS: We report a 54-years old man presenting with a thrombophilic phenotype characterized by two episodes of unprovoked venous thrombosis and a deep vein thrombosis several weeks after myocardial infarction. Recently, he developed A. carotis communis thrombosis and died. Coagulation tests were done using standard procedures. FG genes were screened using direct sequencing. Effect on fibrin clot structure was analyzed by scanning electron microscopy (SEM) and FG chain polymerization was analysed using SDS-PAGE. RESULTS: While thrombophilia testing was negative, we found a decreased concentration of clottable FG (126-148 mg/dl) compared to FG antigen (182-194 mg/dl of normal). The thrombin time was slightly prolonged, while aPTT and reptilase time were within the normal range. A novel deletion in FGG gene (c.637delT) resulting in a frameshift and the premature termination of the γ chain at amino acid position p.228 was identified. SDS-PAGE showed a time-shift in γ-γ and α-α cross linking. SEM showed no statistically significant differences between the patient´s and a healthy control´s fibrin clot structure. CONCLUSIONS: In addition to the reduction of FG concentration expected by the nature of the mutation also a functional defect (hypodysfibrinogenemia) was found. Moreover this mutation seems to increase the risk of thrombosis warranting long term anticoagulation possibly in a combination with antiplatelet drugs.

Urinary excretion of growth factors in patients with ovarian cancer.

The levels of epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) were analysed in 24-h urine samples from patients with ovarian malignancies, benign ovarian tumours, and healthy controls by specific radioimmunoassays. No significant difference in total urinary immunoreactive EGF excretion between the groups was detected. However, 79% (23/29) of the patients with ovarian carcinomas excreted TGF-alpha (median 12.6 pmol/24 h), whereas only 17% (2/12) of the patients with benign ovarian tumours and 23% (3/13) of the controls did so. The difference between cancer patients and controls was highly significant (P < 0.001). Analyses of the urine samples separated by gel filtration revealed a greater molecular heterogeneity of EGF and TGF-alpha in cancer patients than in controls. High and low molecular weight forms of EGF were able to bind to the EGF receptor and to induce anchorage-independent growth. After surgical reduction of the tumour, a distinct decrease of urinary high molecular weight forms was observed. Thus, some macromolecular growth factors seem to be associated with epithelial ovarian carcinomas.

MK-801 reduces retinal ganglion cell survival but improves visual performance after controlled optic nerve crush.

Excitotoxicity is implicated in secondary cell death after ischemic or traumatic brain injury. We therefore evaluated the role of excitotoxicity mediated by the NMDA glutamate receptor subtype on retinal ganglion cell (RGC) survival and visual performance after optic nerve injury in adult rats. To monitor visual deficits after mild optic nerve crush, rats were trained in a two-choice pattern discrimination task. Immediately after the crush and on postoperative day 1, MK-801 (1 nmol), a noncompetitive open channel blocker of the NMDA-receptor, was injected intraocularly. Within the first few days after crush, all rats showed a loss of their discrimination ability that was followed by a significant recovery within a 3-week testing period. Although animals treated with MK-801 had a significantly smaller initial deficit compared with PBS-injected controls, anatomic investigations using retrograde HRP tracing revealed a significant retrograde loss of RGC in lesioned rats that was significantly exacerbated by MK-801. These results confirm our earlier studies suggesting that neuronal damage does not uniformly match behavioral defects in CNS injury paradigms and that near-normal visual performance occurs in rats with only about 10% of RGC being connected to their target. The observation that after traumatic injury MK-801 is neuroprotective functionally while being neurotoxic anatomically is a structural-functional paradox that needs to be explored further.

Basic fibroblast growth factor treatment partially protects from visual deficits but does not increase retinal ganglion cell survival following controlled optic nerve crush.

