Interference of modern antibacterials with bacillus Calmette-Guerin viability

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 Effect of Lubricants on Viability of Bacillus Calmette-Guerin for Intravesical Immunotherapy Against Bladder Carcinoma

Purpose

The viability of bacillus Calmette-Guerin (BCG) is crucial for induction of a local immune response and for effective therapy of recurrent superficial bladder carcinoma. During intravesical instillation of BCG lubricants are administered to assist catheterization, which contain bacteriostatic components that may interfere with the viability of mycobacteria. To verify this assumption, 5 commercially available lubricants were analyzed with regard to inhibition of viable BCG growth.

Materials and Methods

Five different lubricants and their components were co-incubated with Connaught strain BCG and the resultant growth of BCG was assessed. To prove the significant passage of lubricants into the bladder, fluid was recovered from the bladder after catheterization, analyzed with regard to the bacteriostatic effect and compared to normal urine of different acidity.

Results

Significant impairment of BCG viability, dependent on dosage and time of co-incubation, was noted with all lubricants analyzed. Several components, namely lidocaine hydrochloride, glyceryl stearate, propyl-4-hydroxy-benzoate and chlorhexidine digluconate, were identified as responsible for this inhibition. Fluid recovered from the bladder after lubricant assisted catheterization also showed an inhibitory effect, indicating significant mixture of the instillate with lubricants.

Conclusions

Generous use of lubricants to assist catheterization during intravesical BCG therapy will result in a clinically significant decrease in the number of intravesically instilled viable mycobacteria. For this reason, during intravesical immunotherapy with BCG only small amounts of lubricants should be used for urethral catheterization, and use of catheters not requiring lubricants should be considered.     

Optimal treatment of systemic bacillus Calmette-Guérin infection: investigations in an animal model

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Detection of interleukin 2 in the urine of patients with superficial bladder tumors after treatment with intravesical BCG

Adjuvant intravesical BCG therapy is an effective means of treating superficial bladder tumors. The mechanism by which BCG mediates antitumor activity is not known; however, clinical and animal studies suggest that immunological responsiveness to BCG antigens correlates with antitumor activity. In this report the detection of interleukin 2 (IL-2, a lymphokine produced in response to BCG) in urine specimens of patients treated with intravesical BCG is reported. Patients with superficial transitional cell carcinoma of the bladder received intravesical BCG once each week for six weeks. No intradermal injections were administered. Urine specimens were obtained prior to BCG instillation and four, eight and 24 hours afterwards. The specimens were dialysed, concentrated five-fold and assayed for the presence of IL-2 in a biological assay using an IL-2 dependent cultured T-cell line. IL-2 was detected in urine but not serum after intravesical BCG instillation. IL-2 was characterized by absorption against an IL-2-dependent T cell line and neutralization by monoclonal anti-IL-2 antibodies. No IL-2 was detected in specimens obtained prior to BCG instillation or from donors with no detectable bladder pathology. One of 10 urine specimens from patients with urinary tract infections had detectable IL-2 levels. IL-2 production generally peaked during the fourth to sixth intravesical BCG treatment. Production was short-term in that IL-2 levels peaked four to eight hours after BCG instillation and were rarely (six of 54 specimens) observed 24 hours after instillation. Mean IL-2 levels were higher in patients who were rendered tumor free after BCG therapy but statistical significance was not achieved. Ten of 12 patients (83%) who responded to BCG therapy had urine IL-2 levels greater than or equal to 1.6 units/ml. at least once during the six week treatment period while two of six (33%) patients not responding to therapy had similar urine IL-2 levels. These results show that intravesical BCG therapy induces the production of lymphokines including IL-2. The presence of BCG-induced lymphokines may be associated with anti-tumor activity.     

