[UCM Urology Centrum München AG. The Munich model of a network of urologists].
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Cooperative Behavior↗
Biomedical subjects
M Kriegmair
Publications and source records attributed to M Kriegmair.
Whole bladder photodynamic therapy with 5-aminolevulinic acid using a white light source.
OBJECTIVES: To determine whether whole bladder photodynamic therapy after intravesical administration of 5-aminolevulinic acid using a white light source would destroy urothelial carcinoma. We sought to define the optimal target group of patients for this therapy. The side effects of treatment were also assessed. METHODS: We performed whole bladder photodynamic therapy with 100 J/cm(2) white light 2 to 4.5 hours after intravesical administration of 17% 5-aminolevulinic acid in 12 patients with recurring, multifocal, Stage pTa, grade I to III, urothelial tumors of the bladder and carcinoma in situ. RESULTS: Immediately after whole bladder irradiation, histologic examination of biopsies taken from flat suspicious lesions showed no viable cells; remnants of malignant cells were found in papillary tumors. Of the 12 patients, 11 returned for follow-up examination. At a median follow-up of 18 months (range 3 to 25), 3 of the 7 patients with carcinoma in situ and 2 of the 4 patients with papillary tumors were free of disease. In all patients, urinary frequency and urgency subsided within 3 weeks. No decreased bladder capacity or systemic side effects were observed. CONCLUSIONS: Our preliminary data show that whole bladder photodynamic therapy with intravesically applied 5-aminolevulinic acid using a white light source is effective in destroying flat malignant lesions of the bladder such as carcinoma in situ. The procedure is easy to perform and is not associated with any major side effects. The findings warrant long-term and multicenter studies.
Administration, Intravesical↗
Endoscopic detection of transitional cell carcinoma with 5-aminolevulinic acid: results of 1012 fluorescence endoscopies.
OBJECTIVES: The initial encouraging results using 5-aminolevulinic acid (5-ALA) induced fluorescence endoscopy (AFE) have promised a procedure with an outstanding sensitivity for the detection of early stage bladder cancer. Summarized here is our clinical experience and data comprising 1012 fluorescence endoscopies. METHODS: Two hours, 30 minutes before endoscopy, 1.5 g 5-ALA dissolved in 50 mL of 5.7% sodium monohydrogen phosphate was instilled in patients intravesically. Before AFE, all patients underwent white light endoscopy, and a bladder washing cytologic specimen was obtained. A special light source provided blue light (375 to 440 nm) for fluorescence excitation. Suspicious sites were identified by their red fluorescence contrasting against backscattered blue light when observed through the long pass filter (445 nm) integrated into the telescope eyepiece. RESULTS: Two thousand four hundred seventy-five specimens were obtained (2.4 biopsies per AFE). In 552 AFEs (54.5%), neoplastic urothelial lesions were detected, in 34.2% only because of their positive fluorescence; 38.7% of these additionally detected neoplastic foci had poorly differentiated histologic features. CONCLUSIONS: AFE has proved to be a clinically feasible procedure with an outstanding detection rate for flat, urothelial, high-risk lesions.
Administration, Intravesical↗
Clinical experience with 5-aminolevulinic acid and photodynamic therapy for refractory superficial bladder cancer.
