【作者】 刘佳；

【导师】 史河水；

【作者基本信息】 华中科技大学 ， 影像医学与核医学（专业学位）， 2022， 博士

【摘要】 第一部分CMR评价肺癌PD-1/PD-L1抑制剂相关早期心脏毒性的研究目的探究心脏磁共振(CMR)在评价肺癌患者接受程序性死亡因子1(PD-1)及其配体(PD-L1)抑制剂治疗后早期心脏毒性中的可行性及价值。方法本研究前瞻性招募拟接受PD-1/PD-L1抑制剂治疗的肺癌患者,计划在患者接受治疗前(即基线)、第二次治疗前(即第一次复查)、距第一次治疗约3个月时(即第二次复查)分别进行CMR扫描。66名患者接受了第一次复查,被纳入研究进行分析,其中38名患者接受了第二次复查。对CMR图像进行定性分析及定量后处理,定量参数包括:左室射血分数(LVEF)、右室射血分数(RVEF)、左室整体径向应力(LV-GRS)、左室整体环向应力(LV-GCS)、左室整体纵向应力(LV-GLS)、右室整体径向应力(RV-GRS)、右室整体环向应力(RV-GCS)、右室整体纵向应力(RV-GLS)、左房平均长轴应力、右房长轴应力、初始T1值、增强后T1值、细胞外容积值(ECV)、T2值、心外膜脂肪体积(EATV)。使用混合线性模型分析CMR连续变量参数在免疫治疗前后(共三个时间点)随时间的变化,事后两两比较采用Sidak法校正P值。使用卡方检验或Fisher精确检验比较分类变量的变化。免疫治疗前后CMR定量参数的变化值定义为复查值与基线值的差值,变化率定义为变化值与基线值的比值。结果第一次复查(距第一次免疫治疗中位数22天)及第二次复查时(距第一次免疫治疗中位数86天)时,分别有2名(3.0%)、3名(7.9%)患者心包积液较基线增加;免疫治疗前后晚期钆增强(LGE)的表现变化不显著。与基线值相比,LVEF值(52.2%±6.0%vs.49.2%±6.0%)及LV-GRS值(41.1%±10.8%vs.39.3%±13.3%)仅在第二次复查时显著减低(P<0.05),而两次复查时的LV-GCS值(-19.6%±2.5%vs.-18.8%±3.0%vs.-18.7%±2.4%)均显著减低(P<0.05)。与基线值相比,两次复查时的RVEF值(46.4%±7.1%vs.43.3%±7.6%vs.40.8%±9.1%)、RV-GRS值(33.9%±12.8%vs.30.7%±11.1%vs.26.3%±9.5%)显著减低(P<0.05);两次复查时,左房平均长轴应力较基线值未发生显著变化(P>0.05),而右房长轴应力、EATV值均显著低于基线值(P<0.05)。而接受免疫治疗后,左室心肌的整体组织特征参数(初始T1值、增强后T1值、ECV值、T2值)较基线值均未发生显著变化(P>0.05)。相比基线,两次复查时的LVEF变化率与LV-GRS变化率、LV-GCS变化率、LV-GLS变化率均呈显著正相关(P<0.05)。结论肺癌PD-1/PD-L1抑制剂相关心脏毒性早期主要体现为亚临床心功能减低,且LV-GCS可以比LVEF更敏感地识别早期左室收缩功能的受损。整体心肌组织特征参数在应用PD-1/PD-L1抑制剂后的早期亚临床阶段未发生显著变化。第二部分CMR联合临床特征在预测肺癌PD-1/PD-L1抑制剂相关早期心功能障碍中的价值目的本研究旨在分析基线心脏磁共振(CMR)参数、临床特征及CMR参数变化在预测肺癌患者接受程序性死亡因子1(PD-1)及其配体(PD-L1)抑制剂治疗后早期癌症治疗相关心功能障碍(CTRCD)的价值。方法本研究前瞻性招募拟接受PD-1/PD-L1抑制剂治疗的肺癌患者,计划在患者接受治疗前(即基线)、第二次治疗前(即第一次复查)、距第一次治疗约3个月时(即第二次复查)分别进行CMR扫描、12导联心电图检查及实验室检查。66名患者接受了第一次复查,被纳入研究进行分析,其中38名患者接受了第二次复查。CMR参数包括:左室射血分数(LVEF)、右室射血分数(RVEF)、左室整体径向应力(LV-GRS)、左室整体环向应力(LV-GCS)、左室整体纵向应力(LV-GLS)、右室整体径向应力(RVGRS)、右室整体环向应力(RV-GCS)、右室整体纵向应力(RV-GLS)、左房平均长轴应力、右房长轴应力、初始T1值、增强后T1值、细胞外容积值(ECV)、T2值、心外膜脂肪体积(EATV)。CTRCD定义为LVEF值相比治疗前减低程度超过10%至值低于55%。在两次复查时,分别将患者分为CTRCD组和非CTRCD组,进一步比较基线CMR及临床参数、CMR参数变化率。免疫治疗前后CMR定量参数的变化值定义为复查值与基线值的差值,变化率定义为变化值与基线值的比值。多因素逻辑回归采用逐步法(向后)进行分析,应用受试者工作特征曲线,计算曲线下面积(AUC),以评估参数预测CTRCD的能力。结果心电图异常表现形式及各项实验室指标在接受PD-1/PD-L1抑制剂治疗前后无统计学差异(P>0.05)。两次复查分别有15.2%(n=10)和26.3%(n=10)患者发生了CTRCD。第一次复查时,CTRCD组体重指数(BMI)≥25 kg/m2的患者比例(60.0%vs.17.9%,P=0.040)与基线EATV值(84.7 ml±25.7 ml vs.66.1 ml±24.8ml,P=0.034)较非CTRCD组高。而LV-GRS变化率及LV-GCS变化率在两次复查时均显示出CTRCD组和非CTRCD组间的差异(P<0.05)。将两次复查时两组间有差异的参数纳入多因素回归分析模型,结果显示,LV-GRS变化率均为两次复查时CTRCD的独立预测因子,且对诊断第一次、第二次复查时CTRCD的发生有统计学意义(AUC值分别为0.778和0.704,P值分别为0.005和0.047)。结论肺癌患者在接受PD-1/PD-L1抑制剂治疗早期即可发生CTRCD,LV-GRS变化率是治疗早期(3个月内)发生CTRCD的独立预测因子。更多还原

【Abstract】 Part I Assessment of early cardiotoxicity in patients with lung cancer receiving programmed death-1 and its ligand(PD-1/PD-L1)inhibitors by cardiac magnetic resonance Objective To investigate the feasibility and value of cardiac magnetic resonance(CMR)imaging in the evaluation of early cardiotoxicity associated with programmed death-1 and its ligand(PD-1/PD-L1)inhibitors in patients with lung cancer.Methods This study prospectively recruited patients with lung cancer who were ready to receive PD-1/PD-L1 inhibitors.Patients were planned to undergo CMR examinations before the initiation of therapy(baseline),before the second therapy(the first follow-up),and after several times of therapy(3 months after the initiation of therapy;the second follow-up),respectively.Sixty-six patients who received the first follow-up were included for analysis,and 38 patients