非小细胞肺癌患者循环肿瘤DNA的研究进展

摘 要：循环游离DNA以细胞外游离形式存在于血液中,可由正常细胞和癌细胞释放。非小细胞肺癌（NSCLC）患者血液中游离DNA水平高于正常人,且循环游离DNA可以反映癌组织的基因突变,甲基化状态,拷贝数改变,杂合子丢失等特征,是肺癌诊断、治疗、预后检测中具有巨大潜力的生物学指标。本综述简要介绍了循环游离DNA的生物学特性,并对近年来循环游离DNA基因改变检测在NSCLC中的临床应用进行阐述。     

Multicenter Real-World Study on Effectiveness and Early Discontinuation Predictors in Patients With Non-small Cell Lung Cancer Receiving Nivolumab

BackgroundReal-world (RW) evidence on nivolumab in pretreated patients with non-small cell lung cancer (NSCLC) by matching data from administrative health flows (AHFs) and clinical records (CRs) may close the gap between pivotal trials and clinical practice.MethodsThis multicenter RW study aims at investigating median time to treatment discontinuation (mTTD), overall survival (mOS) of nivolumab in pretreated patients with NSCLC both from AHF and CR; clinical-pathological features predictive of early treatment discontinuation (etd), budget impact (BI), and cost-effectiveness analysis were investigated; mOS in patients receiving nivolumab and docetaxel was assessed.ResultsOverall, 237 patients with NSCLC treated with nivolumab were identified from AHFs; mTTD and mOS were 4.2 and 9.8 months, respectively; 141 (59%) received at least 6 treatment cycles, 96 (41%) received < 6 (etd). Median overall survival in patients with and without etd were 3.3 and 19.6 months, respectively (P < .0001). Higher number, longer duration, and higher cost of hospitalizations were observed in etd cases. Clinical records were available for 162 patients treated with nivolumab (cohort 1) and 83 with docetaxel (cohort 2). Median time to treatment discontinuation was 4.8 and 2.6 months, respectively (P < .0001); risk of death was significantly higher in cohort 2 or cohort 1 with etd compared with cohort 1 without etd (P < .0001). Predictors of etd were body mass index <25, Eastern Cooperative Oncology Group performance status >1, neutrophile-to-lymphocyte ratio >2.91, and concomitant treatment with antibiotics and glucocorticoids. The incremental cost-effectiveness ratio of nivolumab was 3323.64 euros ($3757.37) in all patients and 2805.75 euros ($3171.47) for patients without etd. Finally, the BI gap (real-theoretical) was 857 188 euros ($969 050.18).ConclusionWe defined predictors and prognostic-economic impact of nivolumab in etd patients.     

循环肿瘤细胞检测在预测非小细胞肺癌化疗疗效中的应用

目的 探讨循环肿瘤细胞检测在预测非小细胞肺癌化疗疗效中的应用.方法 选择非小细胞肺癌患者(肺Ca组)共25例,另选择慢性阻塞性疾病患者(COPD组)25例作为对比研究.入院后及化疗2个周期后分别采集所有参与研究的人员静脉血7.5 ml,利用密度梯度离心法富积循环肿瘤细胞,分析其与临床特征及化疗疗效的关系.结果 肺Ca组循环肿瘤细胞阳性率达72.00％,而COPD组阳性率为0,差异具有统计学意义(P<0.05).循环肿瘤细胞阳性表达与NSCLC病理类型、患者性别、年龄、吸烟情况等均无明显关系(P>0.05),仅与癌症分期相关(P<0.05).2个周期的化疗结束,发现对循环肿瘤细胞数目的评价与实体肿瘤疗效标准评价大致吻合,差异不具备统计学意义(P>0.05).相关分析发现这两种评价方法 呈负相关关系(γ=-0.465 P=0.021).结论 循环肿瘤细胞的存在与非小细胞肺癌的临床分期及化疗疗效有密切关系,可以用来预测非小细胞肺癌的转归.     

