协同刺激分子B7-H4影响细胞因子诱导的杀伤细胞治疗胃癌预后的多因素COX模型分析

目的 探讨协同刺激分子B7-H4的表达与胃癌的关系,并分析B7-H4在胃癌组织中的不同表达水平对细胞因子诱导的杀伤细胞(CIK)治疗胃癌患者的复发和死亡的风险.方法 对156例胃癌病例(1998年1月1日至2009年12月31日),采用免疫组织化学染色及IHS评估法确定B7-H4的表达状态,使用回顾性队列研究方法调查每位病例的人口学、临床资料及复发时间和死亡时间.应用COX多因素模型分析B7-H4高表达影响胃癌复发和死亡的风险.结果 胃癌组织B7-H4高表达组与B7-H4低表达组比较,患者中位无瘤生存时间(月)及95%CI分别为16(11.9～20.1)和47(22.4～71.6),中位生存时间(月)及95%CI分别为25(19.0～31.1)和43(35.2～50.8).在化学治疗组中,B7-H4低表达患者的中位生存时间明显高于B7-H4高表达患者(36比16),差异有统计学意义(x2=14.14,P<0.01).在化疗联合CIK治疗组中,B7-H4低表达患者的中位生存时间有高于B7-H4高表达患者的趋势(55比34),但差异无统计学意义(x2=1.78,P>0.05).在化学治疗组中,B7-H4低表达患者中位无瘤生存时间高于B7-H4高表达(33比11),差异有统计学意义(x2=18.956,P<0.01).在化疗联合CIK细胞治疗组中,B7-H4低表达患者中位无瘤生存时间显著高于高表达组(90比18),差异有统计学意义(x2=3.842,P<0.05).在调整了性别、年龄等混杂因素后,与B7-H4低表达比较,B7-H4高表达组病例的复发和死亡风险明显增加(RR=2.30,95%CI=1.41～3.75;RR=1.90,95%CI=1.20～3.01).结论 B7-H4高表达可能是提高胃癌复发和死亡风险的独立危险因素.采用CIK细胞回输治疗可控制和干预B7-H4的表达并延长胃癌患者的中位生存时间,胃癌B7-H4低表达可作为CIK细胞治疗的纳入标准.

Multi-factor COX model analysis of impact of costimulatory molecules B7-H4 on gastric cancer prognosis

Objective To study the relation of B7-H4 expression and gastric cancer, and to analyze the impact of different expression levels of costimulatory molecules B7-H4 in gastric cancer tissues on survival time of gastric cancer patients treated with cytokine-induced killer cell biotherapy. Methods 156 gastric cancer patients who received operative treatment and were diagnosed pathologically in the Third Affiliated Hospital, Soochow University, were followed up from Jan. 1, 1998 to Dec. 31,2009. The B7-H4 expression was detected by using immunohistochemical staining and IHS assessment analysis. Demngraphic data, clinical data, recurrence and death time of gastric cancer patients were collected by the method of retrospective cohort study. Impact of B7-H4 high expression on the risk of gastric cancer recurrence and death was analyzed through multi-factor COX model. Results In B7-H4 high expression group and B7-H4 low expression group, the median tumor-free survival time (months) of gastric cancer patients and 95% CI of gastric cancer patients was respectively 16 ( 11.9-20. 1 ) and 47 ( 22.4-71.6 ), and 25 ( 19.0-31.1 )and 43 (35. 2-50. 8). In the chemotherapy group, the median survival time of gastric cancer patients in B7-H4 low expression group was significantly longer than that in B7-H4 high expression group ( 36 vs 16 ,x2 = 14. 14,P <0. 01 ). In the chemotherapy plus CIK treatment group, there was a tendency that the median survival time of gastric cancer patients in B7-H4 low expression group was longer than that in B7-H4 high expression group (55 vs 34), but there was no statistically significant difference (x2 = 1.78 ,P >0. 05). In the chemotherapy group, the median tumor-free survival time of gastric cancer patients in B7-H4 low expression group was significantly longer than that in B7-H4 high expression group (33 vs 11, x2= 18. 956,P <0. 01 ). In the chemotherapy plus CIK treatment group, the median tumor-free survival time of gastric cancer patients in B7-H4 low expression group was significantly longer than that in B7-H4 high expression group (90 vs 18 ,x2= 3. 842, P < 0. 05 ). After confounding factors such as sex, age and so on were adjusted, risk of recurrence and death of gastric cancer patients in B7-H4 high expression group was significantly higher than in B7-H4 low expression group ( RR =2. 30, 95% CI = 1.41-3. 75; RR = 1.90, 95% CI =1.20-3.01, respectively). Conclusion B7-H4 high expression may be an independent risk factor of increasing the risk of gastric cancer recurrence and death. CIK cell transfusion treatment can control and interfere in the B7-H4 expression, and prolong the median survival time of gastric cancer patients. B7-H4 low expression of gastric cancer can be considered as inclusion criteria of CIK cell biotherapy.