Therapy of superficial bladder carcinomas

Treatment of superficial bladder carcinoma was derived by several large randomized trials. This group of cancers is stratified by differentiation grade and stage in three groups of different risk profiles (Ta G1-2 vs. T1 G1-2 vs. Tis/T1 G3). Standard therapy is fractionated transurethral resection (TUR). Adjuvant therapy after transurethral resection is not indicated in primary Ta G1-2 tumors because there is a low recurrence rate and no risk of tumor progression. The recurrence rate can be decreased up to 15% in recurrent Ta or T1 G1-2 tumors by intravesical therapy with mitomycin C (20 mg/instillation) or adriamycin (50 mg/instillation). Therapy should be limited to early (within 24 h post-TUR) and short-term treatment (4 x weekly, 5 x monthly). Alternatively, patients can be treated by intravesical BCG (strain Connaught or strain RIVM). Maintenance therapy is advantageous according to recurrence rate. Tumors with great malignant ability (Tis or T1 G3) will be treated initially with adjuvant BCG. Patients who fail are candidates for radical cystectomy within 3-6 months after initial diagnosis. There is no need - except in clinical trials - for the administration of unverified or not admitted drugs. Copyright Copyright 1999 S. Karger AG, Basel     

The fate of bacillus Calmette-Guerin after intravesical instillation

PURPOSE: 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. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 ablative effect of quarter dose bacillus Calmette-Guerin on a papillary marker lesion of the bladder

PURPOSE: Low dose bacillus Calmette-Guerin (BCG) for stage TaT1 transitional cell carcinoma of the bladder has been given in various studies with the aim of decreasing side effects while maintaining the same efficacy as full dose bacillus Calmette-Guerin. However, its application in clinical practice remains controversial. We examined the ablative activity and incidence of side effects of intravesical quarter dose BCG given for a papillary marker lesion of the bladder. MATERIALS AND METHODS: Included in our study were 44 patients with primary or recurrent, multiple but no more than 10 lesions of stage pTaT1, grades 1 to 2 transitional cell carcinoma of the bladder. Intravesical treatment begun 14 days after the complete transurethral resection of all visible tumors except 1 marker lesion no larger than 1 cm. consisted of instillations of 30 mg. Connaught strain BCG diluted in 50 ml. saline once weekly for 6 consecutive weeks. Two weeks after the last instillation any residual tumor was completely resected. In cases of complete disappearance of the marker lesion deep biopsy of the tumor area was done. Urine cytology was also performed. RESULTS: There was a complete response in 27 of the 44 patients (61%), no response in 12 (27%) and progression to carcinoma in situ in 1 (2%), while the response was not evaluable in 4. Local side effects included dysuria in 54% of cases and macroscopic hematuria in 39%. Neither BCG induced infection nor BCG sepsis was observed. CONCLUSIONS: Quarter dose BCG has a clear ablative effect on superficial bladder cancer with a 61% response rate. Phase III trials are now required to compare its efficacy and toxicity to those of full dose BCG.     

Sepsis und Multiorganversagen nach BCG-Instillation bei Blasenkarzinom

Local Bacillus Calmette-Guerin (BCG) immunotherapy is an effective and widely used treatment for superficial bladder carcino-ma. Local side effects are frequent, where-as systemic side effects are rare, but more serious. Systemic BCG infection as a life-threatening complication of intravesical BCG instillation should be suspected in any patient who presents with persistent fever after BCG instillation for bladder cancer.A 62-year-old patient had been treated with 6 intravesical BCG instillations for recurrent, multifocal bladder carcinoma.4 weeks after the last instillation, he presented with fever, malaise and scleral icterus. Laboratory tests revealed abnormal li-ver function tests, panzytopenia and signs of coagulation disorder. Bone marrow biopsy and liver biopsy showed non-caseating granulomas. Systemic BCG infection was suspected and antituberculous therapy combined with steroids was started. The patient developed severe sepsis and suffered from multiple organ failure. Despite partial improvement, the course was complicated by intracranial sinus thrombosis, and the patient died two month after admission.     

BCG和IL－2膀胱灌注预防膀胱癌复发的疗效观察

为了解ＢＣＧ＋ＩＬ－２联合应用膀胱灌注预防膀胱癌术后复发的疗效，将６０例膀胱癌随机分为两组：一组用ＢＣＧ６０ｍｇ（常用量的１／２）＋ＩＬ－２１００００Ｕ，一组用丝裂霉素Ｃ２０ｍｇ行膀胱内灌注。随访１０～４８个月，平均３３个月，无肿瘤复发者ＢＣＧ＋ＩＬ－２组２６例（８６．７％），丝裂霉素Ｃ组２３例（７６．７％），两组比较有显著性差异。ＢＣＧ＋ＩＬ－２组除有２４小时后自限性的轻微膀胱刺激症状外，无骨髓抑制等全身毒副反应。结果表明，ＢＣＧ＋ＩＬ－２较丝裂霉素Ｃ能更有效地防止膀胱癌术后复发，且可减少ＢＣＧ剂量。     