PURPOSE: We determined whether photodynamic therapy after the oral administration of 5-aminolevulinic acid in patients with superficial bladder cancer that cannot be controlled by transurethral resection and intravesical bacillus Calmette-Guerin (BCG) immunotherapy would preserve the bladder, while stopping tumor progression. Side effects of treatment were also assessed. MATERIALS AND METHODS: We performed photodynamic therapy after the oral administration of 5-aminolevulinic acid in 24 patients with rapidly recurring, multifocal, BCG refractory superficial pTa-pT1 transitional cell carcinoma of the bladder and carcinoma in situ. RESULTS: At a median followup of 36 months (range 12 to 51) 3 of the 5 patients with carcinoma in situ and 4 of the 19 with papillary tumors were free of recurrence. Three patients were rendered disease-free by repeat photodynamic therapy with 5-aminolevulinic acid and 3 underwent cystectomy. Tumor progression was stopped in 20 of our 24 cases. Immediately after the oral administration of 5-aminolevulinic acid hypotension and tachycardia occurred in 19 and 10 patients, respectively, with previously known severe cardiovascular disease. No phototoxic skin reaction or decreased bladder capacity was observed. CONCLUSIONS: These initial clinical results suggest that photodynamic therapy with orally administered 5-aminolevulinic acid is effective as an organ preserving procedure for treating superficial bladder cancer even in patients with bacillus Calmette-Guerin refractory carcinoma. One should be aware of hemodynamic instability after the oral administration of 5-aminolevulinic acid, particularly in patients with cardiovascular co-morbidity.
Adult↗
Quantification of 5-aminolevulinic acid induced fluorescence improves the specificity of bladder cancer detection.
PURPOSE: 5-Aminolevulinic acid induced fluorescence endoscopy has outstanding sensitivity for detecting early stage bladder cancer. Nevertheless, a third of the lesions that show specific fluorescence are histologically benign. We decreased the false-positive rate of 5-aminolevulinic acid induced fluorescence endoscopy by incorporating protoporphyrin IX fluorescence quantification into the standard cystoscopy procedure. MATERIALS AND METHODS: In 25 cases (53 biopsies) of a history of or suspicion for bladder cancer 5-aminolevulinic acid induced fluorescence endoscopy and fluorescence image quantification were performed. For fluorescence image quantification images obtained with a target integrating color charge-coupled device camera were digitized and stored in a personal computer. Red-to-blue ratios were calculated from fluorescence positive lesions and results were correlated with hematoxylin and eosin histology. RESULTS: Malignant fluorescence positive lesions showed significantly stronger fluorescence intensity than fluorescing lesions with benign histology. A threshold was established that decreased the false-positive rate by 30% without affecting sensitivity. CONCLUSIONS: Fluorescence image quantification is a new endoscopic method for objectively selecting multicolor fluorescence bladder lesion images for biopsy. It has the potential of eliminating human error by different surgeons with variable experience in fluorescence endoscopy.
Adult↗
Frequent genetic alterations in simple urothelial hyperplasias of the bladder in patients with papillary urothelial carcinoma.
In order to understand the origin of bladder cancer, very early urothelial lesions must be investigated in addition to more advanced tumors. Tissue from 31 biopsies of 12 patients with urothelial hyperplasias and simultaneous or consecutive superficial papillary tumors were used to microdissect urothelium from 15- microm sections of biopsies. The biopsies were obtained with the recently developed highly sensitive diagnostic method of 5-aminolevulinic acid-induced fluorescence endoscopy (AFE). Besides flat and papillary urothelial neoplasms, the method of photodynamic diagnostics also detects simple urothelial hyperplasias as fluorescent positive lesions. In addition, 12 fluorescence-positive biopsies showing histologically normal urothelium were investigated. Fluorescence in situ hybridization was done using a dual color staining technique of biotinylated centromeric probes of chromosomes 9 and 17 and digoxigenin-labeled gene-specific P1 probes for chromosomes 9q22 (FACC), 9p21(p16/CDKI2), and 17p13(p53). Ten of 14 hyperplasias (70%) showed deletions of chromosome 9. In 7 out of 8 patients with genetic alterations in the hyperplasias the genetic change was also present in the papillary tumor. Six out of 12 samples of microdissected normal urothelium also showed genetic alterations on chromosome 9. Microdissection of urothelial lesions, obtained during AFE, has led to the first unequivocal documentation of genetic changes in urothelial lesions diagnosed as normal in histopathology. Thus, this technical approach is important to provide insight into the earliest molecular alterations in bladder carcinogenesis.
Adult↗
Photodynamic cystoscopy for detection of bladder tumors.
