【作者】 王蕾；

【导师】 初晓霞；

【作者基本信息】 青岛大学 ， 内科学（血液病学）（专业学位）， 2019， 硕士

【摘要】 目的:研究弥漫大B细胞淋巴瘤(Diffuse large B cell lymphoma,DLBCL)患者治疗前外周血中吲哚胺2-3双加氧酶(Indoleamine 2-3 dioxygenase,IDO)的表达情况,分析其与患者临床特征及预后的相关性,探讨化疗能否纠正患者体内的色氨酸代谢紊乱。方法:将青岛大学附属烟台毓璜顶医院血液内科病房自2016年6月1日至2017年6月20日收治的51例初诊DLBCL患者纳入研究。其中6例失访,5例治疗过程中未评估即死亡,最终纳入分析的患者为40例,其中男28例,女12例,男女比例为2.33:1,中位年龄为52(20-81)岁。以20例健康志愿者作为正常对照组,其中男12例,女8例,男女比例为1.5:1,中位年龄为55(26-77)岁。收集患者治疗前及6-8周期化疗结束后的外周血和健康志愿者的外周血,以上标本均需在清晨空腹时采集。用离心机分离出外周血中的血清,采用ELISA法检测血清中IDO的浓度。应用SPSS24软件进行统计学分析。采用秩和检验对比患者治疗前外周血与健康志愿者的外周血中IDO表达水平,初步判断DLBCL患者外周血中是否存在IDO的过表达;对比患者化疗后外周血与治疗前外周血中IDO的表达水平,判断化疗能否纠正DLBCL患者体内的色氨酸代谢紊乱状态。采用卡方检验判断IDO的下降程度与疗效是否相关。收集患者的临床资料包括ECOG评分、IPI评分、有无B症状、Ann-Arbor分期、结外受累部位、肿瘤最大直径、是否为生发中心来源等,以及外周血中乳酸脱氢酶(lactate dehydrogenase,LDH)、β2-MG及IL-6浓度。密切随访40名患者,记录其总生存时间(Overall survival,OS)及无进展生存时间(Progression-free survival,PFS)。以患者治疗前中位IDO浓度为界将40名患者分为高IDO组及低IDO组。应用卡方检验比较两组之间临床特征之间的差异,从而得出IDO与临床特征之间的关系;应用Kaplan-Meier法及COX多因素回归法分析影响DLBCL患者预后的因素,判断外周血IDO表达水平是否与预后相关。结果:20例正常对照组患者外周血中位IDO的浓度为14.45(8.91-23.86)IU/ml,40例DLBCL患者治疗前外周血中位IDO浓度为19.44(9.92-33.25)IU/ml,化疗后外周血中位IDO浓度为14.61(5.33-28.33)IU/ml。DLBCL患者外周血中IDO水平明显高于正常对照组,差异有统计学意义(P=0.01)。患者化疗后外周血中位IDO浓度明显低于治疗前,差异有统计学意义(P=0.002),与正常对照组无明显差异(P=0.689),但是下降程度与疗效无相关性。以患者治疗前外周血中位IDO浓度19.44 IU/ml为界将40例患者分为高IDO组(IDO≥19.44IU/ml)及低IDO组(IDO<19.44IU/ml)。卡方检验结果显示:与低IDO组相比,高IDO组中有更多的患者为非生发中心起源(16对5,P=0.001),且有更高的LDH浓度(380对155,P=0.027)及更高的IPI评分(P=0.011),而其他特征如性别(P=0.301)、年龄(P=0.736)、有无B症状(P=0.744)、ECOG评分(P=1)、Ann-Arbor分期(P=0.197)、有无大包块(P=0.732)、IL-6(P=0.525)、β2-MG(P=0.749)、中期评效(P=0.097)等两组的差异均无统计学意义。所有患者的中位OS及PFS分别为58.5(17-73)月及39(6-73)月。高IDO组的中位OS为45.5(17-70)月,低IDO组的中位OS为63(21-73)月,二者差异有统计学意义(P=0.001);高IDO组的中位PFS为34.5(6-70)月,低IDO组的中位PFS为57.5(12-72)月,差异有统计学意义(0.001)。应用Kaplan-Meier法进行单因素分析显示β2-MG(P=0.026)、高IDO表达(P=0.001)为患者PFS的影响因素;β2-MG(P=0.027)、中期评效(P=0.016)、Hans评分(P=0.013)、高IDO表达(P=0.001)为患者OS的影响因素。应用COX多因素回归法进行多因素分析,结果显示高IDO表达、β2-MG是影响PFS的独立预后因素,同样也是影响患者OS的独立预后因素。结论:与健康对照组相比,DLBCL患者外周血中存在IDO过表达现象,其表达水平与患者一系列的临床特征相关,包括是否为生发中心起源、LDH浓度及IPI评分等。外周血中IDO的表达水平与患者的预后相关,IDO高表达是DLBCL患者OS及PFS独立的预后不良因素。通过化疗可以改变DLBCL患者体内的色氨酸代谢状态。更多还原

