T HELPER 1/2 LYMPHOCYTE URINARY CYTOKINE PROFILES IN RESPONDING AND NONRESPONDING PATIENTS AFTER 1 AND 2 COURSES OF BACILLUS CALMETTE-GUERIN FOR SUPERFICIAL BLADDER CANCER

PURPOSE: Interleukin (IL)-2 and interferon-gamma are released during T helper 1 lymphocyte responses and IL-10 is released during T helper 2 lymphocyte responses. We have previously reported that a T helper 1 lymphocyte urinary cytokine profile is associated with a favorable prognosis after bacillus Calmette-Guerin (BCG) treatment. We evaluated the T helper 1/2 lymphocyte cytokine profiles during courses 1 and 2 of 6 weekly BCG instillations. MATERIALS AND METHODS: Urinary interferon-gamma, IL-2 and IL-10 were measured by enzyme-linked immunosorbent assay after each of 6 weekly instillations of 150 mg. BCG, Pasteur strain, in 19 patients with superficial stages Ta and T1 bladder cancer, and carcinoma in situ. The 11 patients who did not respond to course 1 were re-treated according to the same schedule and reevaluated. RESULTS: During course 1 interferon-gamma was higher than during course 2 (p <0.001), which was associated with nonrecurrence (p <0.001). In contrast, IL-2 cytokine was higher after course 2 (p <0.01), which was associated with a BCG response (p = 0.01). Interferon-gamma and IL-10 correlated during courses 1 and 2 (p = 0.04 and 0.0004, respectively). We distinguished groups 1-immediate T helper 1 lymphocyte profile consisting of responders to course 1 with high interferon-gamma, IL-2 and IL-10, 2-delayed T helper 1 lymphocyte profile consisting of responders to course 2 with early high IL-2 and 3-consisting of nonresponders to the 2 courses with low interferon-gamma, IL-2 and IL-10. CONCLUSIONS: A T helper 1 lymphocyte urinary cytokine profile was associated with a clinical response to BCG. A repeat BCG course induces a favorable immune response in a subset of patients, suggesting that maintenance therapy may be beneficial.     

BACILLUS CALMETTE-GUERIN (BCG) IMMUNOTHERAPY FOR BLADDER CANCER: REVIEW OF COMPLICATIONS AND THEIR TREATMENT

Background: Intravesical bacillus Calmette–Guerin (BCG) is widely used in the management of bladder cancer but because it is a living organism, local and disseminated infection may result. Methods: A prospective assessment of complications of this therapy in 200 patients in Queensland was performed. A review of management of complications of intravesical BCG was also carried out. Results: Major side effects were rare. Cystitis was the most common side effect, being seen to some degree in all patients, although only forcing cessation of BCG therapy in two patients. Two patients developed persistent cystitis necessitating institution of isoniazid and rifampicin. Two patients had culture-proven bladder infection that presented several months after the BCG treatment. These patients also responded to two-drug antituberculous therapy. While low-grade fever is very common with this therapy, seven patients (3.5%) had fevers of > 39°C within 48 h of receiving BCG. Fevers may be an indication of severe disseminated mycobacterial infection, which has a high mortality, so it needs to be treated aggressively. Alternatively bacterial sepsis with Gram-negative bacterial pathogens or a hypersensitivity reaction to BCG may cause this degree of fever, and cannot be rapidly distinguished from fulminant mycobacterial infection. One patient in the present series developed pneumonia attributed to mycobacterial dissemination. Conclusions: The key to appropriate management of complications of BCG therapy is awareness of their possibility, even months or years after the therapy has been given. Appropriate empirical therapy in acute situations and mycobacterial culture in chronic situations can then be performed.     

SCREENING AND MONITORING FOR BLADDER CANCER: REFINING THE USE OF NMP22

PURPOSE: While detecting bladder cancer, bladder tumor markers demonstrate improved sensitivity compared with urinary cytology but the current limitation is the low specificity and positive predictive value, that is high false-positive rate. We examined the clinical categories of the false-positive results, established relative exclusion criteria, and recalculated the specificity and positive predictive value of this assay with these criteria. MATERIALS AND METHODS: A total of 608 patients considered at risk for bladder cancer presented to a urology clinic and submitted a single urine sample. Of the 608 patients 529 (87%) presented with de novo hematuria or chronic voiding symptoms without a diagnosis of bladder cancer. There were 79 (13.0%) patients being monitored with a known history of bladder cancer. Each urine sample was examined via cytology, urinalysis, culture and NMP22 protein assay. All patients underwent office cystoscopy, and transurethral resection and/or biopsy if a bladder tumor was suspected. RESULTS: Of the 608 patients 226 (37.2%) presented with microscopic hematuria, 143 (23.5%) with gross hematuria and 239 (39.3%) had chronic symptoms of urinary frequency or dysuria. There were 52 (8.6%) patients who had histologically confirmed bladder cancer. Of these 52 cancers NMP22 detected 46 (88.5%), whereas cytology identified only 16 (30.8%). When atypical cytology was considered positive, cytology detected 32 (61.5%) cases. In the 135 patients with increased NMP22 values the 46 identified tumors were accompanied by 89 false-positive values yielding a specificity of 83.9% and a positive predictive value of 34.1%. These false-positive results were divided into 6 clinical categories. Exclusion of these categories improved the specificity and positive predictive value of NMP22 to 99.2% and 92.0%, respectively, yielding results similar to urinary cytology (99.8% and 94.1%). CONCLUSIONS: Awareness and exclusion of the categories of false-positive results can increase the specificity and positive predictive value of NMP22, enhancing the clinical use of this urinary tumor marker.