Lack of trophic support after axonal injury leads to the degeneration of neurons. To study whether the application of trophic factor can improve functional recovery and retinal ganglion cell (RGC) survival after unilateral controlled optic nerve crush injury, we have now treated adult rats intraocularly (i.o.) with basic fibroblast growth factor (bFGF). To monitor visual deficits, rats were trained in a two-choice pattern discrimination test. Immediately after the crush, and on postoperative days 3 and 6, either 1.1 µg recombinant bFGF or phosphate buffered saline (PBS) was injected i.o. Sham-operated controls received intraocular injection of PBS or bFGF. Within the first few days after the crush, all animals showed a loss of discrimination ability which was followed by a significant recovery within 2-3 weeks. Animals treated with bFGF had a significantly smaller initial deficit and thus recovered earlier compared to PBS controls. Retrograde RGC death was evaluated using retrograde HRP-tracing technique, but bFGF-treatment had no neuroprotective effect. Thus, the behavioral effects of bFGF could not be related to neuroprotection of RGCs and therefore other mechanisms may have to be considered.

Recovery of metabolic activity in retinofugal targets after traumatic optic nerve injury is independent of retinofugal input.

Traumatic injury of the adult optic nerve causes a progressive degeneration of retinal ganglion cells. Despite this ongoing degeneration, a partial recovery of visual behavioral function and of local cerebral glucose use (LCGU) has been observed. To evaluate whether this partial recovery of LCGU is due to a recovery of visual conductance (extrinsic) or intrinsic neuronal activity, visual stimulation alone and combined with physostigmine,an acetylcholinesterase inhibitor, were used to activate the retinofugal pathway. LCGU was determined in 30 male adult rats with or without physostigmine treatment 2 or 9 days after crush or 8 days after cut of the right optic nerve. Analysis of LCGU in contralateral first-order projection areas revealed no differences 8 days after cut and 9 days after optic nerve crush. Furthermore, LCGU in the contralateral areas could not be stimulated by the treatment with physostigmine. We therefore conclude that the increase in LCGU from 2 to 9 days after crush is not due to a recovery in the conductance of visual input. We hypothesize a relief of an injury-dependent active suppression (diaschisis) of LCGU. This reversal of diaschisis may, in part, account for the return of visual functions after mild optic nerve injury.

Comparison between a nucleic acid sequence-based amplification and branched DNA test for quantifying HIV RNA load in blood plasma.

HIV RNA was quantified in blood plasma from 209 patients and in control specimen comparing the NucliSens HIV-1 QT test (Organon Teknika), which is based on the nucleic acid sequence amplification procedure, and the Quantiplex 3.0 test (Bayer), which uses hybridization signal enhancement by branched DNA (bDNA) probes. A highly significant correlation (P=0.01) was found between the two methods with 88% of the samples showing similar results. In cases of discrepant findings, higher virus load was observed with either test (14xNASBA>bDNA; 12xbNDA>NASBA). Differences could neither be related to clinical features nor to divergent virus subtypes. Standard preparations containing 35000 and 222000 copies were quantified with intra-assay coefficients of variation of <20% using both methods. A preparation of 192 copies was measured with lower precision by both tests, yet was detected more reliably by the bDNA method.

Multicenter evaluation of a new rapid automated human immunodeficiency virus antigen detection assay.

Although human immunodeficiency virus (HIV) antigen assays are of limited value for monitoring antiretroviral therapy, they play an important role for confirmatory testing of fourth generation HIV screening enzyme immunoassay (EIA) reactive samples. In a multicenter study, a new automated rapid p24 antigen assay, Elecsys HIV Ag (Roche Diagnostics Boehringer Mannheim GmbH, Penzberg, Germany), was compared to FDA licensed tests (Abbott HIV-1 Ag monoclonal and Coulter HIV-1 p24 antigen assay). In the evaluation 27 seroconversion panels were included, sera from the acute phase of infection, single and follow-up samples from HIV antibody positive patients, dilution series of HIV antigen positive standards, sera and cell culture supernatants infected with different HIV-1 subtypes (A-H, and O) HIV-2 and recombinant HIV-1 (gag/env) isolates. To challenge the specificity of the new assay, 2565 unselected blood donors, sera from pregnant women, dialysis and hospitalized patients and 407 potentially cross-reactive samples were investigated. Acute HIV infection was detected in three to eight seroconversion panels earlier with Elecsys HIV Ag than with the alternative assays. Higher numbers of serum samples from HIV infected patients tested positive by Elecsys HIV Ag than with the comparative assays. All HIV-1 subtypes and HIV-2 isolates were recognized with Elecsys HIV Ag. Abbott HIV-1 Ag monoclonal and Coulter HIV-1 p24 antigen assay showed a variable sensitivity for the different HIV-1 subtypes. The specificity of Elecsys HIV Ag and Coulter HIV-1 p24 antigen assay were 99.8 and 99.93%, respectively. All the eight sera that were false reactive by Elecsys HIV Ag were tested negative with the Elecsys HIV Ag Neutralization Test. In conclusion, Elecsys HIV Ag was more sensitive than the alternative assays and showed a high specificity in combination with the neutralization assay. The very short incubation time of 18 min and the fully automated procedure of Elecsys HIV Ag which permits direct testing from the primary patient blood collection tube, represent a major improvement for routine laboratory diagnosis in comparison to the alternative assays.

