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ABSTRACT: In Deutschland erkranken jährlich ca. 12.000 Menschen an einem oberflächlichen Harnblasenkarzinom, hinzu kommt die nicht unbeträchtliche
Zahl von Rezidiven. Das Ziel einer optimalen Therapie liegt daher nicht nur in der primären Heilung der Patienten sondern
auch in der Senkung der hohen Rezidivrate durch eine geeignete Prophylaxe. Die Therapieoptionen umfassen nach der transurethralen
Resektion verschiedene topische Modalitäten der Instillationstherapie beispielsweise als Chemotherapie oder Immuntherapie.
Die individuelle Entscheidung, welche Therapie angewandt wird, muss sich am Rezidiv- und Progressionsrisiko des Tumors ausrichten.
Dies ist sowohl vom Tumorstadium, vom Differenzierungsgrad als auch vom Vorliegen eines Rezidivs abhängig. Dabei sind einige
Therapieoptionen wie die Instillation des Bacillus Calmette-Guérin im Sinne der Evidence Based Medicine durch größere randomisierte
Studien abgesichert.
Every year in Germany approximately 12,000 people are afflicted by superficial carcinoma of the urinary bladder. In addition,
the number of recurrences is not inconsiderable. The goal of optimal therapy, therefore, is not only to cure the patients
but also to lower the high rate of recurrence by appropriate prophylaxis. After transurethral resection, treatment options
include various topical modalities of instillation therapy, e.g., chemotherapy or immunotherapy. The individual decision on
which treatment modality is chosen should be based on the risk of relapse and the progression of the tumor. This depends on
tumor stage, degree of differentiation, and the presence of recurrence. Some treatment options, such as instillation of bacillus
Calmette-Guérin, have been validated by large randomized studies in the sense of evidence-based medicine.
Der Urologe 04/2012; 40(6):460-463. · 0.50 Impact Factor
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ABSTRACT: Die korrigierte 5-Jahres-Überlebensrate für Patienten mit pTa-Tumoren beträgt 95%, für das Tumorstadium pT1 G1–2 81% und für
das Tumorstadium pT1 G3–4 64% [28]. Tritt ein Rezidiv auf, verschlechtert sich die Prognose bei pTa-Tumoren auf 77,7%, bei
pT1 G1–2-Tumoren auf 78,6% und bei pT1 G3–4-Tumoren auf 38,7%. Darüber hinaus sind der Differenzierungsgrad und die Multifokalität
des Primärtumors von prognostischer Bedeutung: Während hochdifferenzierte Tumoren nur in 0–6% eine Invasion der Lamina propria
und damit eine Progression aufwiesen, zeigten 22–52% der mittelgradig differenzierten Tumoren und 5–82% der niedrig differenzierten
Tumoren im Verlauf nach transurethraler Resektion ein invasives Wachstum. Primär multifokale Tumoren (mehr als 2 Tumoren bei
Erstdiagnose), ein begleitendes Carcinoma in situ und eine Tumorgröße von >5 cm beeinflussen die Prognose ebenfalls im Sinne
einer Verschlechterung [12].
Der Urologe 04/2012; 40(5):403-411. · 0.50 Impact Factor
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ABSTRACT: Hematogenous spread of bacillus Calmette-Guerin (BCG) after intravesical instillation for bladder cancer is rare but it may result in systemic infection and hypersensitivity reaction. We investigated fluoroquinolones and steroids in an animal model to improve the therapeutic options in local and systemic BCG infection. Furthermore, the antitumor effectiveness of intravesical BCG with simultaneous application of fluoroquinolones and/or steroids was tested.
Oral antimicrobial therapy with and without steroids was started immediately after intraperitoneal injection using fluoroquinolones or trimethoprim-sulfamethoxazole. To evaluate the therapeutic options against a hyperergic reaction after repeat systemic BCG infection re-challenge was performed with intraperitoneal BCG 7 days after primary infection and oral therapy was given with fluoroquinolones or trimethoprim-sulfamethoxazole with and without steroids. The influence of continuous oral fluoroquinolone therapy on the antitumor effect of BCG was also tested in the MB 49 orthotopic murine bladder tumor model.
