Standard of Care Versus Metastases-directed Therapy for PET-detected Nodal Oligorecurrent Prostate Cancer Following Multimodality Treatment: A Multi-institutional Case-control Study.

BACKGROUND: Most prostate cancer (PCa) patients with a biochemical failure following primary multimodality treatment (surgery and postoperative radiotherapy) relapse in the nodes. OBJECTIVE: To perform a matched-case analysis in men with lymph node recurrent PCa comparing standard of care (SOC) with metastasis-directed therapy (MDT). DESIGN, SETTING, AND PARTICIPANTS: PCa patients with a prostate-specific antigen (PSA) progression following multimodality treatment were included in this retrospective multi-institutional analysis. INTERVENTION: The SOC cohort (n=1816) received immediate or delayed androgen deprivation therapy administered at PSA progression. The MDT cohort (n=263) received either salvage lymph node dissection (n=166) or stereotactic body radiotherapy (n=97) at PSA progression to a positron emission tomography-detected nodal recurrence. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint, cancer-specific survival (CSS), was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched analyses. RESULTS AND LIMITATIONS: At a median follow-up of 70 (interquartile range: 48-98) mo, MDT was associated with an improved CSS on univariate (p=0.029) and multivariate analysis (hazard ratio: 0.33, 95% confidence interval [CI]: 0.17-0.64) adjusted for the year of radical prostatectomy (RP), age at RP, PSA at RP, time from RP to PSA progression, Gleason score, surgical margin status, pT- and pN-stage. In total, 659 men were matched (3:1 ratio). The 5-yr CSS was 98.6% (95% CI: 94.3-99.6) and 95.7% (95% CI: 93.2-97.3) for MDT and SOC, respectively (p=0.005, log-rank). The main limitations of our study are its retrospective design and lack of standardization of systemic treatment in the SOC cohort. CONCLUSIONS: MDT for nodal oligorecurrent PCa improves CSS as compared with SOC. These retrospective data from a multi-institutional pooled analysis should be considered as hypothesis-generating and inform future randomized trials in this setting. PATIENT SUMMARY: Prostate cancer patients experiencing a lymph node recurrence might benefit from local treatments directed at these lymph nodes.

[Urotechnology: a new interdisciplinary platform for promoting and managing of technical innovations in urology]. / Urotechnologie : Neue Plattform zur Förderung und zum Innovationsmanagement der medizintechnischen Forschung in der Urologie.

The innovative power in medical engineering and technology development requires a close cooperation between universities and non-university research institutions and a collaboration with industrial partners. German knowledge in the fields of video and micro-optics, microsystem technology and of informational technology and software applications seem to be highly competitive at international level. Germany's previous leadership in the development of technical equipment will be challenged by today's requirements and difficulties in medical engineering. Research and expenses demands for the development of novel medical instruments, products and applications will increase continuously. Transparency and coordinated collaboration between universities and industrial partners will contribute to a substantial improvement in surgical therapy. Medical technology of the future, including urotechnology, requires professional structures and coordination and will have to be based on evidence.

[UroLift®: an operative non-ablative procedure for treatment of benign prostatic syndrome]. / UroLift® : Ein operatives, nicht ablatives Verfahren zur Therapie des benignen Prostatasyndroms.

The implantation of a tissue retractor (UroLift®, Neotract, Pleasanton, CA) allows for the first time as a non-ablative operative technique, moderate deobstruction without removal or destruction of prostate tissue. The achievable treatment results are at least comparable to drug therapy with respect to alleviation of suffering and symptoms (primary treatment aim) and superior with respect deobstruction. The advantage of this method compared to all other conservative and operative therapy procedures is preservation of sexual function. An evaluation of this method is currently being carried out and compared to TURP in prospective, randomized studies (BPH6 study) and the results are expected in 2015.

[The Freiburg Index of Patient Satisfaction: introduction and validation of a new questionnaire]. / Der Freiburger Index für Patientenzufriedenheit. Vorstellung eines neuen Instruments und seiner psychometrischen Eigenschaften.

