Transient anuria requiring nephrostomy after intravesical bacillus Calmette-Guérin instillations for superficial bladder cancer

A 76-year-old man received intravesical bacillus Calmette-Guérin (BCG) instillations for recurrent superficial bladder cancer. He had undergone right nephroureterectomy for right renal pelvic cancer 9 months previously. He presented with anuria and left hydronephrosis after the fourth instillation, with serum creatinine increasing up to 15.7 mg/dL. Percutaneous nephrostomy was indwelled, and antegrade pyelography showed left vesicoureteral obstruction. There was no sign of recurrent bladder cancer or ureteral cancer. He started spontaneous voiding on day 4 and the nephrostomy was removed on day 8. Most of the side-effects of intravesical BCG therapy are minor, and major adverse reactions are rare. Life-threatening ureteral obstruction would be a rare complication of BCG immunotherapy. Although BCG intravesical instillation after nephroureterectomy is a common practice, special care should be taken of renal function in patients with unilateral kidney during BCG therapy.     

Intravesical Bacille Calmette-Guérin Eradicates Bacteriuria in Antibiotic-naïve Bladder Cancer Patients

Background

Intravesical bacille Calmette-Guérin (BCG) therapy is safe and effective in bladder cancer patients who have asymptomatic bacteriuria. BCG induces robust immune responses in the bladder that are responsible for its antitumor effect. We hypothesize that BCG-induced inflammation may eradicate bacterial infection.

Objective

To investigate whether intravesical BCG therapy alone can eradicate bacterial infection in antibiotic-naïve bladder tumor patients who have asymptomatic bacteriuria.

Design, setting, and participants

A single-institution prospective cohort study of bacteriuric adults with non–muscle-invasive bladder tumors who underwent outpatient BCG therapy or surveillance cystoscopy.

Intervention

Ninety high-risk patients received induction intravesical BCG without maintenance BCG, and 95 low-risk patients who had not received BCG underwent outpatient surveillance cystoscopy. Each patient had significant bacteriuria on urine culture, and none received routine antibiotics before, during, or after procedures.

Outcome measurements and statistical analysis

Urine cultures were repeated after 3, 6, and 12 mo. All patients had follow-up cystoscopy every 3 mo and were followed for a minimum of 1 yr. The end point was number of BCG-treated and cystoscopy patients who became bacteria free at 3, 6, and 12 mo.

Results and limitations

Two BCG-treated patients (2.2%) and six patients after cystoscopy (6%) developed febrile urinary tract infection (p = 0.21). All resolved with antibiotics. No patient was admitted for sepsis. Of 88 infected patients who received BCG without routine antibiotics, 58 (66%) were continuously bacteria free at 1 yr compared with 16 of 89 cystoscopy patients (18%; p = 0.001). The prospective observational study design prohibits causal inference of antibacterial effects attributed to BCG over cystoscopy.

Conclusions

Intravesical BCG therapy is associated with clearance of uropathogens in bladder cancer patients, possibly due to augmented innate host immunity.     

Surface antigen expression on bladder tumor cells induced by bacillus Calmette-Guérin (BCG): A role of BCG internalization into tumor cells

BACKGROUND: The antitumor mechanisms of bacillus Calmette-Guérin (BCG) against bladder cancer is still unclear. We previously reported that BCG was internalized by and survived within murine bladder tumor cells (MBT-2) for at least 40 days. In the present study, we investigated the effect of BCG on the surface antigen expression of bladder tumor cells and the characteristics of these cells as antigen-presenting cells in vitro. METHODS: Surface antigen (major histocompatibility complex (MHC) Class II, CD1, CD80 and intercellular adhesion molecule-1 (ICAM-1)) expression on BCG-treated murine (MBT-2) and human (T-24, J82) bladder tumor cells were analyzed using flow cytometry. The production of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) from murine lymphocytes sensitized with BCG or BCG-treated tumor cells were also investigated. RESULTS: The expressions of MHC Class II, CD1, CD80 and ICAM-1 were augmented in all of the bladder tumor cell lines used; however, they were augmented to varying degrees among the cell lines that were treated with live BCG. Heat-killed BCG had little or no effect. When murine lymph node cells sensitized with BCG or BCG-treated MBT-2 cells were cocultured with BCG-treated MBT-2 cells, significant amounts of IL-2 and IFN-gamma were produced in the culture medium. CONCLUSIONS: BCG induced the augmented expression of surface antigens, such as MHC Class II, CD1, CD80 and ICAM-1, of bladder tumor cells. Furthermore, BCG-treated MBT-2 cells could stimulate BCG-sensitized lymphocytes to produce IL-2 and IFN-gamma. These results strongly suggest that bladder tumor cells gained the characteristics and functions of antigen-presenting cells (APC).     