After primary systemic infection fluoroquinolone therapy alone led to significantly prolonged survival in mice (log rank test p = 0.041), whereas trimethoprim-sulfamethoxazole was ineffective. There was no additional effect of steroid administration. Steroids alone led to premature death (log rank test p = 0.022). After secondary BCG infection only steroid treated animals had prolonged survival (log rank test p = 0.032), whereas antimicrobials alone had no effect. The therapeutic efficacy of BCG in the orthotopic bladder tumor model was not affected by continuous oral fluoroquinolones in terms of survival (log rank test p = 0.001) or bladder weight (Wilcoxon test p = 0.001) compared with untreated controls.
In a mouse model fluoroquinolones had a beneficial effect for primary systemic BCG infections, whereas the hyperergic reaction after repeat BCG infection was susceptible only to steroids. Administering fluoroquinolones during an intravesical treatment course does not affect the antitumor efficacy of BCG.
The Journal of Urology 09/2002; 168(2):826-31. · 3.75 Impact Factor
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ABSTRACT: Im europäischen Vergleich liegen die in Deutschland ermittelten Neuerkrankungsraten für Harnblasenkrebs bei Frauen im oberen
und für Männer im mittleren Bereich. Die höchsten Raten findet man bei Männern in Italien und Spanien, bei Frauen in Dänemark.
Die niedrigsten Raten werden bei Männern in Österreich und Irland, bei Frauen in Frankreich und in den Niederlanden gefunden.
Der Onkologe 01/2002; 8(9):929-939. · 0.17 Impact Factor
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ABSTRACT: Every year in Germany approximately 12,000 people are afflicted by superficial carcinoma of the urinary bladder. In addition, the number of recurrences is not inconsiderable. The goal of optimal therapy, therefore, is not only to cure the patients but also to lower the high rate of recurrence by appropriate prophylaxis. After transurethral resection, treatment options include various topical modalities of instillation therapy, e.g., chemotherapy or immunotherapy. The individual decision on which treatment modality is chosen should be based on the risk of relapse and the progression of the tumor. This depends on tumor stage, degree of differentiation, and the presence of recurrence. Some treatment options, such as instillation of bacillus Calmette-Guérin, have been validated by large randomized studies in the sense of evidence-based medicine.
Der Urologe 12/2001; 40(6):460-3. · 0.50 Impact Factor
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Der Urologe 10/2001; 40(5):403-9; quiz 410-1. · 0.50 Impact Factor
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ABSTRACT: Im Mittelpunkt dieser Anwendungsbeobachtung stand die Handhabung der BCG-Instillationstherapie beim oberflchlichen Harnblasenkarzinom in der urologischen Praxis und die Frage, inwieweit sich Inzidenz und Schweregrad von Begleiterscheinungen und Nebenwirkungen im Routineeinsatz (auerhalb klinischer Studien) von den Literaturdaten unterscheiden. Von Februar 1998 bis September 1999 wurde bei 390 Patienten nach transurethraler Resektion eines oberflchlichen Urothelkarzinoms der Harnblase (pTa, pT1 und pTis) die adjuvante Therapie mit BCG-Instillationen (OncoTICE) durchgefhrt. Es konnten die Daten von 371 Patienten ausgewertet werden, mit insgesamt 2503 dokumentierten Instillationen. Die Histologie ergab bei 54,2% einen pTa-Tumor, bei 45,8% einen pT1-Tumor. In 6,2% lag ein primres pTis vor, und bei 4,3% fand sich ein assoziiertes pTis. Begleiterscheinungen oder Nebenwirkungen traten bei 55,8% der Patienten auf, aber nur bei 27,7% der Instillationen. Schwere Nebenwirkungen wurden nicht beobachtet. Die Vertrglichkeit der Behandlung wurde berwiegend als gut oder sehr gut bewertet.
Der Urologe B 09/2001; 41(5):482-487.
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ABSTRACT: Long-term activation of immunocompetent cells of the bladder wall as well as case reports of systemic infections some months or years after intravesical bacillus Calmette-Guerin (BCG) therapy imply that mycobacteria may persist in the body. Therefore. we investigated the fate of BCG in patients after uncomplicated intravesical instillation therapy.
