Mitomycin C and epirubicin: functional bladder damage in rats after repeat intravesical instillations

PURPOSE: We studied functional damage in the bladder after intravesical administration of mitomycin C or epirubicin in rats. MATERIALS AND METHODS: A total of 40 rats were divided into 4 groups. Rats in 3 groups received intravesical instillations of mitomycin C, epirubicin or saline. Rats in group 4 received no intravesical instillations and served as normal controls. The doses of drugs administered were based on those used for therapeutic purposes. Changes in vesical capacity and bladder wall compliance were determined. Compliance was defined as the change in vesical volume induced by a given change in pressure. RESULTS: Weekly instillations of 1 mg/ml mitomycin C caused a statistically significant decrease in vesical volume and compliance, which persisted 3 weeks after the cessation of therapy. Epirubicin also induced changes in vesical volume and compliance but only that in bladder compliance achieved statistical significance. These changes were not seen in NaCl treated animals or in normal controls. CONCLUSIONS: Repeat intravesical instillations of mitomycin C have a prolonged effect on bladder function that is not seen after saline solution or epirubicin instillation.     

Promotive effects of intravesical instillation of dimethylsulfoxide on bladder carcinogenesis in mice]

The effect of intravesical instillation of dimethylsulfoxide (DMSO) on bladder carcinogenesis was examined in mice. Experiment 1: Fifty-five female C3H/He mice were administered 0.05% N-butyl-N-(4-hydroxy-butyl) nitrosamine (BBN) in their drinking water for 8 weeks. In week 9 they were divided into two groups consisting of 25 mice each. Then, under nembutal anesthesia the first group was given weekly intravesical inatillations of 0.1 ml DMSO (minimum 99.0%) for 10 weeks. The second group received no treatment except anesthesia. All mice were killed 30 weeks after the begining of the experiment and their urinary bladder resected for histological examination. The incidence of bladder carcinoma was 93.7% (15.16) and 27.7% (6/22) in groups 1 and 2, respectively. These incidences differed significantly between the two groups. Experiment 2: One hundred and twenty female C3H/He mice were divided into two groups. The first group was given 0.05% BBN in their drinking water for 5 weeks and then tap water. The second group was not given BBN. In week 6, the first group was divided again into three groups (1, 2 and 3) consisting of 28, 26, and 27 mice, respectively. The second group was divided into groups 4 and 5 consisting of 21 and 18 mice, respectively. Under nembutar anaesthesia groups 1 and 4 received weekly intravesical instillation of 0.05 ml DMSO (minimum 99.0%) from weeks 6 to 13, Group 2 received weekly intravesical instillation of 0.05 ml distilled water from weeks 6 to 13. Groups 3 and 5 received no treatment except anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of three schedules of intravesical epirubicin in patients with non-muscle-invasive bladder cancer

OBJECTIVES: To study the additive effect of either an early instillation or maintenance instillations of adjuvant intravesical epirubicin, as compared to the epirubicin "standard" treatment schedule only, in patients with non-muscle-invasive bladder cancer. METHODS: Patients with intermediate- and high-risk urothelial cell carcinoma of the bladder, except carcinoma in situ, were randomised for adjuvant intravesical instillations with 50mg epirubicin/50 ml NaCl for 1h. Group 1 received 4 weekly and 5 monthly instillations (standard schedule), group 2 received the same schedule as group 1, but with an additional instillation <48 h after transurethral resection of bladder tumour (TURBT), and group 3 received the same scheme as group 1, but with additional instillations at 9 and 12 mo (maintenance schedule). Standard follow-up was 5 yr and consisted of cystoscopy, cytology, and registration of adverse events. RESULTS: A total of 731 patients were eligible for quasi intention-to-treat analysis. Side-effects were minimal for all treatment groups. After 5-yr follow-up, respectively, 44.4%, 42.7%, and 45.0% (log-rank test, p=0.712) of the patients in groups 1, 2, and 3 were recurrence free, and 90.0%, 87.7%, and 88.2% (log-rank test, p=0.593) of the patients, respectively, were progression free. CONCLUSIONS: In the quasi intention-to-treat analysis there is no difference in the 5-yr recurrence-free period between the treatment groups, despite one instillation within 48 h of TURBT or two maintenance instillations up to 1 yr, in addition to the "standard" schedule.     