Sufficient prophylactic efficacy with minor adverse effects by intravesical instillation of low-dose bacillus Calmette-Guérin for superficial bladder cancer recurrence

BACKGROUND: Intravesical instillation of bacillus Calmette-Guérin (BCG) is the most efficient strategy for prophylaxis of superficial bladder cancer recurrence. Adverse effects of BCG are major obstacles, but the reduction of BCG dose could minimize these effects. The efficacy and adverse effects of half-dose (40 mg) BCG, Tokyo 172 strain, were prospectively evaluated. METHODS: A total of 93 patients with superficial bladder cancer (pTa or pT1) were sequentially assigned to receive either 40 or 80 mg of BCG after transurethral resection. BCG was administered weekly for 6 weeks postoperatively. Eighty patients observed longer than 12 months after BCG therapy (41, 40 mg group; 39, 80 mg group) were analyzed. RESULTS: BCG therapy course was completed in 71 patients. Tumor recurrence was recognized in 11 of 40 patients in the 40 mg group and in 5 of 31 patients in the 80 mg group. There was no significant difference in tumor recurrence rate between the two groups (P = 0.547). BCG therapy was withdrawn in 1 patient in the 40 mg group and in 8 patients in the 80 mg-group because of BCG-related adverse effects. The morbidity of BCG-related toxicity was significantly higher in the 80 mg group. CONCLUSION: Half-dose of BCG Tokyo 172 strain had a similar efficacy and its toxicity was significantly lower compared to the standard dose. Thus, half-dose of this strain might be suitable, at least for initial BCG therapy, for the prophylaxis of bladder cancer recurrence. Further study would be necessary to clarify the efficacy of low-dose instillation in high-risk patients.     

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.     

Clinical outcomes of bacillus Calmette-Guérin instillation therapy for carcinoma in situ of urinary bladder

Objectives:   We analyzed the clinical outcomes of instillation therapy with Bacillus Calmette-Guerin (BCG) to treat carcinoma in situ (CIS) and searched for prognostic factors that could predict disease progression.
Methods:   Between January 1995 and January 2001, 185 patients (male, 155; female, 30) diagnosed with bladder CIS underwent weekly BCG instillations (80 mg of Tokyo 172 strain) for eight weeks. Primary, concomitant, and secondary CIS was found in 62 (33.5%), 60 (32.4%) and 63 (34.1%), patients, respectively. Seventy-five (40.5%) and 64 (34.6%) patients had limited and extensive CIS, respectively. The median follow up period was 37.5 months (range 4–95 months).
Results:   The overall complete response rate was 86.5%. The five-year progression-free survival rate was 78.5%. Several factors, such as age (<60 or ≥60 years), gender, previous transurethral resection, type of CIS, and CIS extension (three or more positive sites out of four to six biopsy sites was defined as extensive), were examined by multivariate analysis to predict progression. The extension of CIS was the only independent prognostic factor. The five-year recurrence-free rate of complete responders ( n  = 160) was 66.0%. Radical cystectomy was performed in 10 patients (6.3%) during follow up incomplete responders, of whom seven had invasive bladder cancer. Extravesical involvement was identified in 30 patients (16.2%) among whom, 21 (11.3%) had upper urinary tract recurrence and nine (4.9%) had prostatic involvement.
Conclusion:   Therapy with BCG is effective against CIS, the extent of which might be a prognostic factor. Disease progression including extravesical involvement should be carefully monitored over the long-term after BCG therapy.     