Intravesical bacillus Calmette-Guerin instillation therapy of recurrent superficial bladder carcinomas resistant to intravesical anti-cancer chemotherapy

Tokyo strain bacillus Calmette-Guerin (BCG) was instilled in a dose of 80 mg in 40 ml normal saline to the bladder of 8 patients with recurrent superficial bladder carcinoma (Ta, Tl, Tis) resistant to mitomycin C and/or adriamycin intravesical instillation chemotherapy. Instillation was performed weekly for 6 weeks and 3 to 4 weeks after the last instillation, the response was assessed by cystoscopy and urine cytology. Patients who achieved complete response underwent monthly maintenance instillation for a year and inspection with cystoscopy and urine cytology every 3 months. Of the 7 patients who underwent therapeutic instillation, 3 (43%) achieved complete response, and 2 partial response. Two patients with no response had carcinoma in situ of grade 3 anaplasia. Two of the 3 complete responders were free of disease for 11 and 12 months, but another 1 developed intravesical recurrence 13 months later. One patient underwent prophylactic instillation and remained free of disease for 23 months. Side effects included frequency, urgency and pain on urination which were tolerable with anti-analgesics. Two patients underwent total cystectomy because of tumor progression and had typical lesions of prostatic tuberculosis.     

Prophylaxis of superficial bladder tumor with the intravesical instillation of bacillus Calmette-Guerin or anti-cancer agents. A retrospective study]

It was retrospectively analyzed whether intravesical instillation of bacillus Calmette-Guerin (BCG) or anti-cancer agents had prophylactic effect or not after removal of superficial bladder tumors. The results over a follow-up period ranging from 6 to 40 months showed 23.8 per cent recurrence in group 1 patients treated with BCG (21 patients), 46.7 per cent recurrence in group 2 treated with anti-cancer agents (45 patients) and 52.3 per cent recurrence in the group 3 (127 patients) which were not received any intravesical drugs. Long-term results among the 3 groups calculated with Kaplan-Meier method demonstrated that the instillation of BCG or of anti-cancer agents was more useful for prophylaxis, compared with the actuarial non-recurrence rates of group 3. The instillation of BCG showed good prophylactic effects especially in recurrent, grade 2 and pTa bladder tumors. The instillation of anti-cancer agents showed to provide prolonged protection from recurrence, but the instillation of BCG did not.     

A case of interstitial pneumonitis caused by intravesical bacillus Calmette-Guérin instillation]

A 61-year-old man was referred to our hospital due to positive urine cytology. He underwent multiple cold punch biopsies of the bladder and the histopathological finding was transitional cell carcinoma (TCC), carcinoma in situ (CIS), grade 3. He was treated with 121.5 mg of bacillus Calmette-Guérin (BCG) (Connaught strain) suspended in 50 ml of saline instilled into the bladder at weekly intervals. After the third instillation he developed a fever up to 39 degrees C, pain on urination and an elevation of liver enzymes. Antituberculous drugs were administered and he was re-admitted for further evaluation. The chest radiograph showed diffuse extensive bilateral lung densities. His chest computed tomographic (CT) scan showed bilateral interstitial pneumonitis. All cultures from his blood, urine, sputum, and bronchoalveolar lavage remained negative for mycobacteria. He was diagnosed as having a hypersensitivity reaction of bilateral lung after immunotherapy with BCG. Pulse steroid therapy was done. The chest radiograph, findings improved and he was clinically asymptomatic after steroid therapy.     