The use of a photodynamic fluorescence marker for diagnosis of tumors is an intriguing concept to improve thoroughness of surgical tumor resection. Complete surgical resection of multifocal bladder tumors and flat lesions as carcinoma in situ is known to be difficult, and thus a source of recurrencies. We report on the recent experience with the intravesical application of the photosensitizer prodrug 5-aminolevulinic acid (5-ALA), which is a nontoxic physiological heme substrate. Initial results from fluorescence diagnosis using krypton laser light and recent results with a modified incoherent light source constantly showed a 25% increase in urothelial tumor detection compared with white light endoscopy. Because of the high sensitivity, the number of biopsies could be decreased constantly compared with routine random biopsies taken under white light endoscopy. The results show about 25% to 30% of cases with fluorescent lesions, which are histologically benign. 5-ALA is a promising tool for diagnosis of bladder cancer. The outcome of the initial study of 5-ALA in urology in Germany is positive and is continued by prospective multicenter clinical studies to prove the hypothesis of reduction of tumor recurrence with this method. 5-ALA-based fluorescence endoscopy is strongly recommended for further clinical testing.
Adenocarcinoma, Papillary↗
Transurethral resection and surveillance of bladder cancer supported by 5-aminolevulinic acid-induced fluorescence endoscopy.
PURPOSE: We determined whether neoplastic disease, which was missed under white light can be found during transurethral resection of bladder cancer by 5-aminolevulinic acid-induced porphyrin fluorescence. MATERIALS AND METHODS: 5-Aminolevulinic acid-induced fluorescence endoscopy was carried out in 328 cases. A 3% 5-aminolevulinic acid solution was instilled intravesically in a mean time of 2.8 h before endoscopy. The fluorescence was excited by a special incoherent light source which provided blue light in addition to white light. RESULTS: In 82 (25%) cases additional neoplastic lesions were found only because of their red porphyrin fluorescence which was induced by 5-aminolevulinic acid. 31% of these neoplastic foci which were found in normal and nonspecific inflamed mucosa had a poorly differentiated histology. CONCLUSIONS: 5-Aminolevulinic acid facilitates detection of neoplastic disease during transurethral resection of bladder cancer and increases the accuracy of diagnosis.
Adenocarcinoma, Papillary↗
5-Aminolevulinic acid-induced fluorescence endoscopy for the detection of lower urinary tract tumors.
The use of a photodynamic fluorescence marker for diagnosis of tumors is an intriguing concept to improve the thoroughness of surgical tumor resection. Complete surgical resection of multifocal bladder tumors and flat lesions such as carcinoma in situ is known to be difficult, and thus a source of recurrences. We report on the recent experience with the intravesical application of the photosensitizer prodrug 5-aminolevulinic acid (5-ALA), which is a nontoxic physiological heme substrate. Initial results from fluorescence diagnosis using krypton laser light, and recent results with a modified incoherent light source constantly showed a 25% increase in urothelial tumor detection in comparison to white light endoscopy. Due to the high sensitivity, the number of biopsies could be decreased constantly in comparison to routine random biopsies taken under white light endoscopy. The results show about 25-30% of cases with fluorescent lesions which are histologically benign. 5-ALA is a promising tool for the diagnosis of bladder cancer. The outcome of the admission study for 5-ALA in urology in Germany is positive, and is being continued by prospective multicenter clinical studies to prove the hypothesis of reduction of tumor recurrence with this method. 5-ALA-based fluorescence endoscopy is strongly recommended for further clinical testing.
Administration, Intravesical↗
Is everything all right if nothing seems wrong? A simple method of assessing the diagnostic value of endoscopic procedures when a gold standard is absent.