BACKGROUND: In the era of evidence-based medicine health-related quality of life measurements are recognized as valuable indicative factors. Because there was no generally applicable questionnaire addressing patient satisfaction after interventional or surgical procedures, the Freiburg Index of Patient Satisfaction was developed and psychometrically evaluated. METHODS: A preliminary version was evaluated and optimized through structured interviews with 20 patients (qualitative pre-study). The final questionnaire was then applied to 257 urological patients and a comprehensive statistical analysis including validation to a matching questionnaire (ZUF-8, Kriz 2008) was performed. RESULTS: All psychometric qualities scored well. The examined sample showed no missing values and no ceiling effect as otherwise found frequently: the most positive answer categories accounted for 43.6 % of cases. Reliability (Cronbach's Alpha = 0.84, discriminatory power = 0.50) was high. Furthermore the results of a factor analysis proofed unidimensionality of the questionnaire. Validity was shown by a close correlation between FIPS and ZUF-8 scores (r = 0.747, p < .001). CONCLUSION: The Freiburg Index of Patient Satisfaction is a generally applicable questionnaire to evaluate treatment satisfaction after interventional or surgical procedures. The questionnaire can be used to objectify results and increase comparability of clinical studies and quality in health care.

[Empathic leadership: shaping positive change]. / Empathische Führung: Veränderung positiv gestalten.

This paper explains the concept of empathic leadership in the setting of fundamental organisational changes. It deals with the question of how you can establish a culture of leadership, which motivates employees positively and enthuses them for the upcoming changes. It discusses the basics of empathic leadership and considers the question of how handling of emotions influences change processes and how different management styles can be used supportively during changes. With the help of a practical example the different phases of change are presented from a management point of view. Thereby the theory of different levels of employee motivation is explained inter alia. The article shows that empathic leadership also has a lasting economic effect. This can be seen particularly in the power of motivation for change, in addition to recruitment and long-term employee retention.

Genetic association study of the GNB3 C825T, the ACE I/D and the eNOS G894T polymorphisms and the risk to develop erectile dysfunction in a German ED population.

Erectile dysfunction (ED) is often associated with cardiovascular disorders such as hypertension, coronary heart disease, hypercholesterolaemia and diabetes mellitus. The genotypes in the GNB3 C825T, the ACE I/D and the eNOS G894T polymorphisms have been identified as genetic risk factors for cardiovascular disorders. The association between the genotypes in these polymorphisms and the risk to develop ED was analysed. In 455 German ED patients and 111 age-matched healthy controls genotyping in the candidate polymorphisms was performed after DNA extraction from whole blood. Association studies between the genotype distribution in the control group in comparison with the ED-group and age of onset of the disease as well as erectile response to intracorporal prostaglandin injection in dependence of candidate polymorphism genotype were performed using the SPSS-Software(R). Genotype distribution of the GNB3 C825T, the ACE I/D and the eNOS G894T polymorphisms was similar in the ED population and the healthy control group. The age of onset of the disease as well as the erectile response to intracorporal prostaglandin injection was independent of the genotypes in the three candidate polymorphisms. In contrast to the previous studies in this analysis, the risk to develop ED is not influenced by the genotypes in the GNB3 C825T, the ACE I/D and the eNOS G894T polymorphisms.

[Testosterone and psyche]. / Testosteron und Psyche.

Testosterone, like other steroid hormones, crosses the blood-brain barrier, and the androgen receptor is present in most parts of the human brain. Therefore, testosterone has many effects on the psyche, mainly in men but also in women. Most often discussed is its influence on sexuality, especially on desire and sexual fantasies, spontaneous nighttime erections, sexual activity, and the number of orgasms and ejaculations. Mood and energy are also testosterone related. Testosterone deficiency in male patients can lead to depressive disorders. In the past, elevated testosterone levels were seen as responsible for strongly aggressive behaviour. Some cognitive functions (spatial and mathematical sense, verbal skills) are, at least to a certain point, testosterone related. Due to the extremely complex functioning of the human brain, a scientifically exact statement regarding the true relationship between testosterone and human behaviour is not possible. On the one hand, the cause is definitively multifactorial, but on the other, testosterone is metabolised in the brain, and the metabolites act by themselves. Furthermore, a bidirectional relationship exists between hormones and human behaviour: Human behaviour is influenced by hormones, and human behaviour also has a direct influence on the levels of many hormones in the human body. Finally, much data in this field are derived from animal studies; studies on humans cannot be conducted because of ethical reasons or scientific and technical problems.

A bispecific diabody directed against prostate-specific membrane antigen and CD3 induces T-cell mediated lysis of prostate cancer cells.

