Urology and Nephrology Center, Mansoura University, Mansoura, Egypt.
Department of Zoology, Faculty of Science, Damanhour University, Damanhour, Egypt.
BJU Int. 2022 Oct;130(4):444-453. doi: 10.1111/bju.15582. Epub 2021 Sep 13.
To investigate the predictive value of different immunological markers on treatment outcomes after bacille Calmette-Guérin (BCG) induction in high-risk non-muscle-invasive bladder cancer (NMIBC).
Patients who underwent transurethral resection of bladder tumour for NMIBC were assessed for study eligibility. Urine and blood samples were taken from patients at baseline (immediately before first dose of induction) and after induction (4 h after last [sixth] dose). Urine samples were evaluated for interleukin (IL)-2 and IL-10 by solid-phase enzyme-linked immunosorbent assay. Blood samples were evaluated for tumour necrosis factor α (TNF-α), cytotoxic T-lymphocyte antigen 4 (CTLA-4) and transcription factors (TFs) (GATA-binding protein 3 [GATA3], T-box expressed in T cells [T-bet], and forkhead box protein 3 [FoxP3]) using quantitative reverse transcriptase-polymerase chain reaction analysis. Change pattern and fold change of each evaluable marker was assessed in relation to different treatment outcomes (initial complete response [ICR]/recurrence/progression).
Between July 2013 and May 2019, 204 patients were included. Among evaluable markers, urinary IL-2 and serum TNF-α increased in all patients, serum CTLA-4 and FoxP3 showed a predominant decreased pattern in 188 (92.2%) and 192 (94.1%) patients, respectively. An ICR was achieved in 186 (91.2%) patients. Serum TNF-α fold change and urinary IL-10 change pattern were significantly associated with an ICR (P = 0.001 and P = 0.03, respectively). At a median (range) follow-up of 37 (20-88) months, 104 (56%) patients developed recurrence. Urinary IL-10, serum CTLA-4, T-bet , FoxP3 change patterns and GATA3 /T-bet ratio were significantly associated with tumour recurrence (P = 0.001, P = 0.001, P = 0.02, P = 0.009 and P = 0.001, respectively). Tumour progression occurred in 34 (18.3%) patients. Urinary IL-10, serum CTLA-4, serum T-bet change patterns and GATA3 /T-bet ratio were independent predictors of tumour progression (P = 0.001, P = 0.001, P = 0.02 and P = 0.001, respectively).
Urinary IL-10 and serum TNF-α can significantly predict ICR. Moreover, change pattern of urinary IL-10, serum CTLA-4, TFs (GATA3, T-bet and FoxP3) and GATA3 /T-bet ratio after BCG induction can independently predict further BCG response. These markers could be implemented in clinical practice when management options are discussed or in systems with severe BCG shortage.
探讨不同免疫标志物在卡介苗（BCG）诱导高危非肌层浸润性膀胱癌（NMIBC）患者治疗结局中的预测价值。
评估接受经尿道膀胱肿瘤切除术治疗 NMIBC 的患者是否符合研究条件。在基线（首次诱导前）和诱导后（第六次[最后一次]剂量后 4 小时）采集患者的尿液和血液样本。采用固相酶联免疫吸附试验检测尿液中白细胞介素（IL）-2 和 IL-10。采用定量逆转录聚合酶链反应分析检测血液中肿瘤坏死因子-α（TNF-α）、细胞毒性 T 淋巴细胞抗原 4（CTLA-4）和转录因子（GATA 结合蛋白 3 [GATA3]、T 细胞表达的 T 盒 [T-bet]和叉头框蛋白 3 [FoxP3]）。评估每个可评估标志物的变化模式和倍数变化与不同治疗结局（初始完全缓解[ICR]/复发/进展）的关系。
2013 年 7 月至 2019 年 5 月，共纳入 204 例患者。在可评估的标志物中，所有患者的尿 IL-2 和血清 TNF-α均增加，188 例（92.2%）和 192 例（94.1%）患者的血清 CTLA-4 和 FoxP3 呈明显下降趋势。186 例（91.2%）患者获得 ICR。血清 TNF-α倍数变化和尿 IL-10 变化模式与 ICR 显著相关（P=0.001 和 P=0.03）。中位（范围）随访 37（20-88）个月后，104 例（56%）患者复发。尿 IL-10、血清 CTLA-4、T-bet、FoxP3 变化模式和 GATA3/T-bet 比值与肿瘤复发显著相关（P=0.001、P=0.001、P=0.02、P=0.009 和 P=0.001）。34 例（18.3%）患者发生肿瘤进展。尿 IL-10、血清 CTLA-4、血清 T-bet 变化模式和 GATA3/T-bet 比值是肿瘤进展的独立预测因子（P=0.001、P=0.001、P=0.02 和 P=0.001）。
尿 IL-10 和血清 TNF-α可显著预测 ICR。此外，BCG 诱导后尿 IL-10、血清 CTLA-4、TFs（GATA3、T-bet 和 FoxP3）和 GATA3/T-bet 比值的变化模式可独立预测进一步的 BCG 反应。当讨论治疗选择或在 BCG 严重短缺的系统中时，这些标志物可在临床实践中实施。