Systemic and local immunomodulatory effects of intravesical BCG therapy in patients with superficial urinary bladder carcinomas

PURPOSE: The aim of the present study was to elucidate whether only local, or also systemic immunomodulatory effects may be induced by intravesical BCG therapy of superficial urinary bladder cancer. MATERIALS AND METHODS: A total of 37 patients with stages Ta to T1b superficial transitional cell bladder carcinomas received 6 weekly BCG instillations after transurethral resection of the tumor. In a first group of 19 patients blood was taken before each BCG instillation and 6 weeks after the last one. In a second group of 18 patients blood and urine was taken before and 2, 6, and 24 hours after each BCG instillation. In the mitogen-stimulated whole blood cell cultures and in the urine samples the levels of the cytokines IL-1beta, IL-2, IL-10, TNF-alpha and IFN-gamma were determined by enzymoimmunological tests. Additionally, in all plasma and urine samples the levels of TNF-p75-receptor (TNF-p75-R) were measured. RESULTS: Comparison of ex vivo leukocyte cytokine production in the blood cell cultures of the patients of group I revealed no significant change in the levels of the cytokines. In contrast, TNF-p75-R plasma levels increased significantly during the experimental time of 12 weeks (p < or =0.01). In the blood cell cultures of the group II patients a different daytime variation of cytokine production was seen, compared to the 19 healthy controls. After BCG instillation the normal peak cytokine production in the evening was suppressed. A significant rise in plasma TNF-p-75-R levels was measured 24 hours after BCG instillation (p < or =0.05). In the urine of these patients significantly higher levels of all measured cytokines and TNF-p75-R were observed 6 to 24 hours after the instillation. CONCLUSIONS: The results suggest that besides the well known local immune activation, BCG instillation also leads to a modulation of peripheral immune mechanisms.     

Murine β-defensin-2 may regulate the effect of bacillus Calmette-Guérin (BCG) in normal mouse bladder

PurposeWe investigated whether bacillus Calmette-Guérin (BCG)–induced secretion of murine β-defensin-2 (mBD2) and determined whether mBD2 regulated BCG effects in the normal mouse bladder.Materials and methodsA total of 140 C57BL/6 female mice were divided into 28 groups, and the experiment was performed over 3 steps. In the first step (20 groups), mice bladders were stimulated with different doses of BCG (multiplicity of infection [MOI] 0, 1, 10, 30, and 100) and histological analysis was conducted in bladder specimens isolated at different times (0, 4, 8, and 24 h after instillation) to determine optimal dose and time point of BCG internalization and urine mBD2 and cytokine concentration. In the second step (4 groups), BCG internalization and urine cytokine levels were measured after pretreatment of different recombinant mBD2 (rmBD2) (0, 1, 2.5, and 5 ng/ml) at optimal dose and time point. In the third step (4 groups), BCG internalization and urine cytokine levels were compared between pretreatment conditions (control, rmBD2, anti-mBD2 Ab, and rmBD2+anti-mBD2 Ab). Urine was collected for estimating mBD2 levels and a multiplex analysis for 9 cytokines. Real-time polymerase chain reaction assay was used for estimating the relative BCG cell number in mice bladder tissue.ResultsBladder edema was induced by BCG (MOI 30 and 100), which progressed to an inflammatory infiltrate composed primarily of neutrophils and increased mBD2 secretion at 4 hours after instillation. Relative BCG cell number and urinary cytokine levels (interferon-γ and interleukins [IL]-2, -4, -6, and -10) response pattern was characterized by a peak at 4 hours after instillation followed by rapid decline. The levels of interferon-γ, and IL-1β, -2, -4, -6, and -10 and relative BCG cell numbers decreased in a dose-dependent manner according to pretreatment with rmBD2 protein, and the responses were potentiated in the anti-mBD2 pretreatment group at 4 hours after BCG (MOI 30) instillation.ConclusionThe present results suggest that the mouse urothelium produces mBD2 in response to intravesicular BCG as a defense mechanism against BCG, and blocking mBD2 by an anti-mBD2 antibody increased the effectiveness of BCG.     