BACKGROUND: Although cancer of the prostate is one of the most commonly diagnosed cancers in men, no curative treatment currently exists after its progression beyond resectable boundaries. Therefore, new agents for targeted treatment strategies are needed. Cross-linking of tumor antigens with T-cell associated antigens by bispecific monoclonal antibodies have been shown to increase antigen-specific cytotoxicity in T-cells. Since the prostate-specific membrane antigen (PSMA) represents an excellent tumor target, immunotherapy with bispecific diabodies could be a promising novel treatment option for prostate cancer. METHODS: A heterodimeric diabody specific for human PSMA and the T-cell antigen CD3 was constructed from the DNA of anti-CD3 and anti-PSMA single chain Fv fragments (scFv). It was expressed in E. coli using a vector containing a bicistronic operon for co-secretion of the hybrid scFv V(H)CD3-V(L)PSMA and V(H)PSMA-V(L)CD3. The resulting PSMAxCD3 diabody was purified from the periplasmic extract by immobilized metal affinity chromatography (IMAC). The binding properties were tested on PSMA-expressing prostate cancer cells and PSMA-negative cell lines as well as on Jurkat cells by flow cytometry. For in vitro functional analysis, a cell viability test (WST) was used. For in vivo evaluation the diabody was applied together with human peripheral blood lymphocytes (PBL) in a C4-2 xenograft-SCID mouse model. RESULTS: By Blue Native gel electrophoresis, it could be shown that the PSMAxCD3 diabody is mainly a tetramer. Specific binding both to CD3-expressing Jurkat cells and PSMA-expressing C4-2 cells was shown by flow cytometry. In vitro, the diabody proved to be a potent agent for retargeting PBL to lyze C4-2 prostate cancer cells. Treatment of SCID mice inoculated with C4-2 tumor xenografts with the diabody and PBL efficiently inhibited tumor growth. CONCLUSIONS: The PSMAxCD3 diabody bears the potential for facilitating immunotherapy of prostate cancer and for the elimination of minimal residual disease.

A recombinant PSMA-specific single-chain immunotoxin has potent and selective toxicity against prostate cancer cells.

Prostate cancer is the most commonly diagnosed form of cancer and the second leading cancer-related death among men in the Western civilization. Since no effective therapy exists for this tumor after progression beyond resectable boundaries, there is an urgent need for new treatment strategies. Prostate specific membrane antigen (PSMA) represents an excellent target on prostate cancer cells, and therefore specific immunotherapy may be a novel therapeutic option for the management of this tumor. We constructed a fully recombinant immunotoxin (A5-PE40) from a single-chain antibody fragment (scFv) against cell-adherent PSMA and a truncated form of Pseudomonas exotoxin A (PE40) lacking its natural binding domain Ia. The scFv A5 was obtained from a mAb elicited with native PSMA by phage display technology and direct selection on cells carrying the antigen. The bacterially expressed and purified immunotoxin A5-PE40 specifically binds to PSMA-positive prostate cancer cells and induces a 50% reduction of viability (IC50) at a concentration of 20 pM, while PSMA-negative cells remain unaffected. Due to its high and specific toxicity this recombinant immunotoxin is a promising candidate for therapeutic applications in patients with prostate cancer.

Reconstruction of seminal ducts in obstructive azoospermia.

Depending on the localization of the obstruction of the seminal ducts, either a microsurgical reconstruction (tubulovasostomy, vasovasostomy) or a transurethral resection of the ejaculatory ducts is carried out. We have compared the effectiveness and economic advantages of reconstructive microsurgery of the epididymis and vas deferens with standard procedures in animal experiments. Microsurgical invagination techniques in tubulovasostomy are equal to the standard procedure from the point of view of the patency and fertility rates. They are also easier to learn and carry out. Less time is required for the invagination technique, and also less microsurgical suture material. The double-layer technique in vasovasostomy is equal to the one-layer microsurgical technique from the point of view of patency and fertility rates. The one-layer technique requires less time and suture material. It seems that the discrepancy between the patency and the fertility rate is related to immunological processes after reconstruction of the seminal ducts. In cases of obstructive azoospermia it is necessary to investigate the individual conditions and possibilities of the infertile couple. As a result of the high success rate obtainable today by surgical reconstruction of the seminal ducts, this must constitute the first type of treatment to be considered, before any of the procedures of reproductive medicine are undertaken.

Antitumoral effect of recombinant mistletoe lectin on chemically induced urinary bladder carcinogenesis in a rat model.