A total of 49 patients were included in the study, from whom various numbers of specimens were used for mycobacterial culture and molecular biological detection techniques. In 23 patients who received a total of 128 instillations urine, sputum, venous blood and bladder biopsies were screened for BCG by acid-fast staining and culture at different times before and after instillation. From 16 of the 23 patients and from an additional 26 a total of 180 bladder biopsies obtained at intervals 3 to 30 months after instillation were screened for mycobacterial 16S ribosomal DNA by a nested polymerase chain reaction protocol.
No viable BCG was found in venous blood or in 127 of 128 sputum specimens before and 2 hours after instillation. Two of 56 bladder biopsies were culture positive. In urine BCG was detected in 96.4% of the specimens after 2 hours and in 67.9% after 24 hours after instillation. The number of positive specimens decreased and it was 27.1% on day 7 immediately before the next instillation. In 14 of 44 bladder biopsies (31.8%) mycobacterial ribosomal DNA was found within 1 week after the sixth instillation. A positive polymerase chain reaction was evident up to 24 months in between 4.2% and 37.5% of the investigated biopsies. After 30 months no ribosomal DNA was evident in the 6 samples available for testing.
Nontraumatic intravesical instillation of BCG is not accompanied by systemic mycobacterial spread. Local persistence during the instillation course is evident since viable BCG is commonly found in the urine. Long lasting and persistent BCG DNA in the bladder wall may account for long-term immuno-activation. However, the remaining BCG may be a possible source of late systemic infections.
The Journal of Urology 06/2001; 165(5):1765-8. · 3.75 Impact Factor
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ABSTRACT: Immunotherapy with Bacillus Calmette-Guérin (BCG) is clinically established in the treatment of superficial bladder cancer. In our attempt to clarify the underlying immunological mechanism, we could previously show that stimulation of PBMC with BCG leads to the generation of cytotoxic BCG-activated killer (BAK) cells. Among others, these BAK cells as well as lymphokine-activated killer (LAK) cells have been suggested as possible effector cells during BCG therapy. To understand BCG-induced activation of effector lymphocytes more precisely, we investigated the lytic pathways of human BAK cells and compared BAK cell cytotoxicity with LAK cell cytotoxicity. Perforin and Fas ligand (FasL) are the major cytolytic molecules of cytotoxic lymphocytes. Our results demonstrate that BAK and LAK cells showed an increased expression of perforin and FasL as compared with unstimulated controls. Killing of T-24 bladder tumor as well as Jurkat cells by BAK and LAK cells was predominantly mediated via perforin as demonstrated by a drastically reduced lysis in the presence of concanamycin A and EGTA/MgCl2, respectively. In contrast, lysis (radioactive release assay) and membrane disintegration (Annexin V binding) of both targets by BAK and LAK cells could not be blocked with an inhibitory anti-FasL monoclonal antibody (NOK-1). Nevertheless, T-24 and Jurkat were susceptible to killing by recombinant soluble FasL and by Chinese hamster ovary cells expressing membrane-bound FasL. We conclude that cellular mediators of BCG effector mechanisms, such as BAK and LAK cells, kill their targets via perforin and independent of the FasL pathway. Because we also found increased numbers of perforin-expressing lymphocytes in patients after BCG therapy, our findings have potential clinical relevance because BCG therapy would not be impaired by FasL resistance of target cells, which recently has been described for some tumors.
Clinical Cancer Research 10/2000; 6(9):3729-38. · 7.74 Impact Factor
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ABSTRACT: The viability of bacillus Calmette-Guérin (BCG) in intravesical instillation therapy has been demonstrated to be crucial for the prevention of bladder tumour recurrence. The aim of the present study was to determine the effects of modern antibacterial chemotherapeutics on BCG viability, particularly cycloserine, which has been recommended in the treatment of BCG-induced sepsis. The minimal inhibitory concentrations (MICs) of 32 antibacterial drugs potentially effective against the Connaught BCG strain were measured in vitro by the radiometric BACTEC 460TB method. The MICs were compared with the drug concentrations achievable in blood and urine. Susceptibility testing of cycloserine was performed with three different strains (Connaught, Tice and RIVM), using the modified proportion method, as defined in the German guidelines for anti-tuberculosis drug testing. The Connaught BCG strain was highly susceptible to fluoroquinolones, but was resistant to beta-lactams, macrolides (except clarithromycin), and some aminoglycosides. It was also sensitive to doxycycline and gentamicin at dosages that typically occur in the urine of patients after a normal dose. Connaught BCG was susceptible to all the tuberculostatic drugs tested, except for pyrazinamide. All the BCG strains analysed were resistant to cycloserine. During intravesical BCG instillation therapy, simultaneous administration of fluoroquinolones, doxycycline or gentamicin should be avoided. In cases of severe systemic complications, or if one of the antituberculosis drugs is not tolerated, fluoroquinolones may be used. Cycloserine is no longer recommended for the early treatment of BCG sepsis.