Effect of liarozole on the cell proliferation activity in the rat urinary bladder epithelium induced by N-butyl-N-(4-hydroxybutyl) nitrosamine

INTRODUCTION AND OBJECTIVES: Recently, the chemopreventive effects of various drugs on N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN) induced rat urinary bladder carcinogenesis have been reported. The aim of this study was to evaluate the effect of liarozole, an antitumor agent that inhibits the metabolism of retinoids, on the initial stage of BBN induced rat urinary bladder carcinogenesis. MATERIALS AND METHODS: Seven-week-old, male Wistar rats were used. The rats were divided into four groups. All groups except control were allowed free access to the drinking water containing 0.05% BBN. Groups Lz40 (n = 5) and Lz80 (n = 5) were administered the liarozole solution, twice daily by gavage (40 mg/kg/day and 80 mg/kg/day, respectively). Group BBN (n = 5) was given no liarozole. The control group (n = 4) received no carcinogen. At 9 weeks after the start of the experiment, all rats were killed by ether anesthesia and their urinary bladders were taken for evaluation. The urinary bladders were fixed in 10% buffered formalin, embedded in paraffin, sectioned, and immunohistochemical staining using anti-proliferative cell nuclear antigen (PCNA) antibody was performed by the avidin-biotin-peroxidase complex (ABC) method. We calculated the PCNA positive rate and compared among the four groups. RESULTS: The PCNA positive rate of group BBN was 23.5 +/- 3.7%. Compared with group BBN, the PCNA positive rate of groups Lz40 and Lz80 were statistically less (16.4 +/- 4.3% and 9.8 +/- 2.6%, respectively). Furthermore, the PCNA positive rate of group Lz80 was statistically less than that of group Lz40. CONCLUSION: The results indicate that liarozole may inhibit the activity of cell proliferation in the initial stage of BBN-induced rat urinary bladder carcinogenesis and may be dose-dependent.     

Antitumour effects of the angiogenesis inhibitor AGM-1470 on rat urinary bladder tumours induced by N-butyl-N-(4-hydroxybutyl) nitrosamine

OBJECTIVE: To examine the antitumour effects of the angiogenesis inhibitor AGM-1470 (TNP-470) on rat urinary bladder tumours induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). MATERIALS AND METHODS: Fischer-344 rats were allocated to one of four groups of 15 rats each; in group 1, rats were administered AGM-1470 intraperitoneally, with group 2 acting as the control and given only saline; in group 3, AGM-1470 was instillation intravesically and group 4 acting as control (intravesical saline). All rats were given 0.05% BBN in their drinking water for 8 weeks and then given water with no BBN. AGM-1470 was administered at a dose of 30 mg/kg every other day for 6 weeks in group 1 and at 15 mg/kg once a week for 6 weeks in group 3. This treatment was commenced at 21 weeks after the start of BBN treatment, when tumorigenesis was apparent in all rat bladders; approximately 70-80% of the tumours were carcinomas. All rats were killed in the 27th week. The antitumour effects of AGM-1470 on the BBN-induced bladder tumours were evaluated macroscopically and histologically. The inhibitory effect of AGM-1470 on endothelial cell proliferation was assessed in groups 1 and 2 by immunohistochemical staining for Factor VIII-related antigen and by counting the microvessels. RESULTS: The number and volume of bladder tumours were significantly less in group 1 than group 2. In the latter, at least one bladder tumour developed in each of the 15 rats. Histologically, transitional cell carcinoma (TCC) was found in 13 rats and papilloma in two, with invasive cancer in three of the 13 TCCs. Bladder tumours developed in only four of the 15 rats in group 1. Carcinomas were found in three of these four rats and no invasive cancer was detected. The rats in group 1 had significantly fewer microvessels than the controls. The rats in group 4 also showed slightly but insignificantly less tumour growth and fewer carcinomas. In neither experiment were any major side-effects seen except for mild weight loss after AGM-1470 treatment. CONCLUSION: AGM-1470 inhibited the growth and malignant progression of BBN-induced bladder tumours in rats, apparently mainly by the inhibition of tumour vessel development. The intraperitoneal administration of AGM-1470 produced better results than did intravesical instillation. These results suggest that the angiogenesis inhibitor AGM-1470 is a promising agent for the treatment of human bladder cancer.     