BACKGROUND: The objective of this study was to determine the effect of intravesically applied, recombinant, galactoside specific mistletoe lectin (rML) on chemically induced tumor development in the urinary bladder of rats. METHODS: For tumor induction, rats were treated with four biweekly 1.5 mg doses of N-methyl-N-nitrosourea (NMU) intravesically (Weeks 0, 2, 4, and 6). The control group (n = 39 + 17 rats) received no other treatment. The four therapy groups also received rML twice weekly according to one of the following instillation regimens: 1) 30 ng rML per instillation from Week 8 to Week 13 (Group a: n = 14 rats), 2) 150 ng rML per instillation from Week 8 to Week 13 (Group b: n = 23 + 15 rats), 3) 30 ng rML per instillation from Week 14 to Week 19 (Group c: n = 22 rats), and 4) 150 ng rML per instillation from Week 14 to Week 19 (Group d: n = 19 rats). After the rats were asphyxiated at Week 21, the urinary bladders were excised in toto and examined histopathologically. To study the immunomodulatory effects of intravesically applied rML, 17 animals from the control group and 15 animals from Group b were asphyxiated at Week 13, and urinary bladder tissue was analyzed by semiquantitative reverse transcriptase-polymerase chain reaction analysis for mRNA expression of interferon-gamma, interleukin-10, and Fas ligand. RESULTS: By Week 21, atypical hyperplasia and neoplastic transformation were found in 82% of the animals in the control group. In contrast, in all four cohorts that were treated with rML, significantly lower rates of atypical hyperplasia and neoplastic transformation were found (Group a, 50%; Group b, 52%; Group c, 45%; and Group d, 42%). By Week 13, in the bladder tissue of 15 rML-treated animals from Group b, lower expression of interleukin-10 mRNA was measured, whereas the expression levels of interferon-gamma mRNA and Fas ligand mRNA were comparable to those of 17 animals from the control group. CONCLUSIONS: The current data provide evidence for an inhibitory effect of rML on experimental urothelial carcinogenesis that does not seem to be due to interferon-gamma and/or interleukin-10 dependent mechanisms.

[Prescribing of sildenafil by national insurance program physicians. What basic sexual medicine qualification is required?]. / Kassenärztliche Verordnung von Sildenafil. Welche sexualmedizinische Basisqualifikation ist zu fordern?

The role of sildenafil in the treatment of erectile dysfunction is discussed. Especially in primary care there is a necessity to weigh the individual cost-benefit-ratio. Functional analysis of erectile dysfunction, exclusion of psychiatric and organic comorbidity, identification of sexual deviance and couple counseling about the advantages and disadvantages of sildenafil prescription are the core prerequisites of sildenafil application in primary care. The counseling model of PLIS-SIT is proposed as a guideline for counseling process. Current approaches of education for general practitioners are reviewed and the integration in a recently developed training for management of psychiatry and psychosomatic illness in general medical settings is proposed. Finally open questions for research and quality management are discussed.

Enhanced expression of IFN-gamma mRNA in CD4(+)or CD8(+)tumour-infiltrating lymphocytes compared to peripheral lymphocytes in patients with renal cell cancer.

The mRNA expression of the cytokines IFN-gamma, IL-10 and TNF-alpha and the proapoptotic factor Fas ligand (FasL) was compared in freshly isolated CD4(+)and CD8(+)tumour-infiltrating lymphocytes (TIL) and simultaneously obtained autologous CD4(+)and CD8(+)peripheral blood lymphocytes (PBL) from 20 patients with renal cell carcinomas (RCC). TIL were isolated from mechanically disaggregated tumour material and PBL from peripheral blood by gradient centrifugation. The cells of the interphase were depleted from tumour cells with anti-human epithelial antigen magnetic beads and then positive selection was performed with anti-CD4 or anti-CD8 magnetic beads. In these pure lymphocyte preparations the constitutive expression of cytokine and FasL mRNAs was determined by using a PCR-assisted mRNA amplification assay. In the CD4(+)TIL from the 20 patients with RCC, levels of mRNAs encoding for IFN-gamma (P

Comparison of the activation status of tumor infiltrating and peripheral lymphocytes of patients with adenocarcinomas and benign hyperplasia of the prostate.