Combination of open field and elevated plus-maze: a suitable test battery to assess strain as well as treatment differences in rat behavior.

1. A test battery consisting of a standard open field, an enriched open field and an elevated plus maze was used to study behavior in rats. 2. Male rats of the strains PVG/OlaHsd (PVG) and Sprague-Dawley-Hsd (SPRD) (150-200 g body wt) were used to assess interstrain differences as well as handling effects. In a subsequent experiment an other set of male PVG rats (150-200 g body wt) treated either with diazepam or zolpidem was used to evaluate the test battery for pharmacological purposes. 3. SPRD rats displayed higher motor activity levels and also higher levels of exploratory behavior than the PVG rats. In contrast plus-maze activity indicated more anxiety of SPRD than PVG rats. One week pre-test handling increased the activity of both strains but it increased explorative behavior in the enriched open field only in SPRD rats. Diazepam had a substantial anxiolytic effect. Zolpidem enhanced the explorative activity in a differently to diazepam and exerted only minor anxiolytic properties. 4. We concluded that the test battery used here enables to reveal differentially strain, and treatment effects in rats.

Behavioral analysis indicates benzodiazepine-tolerance mediated by the benzodiazepine binding-site at the GABA(A)-receptor.

1. GABA(A)-receptor induced changes in locomotion and anxiety-like behaviors were studied in rats using an open-field and an elevated plus-maze. Acute and chronic doses of the benzodiazepine diazepam without and in combination with the GABA uptake inhibitor SKF-89976A were investigated. 2. Fifty-six male rats of the strain PVG/OlaHsd (PVG; 180-200 g body wt) were used to assess the influence of the benzodiazepine binding-site to the development of tolerance. Rats were divided into six groups: The first receiving saline (0.9%), the second and third diazepam (10.0 mg/kg) daily for 23 days with or without an acute challenge of 2.0 mg/kg diazepam. The fourth group received diazepam (10.0 mg/kg) daily and acutely SKF-89976A (15.0 mg/kg) plus diazepam and the fifth and sixth group received acute treatment with diazepam (2.0 mg/kg) or SKF-89976A (15.0 mg/kg). 3. Under chronic treatment with diazepam the animals became tolerant to acute doses of diazepam in activity and anxiety-related behaviors. Acute treatment with SKF-89976A increased exploration. Parameters expressing anxiolytic-like behaviors were increased, too, but not all of them significantly. In diazepam tolerant animals SKF-89976A produced anxiolytic-like behaviors 4. We conclude that the BZ- and not the GABA-binding site at the GABA(A)-receptor is involved in the development of BZ-tolerance.

Chronical haloperidol and clozapine treatment in rats: differential RNA display analysis, behavioral studies and serum level determination.