PURPOSE: We demonstrate a simple yet comprehensive method to evaluate the sensitivity of endoscopic procedures when no gold standard is available. MATERIALS AND METHODS: In 208 consecutive patients with superficial bladder cancer 328 endoscopies were performed to compare the sensitivity of white light and 5-aminolevulinic acid induced fluorescence endoscopy. Both procedures were performed during the same session. RESULTS: The maximum interval of observable sensitivity for 5-aminolevulinic acid induced fluorescence endoscopy ranged between 78 and 97.5%, and the best estimate for sensitivity based on realistic assumptions was 93.4% (95% confidence intervals 90 to 97.3). The best sensitivity estimate for white light endoscopy was 46.7% (95% confidence intervals 39.4 to 54.3, maximum range 47.2 to 53%). CONCLUSIONS: This method to determine the maximum possible range of sensitivity estimates for endoscopic procedures without a gold standard is easily applied. Depending on the assumptions a range of reasonable scenarios can be constructed and the corresponding sensitivities can be reported. This approach gives fast and valid results, and could further indicate the diagnostic superiority of 5-aminolevulinic acid induced fluorescence compared to white light endoscopy.
Adolescent↗
Early clinical experience with 5-aminolevulinic acid for the photodynamic therapy of upper tract urothelial tumors.
PURPOSE: Photodynamic therapy is effective in the treatment of superficial urothelial cancer of the bladder. We report our experience with photodynamic therapy for the treatment of upper urinary tract transitional cell carcinoma. MATERIALS AND METHODS: Photodynamic therapy after oral administration of 5-aminolevulinic acid was performed in 4 patients with widespread superficial papillary tumors of the upper urinary tract. RESULTS: Complete remission occurred in 2 patients who remained free of local recurrence at 7 and 17 months of followup. In the other 2 patients residual tiny papillary tumors were found in the distal ureter after photodynamic therapy. These tumors were coagulated with neodymium:YAG laser irradiation. Both patients are disease-free at 24-month followup. CONCLUSIONS: Photodynamic therapy with 5-aminolevulinic acid is a minimally invasive approach for organ preserving treatment of multifocal superficial transitional cell carcinoma of the upper urinary tract.
Aged↗
A study of reflux in patients with an ileal orthotopic bladder.
OBJECTIVE: To determine whether there is vesico-ureteric reflux during voiding in patients who had undergone an ileal bladder substitution after cystectomy. PATIENTS AND METHODS: The study comprised 15 patients (13 men and two women) who had undergone radical cystectomy and construction of a Studer ileal neobladder. At 1-24 months (median 4) after the operation indirect radionuclide cystography (IRC) was performed after isotopic renography (using 99m-technetium mercapto-acetyltriglycine) and voiding cysto-urethrography (VCUG). RESULTS: None of the patients had reflux during voiding, either on IRC or on VCUG. Renal function and morphology remained stable in all patients. Despite bacteriuria occurring in four patients, no episode of pyelonephritis was reported. CONCLUSION: There was no vesico-ureteric reflux during voiding in patients with a Studer ileal bladder substitution. However, long-term follow-up is needed to finally determine whether an antirefluxive ureteric implantation is required to protect the upper urinary tract in patients with ileal low-pressure bladder substitutions.
Adult↗
Phase I and pharmacokinetic study of the P-glycoprotein modulator dexniguldipine-HCL.
