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The administration of intravesical bacille Calmette-Guérin (BCG) in early stages of bladder cancer is usually a safe therapy. Side-effects of BCG immunotherapy can be of both local and systemic nature. We report the first case of Henoch-Schönlein purpura following intravesical administration of BCG.
Intravesical administration of bacillus Calmette-Guerin (BCG) is an effective treatment for superficial carcinoma of the bladder. The authors report a pulmonary complication characterized by miliary infiltration on chest roentgenogram and caseating granulomata on lung biopsy specimens. This case and three prior reports suggest that this complication may be a form of hypersensitivity rather than true BCG infection.
Local intravaginal application of oestriol is part of the therapeutical programme of sensory urge-incontinence. The effectiveness of a new method--intravesical administration of 1 mg oestriol versus a placebo--has been proved in a prospective randomised study. 21 patients each were treated over a period of three weeks with oestriol or with the placebo-substance intravesically. The effectiveness of the administered therapy was checked with clinical and urodynamic parameters. The intravesical administration of 1 mg oestriol proved to be efficient and free of side effects in respect of the parameters such as imperative micturition, bladder capacity, of the maximum urethral closure pressure as well as the number of micturitions per diem. The intravesical administration of oestriol may be considered as additional method of therapy for treatment of sensory urge-incontinence.
Although an immune response to bacillus Calmette Guérin (BCG) has often been associated with antitumor activity, the action mechanism(s) of intravesical BCG therapy for prophylaxis and treatment of superficial bladder cancer is not clearly understood. In an attempt to evaluate the roles of tumor necrosis factor (TNF)-alpha and lymphotoxin (LT) in the antitumor activity, TNF-alpha productivities by peripheral blood monocytes, serum levels of TNF-alpha, and LT productivities by peripheral blood lymphocytes were studied in superficial bladder cancer patients after six intravesical administrations of BCG. TNF-alpha productivities by peritoneal macrophages of guinea pigs were also studied after six intravesical administrations of BCG. The maximum TNF-alpha productivities by peripheral blood monocytes of superficial bladder cancer patients were seen after the fourth week of administration of BCG, and the serum TNF-alpha levels were also slightly increased after intravesical BCG administration in the superficial bladder cancer patients. LT productivities by peripheral blood lymphocytes of superficial bladder cancer patients were significantly enhanced and the maximum LT productivity was also seen after the third or fifth BCG administration. TNF-alpha productivities by peritoneal macrophages of guinea pigs were significantly enhanced and the maximum TNF-alpha productivity was seen after the second or third BCG administration. Our data might suggest that six consecutive intravesical BCG administrations could induce the increased productions of TNF-alpha and LT, which might play an important role in the antitumor activity in superficial bladder cancer.
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In a prospective study, 31 unselected patients with urge or urge incontinence, where previous treatment had been unsuccessful, were given repeated instillations of Lidocain gel for 11 days. Detailed histories were obtained by questionnaire both before instituting and after termination of the therapy. A cystourethrotonometric examination was also performed by the microtransducer method. The urge symptoms improved in almost all the patients. There was also a distinct improvement in subjective feelings of incontinence. There was a statistically significant reduction in mean micturition frequency. In 50% of the patients it was no longer possible to detect hypertonic bladder tone and pathologic detrusor contractions by cystourethrotonometry. Patients who had had lower bladder capacity prior to therapy showed a tendency to increased capacity after treatment. While there was no change in functional urethral length, there was a significant increase in maximum urethral closing pressure. Tonometrically detectable stress incontinence disappeared in one-fourth of the patients. No side effects were observed. In view of the high rate of success and the acceptance of intravesicular Lidocain therapy, it can also be recommended for cases resistant to therapy and, if necessary, can be included in an all-embracing therapeutic concept for urge incontinence.
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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.