Histological study on intravesical instillation of Bacillus Calmette Guerin (BCG) and adriamycin for BBN-induced bladder tumor in rats]

We evaluated histological changes induced by intravesical instillation of Bacillus Calmette Guerin (BCG) and doxorubucin hydorochloride (Adriamycin, ADM) for transitional cell carcinoma of the experimental bladder tumor. We administered rats N-butyl-N (4-hydroxybutyl) nitrosamine (BBN) by mixing it in the drinking water, and performed intravesical instillation of BCG, ADM or physiological saline solution as control in the 16th and 17th weeks and sacrificed in the 18th week after BBN exposure, and observed histological changes by light microscopy and electron microscopy. In the BCG group, the enlargement of the intercellular spaces of superficial tumor cells was found, and electron microscopic findings revealed a decrease or disappearance of the junctional complex. In the ADM group, hydrolytic and vacuolated cytoplasm was revealed. But such change as that in the BCG group was not found in the ADM and control groups. These results indicate that BCG may enlarge the intercellular spaces by changing the junctional complex, and lead to desquamate the tumor cells from the superficial cell layer.     

Morphological changes of urothelial and intestinal mucosa after ureterosigmoidostomy during experimental urogenic carcinogenesis

Summary To analyze the effect of chemical carcinogens on urothelial and intestinal mucosa on 214 female Wistar rats an ureterosigmoidostomy was performed. After 10–14 days 123 surviving rats were randomly divided into 4 groups: Group I–III received 0.05 per cent N-Butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) in drinking water over a period of 15 weeks. Group IV received normal drinking water over the same period. The defunctionalized bladders were instilled each second day: Group I: physiologic saline solution, Group II: urine of normal rats, Group III and IV: urine of BBN-treated rats. 30 rats without diversion but BBN treatment served as a control. The evaluation of the histological data gave the following results: In the control group urothelial tumors were found in the bladder exclusively. Dependent on the grade of obstruction in the BBN-treated groups, with diversion urothelial tumors in the renal pelvis and ureter could be documented, whereas in the bladder no tumor growth could be shown. In the intestinal mucosa of BBN-treated animals a high incidence of adenocarcinoma was found. The chemical tumor induction by BBN is related to the urine and takes place by direct contact to rhe mucosa when the metabolites excreted by the kidneys are activated in the urine. BBN or other urogenic carcinogens seem to have no urothelial specificity. The incidence of bowel carcinoma after diversion must lead to intensive long-term follow up.Part of this paper was presented at the 9th Symposium of the Association for Experiemental Urology of the German Urological Society, June 17–18, 1988, Aachen, Federal Republic of GermanySupported by a grant from the Minister for Science and Research of Nordrhein-Westfalen, Düsseldorf, FRG     

Inhibitory effect of intravesically applied botulinum toxin A in chronic bladder inflammation

PURPOSE: We evaluated a putative inhibitory effect of intravesical botulinum toxin A (BTX-A) on afferent pathways in conditions of chronic bladder inflammation. MATERIALS AND METHODS: Female Sprague-Dawley rats were divided into 4 groups, namely group 1-saline treated, group 2-BTX-A treated, group 3-cyclophosphamide (CYP) treated and group 4-BTX-A and CYP treated. At the beginning of the treatment period all animals received intravesical protamine sulfate (1%), followed by intravesical BTX-A or saline. Subsequently CYP or saline was injected intraperitoneally every 3 days for 10 days. The rats then underwent cystometrogram evaluation prior to spinal cord harvest. Sections from the L6 and S1 spinal cord segments were examined for the total number of Fos immunoreactive cells. RESULTS: Comparisons of the L6 and S1 sections showed a significant difference among groups (p <0.05). CYP treated animals had a significant increase in L6 and S1 (78% and 107%, respectively) c-fos expression compared with saline controls (p <0.001). Comparison of the CYP and BTX-A/CYP groups showed a significant decrease in L6 and S1 in c-fos expression (50% and 52%, respectively) in the BTX-A/CYP treated group (p <0.001). No significant difference was present between the saline and BTX-A alone groups. Cystometrogram studies revealed that the nonvoiding intercontractile interval increased by more than 10-fold in BTX-A/CYP treated animals compared with CYP treated rats (p <0.01). CONCLUSIONS: In a CYP model of chronic bladder inflammation intravesical BTX-A significantly inhibits the afferent neural response without impairing efferent bladder function.     