Dexniguldipine (DNIG) is the R-enantiomer of the dihydropyridine derivate niguldipine. DNIG showed a binding affinity to the P-glycoprotein (P-gp) and therefore it is to be assumed to block the P-gp pumping mechanism. This open phase I study was conducted to determine the maximal tolerated dose (MTD) and safety of intravenously administered DNIG alone and in combination with vinblastine in patients with a metastatic or locally advanced cancer. Additionally, serum levels of DNIG were assessed and compared between dosage groups to investigate the intravenous dose linearity. The study was divided into two parts concerning DNIG administration. In part I the patients received DNIG for four hours daily over four consecutive days and additionally 0.15 mg/kg vinblastine at day 3. Treatment was started with 1 mg/kg/4h, and whenever the drug was well tolerated the dosage was increased. In part II the patients received up to three courses of a four-hour infusion (5 and 7 mg/kg/4h) of DNIG followed by a continuous infusion for 48 hours (5 and 7 mg/kg/24h). Twenty-six patients entered this trial and were given at least one infusion of DNIG; vinblastine was given immediately after the 4-hour infusion. One to seven courses and dosages from 1-11 mg/kg were administered. In five patients the dose limiting toxicity was seen in cardiovascular adverse events such as a drop in blood pressure, decreased heart rate and in one patient an AV block III. Most frequent adverse events were nausea, dizziness, vomiting, peripheral paresthesia, atactic gait, mild constipation, polyuria, hypocalcemia; all disappeared within 24 hours after discontinuation of infusion. A linear increase in DNIG serum concentration with increasing doses was found following intravenous infusion of DNIG over a four-hour period. Long-term infusion regimes over a period of two or five days resulted in reasonably constant DNIG serum levels. MTD was determined at 5 mg/kg/4h. It is to be assumed that the MTD for continuous infusion of DNIG is higher than 5 mg/kg/24h, but this was not followed up in the study and must be the aim of a later trial.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
[Immunotherapy of metastatic renal cell carcinoma. Is clinical use justified in view of outcome, side effects and costs?].
The immunogenic potential of renal cell carcinoma and the resistance of its metastases against chemotherapy, radiation and hormonal treatment have led to the development of a great number and variety of different strategies, summarized under the term immunotherapy. Objective remissions can be expected in about 20-40% of patients. Another 30-40% show stable disease for a limited time, only occasionally for longer. Most results are from uncontrolled phase II studies. A cancer cure can usually not be expected, long-term remissions are rare (5%), and high remission rates are only observed in studies with strong patient selection. Some authors have reported a higher survival rate in patients treated with IL-2 or IFN. Survival of patients with objective remissions is significantly improved. A standard therapy cannot be defined. Even presuming an increased survival rate, the toxicity, which can lead to a dramatic reduction in quality of life, and the high costs have to be considered carefully. We think that in view of the lack of therapeutic alternatives, the improving efficacy, the potential survival benefit, the reduction of toxicity and the perspectives, immunotherapy is essential in the treatment of metastatic renal cell carcinoma. Its use should be confined to clinical studies.
Carcinoma, Renal Cell↗
Pharmacokinetics of 5-aminolevulinic acid-induced protoporphyrin IX in skin and blood.
The fluorescence and photosensitivity of endogenously synthesized protoporphyrin IX (PPIX) is increasingly used for the diagnosis and treatment of malignant and certain non-malignant diseases. A selective accumulation of PPIX can be induced by application of 5-aminolevulinic acid (5-ALA), which is a precursor of PPIX in the cellular biosynthetic pathway of heme. The purpose of this study was to monitor the in vivo accumulation of PPIX in different locations of the skin after oral ingestion and to determine the pharmacokinetics of 5-ALA and PPIX in human blood plasma for various routes of application. At the same time we wanted to achieve an optimal treatment scheme but also study possible side-effects of 5-ALA administration. After oral application of 5-ALA in a concentration of 40 mg kg-1 body weight, the fluorescence intensities of PPIX in the skin showed maxima between 6.5 and 9.8 h depending on the location and decreased to values lower than 5% related to the maximum after a mean time of about 40 h. The measured absolute intensities of PPIX fluorescence varied strongly between different patients and different locations on one patient. In the plasma of blood samples, PPIX could be detected via its fluorescence for all studied routes of application with the exception of the ointment, where PPIX levels were below the detection limit of 1 microgram l-1. The highest mean concentration of 742 micrograms l-1 PPIX in the plasma was measured 6.7 h after oral application. For inhalation of 5-ALA, a mean maximum concentration of 12 micrograms l-1 could be detected 4.1 h after application, for intravesical instillation, the mean maximum concentration was found to be 1 microgram l-1 2.9 h after application. The kinetics of 5-ALA in the plasma peaked much earlier with a maximum concentration of 32 mg l-1 about 30 min. after oral administration. The 5-ALA levels did not exceed normal reference values after topical application. The results of our experiments suggest that for a systemic application of 5-ALA side-effects in sensitive patients cannot be excluded.