BACKGROUND: The presence of lymphocytic infiltration in prostate carcinomas has been shown to have prognostic relevance. However, it is not yet clear if this infiltrate represents a tumor-specific activated cell population or not. Therefore, the aim of the present study was to characterize the activation status of freshly isolated tumor infiltrating lymphocytes (TIL) from prostate carcinomas (PCa) and benign hyperplasia (BPH) with respect to the mRNA expression of cytokines and apoptotic factors. METHODS: TIL were isolated from mechanically disaggregated tumor material by gradient centrifugation. The cells of the interphase were depleted from epithelial cells with anti-human epithelial antigen magnetic beads and then CD3(+)- lymphocytes were selected with magnetic beads against this determinant. In these pure lymphocyte preparations the mRNA expression of IL-1, IL-10, IFN-gamma, TNF-alpha, Fas and Fas ligand was determined by using a semiquantitative RT-PCR. Contamination with tumor cells was excluded by a PCR for PSA and PSMA. RESULTS: The CD3(+)-TIL from 21 patients with PCa and 20 patients with BPH expressed significantly higher levels of IL-10- and Fas ligand-mRNA compared to the autologous CD3(+)- PBL, whereas the expression of IL-1-, TNF-alpha- and Fas-mRNA was not different in either cell population. In contrast, the mRNA levels of IFN-gamma were significantly higher only in the CD3(+)-TIL from the carcinomas but not from the BPH compared to autologous CD3(+)-PBL. CONCLUSIONS: Since high levels of IFN-gamma have been reported to be produced by specifically lytic lymphocytes, our results suggest the presence of specifically activated TIL in the prostate carcinomas but not in the BPH, whereas inflammatory activated TIL are present both in the carcinomas and the BPH.

Construction and in vivo evaluation of an anti-PSA x anti-CD3 bispecific antibody for the immunotherapy of prostate cancer.

BACKGROUND: Cross-linking of tumor antigens with the T-cell associated CD3 antigen can be effectively achieved by bispecific monoclonal antibodies and lead to an increase in antigen-specific cytotoxicity in T cells. Because of the high organ specificity of the prostate specific antigen (PSA), a bispecific antibody (BiAb) directed against this antigen and CD3 may be a tool for a highly specific immune therapy of prostate cancer. METHODS: For generating BiAb, the quadroma technique was used. Binding properties both to CD3 and PSA were shown by flow cytometry with the CD3 expressing Jurkat cell line and fluorescein-labeled PSA. Specific tumor cell lysis was tested with the PSA expressing prostate carcinoma cell line LNCaP as target and interleukin-2 activated human peripheral blood lymphocytes as effector cells in a chromium-51-release assay. For in vivo evaluation of the BiAb, a nude mouse model was used. The mice were inoculated with LNCaP prostate carcinoma cells. Animals with growing tumors were treated with 100 micrograms BiAb and 5 x 10(6) effector cells. RESULTS: Three stable quadromas producing anti-CD3 x anti-PSA BiAb were established. From the culture supernatant of one quadroma, BiAb was separated by affinity chromatography and tested in vitro and in vivo for its ability to target effector T lymphocytes against appropriate tumor cells. In vitro, a specific lysis of PSA expressing prostate carcinoma cells was demonstrated. In vivo, a significant reduction in tumor growth (p < 0.05) could be shown in nude mice treated with BiAb and effector cells as compared to a group treated only with effector cells and an untreated control group. CONCLUSION: In the present study, an anti-CD3 x anti-PSA-BiAb was demonstrated to be effective against prostate carcinoma cells in vitro and in vivo. Therefore this BiAb may be a tool for the immunotherapy of prostate cancer.

Intravesical administration of 5-aminolevulinic acid (5-ALA). Safety and pharmacokinetics of 5-ALA and its metabolite protoporphyrin IX.

OBJECTIVE: In an open study, the local and systemic side effects and pharmacokinetics of 5-aminolevulinic acid (5-ALA) and the fluorescent metabolite protoporphyrin IX (PPIX) were investigated after intravesical administration for the fluorescent photodetection of superficial bladder carcinoma. PATIENTS AND METHODS: In 20 patients with confirmed bladder carcinoma, 5-ALA was introduced into the bladder 2 h (15 patients) and 4 h (5 patients) before an elective endoscopic resection. The 5-ALA and PPIX levels in the plasma were determined before and up to 10 h after application, and in the urine 2 h or 4 h after application. RESULTS: The plasma level of 5-ALA rose rapidly, the maximal concentration (340 ng/ml) being reached in 0.55 h (2 h) or 0.62 h (4 h). The elimination half-life of 5-ALA amounted to 0.74 h (2 h) or 0.79 h (4 h). In five of the patients, there was a measurable plasma concentration which ranged from the detection limit of 4.3 ng/ml to 14 ng/ml between 2 h and 5 h after application, and then fell below the detection limit after 9 h. Absorption of 5-ALA by the bladder was low, i.e. less than 1% of the total amount applied. During a period of observation of 96 h, no 5-ALA-specific side effects appeared. CONCLUSION: Because of the small quantity of 5-ALA resorbed following its intravesical administration, only minimal concentrations of PPIX that are responsible for producing side effects can be metabolised in the plasma. Therefore, no systemic side effects are to be expected after the intravesical administration of 5-ALA.