Forty-five patients known or suspected to have transitional cell carcinoma of the urinary bladder underwent intravesical administration of either AUA1 tumor-associated monoclonal antibody or 11.4.1. nonspecific monoclonal antibody. Antibodies were radiolabeled with iodine-131, diluted in 50 ml normal saline and remained in the bladder for up to 1 h. During cystoscopy or transurethral resection of the tumor, tissue samples were taken from normal and malignant areas and were counted for radioactivity in a gamma counter. Blood samples were also measured for radioactivity. Mean uptake of AUA1 at 2, 20, 40 and 60 h after administration (expressed as 10(3) x percentage of injected dose/gram of tissue) was: 1.77 +/- 3.2, 1.28 +/- 1.67, 0.72 +/- 0.94 and 0, respectively in the tumor and 0.79 +/- 0.83, 0.14 +/- 0.34, 0.033 +/- 0.06 and 0 in normal tissue. Mean uptake of 11.4.1 at 2 and 20 h was: 0.47 +/- 0.42 and 0.018 +/- 0.015, respectively, in tumor and 0.2 +/- 0.19 and 0.013 +/- 0.002 in normal samples. No remarkable radioactivity was found in blood samples. Conventional and immunoperoxidase staining were also performed. Mean uptake of AUA1 by the tumor increased as the degree of tumor differentiation decreased. Our findings indicate that intravesical administration of AUA1 results in selective immunolocalization of AUA1 in intermediate and high-grade transitional cell carcinoma. This may allow the development of a new method for bladder carcinoma treatment or prophylaxis against recurrence.
The effect of intravesical administration of tumor necrosis factor (TNF) on the implantability and growth of bladder cancer was studied using the murine tumor model, MBT-2. Crude TNF was prepared from serum (TNS) of BCG infected rats after injection of endotoxin or the recombinant product of human TNF-alpha was used. Treatment was begun 24 hr. or seven days after tumor instillation and repeated three times. Tumor implantability and tumor weight were determined on day 21. Low dose TNF (200 U), given in the form of TNS, failed to suppress the growth of established tumors (seven-day tumor). It did, however, significantly reduce tumor implantability. The growth of seven-day tumors was significantly suppressed by administration of higher dose of TNF (3,700 U) given in recombinant form.
The effect of intravesical administration of high dose recombinant tumor necrosis factor-alpha (rTNF) and in combination with systemic recombinant gamma-interferon (rIFN) on murine bladder cancer was studied. RTNF was given at 12.5 micrograms/mouse on days 7, 11 and 15 after tumor instillation or at 2.5 micrograms/mouse on days 7, 9, 11, 13 and 15. Some groups were also injected i.v., 24-h prior to each rTNF treatment with rIFN at a dose of 1.3 micrograms/mouse. RTNF treatment suppressed tumor growth up to 48% of control, although the difference was not statistically significant. Combined administration of rIFN did not provide additional benefit.
In the present study, the systemic absorption of hypericin was investigated after intravesical instillation of the compound in nine patients with superficial transitional cell carcinoma (TCC) bladder tumors. Hypericin (8 microM) was instilled in the bladder for 2-3 h before photodynamic diagnosis of bladder tumors. Blood was then collected from a peripheral vein 1 h after termination of the instillation. Solid phase extraction with ammonium acetate buffer and methanol was used to extract hypericin from the plasma. A reversed-phase high performance liquid chromatographic method with fluorescence detection was used to identify and quantify hypericin in the extracts from plasma samples. Analysis of standard plasma samples, which were spiked with known amounts of hypericin, indicated that the pH of the buffer was a determining factor in the extraction yield. The results obtained using ammonium buffer (pH 3.5) and methanol showed the mean extraction recovery of hypericin to be 64% (RSD=12%, n=6). The limits of detection and quantification were 6 and 20 nM, respectively. Extraction and analysis of the plasma of patients after intravesical administration showed hypericin concentrations below the detection limit (<6 nM). In addition, photodynamic treatment of in vitro cultured HeLa cells incubated with 1-100 nM hypericin concentrations showed that lower concentrations (1-20 nM) of hypericin do not induce significant photocytotoxic effects. Taken together, these results imply that photosensitization or other systemic side effects in patients are not to be expected after photodynamic diagnosis of TCC bladder tumors with hypericin.