Epididymo-orchitis caused by intravesically instillated bacillus Calmette-Guérin: Genetically proven using a multiplex polymerase chain reaction method

The intravesical instillation of bacillus Calmette-Guérin (BCG) is a standard therapy for superficial bladder carcinoma. Tuberculosis-like inflammation in the genitourinary tract is a serious complication of BCG. It can occur after a long interval from the cessation of the intravesical BCG therapy. If inflammation occurs, it is necessary to test whether the BCG strain has caused it or another mycobacterium species has. However, there has never been a report that proves BCG causes the inflammation, because BCG is difficult to differentiate from other strains of Mycobacterium bovis and other members of the Mycobacterium tuberculosis complex by conventional tests, including regular polymerase chain reaction (PCR). We first present a case of epididymo-orchitis, which developed 31 months after the cessation of BCG therapy, detected using a multiplex PCR method as having been caused by BCG. Our report illustrates the efficacy of this method to detect the responsible microbe that is thought to be transmitted from the instillated BCG strain.     

Local Toxicity Patterns Associated with lntravesical bacillus Calmette-Guérin: A Southwest Oncology Group Study

Background: While the efficacy of bacillus Calmette-Cuérin (BCG) immunotherapy has been demonstrated, the relative benefit, given a seemingly high incidence and severity of toxicities, remains an issue. Adequate understanding and management of toxicities can maximize the safety of the treatment and enable the administration of required doses of BCC intravesical therapy.
Methods: All week-to-week symptoms recorded for the 143 immunotherapy-naive participants assigned to the BCG arm of SWOG-8216, BCG vs. Doxorubicin in Superficial Bladder Cancer were analyzed in order to document the pattern of toxicities in the first six week induction course of intravesical BCC treatments. The statistical analysis consisted of fitting logistic regression models to these data for the probability of irritative bladder symptoms (16s).
Results: In the optimal model, the probability of IBS depends only on whether there was IBS associated with the previous treatment, and not on which treatment. The estimated probability of having IBS when there were no 16s associated with the previous instillation is 0.136, whereas the estimated probability of having IBS when there was IBS associated with the previous instillation is 0.689.
Conclusions: Irritative bladder symptoms are unlikely in the week after the first intravesical BCG treatment. Once a patient experiences IBS, he or she is more likely to have IBS with the next and subsequent treatments. Clinicians can use the findings of this analysis when informing their patients about the treatment course and when making decisions about continuing treatments.     

Clinical outcome of bacillus Calmette-Guérin perfusion therapy for carcinoma in situ of the upper urinary tract.

BACKGROUND: The objective of this study was to evaluate the efficacy of intrarenal bacillus Calmette-Guérin (BCG) instillation for the treatment of carcinoma in situ (CIS) of the upper urinary tract. METHODS: Sixteen patients who were diagnosed as having CIS of the upper urinary tract were treated with intrarenal BCG instillation. BCG (80 mg) in normal saline was administered once weekly, 6 times in total as one course through a percutaneous nephrostomy tube in 5 patients, and a retrograde ureteric catheterization using a Single-J or Double-J stent in 2 and 9 patients, respectively. RESULTS: During the median follow-up period of 30 months (range: 9-90 months), no patients died, and 13 patients remained cytologically negative in urine collected from the upper urinary tract after BCG treatment was completed. However, one of these 13 patients had CIS in the bladder and prostatic urethra 34 months after the BCG therapy and had to undergo radical cystectomy. The remaining 3 patients experienced recurrence in the upper urinary tract 4, 8, and 11 months after treatment, despite a favorable response to the initial BCG instillation. Of these 3 patients, one patient received an additional course of BCG therapy, while the remaining 2 underwent nephroureterectomy. Bladder irritability or a fever higher than 38 degrees C was observed in 12 or 9 patients, respectively; however, such side-effects were not clinically significant, and no patient received antitubercular treatment. CONCLUSION: Intrarenal instillation of BCG appears to be effective and safe for treatment of CIS of the upper urinary tract; however, further experience and longer follow-up studies of this treatment are required.     