1. Adult, female rats were treated orally for 23 days with 1.6 mg/kg haloperidol or 36 mg/kg clozapine per day, to study chronic effects of the two neuroleptics. 2. At five time points during the neuroleptic treatment, animal behavior was recorded in an open field and locomotive activity was analysed. At the end of the experiment, rats were decapitated, blood samples were collected and serum concentrations of haloperidol and clozapine were determined by a radioreceptor or HPLC assay, respectively. RNA was isolated from each brain, without cerebellum, and subjected to differential RNA display. 3. Mean serum concentrations were 8 ng/ml for haloperidol and 21 ng/ml for clozapine. Analysis of open field behavior showed that haloperidol and clozapine decreased the total distance moved and the velocity as measures of the overall activity, whereas the number of rearings and the number of entries into the center, reflecting risk assessment behavior, were differentially affected. Three neuroleptic-regulated gene fragment bands were identified in differential RNA display experiments. Two gene fragments of 281 bp and 266 bp were sequenced. 4. We conclude that our study design that used behavioral, pharmacokinetic and molecular analysis increase the likelihood of finding relevant molecular events underlying the pharmacotherapeutic effects of neuroleptics in animal models.

Numerical aspects of spatio-temporal current density reconstruction from EEG-/MEG-data.

The determination of the sources of electric activity inside the brain from electric and magnetic measurements on the surface of the head is known to be an ill-posed problem. In this paper, a new algorithm which takes temporal a priori information modeled by the smooth activation model into account is described and compared with existing algorithms such as Tikhonov-Phillips.

Pro-gastrin-releasing peptide (ProGRP)--a useful marker in small cell lung carcinomas.

Gastrin-releasing-peptide (GRP), the mammalian counterpart of amphibian bombesin, has been reported to be produced by cells of SCLC. Using recombinant ProGRP Yamaguchi et al developed an enzyme immunoassay for the measurement of this more stable precursor of GRP. We focused our interest on the comparability of ProGRP to neuron specific enolase (NSE), CYFRA 21-1 and CEA. For this purpose we investigated the sera of 272 patients with histologically proven carcinomas of the lung (87 SCLC, 185 NSCLC). The sera of 74 patients with benign diseases of the lung and smokers served as a reference group. At a specificity of 95% ProGRP and NSE possessed comparable sensitivities (47% versus 45%) in small cell lung carcinomas. ProGRP showed only a few more positive test results than NSE, but reached much higher value levels than NSE. ProGRP and NSE showed a clear additive sensitivity of about 20%. In NSCLC CYFRA 21-1 was the leading marker with 63% sensitivity, whereas ProGRP seldom showed a "false positive" test result. ProGRP proved a very high specificity and good sensitivity for small cell lung carcinomas and therefore enables diagnosis of small cell lung carcinoma in patients with lung tumours of unknown origin as well as good control of efficiency of therapy.

The significance of Tenascin-C serum level as tumor marker in squamous cell carcinoma of the head and neck.

BACKGROUND: Tenascin, an extracellular matrix glycoprotein, is transiently present in embryonic tissue, in benign granulation tissue, but also in several highly anaplastic tumors like fibrosarcoma, melanoma and squamous cell carcinoma of the skin. This study was performed to validate elevated Tenascin serum levels as a possible marker for head and neck squamous cell carcinomas (HNSCC). PATIENTS AND METHODS: Tenascin serum levels were evaluated in patients with primary (n = 92) and with recurrent (n = 28) HNSCC. Patients with benign, non inflammatory ear, nose and throat diseases (n = 16) served as the control. The Tenascin serum levels were measured by ELISA (Aventis). RESULTS: Serum Tenascin concentrations of patients with benign ENT diseases ranged between 0.37 and 2.19 micrograms/ml (n = 16, mean +/- SD: 1.23 +/- 0.59 micrograms/ml), of patients with HNSCC (primary diagnosis) between 0.05 and 8.75 micrograms/ml (n = 92, mean +/- SD: 1.81 (1.36 micrograms/ml) and of patients with recurrent HNSCC between 0.53 and 10.0 micrograms/ml (n = 28, mean +/- SD: 2.78 +/- 2.2 micrograms/ml). CONCLUSION: We found a significant elevation of Tenascin serum levels only in patients with higher tumor stages (T4/UICC4) (p < 0.01/p < 0.1) or recurrent disease compared to Tenascin serum levels in healthy controls. Thereby Tenascin serum levels cannot be used clinically as a routine serum marker for the control of head and neck cancer. Further investigations are necessary to evaluate whether the measurement of Tenascin levels as tumor markers could offer additional information to the clinical outcome of patients with HNSCC.