肿瘤转移相关因子在非小细胞肺癌中表达及预后意义

目的:探讨组织蛋白酶D(CD)、表皮生长因子受体(EGFR)、转移抑制基因nm23、抑癌基因p16在非小细胞肺癌(NSCLC)中表达的意义。方法:采用快速免疫组化法检测64例肺癌标本四种蛋白的表达。结果:肺癌组织CD、EGFR、nm23和p16表达的阳性率分别为65.6%、67.2%、60.9%和51.6%,p16蛋白表达缺失率达48.4%,CD和EGFR表达与肺癌患者临床分期(P<0.05,P<0.01)、淋巴结转移(P<0.01,P<0.05)密切相关。COX比例风险模型分析和Kaplan-Meier生存曲线分析显示CD和EGFR是影响肺癌患者预后的重要因素(P<0.05)。结论:在NSCLC中nm23、p16、CD和EGFR异常改变的频率很高,在NSCLC的发展中可能起促进作用。CD和EGFR可作为评价NSCLC患者的预后指标。     

Comparison of Metabolic and Anatomic Response to Chemotherapy Based on PERCIST and RECIST in Patients with Advanced Stage Non-small Cell Lung Cancer

Background: The aim of this study was to explore the prognostic role of metabolic response to chemotherapy,determined by FDG-PET, in patients with metastatic non-small-cell lung cancer (NSCLC). Materials and Methods:Thirty patients with metastatic NSCLC were analyzed for prognostic factors related to overall survival (OS) andprogression free survival (PFS). Disease evaluation was conducted with FDG-PET/CT and contrast-enhanced CTprior to and at the end of first-line chemotherapy. Response evaluation of 19 of 30 patients was also performedafter 2-3 cycles of chemotherapy. Morphological and metabolic responses were assessed according to RECISTand PERCIST, respectively. Results: The median OS and PFS were 11 months and 6.2 months, respectively. Atthe end of first-line chemotherapy, 10 patients achieved metabolic and anatomic responses. Of the 19 patientswho had an interim response analysis after 2-3 cycles of chemotherapy, 3 achieved an anatomic response, while9 achieved a metabolic response. In univariate analyses, favorable prognostic factors for OS were number ofcycles of first-line chemotherapy, and achieving a response to chemotherapy at completion of therapy accordingto the PERCIST and RECIST. The OS of patients with a metabolic response after 2-3 cycles of chemotherapywas also significantly extended. Anatomic response at interim analysis did not predict OS, probably due to fewpatients with anatomic response. In multivariate analyses, metabolic response after completion of therapy wasan independent prognostic factor for OS. Conclusions: Metabolic response is at least as effective as anatomicresponse in predicting survival. Metabolic response may be an earlier predictive factor for treatment responseand OS in NSCLC patients.     

一种肿瘤相关抗原在非小细胞肺癌中的鉴定和表达

[目的]运用血清蛋白质组分析技术(SERPA)鉴定非小细胞肺癌(NSCLC)的肿瘤相关抗原.[方法]提取NSCLC肿瘤组织的胞浆蛋白,经二维凝胶电泳分离后转膜,用患者或健康对照血清为一抗进行免疫印迹分析,比较免疫印迹的结果,在未转膜的参比凝胶上找到差异蛋白点,进行MALDI-TOF鉴定;用免疫组化方法验证NSCLC组织中候选抗原的表达.[结果]本研究共鉴定4个候选蛋白.CCT5在肺鳞癌和肺腺癌组织中表达明显升高,且主要定位于癌细胞浆,胞核未检测到表达.[结论] CCT5可能是NSCLC的肿瘤相关抗原.     