吡柔比星加卡介苗膀胱灌注预防肿瘤复发的效果及尿中IL-8变化的临床意义

目的 比较吡柔比星（THP）加卡介苗或单用卡介苗膀胱灌注预防膀胱肿瘤复发的疗效，并测定灌注后IL-8的变化，探讨其与疗效的关系。方法对62例膀胱部分切除术后患者分别给予THP加卡介苗或单用卡介苗膀胱灌注预防复发，用酶联免疫学方法测定灌注前后尿中IL-8的浓度。赔果联合用药组复发率明显低于单用BCG组，两组灌注后尿中IL-8的浓度均有明显的变化，但两组之间无显著性差别。结论THP加BCG膀胱灌注可有效降低膀胱肿瘤复发率，而这一效果是作用机制不同药物的叠加作用，而不是化疗药物对免疫药物疗效的放大作用。     

Arthritis following intravesical instillation of BCG for urothelial cancers

BACKGROUND: Intravesical instillation of bacillus Calmette-Guerin (BCG) is efficient for prophylaxis of superficial bladder cancer and treatment for carcinoma in situ (CIS) of the upper urethelial cancer. However, the incidence of adverse effects is relatively high, and those include reactive arthritis. We retrospectively evaluated the incidence and the outcome of reactive arthritis following intravesical BCG therapy for urothelial cancers. PATIENTS AND METHODS: Intravesical instillations of BCC were performed in 192 cases (218 courses) between January 1998 and January 2002. BCG was instilled for prophylaxis of superficial bladder cancer recurrence in 170 (195 courses), treatment for CIS in 7 (8 course), and treatment for CIS in 7 (8 courses), and treatment for CIS in upper urinary tract in 15 (15 courses). RESULTS: Arthritis was recognized in 8 cases (3.7%, 8/218 courses), and 7 of them were identical to reactive arthritis following BCG therapy. Remaining 1 patient was diagnosed as rheumatoid arthritis (RA), and the relation between arthritis and intravesical BCG instillation was unclear. Mean number of BCG instillation was 5.6 (3-8 times). All reactive arthritis were occurred within 4 weeks after the last BCG instillation, i.e., BCG induced urinary tract infection, and 6 of them were polyarthritis. Concurrence of conjunctivitis was seen in one patient. HLA-B27 was negative in 4 examined patients. A nonsteroidal anti-inflammatory drug (NSAID) was used in all 8 patients, anti-tuberculous agents were used in 3, and prednisolone was added in 3, Arthritis was improved within 2 months in patients received prednisolone, however, it persisted longer than 3 months in patients without prednisolone. CONCLUSION: Arthritis was recognized in higher incidence than previous reports following intravesical instillation of BCG. All cases except one, diagnosed as RA, were diagnosed as reactive arthritis (Reiter's syndrome). However, correlation between HLA-B27 and arthritis was not clear in this study. Administration of steroidal drug was thought to improve arthritis in shorter duration.     

羟丙基纤维素与丝裂霉素联合膀胱灌注药动力学的研究

目的：探讨粘膜粘附缓释剂羟丙基纤维素（HPC）与丝裂霉素C（MMC）联合膀胱灌注对MMC在膀胱中保留的效果。方法：20例膀胱肿瘤患者分为HPC－MMC联合组和单纯用MMC（S－MMC）组，行TURBT或膀胱部分切除术后分别用1％HPC－MMC和S－MMC行膀胱灌注，采用高压液相法检测尿中MMC浓度，并对比研究两者尿药动力学改变。结果：HPC－MMC组膀胱灌注后，MMC在膀胱尿中的滞留时间，满足留量明显优于S－MMC灌注组，临床应用未见副作用发生。结论：HPC与MMC联合注膀胱可使MMC持续保留，值得在临床推广。     

Impaired immune response by isoniazid treatment during intravesical BCG administration in the guinea pig.

At present, isoniazid (INH) is being used prophylactically to reduce the side effects of intravesical BCG therapy for superficial bladder cancer, although it is not clear whether or not this reduces the antitumor efficacy of BCG. In this study the impact of INH treatment on the immune response after repeated intravesical BCG administration was investigated in guinea pigs. INH was given on the 3 days around each BCG instillation. We found that the administration of INH severely impaired the immunological effects of BCG. The induction of mononuclear cell infiltration in the bladder wall was reduced. Enlargement of the regional lymph nodes (weight and number of cells), and increase of MHC Class II expression on the lymph node cells, normally observed after intravesical BCG administration, were inhibited by INH. Systemic immunity, measured by the DTH reaction in the skin to PPD, was also diminished due to the combined treatment of BCG with INH. When INH was administered during the last 4 of 6 BCG instillations, the immune response to BCG was still impaired. A five-fold increase of the dose of BCG did not overcome the effect of INH. INH probably did not exert a direct suppression of the immune system of the guinea pig as the DNCB skin reactivity was not influenced. Although INH concentrations in the urine were high at the onset of the instillation, in vitro experiments indicated that the effect of INH may not be caused by killing of the BCG organisms shortly after application in the bladder. In conclusion, our data in guinea pigs suggest that the use of INH may impair the immune response to intravesical BCG. As this response may be important for the antitumor effect of BCG, urologists should be cautious with the prophylactic use of INH. The influence on the antitumor efficacy is now investigated in man.     