of them received the second follow-up.Qualitative analysis and quantitative post-processing of CMR images were performed.Quantitative parameters included: left ventricular ejection fraction(LVEF),right ventricular ejection fraction(RVEF),left ventricular global radial strain(LV-GRS),left ventricular global circumferential strain(LVGCS),left ventricular global longitudinal strain(LV-GLS),right ventricular global radial strain(RV-GRS),right ventricular global circumferential strain(RV-GCS),right ventricular global longitudinal strain(RV-GLS),average left atrial long-axis strain,right atrial longaxis strain,native T1 value,post-contrast T1 value,extracellular volume(ECV)value,T2 value,and epicardial adipose volume(EATV)value.Mixed linear models were performed to test for longitudinal changes in CMR parameters over time,and sidak adjustment was utilized for pairwise comparisons of the three time points.Chi-square test or Fisher’s exact test were applied to compare categorical variables.The change value of CMR quantitative parameters was defined as the difference between the follow-up value and the baseline value,and the change ratio was defined as the ratio of the change value to the baseline value.Results At the first follow-up(a median time of 22 days after the first therapy)and the second follow-up(a median time of 86 days after the first therapy),increased pericardial effusion was observed in 2(3.0%)patients and 3(7.9%)patients,respectively.Late gadolinium enhancement manifestations did not change significantly after ICI therapy.Compared with baseline values,LVEF(52.2% ± 6.0% vs.49.2% ± 6.0%)and LV-GRS(41.1% ± 10.8% vs.39.3% ± 13.3%)significantly decreased at the second follow-up(P < 0.05).LV-GCS(-19.6%± 2.5% vs.-18.8% ± 3.0% vs.-18.7% ± 2.4%)at two follow-up CMRs significantly decreased(P < 0.05).Compared with baseline values,RVEF(46.4% ± 7.1% vs.43.3% ±7.6% vs.40.8% ± 9.1%),RV-GRS(33.9% ± 12.8% vs.30.7% ± 11.1% vs.26.3% ± 9.5%)at two follow-up CMRs were significantly reduced(P < 0.05).Average left atrial long-axis strain didn’t show significant difference compared with baseline values(P > 0.05),while right atrial long-axis atrain,and EATV value showed decreasing trends after receiving PD-1/PD-L1 inhibitors,and the differences were significant compared with baseline values(P< 0.05).During follow-ups,tissue characteristic parameters of global left ventricular myocardium(native T1 value,post-contrast T1 value,ECV value,T2 value)showed no significant differences compared with baseline values(P > 0.05).Compared with baseline,the change ratios of LVEF at two follow-up CMRs both showed significantly positive correlations with the change ratios of LV-GRS,LV-GCS,and LV-GLS(P < 0.05).Conclusions PD-1/PD-L1 inhibitors related cardiotoxicity in patients with lung cancer mainly manifested as subclinical cardiac dysfunction in the early stage.LV-GCS can detect the impairment of left ventricular systolic function ealier than LVEF.Tissue characteristic parameters of left ventricular myocardial did not show significant changes in the subclinical stage after receiving PD-1/PD-L1 inhibitors.Part II The value of cardiac magnetic resonance combined with clinical features in predicting early cardiac dysfunction in patients with lung cancer receiving programmed death-1 and its ligand(PD-1/PD-L1)inhibitorsObjective The aim of this study was to explore