Intravesical mitomycin C therapy for superficial bladder cancer. Report of a multicentre phase II study

Twenty-five patients with early transitional cell carcinoma of the bladder (Tis Ta T1) received intravesical instillations of 40 mg mitomycin C in 40 ml water weekly for 7 weeks. The overall response rate was 70% (complete response 40%). In patients with Ta tumours the response rate was 86%. Minor toxic side effects occurred in four patients and only one patient was unable to complete the course of treatment because of side effects.     

A randomized controlled trial of short-term versus long-term prophylactic intravesical instillation chemotherapy for recurrence after transurethral resection of Ta/T1 transitional cell carcinoma of the bladder

PURPOSE: In a prospective randomized controlled study, we investigated the optimal schedule for intravesical instillation of epirubicin for maximizing its effect on prophylaxis and disease progression after transurethral resection of newly diagnosed Ta/T1 bladder cancer. MATERIALS AND METHODS: The patients were instilled with epirubicin (30 mg/30 ml in normal saline) within 24 hours after transurethral resection and then randomized into 2 groups after a definite histopathological diagnosis of Ta/T1 bladder cancer. One group of 77 patients received 19 intravesical instillations of epirubicin in the year after transurethral resection (group 1). The second group of 73 patients received 9 intravesical instillations of epirubicin during the 3 months after transurethral resection (group 2). Nonrecurrence rates and toxicity were compared. RESULTS: In the followup period, 10 group 1 patients (13.0%) and 23 group 2 patients (31.5%) had recurrent disease. The 3-year nonrecurrence rate was 85.2% in group 1, whereas it was 63.9% in group 2. The nonrecurrence rate of group 1 was significantly higher than that of group 2 throughout the observation period (p = 0.005). The incidence and severity of toxicity were not significantly different between the 2 groups. CONCLUSIONS: Our study indicates that long-term instillation of epirubicin is more effective than short-term instillation in preventing recurrence after transurethral resection of Ta/T1 bladder cancer.     

Effects of sequential intravesical administration of mitomycin C and bacillus Calmette-Guérin on the immune response in the guinea pig bladder

It has been suggested that intravesical treatment with mitomycin C (MMC) before instillation of bacillus Calmette-Guérin (BCG) improves the antitumor activity of BCG in human bladder cancer. Therefore, we studied the immunological effects of sequential intravesical treatment with MMC and BCG in the guinea pig. Four weekly intravesical instillations with MMC preceded six weekly intravesical BCG instillations. The delayed-type hypersensitivity (DTH) skin reaction evoked by tuberculin purified protein derivative (PPD) in guinea pigs receiving BCG intravesically appeared slightly earlier in animals pretreated intravesically with MMC than in phosphatebuffered saline (PBS)-pretreated animals. However, after completing BCG instillations no differences in DTH reaction were observed between these treatment groups. The extent of the local inflammatory reaction in the bladder wall, as well as the parameters measured in the draining iliacal lymph nodes (i.e., the weight, the number of leukocytes, and the composition of leukocyte, subpopulations), did not differ in animals treated with GCG alone or in combination with MMC. A slight increase in the MHC class II expression on the bladeer urothelium was shown if MMC and BCG treatment was combined. The adherence of mycobacteria to the bladder wall, measured using ³H-labeled mycobacteria, dit not differ between MMC/BCG-and BCG-treated animals. We conclude that MMC does not enhance the immune response against mycobacteria. Therefore, we hypothesize that a possible increased antitumor activity by the combination of MMC and BCG might be due to separate, rather than synergistic, effects of the drugs, namely a cytostatic effect of MMC on tumor cells and a local immune response in the bladder evoked by BCG.     