肿瘤抗原诱导的T淋巴细胞膀胱灌注预防膀胱癌复发

目的探讨一种预防膀胱癌术后复发的新方法.方法由手术切除的膀胱癌组织制备肿瘤可溶性抗原,以卡介苗为佐剂,诱导人外周血单个核细胞成为细胞毒性T细胞(CTL).用培养8～10d的CTL及其培养上清为37例膀胱癌切除术后患者进行膀胱腔内灌注治疗.定期膀胱镜复查,SAP免疫组化法检测外周血T淋巴细胞亚群分布的变化,ELISA法测定血清及尿液中IL-2等细胞因子含量,观察疗效.结果患者外周血CD3+、CD4+T细胞亚群的比例增加显著(P＜0.01);CD4+/CD8+T细胞比例明显提高(1.60±0.20,P＜0.01)血清及尿液中白细胞介素2、肿瘤坏死因子α、干扰素γ的水平均较治疗前明显提高(P＜0.01);组织学观察显示膀胱粘膜呈轻度非特异性炎症反应.随访6～26个月(中位时间为16个月),复发率2.7%,未见有严重不良反应.结论CTL及其培养上清膀胱腔内灌注治疗能够提高膀胱癌术后患者膀胱局部和全身的免疫水平,有效降低膀胱癌的术后复发率.     

Innate immune memory is associated with increased disease-free survival in bladder cancer patients treated with bacillus Calmette-Guérin

IntroductionWhile studies suggest that innate immune memory acquired by circulating monocytes may mediate the benefit of bacillus Calmette-Guérin (BCG) in the treatment of patients with high-risk non-muscle-invasive bladder cancer (NMIBC), prospective studies are lacking. Innate immune memory is defined by enhanced release of pro-inflammatory cytokines by innate immune cells following a secondary challenge with pattern recognition receptor (PRR) ligands.MethodsPeripheral blood monocytes isolated from 33 patients with intermediate- or high-risk NMIBC before and after two or five induction BCG instillations were stimulated with the PRR ligand lipopolysaccharide (LPS). Inflammatory cytokine levels in the culture medium were measured. Extent of innate immune memory acquisition was determined by dividing the levels of cytokines released after BCG instillation by the levels released prior to BCG therapy.ResultsMonocytes secreted variable levels of TNFα, IL-1β, IL-6, IFNγ, IL-12, and IL-10. Compared with patients with recurrences, the post-BCG:pre-BCG ratio of IL-12 in monocyte cultures from patients without recurrences after five BCG instillations was significantly increased. Patients with no innate immune memory (based on IL-12 ratios) had significantly shorter time to recurrence than patients with innate immune memory (p<0.001). Eighty-four percent (16/19) of patients with innate immune memory vs. only 22% (2/9) of patients without memory had disease-free survival of over 500 days.ConclusionsResults demonstrate a potential link between BCG-induced innate immune memory peripherally and local anti-tumor responses. Further validation will increase our understanding of the mode of action of BCG and, therefore, will be used to enhance its effectiveness.     

Penile edema and meatal ulceration after intravesical instillation with Bacillus Calmette-Guérin

Bacillus Calmette-Guérin (BCG) bladder instillation is an accepted treatment modality in the management of superficial transitional cell carcinoma but is associated with frequent side effects. A report of intravesical BCG-induced penile edema and meatal ulceration that occurred in 2 patients is presented. During induction therapy, both patients complained of progressive penile edema. In 1 patient the edema appeared after the second instillation and in the other after the fourth instillation. Edema was associated with ensuing meatal ulceration and enlarged inguinal lymph nodes. BCG instillation was aborted, and oral antituberculous treatment was initiated. There was no report of external spillage during the administration of BCG or of genital or urethral trauma during catheterization. Patients were treated at different clinics but with BCG of the same strain and batch. Symptoms continued for 6 weeks until they abated. Both patients were managed with oral antituberculous drugs for a period of 3 months. Adverse effects of BCG intravesical administration affect several organs in the genitourinary system. The penis and urethra may also be involved, presenting as penile edema and meatal ulceration. Physicians who administer BCG must be familiar with the possible complications and their appropriate management.     