Nuclear mitotic apparatus protein (NuMA) in benign and malignant diseases.

Nuclear mitotic apparatus protein (NuMA) is a 239 kDa internal nuclear matrix protein described to be elevated in cancer patients, especially in colorectal carcinoma and early colorectal cancers. We tested the significance of NuMA as tumour marker in colorectal cancer and also the sensitivity/specificity profile in general. Therefore, we investigated in a retrospective clinical study 507 sera from patients suffering from solid tumours, with the main emphasis on colorectal carcinoma, and 418 sera from patients with benign diseases and healthy individuals. Testing was done with a double monoclonal enzyme immunoassay detecting head and rod domain of NuMA and results were compared to the established tumour associated antigens. Based on a specificity of 95% versus the benign reference group of gastrointestinal diseases, we found--at the time of primary diagnosis--a sensitivity for colorectal cancer of 8% for NuMA, 36% for CEA and 17% for CA 19-9. Regarding T-stages of colorectal cancer no marker detected T1 when regarding 95% specificity-cut-off value but NuMA showed little more sensitivity when based on a 95% specificity cut off value versus healthy. This could not be shown in Dukes' stages. Regarding all other solid tumours tested--all based on a specificity of 95% for the corresponding benign reference groups--no advantage of NuMA in sensitivity for all other solid tumours investigated was found. No additional sensitivity could be observed. Based on our results, the NuMA-assay in its present form has no clinical relevance.

Tumour markers CEA and CA 15-3 as Prognostic factors in breast cancer--univariate and multivariate analysis.

Tumour markers are putative prognostic indicators for patients with breast cancer, but have not been elevated independently by multivariate analysis in a large patient number. In 550 patients with breast cancer without known metastases the levels of the serum tumour markers CEA und CA 15-3 were determined preoperatively and during follow-up. The prognostic relevance of these markers for recurrence (n = 128/487) and death of disease (n = 55/550) was evaluated in relation to established prognostic factors. In univariate analysis tumour size, lymph nodes, histological grading, age, hormone receptors, preoperative value of CEA (cut-off 2 ng/mL) and CA 15-3 (cut-off 25 U/mL) and their decrease of more than 33% within seven months after operation were significant for relapse. The results for death of disease were similar except for age. In multivariate analysis tumour size, lymph nodes and decrease of CEA > 33% (p < 0.001) were independent prognostic factors for recurrence. For overall survival tumour size, lymph nodes, histological grading and preoperative levels of CEA > or = 2 ng/mL (p = 0.038) and of CA 15-3 > or = 25 U/mL (p = 0.007) were independent prognostic factors. Pre- and postoperative values of the tumour markers CEA und CA 15-3 are strong independent prognostic factors for relapse and survival in breast cancer patients.

BTA-TRAK--a useful diagnostic tool in urinary bladder cancer?

During recent years the BTA-TRAK-assay (Bard Diagnostics, Redmont, USA) has been described in several investigations to be of clinical utility for patients suffering from bladder cancer. In a prospective study we investigated over four months the voided urine samples of all consecutive patients undergoing cystoscopy independent of their clinical background (n = 244) with the BTA-TRAK-assay. With a specificity of 95% for benign urological diseases (cut off: 1300 U/mL) we found a sensitivity of 13% for active bladder tumours. Using healthy individuals as a reference group (cut off: 40 U/mL) we found a sensitivity of 56% (specificity 67%). Using the cut off value recommended by the manufacturer (14 U/mL) a specificity of 54% and a sensitivity of 62% was found. For patients without relapse (NED) versus patients with active bladder tumours we got a specificity of 55% and a sensitivity of 62%. Due to an insufficient specificity and sensitivity the BTA-TRAK-test is not able to replace cystoscopy nor to improve existing diagnostic strategies in bladder cancer.