de Reijke T M, de Boer E C, Kurth K H, Schamhart D H
Department of Urology, University of Amsterdam, The Netherlands.
J Urol. 1996 Feb;155(2):477-82.
An accurate prognostic indicator to identify nonresponding patients with superficial transitional cell carcinoma of the bladder at an early stage of intravesical bacillus Calmette-Guerin (BCG) therapy is urgently needed.
The processing conditions and stability of several BCG induced urinary cytokines were analyzed, as was the possible correlation between these cytokines (indicating immune responsiveness to BCG) and bladder tumor recurrence. We studied 23 patients with superficial transitional cell carcinoma of the bladder. Monitoring was performed by serial collection of urine during the first 24 hours after each of the 6 consecutive weekly intravesical BCG instillations. Baseline pre-therapy cytokine levels were 3.9 +/- 4.7 pg./mumol creatinine for interleukin-6 and 0.1 +/- 0.2 pg./mumol creatinine for tumor necrosis factor-alpha (all measured by enzyme-linked immunosorbent assay). To investigate the correlation between interleukin-2 and bladder tumor recurrence, patients were stratified into 2 groups based on an early (6 months or less) or late (greater than 6 months) recurrent tumor. For each patient the highest cytokine value measured during the 6-week BCG treatment course was evaluated.
The results were positive if the level in urine exceeded 0.34 units interleukin-2 per mumol. creatinine. A significant correlation between urinary interleukin-2 and tumor recurrence was found (p = 0.003, 23 patients). Of the studied cytokines obtained from BCG treated patients, interleukin-1 beta, 2 and 6 but not tumor necrosis factor-alpha were stable in urine at 4C and 20C. At 37C all cytokines were unstable. Interferon-gamma could only be detected in immediately dialyzed urine and its occurrence correlated most with that of interleukin-2. Processing of urine by centrifugation to remove leukocytes immediately after collection was not required for reliable measurements of interleukins-2 and 6. Based on these results interleukins-2 and 6 were preferred for extensive monitoring of the BCG induced immune reaction.
Our study provides significant evidence for a correlation between urinary cytokine induction and clinical response following intravesical BCG therapy. Particularly, monitoring of interleukin-2 may have the potential for prognostic value provided that strict precautions regarding urine collection, such as maximal 2-hour sampling and immediate cooling, are taken.
迫切需要一种准确的预后指标，以便在膀胱内卡介苗（BCG）治疗的早期阶段识别对卡介苗无反应的浅表性膀胱移行细胞癌患者。
分析了几种卡介苗诱导的尿细胞因子的处理条件和稳定性，以及这些细胞因子（表明对卡介苗的免疫反应性）与膀胱肿瘤复发之间的可能相关性。我们研究了23例浅表性膀胱移行细胞癌患者。在连续6周每周一次膀胱内灌注卡介苗后的头24小时内，通过连续收集尿液进行监测。治疗前细胞因子的基线水平为白细胞介素-6 3.9±4.7 pg/μmol肌酐，肿瘤坏死因子-α 0.1±0.2 pg/μmol肌酐（均通过酶联免疫吸附测定法测量）。为了研究白细胞介素-2与膀胱肿瘤复发之间的相关性，根据肿瘤早期（6个月或更短时间）或晚期（超过6个月）复发将患者分为两组。对于每位患者，评估在6周卡介苗治疗过程中测得的最高细胞因子值。
如果尿液中白细胞介素-2的水平超过每μmol肌酐0.34单位，则结果为阳性。发现尿白细胞介素-2与肿瘤复发之间存在显著相关性（p = 0.003，23例患者）。在卡介苗治疗患者获得的研究细胞因子中，白细胞介素-1β、2和6在4℃和20℃的尿液中稳定，但肿瘤坏死因子-α不稳定。在37℃时，所有细胞因子均不稳定。干扰素-γ只能在立即透析的尿液中检测到，其出现与白细胞介素-2的相关性最大。收集尿液后立即通过离心去除白细胞对可靠测量白细胞介素-2和6并非必需。基于这些结果，白细胞介素-2和6更适合广泛监测卡介苗诱导的免疫反应。
我们的研究为膀胱内卡介苗治疗后尿细胞因子诱导与临床反应之间的相关性提供了重要证据。特别是，如果采取严格的尿液收集预防措施，如最长2小时采样和立即冷却，监测白细胞介素-2可能具有预后价值。