BCG膀胱灌注对局部免疫细胞功能的影响

对２７例表浅膀胱癌术后ＢＣＧ膀胱灌注前后膀胱壁Ｔ＿３、Ｔ＿４、Ｔ＿８、ＩＬ－２Ｒ表达及尿液中肿瘤坏死因子（ＴＮＦ）含量进行了研究。结果表明，ＢＣＧ膀胱灌注后膀胱壁大量淋巴细胞浸润，Ｔ＿４／Ｔ＿８比值由灌注前０．６上升至１．９，２０例患者膀胱壁形成淋巴肉芽肿，粘膜下散在淋巴细胞表面广泛表达ＩＬ－２Ｒ，但肉芽肿淋巴细胞表面几乎不表达ＩＬ－２Ｒ。灌注后２４小时尿液中ＴＮＦ含量显著升高（Ｐ＜０．０１），实验结果提示：Ｔ＿４、巨噬细胞在ＢＣＧ抗肿瘤效应中起着非常重要的作用。     

Photodynamic Diagnosis (5-Aminolevulinic Acid) of Transitional Cell Carcinoma After Bacillus Calmette-Guérin Immunotherapy and Mitomycin C Intravesical Therapy

Background

Photodynamic diagnosis (PDD) is a technique that enhances the detection of occult bladder tumors during cystoscopy using a fluorescent dye.

Objective

To study the differential effects of bacillus Calmette-Guérin (BCG) and mitomycin C (MMC) intravesical therapy on the false-positive rate of PDD of bladder cancer.

Design, setting, and participants

This study included 552 procedures and 1874 biopsies.

Intervention

Tumors were resected and biopsies were taken from suspicious areas, under guidance of white-light endoscopy and 5-ALA (5-aminolevulinic acid)–induced fluorescence cystoscopy.

Measurements

The influence of intravesical BCG immunotherapy and intravesical MMC chemotherapy on pyuria, inflammation, and PDD specificity was examined in univariate analyses.

Results and limitations

BCG significantly results in inflammation (odds ratio [OR]: 1.53, p = 0.002), leukocyturia (OR: 1.84, p = 0.034), and false positives in PDD (OR: 1.49, p = 0.001). However, a single BCG instillation within 3 mo before PDD is most likely not associated with increased false-positive rates (OR: 0.35, p = 0.26). Leukocyturia normalizes within 6 wk after the last BCG instillation, but PDD specificity is reduced up to 3 mo.

Conclusions

BCG is an important predictor for false positives in PDD (5-ALA). More than one BCG instillation within 3 mo before fluorescence cystoscopy decreases the specificity of PDD.     

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.     

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.     

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.     

Systemic bacillus Calmette-Guérin infection, 'BCGitis', in patients treated by intravesical bacillus Calmette-Guérin therapy for bladder cancer

Among 169 patients treated for supeficial bladder tumor with 150 mg Pasteur-strain bacillus Calmette-Guérin (BCG) intravesical instillation, 5 cases of 'BCGitis' were observed, i.e. a severe systemic BCG infection with bronchopulmonary lesions and granulomatous hepatitis. In 4 cases, the complications appeared at the early stage of treatment (after the 3rd, 6th, 6th and 8th instillations, respectively). In 1 case, treated with monthly maintenance therapy for 2 years, BCGitis appeared 6 months after treatment had been completed and, in addition to pulmonary basal infiltrate and granulomatous hepatitis, intramedullary granulomatosis was observed. In 3 patients, trauma must be taken into consideration as BCGitis appeared after traumatic instillation with bleeding. All patients were cured by treatment with rifampicin, isoniazid and prednisone.