Tumor Immune-Infiltrate Landscape After Chemo-Radiotherapy in a Case Series of Patients with Non-small Cell Lung Cancer: Pretreatment Predictors and Correlation With Outcome

IntroductionData on tumor immune-milieu after chemo-radiation (CT-RT) are scarce. Noninvasive tools are needed to improve the treatment of non–small cell lung cancer (NSCLC), especially in the locally advanced (LA) setting.MethodsWe collected a series of superior-sulcus (SS)- patients with NSCLC referred to our Institute (2015-2019), eligible for a preoperative CT-RT. We characterized tumor-infiltrating immune cells (TIICs), determined PD-L1-TPS and the residual viable tumor cells (RVTC). Radiological and metabolic responses were reviewed. We calculated pre-surgery neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR).ResultsEight patients were included. Radiological responses were 6 disease stabilities (SD) and 2 partial responses (PR). Metabolic responses were 4 SD and 4 PR. CD68+-TIICs were correlated with metabolic response and lower RVTC. CD68+-TIICs were associated with higher PLR. Higher PLR values seemed linked with lower RVTC.ConclusionsThese preliminary results could be useful for consolidation treatment selection for patients with LA-NSCLC without evaluable baseline PD-L1 and higher PLR values.     

非小细胞肺癌患者化疗对血清肿瘤标记物和一氧化氮的影响

[目的]观察MVP化疗方案治疗非小细胞肺癌 (NSCLC)对血清肿瘤标记物 (TM)癌胚抗原 (CEA)、CYFRA21_1、神经烯醇酶(NSE)和血清一氧化氮 (NO)的影响。[方法]84例诊断明确的NSCLC患者采用MVP(MMC、VDS、DDP)联合化疗 ,化疗前后测定血清TM(CEA、CYFRA21_1、NSE)和NO。[结果]CR0,PR36例 (42.9 % )、SD38例 (45.2% ),PD10例 (11.9% )。PR和SD组患者血清NO均较化疗前明显增高 (P<0.05～0.01) ,PD组有降低趋势 ,但统计学上无明显差异 (P>0.05)。PR和SD组患者血清CEA和CYFRA21_1均较化疗前明显降低 (P<0.05～0.01) ,PD组有增高趋势 ,但统计学上无明显差异 (P>0.05)。血清NSE则无明显改变 (P>0.05)。[结论]MVP化疗后有效者TM指标明显下降 ,血清NO则明显上升。血清TM和NO的变化有助于对肺癌患者疗效的评价。     

Real-World EQ5D Health Utility Scores for Patients With Metastatic Lung Cancer by Molecular Alteration and Response to Therapy

Introduction

Economic analyses of upcoming treatments for lung cancer benefit from real-world health utility scores (HUSs) in an era of targeted therapy.

常用血清肿瘤标志物在可手术肺癌患者预后中的价值

目的 探讨血清CEA、CA125、CA199、NSE、CYFRA21-1和SCC-Ag水平在评估非小细胞肺癌根治手术后的预后价值,以期合理选择术前的检验指标。方法 收集1 851例行肺癌根治手术的患者术前血清肿瘤标志物的检验值、临床病理和随访信息,进行差异及生存分析。结果 CEA、CA125、CA199、CYFRA21-1和SCC-Ag的阳性率在不同病理分期中差异有统计学意义（P<0.001）,Ⅱ和Ⅲ期的患者阳性率明显高于Ⅰ期患者,而NSE差异无统计学意义（P=0.743）。CEA、CA125、CA199、CYFRA21-1阴性组患者的生存率显著高于阳性组（P<0.05）。NSE阴性的患者远期生存率劣于阳性组患者（P=0.033）。SCC-Ag阳性与阴性患者的远期生存率差异无统计学意义（P=0.072）。Cox回归比例风险模型分析发现CEA（HR=1.572, 95%CI: 1.117~2.214, P=0.010）、CA125（HR=2.464, 95%CI:1.610~3.772, P<0.001）和CYFRA21-1（HR=1.445, 95%CI: 1.044~2.000, P=0.027）是评价非小细胞肺癌手术预后的独立危险因素。结论 CEA、CA125和CYFRA21-1在评价非小细胞肺癌手术预后方面有良好的应用价值,而CA199、NSE和SCC-Ag等指标价值有限。