Inhibition of urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine in rats by green tea

BACKGROUND: Recently, the anticarcinogenic effects of green tea have been studied in sites other than the urinary tract. The present study examined the inhibition by green tea of vesical tumors induced in rats by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). METHODS: In the first series of experiments, 0.05% BBN was added to the drinking water of rats and remained present for 5 weeks. In one experiment, six groups of animals received either tap water, green tea, matcha, hojicha, oolong tea or black tea from week 6. In a second experiment, three groups of rats received either tap water, green tea extract or powdered green tea mixed into a pellet diet from week 6. In a third experiment, five groups of rats were fed a pellet diet with addition of either 0, 0.15, 1.5 or 3.0% powdered green tea from week 6. All rats were killed and examined at 40 weeks. RESULTS: Green tea, particularly green tea leaves, dose-dependently inhibited the growth of BBN-induced urinary bladder tumors when given after the carcinogen. CONCLUSIONS: Green tea may inhibit bladder tumor growth.     

Influence of pertussis toxin on superficial bladder carcinoma in rats

The proliferation and migration of cells is a fundamental process for the metastasis of malignant tumour cells. In several in vitro studies, pertussis toxin (PTX) inhibited cell proliferation and cell motility in the human transitional cell carcinoma cell line J82. The present study investigated the effect of the intravesical application of PTX on the development of superficial bladder cancer in rats. We used the model of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN, 0.05% via drinking water x10 weeks) to induce superficial bladder carcinomas in 40 female rats. After 16 weeks the rats were treated in two groups with 0.4 ml PTX (1 microg/ml) or 0.4 ml phosphate buffered saline (PBS) by intravesical application (once a week for 10 weeks). In the 25th week urine cytology was determined and all rats were killed at week 26 followed by histological evaluation. In the control group, the urine cytology was positive for G2/G3 cells in ten of 17 rats. In the PTX group G2/G3 cells were determined in five of 20 rats ( P two tailed <0.05). Histopathologically 12 rats (71%) of the control group and 11 rats (55%) of the PTX group developed T1-T2 transitional-cell carcinomas. No local or systemic side effects were disclosed. PTX treatment reduces the development of G3 transitional cell carcinomas in rats and may represent a new approach for local therapy in superficial bladder cancer.     

Intravesical interferon alfa-2b administration in the treatment of superficial bladder tumors

This study was undertaken to assess the value of intravesical interferon alfa-2b treatment in preventing the recurrences of superficial transitional cell carcinoma of the bladder. A total of 30 patients aged from 33 to 78 entered the protocol. The intravesical instillations were performed once a week for 8 weeks. A solution of 10 x 10(6) IU interferon alfa-2b in 30 ml of normal saline was used. Follow-up ranged from 12 to 28 months. Of the 30 patients, 19 (63.33%) were tumor free at the end of follow-up. Of the remaining 11 patients, 7 presented with recurrent superficial tumors and 4 with invasive bladder tumors. No side effects were noted.     

Anti-tumor effect of intravesical instillation of OK432 against rat bladder tumor induced by N-butyl-N-(4-hydroxybutyl) nitrosamine

Summary The anti-tumor effect of OK432 instilled into the bladder was evaluated in rat bladder tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). In experiment I, the rate of the natural killer (NK) activity was determined with cells from spleen and mesenteric lymph nodes. Intravesical OK432 instillation enhanced NK activity; however, this activity was not dose-dependent and was not augmented by OK432 inoculation into the foot pad. In experiment 2, the therapeutic effect of intravesical OK432 instillation was examined in rat bladder tumors induced by BBN. OK432 was instilled weekly for six weeks. Rats given BBN for 10 weeks were divided into six groups: 1) control; 2) saline; 3) OK432 0.05 KE/ml; 4) OK432 0.05 KE/ml bladder instillation with 0.01 KE/ml foot pad inoculation; 5) OK432 0.05 KE/ml, every other week; and 6) OK432 0.5 KE/ml. Weekly OK432 instillation significantly reduced tumor weight and the incidence of tumor development; however, this inhibition was not dose-dependent and was not enhanced by OK432 inoculation into the foot pad. In rats given OK432 weekly, the augmentation of NK activity and increase in tissue infiltrating lymphocytes were significant. These results suggest that intravesical OK432 instillation is effective in the management of superficial bladder tumors. The study further emphasizes that the dose and method of administration are critical variables in determining the efficacy of immunotherapy.     