Biological effects of natural and recombinant mistletoe lectin and an aqueous mistletoe extract on human monocytes and lymphocytes in vitro.

Mistletoe lectin is thought to constitute the active principle in extract preparations from mistletoe, which are widely used as immunomodulators in adjuvant tumor therapy. However, no study exists which compares the immunological potency of different well-defined mistletoe lectin preparations on human immune cells. Therefore, in the present study the biological effects of an aqueous mistletoe extract, standardized for mistletoe lectin I (eML), the isolated natural mistletoe lectin (nML), and the recombinant form of this lectin (rML) on human peripheral blood monocytes and lymphocytes were compared with respect to cell viability and cytokine induction. After 48-hr incubation of peripheral blood mononuclear cells (PBMC) with rML, nML, and eML, a continuous concentration-dependent decrease in cell viability was found with an IC50 of about 3 ng/ml for rML and nML and 10 ng/ml for eML, respectively. This effect also was seen when isolated lymphocytes and monocytes were separately incubated with the lectin preparations. After incubation of PBMC and isolated monocytes of 5/10 blood donors with eML, an increase in cell viability was found at lectin concentrations between 10 and 1,000 pg/ml. This effect was not seen with the pure lectin preparations nML and rML. After 48-hr incubation of PBMC with rML, nML, and eML, induction of IL-1-beta, TNF-alpha, IL-2, IL-6, and IL-10 but not IFN-gamma was measured. For IL-1-beta it could be shown that cytokine induction took place at a broad lectin concentration range (0.1-100 ng/ml). Cytokine levels varied greatly in the PBMC cultures of the different blood donors. When monocytes were separately incubated with eML, nML, and rML for 48 hr, high levels of IL-1-beta were found. In contrast, in cultures of separated lymphocytes from the same donors only a minimal production of IL-1-beta and no production of IFN-gamma was found after incubation with rML, nML, and eML. It is concluded that there are quantitative differences in the immunomodulatory effects of the mistletoe lectin preparations on human monocytes and lymphocytes. Therefore, measurement of cell viability and cytokine induction may be a diagnostic laboratory tool to determine the immunological potency of various mistletoe preparations and may help to clarify the clinical benefit of therapies with these substances.

Systemic and local immunomodulatory effects of intravesical BCG therapy in patients with superficial urinary bladder carcinomas.

PURPOSE: The aim of the present study was to elucidate whether only local, or also systemic immunomodulatory effects may be induced by intravesical BCG therapy of superficial urinary bladder cancer. MATERIALS AND METHODS: A total of 37 patients with stages Ta to T1b superficial transitional cell bladder carcinomas received 6 weekly BCG instillations after transurethral resection of the tumor. In a first group of 19 patients blood was taken before each BCG instillation and 6 weeks after the last one. In a second group of 18 patients blood and urine was taken before and 2, 6, and 24 hours after each BCG instillation. In the mitogen-stimulated whole blood cell cultures and in the urine samples the levels of the cytokines IL-1beta, IL-2, IL-10, TNF-alpha and IFN-gamma were determined by enzymoimmunological tests. Additionally, in all plasma and urine samples the levels of TNF-p75-receptor (TNF-p75-R) were measured. RESULTS: Comparison of ex vivo leukocyte cytokine production in the blood cell cultures of the patients of group I revealed no significant change in the levels of the cytokines. In contrast, TNF-p75-R plasma levels increased significantly during the experimental time of 12 weeks (p < or =0.01). In the blood cell cultures of the group II patients a different daytime variation of cytokine production was seen, compared to the 19 healthy controls. After BCG instillation the normal peak cytokine production in the evening was suppressed. A significant rise in plasma TNF-p-75-R levels was measured 24 hours after BCG instillation (p < or =0.05). In the urine of these patients significantly higher levels of all measured cytokines and TNF-p75-R were observed 6 to 24 hours after the instillation. CONCLUSIONS: The results suggest that besides the well known local immune activation, BCG instillation also leads to a modulation of peripheral immune mechanisms.