European Urology 02/2000; 37 Suppl 1:21-5. · 8.49 Impact Factor
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ABSTRACT: We determine the effects of modern antibacterial chemotherapeutics on bacillus Calmette-Guerin (BCG) viability, particularly those of cycloserine, which has been recommended for treating BCG induced sepsis.
The minimal inhibitory concentrations of 31 antibacterial drugs against Connaught BCG strain were determined in vitro by the radiometric BACTEC 460TB method. Minimal inhibitory concentrations were compared with the drug concentrations achievable in blood and urine to estimate systemic or intravesical susceptibility. Susceptibility testing of cycloserine was performed with Connaught, Tice and RIVM BCG strains, using the modified proportion method on Lowenstein-Jensen agar.
Connaught BCG was susceptible to quinolones in systemic infections but resistant to beta-lactams, macrolides and some aminoglycosides. It was resistant to pyrazinamide but showed good susceptibility toward the other antituberculosis drugs tested. All 3 BCG strains analyzed were resistant to cycloserine. Most antibacterials may interfere with BCG in the bladder because of high urinary recovery.
Antibacterial drug interference with BCG viability should be avoided during intravesical instillation therapy. In cases of severe complications quinolones rather than cycloserine may be given in addition to standard triple antituberculosis drug therapy or if one of these drugs is not tolerated. Our data may contribute toward enhancing the therapeutic safety and efficacy of intravesical BCG immunotherapy by the appropriate use of antibacterial drugs.
The Journal of Urology 01/2000; 162(6):1959-62. · 3.75 Impact Factor
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ABSTRACT: With regard to side-effects in intravesical bacillus Calmette-Guérin instillation therapy and the limited efficacy of intravesical chemotherapy, there is still a need for improvement of these standard therapies. Recently, technical adjuvant means or the modification of cytostatic drugs have been undertaken to improve the efficacy of intravesical chemotherapy. Prognostic indicators of the response to bacillus Calmette-Guérin immunotherapy have been identified, but indicators of side-effects are needed in order to improve the benefit-to-risk ratio of bacillus Calmette-Guérin instillation therapy. Many innovative treatment options, however, still require a definition of their clinical value.
Current Opinion in Urology 10/1999; 9(5):407-11. · 2.59 Impact Factor
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ABSTRACT: To study adhesion, penetration and internalization of BCG and effector-cells to and into three-dimensional in vitro cell aggregates from benign and malignant urothelial origin mimicking small in vitro tumors.
Multicellular spheroids (MCS) were generated by "liquid-overlay" technique. Adhesion and penetration of viable FITC-labelled BCG into MCS from urothelial cancer cell lines and normal urothelial cells was studied by electron microscopy (TEM) and fluorescence microscopy. Spheroid growth during BCG-co-incubation was determined by light microscopy. Peripheral blood mononuclear cells (PBMC) were stimulated with BCG to generate BCG-activated-killer (BAK) cells. The infiltration of these effectors and of lymphokine-activated killer (LAK) cells into MCS was examined at different intervals by means of immunohistochemistry. The resulting cytotoxicity was judged in a 3H-l-methionine release assay.
BCG adhered to MCS from tumor cells but not to benign cell MCS. Intracellular internalization of the bacteria was detectable in superficial tumor cell-layers (1-5) whereas BCG was not found in deeper layers. Proliferation of malignant MCS was reduced in the presence of BCG. Benign MCS showed contact inhibition growth arrest, which was not altered by BCG. BAK and LAK effector cells both infiltrated tumor cell MCS as opposed to unstimulated PBMC. In contrast to LAK cells, BAK cells did not infiltrate into benign cell MCS and were not cytotoxic towards them.
With regard to the clinical situation the selective adhesion and internalization of BCG to malignant cells might explain why BCG has been rarely found in follow-up biopsies in tumor free patients. More interestingly, the selective adhesion of BCG to and infiltration of BAK effector cells into malignant cell spheroids suggests a selective mode of action of BCG.