Experimental intravesical therapy for superficial transitional cell carcinoma in a rat bladder tumor model

A rodent bladder cancer model that is induced by intravesical instillation of N-methyl-N-nitrosourea (MNU) was characterized. Cohorts of four to five week old female Fisher 344 rats received four biweekly 1.5 mg. doses of intravesical MNU and were sacrificed at various intervals. By week 13 all animals had flat atypia and/or papillary transitional cell tumors, and 67% of the lesions were moderately (grade II) or poorly differentiated (grade III). By week 20, 83% had gross muscle invasive tumors that eventually killed the host. A cohort of 40 MNU treated animals was subsequently treated commencing at week 17 after initiation of MNU with one of three intravesical six week regimens: 1) saline; 2) BCG (Tice strain); or 3) recombinant human tumor necrosis factor (RTNF) plus adriamycin. There was no difference in animal survival or tumor growth in any group of animals commencing therapy at week 17. A second cohort of 107 animals commenced therapy at 13 weeks after initiation of MNU with one of five intravesical six week regimens: 1) intravesical BCG (Tice strain); 2) adriamycin; 3) recombinant human tumor necrosis factor (RTNF); 4) RTNF plus adriamycin; or 5) BCG plus adriamycin. BCG, RTNF or adriamycin alone had no effect on tumor growth; however, BCG plus adriamycin and RTNF plus adriamycin commencing at week 13 significantly inhibited tumor growth and progression. In conclusion, this autochthonous intravesical rodent transitional cell carcinoma model appears useful for the following reasons: 1) it closely resembles human transitional cell carcinoma histologically and biologically in that all animals develop neoplastic changes in-situ that progress to muscle invasion and kill the host; 2) as with human bladder cancer these tumors do not respond to intravesical therapy if treated when tumor burden is large; however, tumor growth is inhibited when treated early; and 3) this model appears appropriate for screening and developing new intravesical treatments for superficial bladder cancer.     

Effect of intravesical instillation of antitumor drugs in the development of N-butyl-N-(4-hydroxybutyl) nitrosamine-induced bladder tumors in rats

We examined the effects of intravesical instillation of adriamycin (ADM) and cis-diammine-dichloroplatinum (CDDP) on the development of bladder tumors induced by 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in 115 rats. Intravesical instillation was performed in two ways; continuous administration (5 times a week for 5 weeks) and intermittent administration (once a week). Group 1 (control group) did not receive intravesical instillation. Group 2 I(ADM), group 3 (CDDP) and group 4 (physiological saline) were continuous type. Group 5 (ADM), group 6 (CDDP) and group 7 (physiological saline) received intermittent administration. Bladder weight was significantly higher in group 4 than in groups 1 or 7, and that in groups 2 and 3 than that in group 5 and 6. In groups 2, 3, 5 and 6 bladder weight was almost normal or higher than in the control group, and in group 3 histologically cancer was not seen in one rat. Physiological saline had promoting activity, and ADM and CDDP had both inhibitory and promoting activities. Also, intravesical instillation itself was suggested to promote tumor development under carcinogenic circumstances. We conclude that intermittent intravesical instillation should be performed to inhibit tumor recurrence and intravesical instillation therapy should not be performed clinically for a long period.     

Intravesical hyaluronic acid for interstitial cystitis/painful bladder syndrome: A comparative randomized assessment of different regimens