Aged↗
Wavelength dependent photodynamic effects on chemically induced rat bladder tumors following intravesical instillation of 5-aminolevulinic acid.
PURPOSE: The aim of the study was to determine photodynamic effects in chemically induced rat bladder tumors after intravesical instillations of 5-aminolevulinic acid (5-ALA) and PDT-dependence on laser wavelength and light dose. MATERIAL AND METHODS: Following intravesical instillation of a 5-ALA solution (40 mg 5-ALA in isotonic saline and sodium-bicarbonate) rat bladder tumors have been treated with integral irradiation using laser light at wavelengths of lambda = 630 nm and lambda = 635 nm in a light dose range of 15 to 100 J/cm2. RESULTS: A significantly higher amount of necrosis including damage of normal urothelium was obtained in rat bladder tumors using laser light at lambda = 635 nm. CONCLUSIONS: For 5-ALA assisted photodynamic treatment of superficial bladder cancer in patients the irradiation wavelength of lambda = 635 nm is recommended.
Aminolevulinic Acid↗
Photodynamic effects of 5-aminolevulinic acid-induced porphyrin on human bladder carcinoma cells in vitro.
The efficiency of 5-aminolevulinic acid (ALA) in photodynamic therapy (PDT) was investigated in vitro using urothelial carcinoma cells of various differentiation. HCV29, RT4 and J82 cells were cultured in 96-well plates, incubated with 25-100 micrograms/ml ALA in serum-containing medium for 4 h, and irradiated at 630, 635 and 640 nm wavelength with light doses of 15-100 J/cm2. The degree of reduced tetrazolium bromide corresponding to cell viability was determined with a colorimetric MTT assay 0, 24 and 48 h after PDT. A remarkable reduction of mitochondrial activity occurred in poorly (J82) and well differentiated (RT4) malignant urothelial cells. Twenty-four hours after photodynamic treatment with 100 micrograms/ml ALA and 50 J/cm2, the metabolic activity of malignant cells was nearly extinguished, while HCV29 cells, derived from normal urothelium, behaved similarly to non-irradiated control cells. The photosensitivity of cells depended on presence or absence of fetal bovine serum (FBS) in the ALA-incubation medium. A wavelength of 635 nm was up to 60% more effective compared with 630 nm, which is more frequently applied in PDT. From the results of our in vitro studies, we can define a "therapeutic window" for malignant cells without damaging benign cells. The time delayed effects and the strong wavelength dependence are important factors for a clinical application.
Aminolevulinic Acid↗
Early clinical experience with 5-aminolevulinic acid for the photodynamic therapy of superficial bladder cancer.
OBJECTIVE: To report clinical experience with intravesical instillations of 5-aminolevulinic acid (ALA) for the photodynamic therapy of superficial bladder cancer and to assess any side-effects of the treatment. PATIENTS AND METHODS: Ten patients (six men and four women, mean age 62.3 years, range 42-73) with refractory superficial bladder cancer were treated with photodynamic therapy using 5 g of ALA dissolved in 30 mL sodium bicarbonate instilled intravesically. After a mean retention of 5.1 h, the bladder interior was illuminated transurethrally at radiation integrals of 15, 30 or 60 J/cm2. At integrals of 15 or 30 J/cm2 red light (635 nm) was used and at 60 J/cm2, green light (514 nm, 40 J/cm2) was combined with a subsequent application of red light (635 nm, 20 J/cm2). RESULTS: After 10-12 weeks, four patients had a complete remission, two a partial remission, there was no change in three and one had progressive disease. Of those patients responding, the bladder was preserved in five after a mean follow-up of 15 months (range 6-27). There were no photodermatoses or bladder shrinkage in any patient. CONCLUSIONS: Photodynamic therapy with intravesically applied ALA is effective in destroying superficial urothelial carcinomas of the bladder. There were no serious side-effects which could preclude further clinical testing.
Administration, Intravesical↗