BACKGROUND: Many reports have shown that the efficacy of intravesical therapy for bladder cancer is in part limited by the poor penetration of drugs into the urothelium. The present study evaluated the effect of glyceryl monooleate (GMO) on the absorption of intravesically administered paclitaxel in a rabbit model of bladder cancer. METHODS: Urine, plasma, and tissue pharmacokinetics were determined in rabbits treated for 120 min with paclitaxel (500 microg/20 ml) by intravesical instillation. Two formulations of GMO/paclitaxel were evaluated using different proportions of water, 15 and 30%, and Taxol was used as a control. Animals were observed for clinical signs of toxicity and necropsy was performed. RESULTS: 120 min after instillation, the bladder was emptied and excised. In the urine, paclitaxel concentration was decreased by 39.6 and 41.2% in the two experimental groups and by 25.2% in the control group. The paclitaxel concentrations in the urothelium were 53 and 56% of the urine concentration in both experimental groups, but 11% in the control group. The concentration then declined exponentially in the underlying capillary-perfused tissues, reaching equilibrium at a depth of 1,400-1,700 microm. The plasma concentrations were extremely low compared with concentrations in urine and bladder tissues and were not associated with clinical toxicity. CONCLUSIONS: We conclude that GMO has a significantly increased bioadhesiveness to bladder mucosa. Therefore, intravesical administration of GMO/paclitaxel/water provides a significant advantage for drugs targeting the bladder tissue, and paclitaxel represents a viable option for intravesical bladder cancer therapy.
We conducted a phase I/II clinical trial of the safety and efficacy of intravesical administration of autologous IFN-gamma-activated macrophages (MAK) in patients with superficial bladder cancer. Monocyte-derived MAK cells were prepared in vitro and patients received six instillations of 1.4 x 10(8) to 2.5 x 10(8) cells, once a week, for five consecutive weeks. Treatment was well tolerated, with seven grade 1 and five Grade 2 protocol-related adverse effects. Nine out of 17 included patients had no recurrences during the year following the first instillation of MAK. The aim of the present study was to search for immune parameters related to local immunostimulation induced by MAK. Monitoring of the patients showed that urinary IL-8, GM-CSF and, to a lesser extent, IL-18 were increased following MAK instillations, with inter-individual differences. The urinary IL-8 level was about 10-fold higher than that observed for other cytokines, and its biological activity was reflected by a concomitant increase of urinary elastase, indicating neutrophil activation and degranulation. We also showed that nine out of 12 patients investigated presented an increase of urinary neopterin, a marker of IFN-gamma-activated macrophages, 7 days after MAK instillation, while serum neopterin levels were almost stable. These results are in line with persistence of activated macrophages in the bladder wall after infusions. Moreover, there was evidence of macrophages in urine smears 2 months after the sixth MAK instillation, and the score of macrophages correlated with the quantity of neutrophils in the urine. Overall, this study provides evidence of a local immunostimulation induced by this novel and safe immunotherapeutic approach of MAK instillations in patients with superficial bladder cancer.
Tumor associated AUA1 monoclonal antibody and 11.4.1. nonspecific monoclonal antibody, which does not react with human tissues, were radiolabeled with 111In and administered intravesically to 23 patients undergoing cystoscopy for bladder carcinoma. The antibody solution remained in the bladder for 1 h and then was washed out prior to cystoscopy. Tumor and nontumor samples were obtained during cystoscopy and were counted in a gamma counter. Conventional and immunoperoxidase staining with both antibodies were also performed. AUA1 reacted with all bladder carcinomas while 11.4.1. was negative in all cases. The mean uptake of AUA1 at 2, 24, and 48 h after the instillation (expressed as 10(3) x percentage of injected dose/g of tissue) was: 6.12 +/- 5.50 (SD), 1.70 +/- 2.57, 0.30 +/- 0.17 in the tumors and 0.32 +/- 0.50, 0.22 +/- 0.30, 0 in the nontumor areas, and for 11.4.1. it was: 0.075 +/- 0.075, 0.025 +/- 0.025 in the tumors and 0.30 +/- 0.42, 0.15 +/- 0.26 in the nontumor areas. The uptake of AUA1 by the tumors correlated with the tumor grade. There was no radioactivity in the blood at 2 h, and at 1, 2, and 3 days after the instillation. Our results indicate that intravesical administration of radiolabeled monoclonal antibody AUA1 targets selectively to tumor tissue without any significant normal tissue uptake. This finding might allow the development of a nontoxic and specific therapeutic approach for superficial bladder carcinoma.
A total of 62 patients at high risk for recurrence of superficial bladder cancer were selected for a study designed to compare the prophylactic efficacy of different doses and schedules of sequential intravesical instillations of epirubicin and interferon-alpha-2b and to evaluate which sequence could enhance the release of cytokines in the urine. Our investigations showed a significant increase in urinary concentrations of interleukins in patients who received the sequential intravesical administration of epirubicin and interferon-alpha-2b. Higher urinary concentrations of interleukins and a lower recurrence rate were detected in patients who received interferon-alpha-2b 24h after epirubicin instillation.