Objectives: To compare the clinical effectiveness of different regimens of intravesical hyaluronic acid instillation for patients with interstitial cystitis/painful bladder syndrome. Methods: A total of 60 patients (age 16–77 years) diagnosed with interstitial cystitis/painful bladder syndrome were enrolled in this prospective, randomized study. A total of 30 patients were assigned to receive four weekly intravesical instillations of 40 mg of hyaluronic acid followed by five monthly instillations (hyaluronic acid‐9 group). Another 30 patients received 12 intravesical instillations of 40 mg hyaluronic acid every 2 weeks (hyaluronic acid‐12 group). Symptomatic changes after hyaluronic acid treatments were assessed using Interstitial Cystitis Symptom and Problem Indexes, pain visual analog scale, functional bladder capacity, frequency and nocturia in voiding diary, maximum flow rate, voided volume, postvoid residual volume, and Quality of Life Index at 1, 3 and 6 months. Results: Of the 60 patients, 59 were evaluable at the end of the study. The Interstitial Cystitis Symptom Index, Interstitial Cystitis Problem Index and total score, pain visual analog scale, functional bladder capacity, maximum flow rate, and Quality of Life Index improved significantly after 6 months in both groups. The frequency and voided volume improved significantly only in the hyaluronic acid‐12 group. However, patients with moderate and marked improvement were clinically similar in both groups. The measured variables did not differ between the two groups over the course of the study. Conclusion: No significant difference was noted in the therapeutic effect between two hyaluronic acid instillation regimens for treatment of interstitial cystitis/painful bladder syndrome patients. Both groups showed significant improvement in symptom scores and Quality of Life Index.     

Safety and immunoresponse study of intravesical instillation of Taipei-NIPM bacillus Calmette-Guérin.

The intravesical instillation of bacillus Calmette-Guérin (BCG) has proved to be an effective modality for prophylaxis of recurrent superficial bladder cancer and treatment of carcinoma in situ. The domestic BCG, named Taipei-NIPM, which is produced by the National Institute of Preventive Medicine, has been used as an anti-TBC vaccine in Taiwan for decades. In this study, we have investigated the safety and immune response in animals after intravesical BCG treatment to test its feasibility in future clinical application. Weekly instillation of BCG (1 mg/ml, 5-8 x 10(7) CFU/mg) for 6 instillations could induce lymphocytic infiltration, submucosal fibrosis, and granulomatous reaction after 4 weeks with mild decrease of bladder weight and high incidence of hematopyuria (75%). No changes in appetite, body weight, and splenic weight were noticed in the chronically treated rats. A delayed hypersensitivity test through foot pad swelling measurement reached 80% positive rates at 2 weeks. Cystometric study revealed a mild decrease in bladder capacity (33.3%) at 2 weeks and of contractile pressure of the urinary bladder in rats receiving BCG instillations. In addition, increase in lymphocytic infiltration by natural killer (NK) cells against YAC-1 cells could be detected after BCG treatment and this was related to dosage of BCG. The urothelial damage by cauterization and the number of instillations could also enhance NK cell activity. Low toxicity and high safety of intravesical instillation of the domestic BCG are demonstrated by this pilot animal study. This information on local and systemic immune responses can provide a solid base for future efficacy of BCG immunotherapy in bladder cancer patients using this domestic strain BCG.     

Prophylactic intravesical instillation therapy in patients with superficial bladder cancer--results of a randomized prospective study]

A randomized prospective study was conducted for the purpose of investigating the efficacy of intravesical chemoprophylaxis of superficial bladder cancers. Eligible patients were randomized into three groups: 1) adriamycin (ADM) group; intravesical instillation with 50 mg of ADM dissolved in 100 ml physiological saline, 2) mitomycin C (MMC) group; intravesical instillation with 30 mg of MMC dissolved in 100 ml of physiological saline, 3) control group; transurethral resection or transurethral coagulation only. The characteristic features of our protocol consisted of frequent (six times) instillations of the drugs within two weeks after transurethral resection, followed by instillations on two consecutive days at four-week intervals for two years. Furthermore, large quantities (100 ml) of instillation fluid containing relatively low concentrations of the drugs (500 micrograms/ml for ADM or 300 micrograms/ml for MMC) were employed. One hundred and forty-four patients have been submitted to the study; 110 patients were fully evaluable for recurrence and 34 patients were eliminated as non-evaluable patients. The cumulative five-year non-recurrence rates of the patients with multiple tumors were 32% in the MMC group, 25% in the ADM group and 7% in the control group. The cumulative non-recurrence rates of the ADM and MMC groups were significantly higher than that of the control group. It is considered that this instillation therapy with ADM and MMC is useful for preventing the recurrence of superficial bladder cancers.