The Journal of Urology 09/1999; 162(2):600-5. · 3.75 Impact Factor
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ABSTRACT: Colony-stimulating factors (CSF) are used clinically in the treatment of chemotherapy-induced myelosuppression and in support of bone marrow transplantation. As CSF are known to have pleiotropic functions, their effects on cellular cytotoxicity were analysed in vitro against bladder carcinoma cell lines. By means of an L-[3H]methionine-release assay, the cytotoxicity of peripheral blood mononuclear cells against the natural-killer(NK)-cell-resistant bladder carcinoma cell lines BT-A and SBC-7 was measured using different effector/target-cell ratios. Costimulatory effects of granulocyte-colony-stimulating factor (G-CSF), granulocyte/macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3) and stem cell factor (SCF) on the generation of lymphokine-activated killer (LAK), bacillus Calmette-Guérin-activated killer (BAK) and natural killer (NK) cell cytotoxicity were investigated in this assay. Furthermore, the effect of CSF on proliferation of urothelial tumor cells in vitro was determined by a [3H]thymidine DNA-labelling technique. GM-CSF, but not G-CSF, IL-3 or SCF, was able to increase NK, BAK and LAK cytotoxicity in a dose-dependent manner. No acceleration of carcinoma cell proliferation was evident under the conditions of our assay. These data indicate the costimulatory effect of GM-CSF on cellular cytotoxicity, which might be used for immunotherapeutic purposes.
Cancer Immunology and Immunotherapy 04/1997; 44(1):35-40. · 3.70 Impact Factor
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ABSTRACT: We report our experience with bilateral laparoscopic nephrectomy after renal transplantation.
Between August 1994 and October 1995, 11 patients who had previously undergone renal transplantation underwent bilateral laparoscopic nephrectomy at our hospital due to poorly controlled hypertension. The records of 10 patients undergoing bilateral open nephrectomy were reviewed for comparison.
Mean operative time in the laparoscopy group was 195 minutes (range 125 to 270). Mean blood loss was 345 ml. and 1 patient required conversion to an open operation. Oral intake and mobilization were begun 1 day postoperatively. Mean postoperative morphine equivalent consumption was 14 mg., mean hospital stay was 4.2 days (range 3 to 6) and mean return to normal activities was 14 days. At a mean followup of 10.4 months blood pressure had improved significantly in 8 patients (73%). Mean operative time in the open surgery group was 145 minutes (range 115 to 170) and mean postoperative morphine equivalent required was 44 mg. Compared to the laparoscopy group the interval to resumption of oral intake (3.5 days), duration of hospital stay (10.7 days) and return to normal activities (36 days) were prolonged in the open surgery group.
According to our results, bilateral laparoscopic nephrectomy could be an effective alternative for the treatment of severe hypertension after renal transplantation. Compared to open nephrectomy most patients benefit from the laparoscopic approach.
The Journal of Urology 03/1997; 157(2):445-9. · 3.75 Impact Factor
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Investigative urology (Berlin, Germany). 02/1994; 5:233-5.
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ABSTRACT: Patients with metastasized renal cell carcinoma have a poor prognosis with conventional therapies. The feasibility and safety of donating purified natural killer (NK) cells without additional cytokines were evaluated. In contrast to all previous studies, the NK cells were derived from allogenic donors. The NK cell donors were HLA-C matched to enable NK cell inhibition via killer cell inhibitory receptors and HLA-C. This should obviate a graft-versus-host reaction against nonmalignant HLA-expressing tissues in the allogenic constellation. The average number of cells applied per transfusion was 1.02 +/- 0.265 x 10(9). The purity of the NK cells was 85% to 95%, and most of the contaminating cells were monocytes. Twenty-six transfusions given to 11 patients did not cause any minor or major adverse effects, with the exception of one episode of transient fever. One patient had an objective regression of his lung metastases that had been progressing continuously before. No cytotoxic HLA antibodies could be detected 3 weeks after the transfusions. The observed tolerance to this therapeutic regimen suggests the need for further studies with increased doses of cytokine-activated NK cells.
Journla of Immunotherapy 23(4):499-504. · 3.27 Impact Factor