【Abstract】 Objective To investigate the expression of indoleamine 2-3 dioxygenase（IDO）in peripheral blood of patients with diffuse large B-cell lymphoma（DLBCL）before treatment,analyze its correlation with clinical characteristics and prognosis and explore whether chemotherapy can correct tryptophan metabolic disorder in patients.Methods 51 patients with DLBCL who were admitted to the hematology ward of Yantai Yuhuangding Hospital Affiliated to Qingdao University from June 1^st,2016 to June 20^th,2017 were studied retrospectively.There were 11 patients quitted the study due to loss of follow-up,death without evaluating therapy effect during treatment and death for other reasons.Forty patients were included in the final analysis,including 28 males and 12females.The ratio of males to females was 2.33:1,and the median age was 52（20-81）.Twenty healthy volunteers served as control group,including 12 males and 8 females,with a male-to-female ratio of 1.5:1 and a median age of 55（26-77）years.Fasting peripheral blood of patients before treatment,healthy volunteers and patients after 6-8cycles of chemotherapy were collected.Serum was separated from peripheral blood by centrifuge and the concentration of IDO in serum was detected by ELISA.SPSS24 was used for statistical analysis.The expression level of IDO in peripheral blood of DLBCL patients and healthy volunteers was compared by rank sum test to determine whether there was overexpression of IDO in peripheral blood of DLBCL patients.The expression of IDO in peripheral blood after chemotherapy was compared with that before treatment and determine whether chemotherapy can correct tryptophan metabolic disorder in DLBCL patients.Chi-square test was used to determine whether the degree of decline of IDO was related to the treatment effect.Clinical data were collected including ECOG score,IPI score,B symptoms,Ann-Arbor stage,site of extranodal involvement,maximum diameter of tumors and whether they were origin of germinal center,as well as lactate dehydrogenase（LDH）,β2-MG,IL-6 expression level in peripheral blood.Overall survival（OS）and progression-free survival（PFS）were followed up in 40 patients.The 40patients were divided into high IDO group and low IDO group based on median IDO concentration.Chi square test was used to compare the differences between the two groups in clinical characteristics,and the relationship between IDO and clinical characteristics was obtained.Kaplan-Meier method and COX multivariate regression method were used to analyze the factors affecting the prognosis of DLBCL patients,and to determine whether the expression of IDO in peripheral blood was related to prognosis.Results The median concentration of IDO in peripheral blood of normal control group was 14.45（8.91-23.86）IU/ml,DLBCL patients before treatment was 19.44（9.92-33.25）IU/ml,and that of patients after 6-8 cycles of chemotherapy was 14.61（5.33-28.33）IU/ml.The level of IDO in peripheral blood of DLBCL patients before treatment was significantly higher than that of normal control group（P=0.01）.The level of IDO in peripheral blood of patients after 6-8 cycles of chemotherapy was significantly lower than that of patients before treatment（P=0.002）,while there was no significant difference between patients and normal control group（P=0.689）.However,there was no correlation between the degree of decline and the treatment effect.Based on the median IDO concentration of 19.44 IU/ml in peripheral blood of DLBCL patients before treatment,40patients were divided into high IDO group（IDO>19.44 IU/ml）and low IDO group（IDO<19.44 IU/ml）.Compared with the low IDO group,more patients in the high IDO group had non-germinal center origin（16 vs 5,P=0.001）and patients in the high IDO group had higher LDH concentration（380 vs 155,P=0.027）and higher IPI score（P=0.011）,while there were no significant differences in other characteristics such as gender（P=0.301）,Age（P=0.736）,B symptoms（P=0.744）,ECOG score（P=1）,Ann-Arbor staging（P=0.197）,IL-6（P=0.525）,β2-MG（P=0.749）and Mid-term evaluation（P=0.097）between these two groups.The median OS and PFS of all patients were 58.5（17-73）months and 39（6-73）months,respectively.The median OS of high IDO group was 45.5（17-70）months,and that of low IDO group was 63（21-73）months.The difference was statistically significant（P=0.001）;the median PFS of high IDO group was34.5（6-70）months,and that of low IDO group was 57.5（12-72）months,the difference had statistical significance（P=0.001）.Single factor analysis by Kaplan-Meier method showed thatβ2-MG（P=0.026）and high IDO expression（P=0.001）were the influencing factors of PFS;beta 2-MG（P=0.027）,mid-term evaluation（P=0.016）,Hans score（P=0.013）and high IDO expression（P=0.001）were the influencing factors of OS.COX multivariate regression analysis showed high IDO expression andβ2-MG were independent prognostic factors for OS and PFS.Conclusion Compared with healthy control group,overexpression of IDO in peripheral blood of DLBCL patients was observed in DLBCL patients.The expression of IDO was correlated with a series of clinical features,including germinal center origin,LDH concentration and IPI score.IDO in peripheral blood is correlated with prognosis of patients and high expression of IDO is an independent prognostic factor for OS and PFS in DLBCL patients.Chemotherapy can change tryptophan metabolism in DLBCL patients.更多还原