A clinical survey of bacteria isolated from urine specimens of patients with various urological disease

We have clinically surveyed the distribution and disk sensitivity of bacterial strains obtained from urine of patients with various urological disease at our department during three (1975-1977) and four (1980-1983) years. Escherichia coli was the most frequently isolated (29.4%) from the outpatients, followed by Staphylococcus epidermidis (17.5%), Pseudomonas cepacia (11.2%) and Serratia marcescens (11.2%). Pseudomonas cepacia was the most frequently isolated (28.0%) from the inpatients, followed by Staphylococcus epidermidis (16.3%) and Serratia marcescens (15.9%). Pseudomonas cepacia which has been increasing was first isolated in 1977 and Serratia marcescens in 1976. They have become the main bacteria causing infections in our hospital. Pseudomonas cepacia was frequently isolated after postoperative prophylactic chemotherapy and Serratia marcescens in the late period of admission. The majority of Pseudomonas cepacia was resistant to all agents except chloramphenicol and doxycycline. Serratia marcescens was also resistant except to gentamicin and doxycycline. In Escherichia coli species, resistant strains increased gradually but they have good sensitivity to gentamicin, dibekacin, colistin and doxycycline. Staphylococcus epidermidis isolated from outpatients had good sensitivity to all agents but increased in incidence of resistant strains isolated from inpatients.     

ＭＭＣ和ＢＣＧ交替灌注防治膀胱癌术后复发

目的：观察丝裂霉素Ｃ（ＭＭＣ）和卡介苗（ＢＣＧ）化学免疫预防膀胱癌术后复发的疗效。方法：对８６例浅表性膀胱癌患者术后应用ＭＭＣ２０mg和ＢＣＧ６０mg,每周１次进行交替膀胱藻注,共灌注１２次,以后每间隔３个月灌注１次,持续２年,结果：随记２．４－８年,平均４．８４年,肿瘤复发率为８．１％,结论：ＭＭＣ和ＢＣＧ交替膀胱灌注可减少膀胱癌术后复发率。     

Prophylactic intravesical BCG for bladder tumor after surgery of upper tract urothelial carcinoma

We report the result of prophylactic intravesical instillation of BCG after surgery of upper tract urothelial carcinoma. The BCG Tokyo 172 strain was given preoperatively and/or postoperatively, as a rule, in a dose of 80 mg in 30 ml saline instilled into the bladder. Only one (14.3%) of the 7 patients with intravesical BCG developed bladder tumor at 14 month after surgery, while (45.4%) of 11 patients who did not receive intravesical BCG suffered from bladder tumor within 2 years after surgery. Prophylactic intravesical instillation of BCG reduced significantly (p less than 0.005) the recurrence of bladder tumor after the surgery of renal pelvis and ureteral tumor.     

Role of interleukin-8 in onset of the immune response in intravesical BCG therapy for superficial bladder cancer

In intravesical therapy for superficial bladder carcinoma urothelial cells may, through the production of cytokines, contribute to the bacillus Calmette-Guérin (BCG)-induced local immunological reaction and associated antitumor efficacy. The aim of this study was to investigate such a role for the neutrophil-attracting cytokine interleukin-8 (IL-8). The appearance of IL-8 in patients' urine after BCG therapy was compared with BCG-induced IL-6 and IL-2 and the stability of IL-8 in urine was tested. Compared to IL-6 and IL-2, a rapid induction of IL-8 was observed, occurring after the first BCG instillation. Urinary IL-8 was highly stable, even after 24 h incubation at 37°C. The IL-8 concentration after the first instillation seemed to be associated with subsequent development of an immune response. Consequently, IL-8 seems an attractive candidate for investigation of its prognostic value for a clinical response to BCG therapy.