the value of baseline cardiac magnetic resonance (CMR)parameters,clinical features,and changes in CMR parameters in predicting early cancer therapy-related cardiac dysfunction(CTRCD)after receiving programmed death-1 and its ligand(PD-1/PD-L1)inhibitors.Methods This study prospectively recruited patients with lung cancer who were ready to receive PD-1/PD-L1 inhibitors.Patients were planned to undergo CMR,12-lead electrocardiogram(ECG)and laboratory examinations before the initiation of therapy(baseline),before the second therapy(the first follow-up),and after several times of therapy(3 months after the initiation of therapy;the second follow-up),respectively.Sixty-six patients who received the first follow-up were included for analysis,and 38 patients of them received the second follow-up.Quantitative parameters included: left ventricular ejection fraction(LVEF),right ventricular ejection fraction(RVEF),left ventricular global radial strain(LV-GRS),left ventricular global circumferential strain(LV-GCS),left ventricular global longitudinal strain(LV-GLS),right ventricular global radial strain(RV-GRS),right ventricular global circumferential strain(RV-GCS),right ventricular global longitudinal strain(RV-GLS),average left atrial long-axis strain,right atrial long-axis strain,native T1 value,post-contrast T1 value,extracellular volume(ECV)value,T2 value,and epicardial adipose volume(EATV)value.CTRCD was defined as a reduction of more than 10% to less than 55% in LVEF compared to baseline.At the two follow-up CMRs,patients were divided into CTRCD group and non-CTRCD group,respectively.Baseline CMR parameters,clinical features,and changes in CMR parameters were further compared between groups.The change value of CMR quantitative parameters was defined as the difference between the follow-up value and the baseline value,and the change ratio was defined as the ratio of the change value to the baseline value.Multivariate logistic regression was performed using a stepwise method(backwards).Receiver operator characteristic curve was drawn and area under the curve(AUC)was calculated to assess the ability of parameters to predict CTRCD.Results The abnormal ECG results and laboratory indexes did not change significantly after receiving PD-1/PD-L1 inhibitors(P > 0.05).CTRCD was observed in 15.2%(n=10)and 26.3%(n=10)patients at two follow-up CMRs,respectively.At the first follow-up,the proportion of patients with body mass index(BMI)≥ 25 kg/m2 in CTRCD group(60.0% vs. 17.9%,P = 0.040)and baseline EATV values(84.7 ml ± 25.7 ml vs.66.1 ml ± 24.8 ml,P = 0.034)were both higher than those in non-CTRCD group.The change ratios of LV-GRS and LV-GCS showed differences between CTRCD group and non-CTRCD group at both time points during follow-up(P < 0.05).Parameters with significant differences between two groups at the two follow-ups were included into the multivariate regression analysis models.And the results showed that the change ratio of LV-GRS at both time points during follow-up showed as an independent predictor of early CTRCD,and had potential diagnostic ability for CTRCD(AUC values were 0.778 and 0.704,P values were 0.005 and 0.047,respectively).Conclusions Patients with lung cancer can develop CTRCD in the early stage of ICI therapy.The change ratio of LV-GRS was an independent predictor of CTRCD after ICI therapy within three months.更多还原