二次TURBt联合膀胱灌注化疗及肿瘤细胞抗原负载的树突状细胞治疗非肌层浸润性膀胱癌的临床研究

Clinical study of second transurethral resection combined with instillation therapy and transfusion therapy of dendritic cells pulsed with tumor cells in non muscle-invasive bladder cancer

目的观察二次TURBt联合膀胱灌注化疗及肿瘤细胞抗原负载的树突状细胞（DC）治疗非肌层浸润性膀胱癌的安全性及疗效。方法T1期膀胱尿路上皮癌患者80例。男59例，女21例。年龄30～85岁，平均65岁。入组患者均在第一次TURBt术后4～6周行二次TURBt，术后常规膀胱灌注化疗。分为2组：DC组40例，对照组40例。DC组自外周血分离出单核细胞，体外诱导分化为DC，加入该患者的肿瘤抗原共培养，获取负载肿瘤细胞抗原的DC；在二次TURBt术后6～8周将肿瘤细胞抗原负载的DC回输，每周1次，共4次，每次腹股沟皮下注射细胞数不低于1×10^6个，每疗程回输细胞总数〉4×10^6个。观察DC组免疫指标改变及不良反应，比较2组患者肿瘤复发比例。结果80例患者第一次TURBt病理分级G，17例（21．3％）、G254例（67．5％）、G39例（11．2％）；二次TURBt病理检查发现残存肿瘤27例，总阳性率33．7％；Ta期8例（29．6％）、T1期19例（70．4％）；G1 3例（11．1％）、G219例（70．4％）、G3 5例（18．5％）。二次TURBt时T。期8例中分级同第一次TURBt6例，分级升高2例；T．期19例中分级同第一次TURBt12例，分级升高5例，降级2例。单发16例，均位于原电切处；多发11例，其中原电切处可见菜花样肿瘤7例。DC回输治疗时出现寒战、发热5例，给予地塞米松10mg静脉推注治疗后缓解。治疗前、治疗后1年及2年患者血中自细胞、SCr、ALT值比较差异无统计学意义（P〉0．05）。与治疗前比较，治疗后1年及2年CD4、CD8、CD4／CD8等指标比较差异均有统计学意义（P〈0．05），而治疗后1年后及2年各指标比较差异无统计学意义。DC组1年内复发1例（2％），2年内复发3例（6％）；对照组中1年内复发6例（20％）；2年内复发9例（30％），2组复发率比较差异有统计学意义（P〈0．05）。结论二次TURBt联合膀胱灌注及肿瘤细胞抗原负载的DC回输治疗是降低非肌层浸润性膀胱癌复发率较有效的方法。

Objective To observe the clinical efficacy and safety of second transurethral resection combined with instillation therapy and transfusion therapy of dendritic cells pulsed with tumor cells on non muscle-invasive bladder cancer. Methods Eighty patients with stage T1 non muscle-invasive bladder cancer were included in this protocol in which all patients prospectively received second transurethral resection within 4 to 6 weeks following initial resection. All 80 cases were divided into a DC group and a control group. In the DC group, dendritic cells pulsed with tumor cells were transfused between 6 - 8 weeks. Bladder instillation therapy and follow-up was applied on the control group. The recurrence rate, the clinical efficacy and adverse reactions were observed and compared between the two groups. Results In the initial resection, 21. 3% , 67.5% and 11.2% had G1 , G2 and G3 transitional cell carcinoma, respectively. Twen- ty-seven （33.7%） had residual tumors at the second TUR, 8 patients had T （29.6%） and 19 had T1 （70.4%）. After the initial TUR-Bt, residual tumors were detected in 11.1% , 70.4% and 18.5% in Gl, G2 and G3 , respectively, In the 8 T cases, 2 cases moved to a higher grade, while the grade was unchanged in 6 cases. In the 19 cases with stage T1 , 12 had a higher grade, 5 had a lower grade and 2 remained the same. In the DC group, 5 cases suffered chills and fever when dendritic cells were transfused. The fever was releaved when dexamethasone was administered. The white blood cells count, creatinine and alanine aminotransferase had no statistically significance change at pre-therapy, one year after therapy and two years after therapy （P 〉 0.05）. The index of CD4 ,CDs ,CD4/CDs had statistically significance change at pre-therapy, one year after therapy and two years after therapy （P 〈 0.05） , while the difference between one year after therapy and two years after therapy was not statistically significance（ P 〉0. 05 ）. The first and second year recurrence rate was 2% and 6% in the DC group, while in the control group it was 20% and 30%. The difference was statistically significant （P 〈 0.05）. Conclusion Second transurethral resection combined with instillation therapy and transfusion therapy of dendritic cells pulsed with tumor cells could be an effective therapeutic approach to lower the recurrence rate on non muscle-invasive bladder cancer.