基于ctDNA的分子残留病灶检测对非小细胞肺癌根治术后生存的预测效能

目的 探讨基于循环肿瘤DNA(ctDNA)的分子残留病灶（MRD）检测对非小细胞肺癌（NSCLC）患者根治术后近远期生存的预测效能。方法 选取重庆医科大学附属第一医院胸外科行根治术治疗的114例NSCLC患者为研究对象,于术后1周采集患者静脉血,采用液态活检和二代测序技术检测ctDNA MRD。统计患者术后MRD阳性率,并分析其与临床病理特征的关系。记录患者术后1年、5年生存情况,采用Kaplan-Meier生存曲线比较MRD阳性和阴性患者的近远期生存率,采用Cox回归模型分析NSCLC根治术后近远期生存的影响因素,分析MRD检测对NSCLC根治术后近远期生存的预测效能。结果 NSCLC患者术后MRD阳性率为36.84%,低/未分化、肿瘤直径>3 cm、纵隔淋巴结转移、TNM分期ⅢA期的NSCLC患者MRD阳性率分别高于高/中分化、肿瘤直径≤3 cm、无纵隔淋巴结转移、TNM分期Ⅰ～Ⅱ期患者（P<0.05）。NSCLC患者术后1年、5年生存率分别为83.33%、52.63%,MRD阳性患者近远期生存率均低于MRD阴性患者（P<0.001）。低/未分化、肿瘤直径>...     

非小细胞肺癌免疫治疗研究进展

肺癌是全球范围内发病率和死亡率最高的恶性肿瘤之一。而非小细胞肺癌（NSCLC）占肺癌的85％,5年生存率仅约为15％。大部分患者就诊时已属晚期,即使有手术机会,40％以上患者也会出现局部复发或远处转移。虽然多学科综合治疗使晚期NSCLC患者的治疗有了较大进步,但仅部分患者显示出较好的临床获益,其治疗效果仍不理想。近年来,随着分子免疫机制的研究进展,过继免疫治疗、靶向免疫治疗、疫苗以及基因治疗等研究取得了很大的进展,为NSCLCS的治疗提供了新的治疗思路。     

外排体在非小细胞肺癌中的研究进展

外排体是一种由细胞产生并主动分泌的囊泡样结构,内含蛋白质、核酸和脂质类物质,主要功能为在细胞间传递相应物质以完成细胞间的通信,并且可以调节微环境的免疫反应。研究表明外排体对肺癌的发生和发展均有重要作用。外排体的蛋白质和microRNA在作肺癌的诊断、预后和预测的生物标志物,以及在肺癌的免疫治疗和抗肿瘤药物的靶向递送方面都有巨大潜能。     

miRNAs在非小细胞肺癌应用中的研究进展

肺癌位列全球癌症相关死亡因素之首,五年生存率小于15％.其中,约85％的肺癌患者为非小细胞肺癌(NSCLC)患者[1].miRNAs是一类小的、非蛋白编码的RNA,主要生理功能包括调控细胞和器官的生长、发育,调节细胞增殖和凋亡,参与代谢和应激反应等[2].随着分子水平研究的发展,临床已逐步开始对非小细胞肺癌患者进行分类靶向治疗,并取得部分成效.然而,潜在的肿瘤异质性相关机制依旧为人所知甚少[3].本文简要概括了miRNAs与肺癌的研究历史及研究成果;全面叙述了miRNAs在正常细胞和NSCLC细胞中可能存在的作用机制;强调了miRNAs在非小细胞肺癌的早期诊断和预后判断中起的作用;总结了miRNAs对NSCLC患者的治疗做出的贡献;客观地评价了miRNAs在NSCLC中广阔的临床应用前景及现今其科学研究仍旧存在的问题.     

吉非替尼在非小细胞肺癌中的研究进展

随着非小细胞肺癌的发病率不断升高,传统的含铂双药联合化疗的疗效并没有取得令人满意的效果,以吉尼替尼为代表的分子靶向药物对 EGFR突变型NSCLC取得了较好的疗效,鉴于此,进一步研究EGFR基因的突变的情况,寻找与吉非替尼敏感性的其他因素,对于提高NSCLC患者治疗疗效具有重要意义。     

ERCC1在非小细胞肺癌个体化治疗中的研究进展

非小细胞肺癌的发病率和病死率近年呈上升趋势,化学治疗(化疗)是治疗非小细胞肺癌的主要手段;但是由于耐药的存在,化疗疗效有效率有限,目前一线化疗联合方案的有效率仅为20%~40%。近年来随着肿瘤分子生物学的发展,已发现ERCC1等基因的表达水平和化疗药物疗效及预后密切相关,ERCC1的表达水平有可能成为预测疗效进行个体化治疗的重要指标。根据基因表达水平及药物敏感情况选择个体化的化疗方案是肿瘤学研究和临床肿瘤化疗的趋势。     

ROS1融合基因在非小细胞肺癌中的研究进展

非小细胞肺癌(non-small cell lung cancer,NSCLC)的分子靶向治疗是目前的研究热点,继EGFR、ALK基因等靶点之后不断有新的肿瘤标志物被发现。ROS1基因重排作为一种新发现的NSCLC亚型,其发生率约占NSCLC的1%~2%,优势人群通常为年轻、不吸烟的肺腺癌患者,这些临床特征与ALK重排的NSCLC患者类似。本文将NSCLC中发现的ROS1融合基因的研究进展及其在NSCLC中的临床、功能和结构特征进行阐述。     

非小细胞肺癌分子靶向治疗药物研究进展

分子靶向药物作为一种新型治疗药物,与传统治疗药物相比具有更强的针对性,可以增强对肿瘤的杀伤力,并减少对正常细胞的毒副作用,现已成为非小细胞肺癌(NSCLC)药物治疗的研究热点。近年来,一些分子靶向药物投入临床应用,其有效性和安全性也得到了进一步证实。本文对近年来NSCLC分子靶向治疗药物的研究进展作一综述。     

Current concepts on the molecular pathology of non-small cell lung carcinoma

Recent advances in the understanding of the complex biology of non-small cell lung carcinoma (NSCLC), particularly activation of oncogenes by mutation, translocation and amplification, have provided new treatment targets for this disease, and allowed the identification of subsets of NSCLC tumors, mostly with adenocarcinoma histology, having unique molecular profiles that can predict response to targeted therapy. The identification of specific genetic and molecular targetable abnormalities using tumor tissue and cytology specimens followed by the administration of a specific inhibitor to the target, are the basis of personalized lung cancer treatment. In this new paradigm, the role of a precise pathology diagnosis of lung cancer and the proper handling of tissue and cytology samples for molecular testing is becoming increasingly important. These changes have posed multiple new challenges for pathologists to adequately integrate routine histopathology analysis and molecular testing into the clinical pathology practice for tumor diagnosis and subsequent selection of the most appropriate therapy.     

Vascular invasion in non-small cell lung carcinoma.

AIMS: To determine if there is any correlation between vascular invasion and prognosis in non-small cell carcinoma of the lung; and to look specifically at invasion of vascular channels by tumour cells. METHODS: Eighty seven patients undergoing lobectomy or pneumonectomy for adenocarcinoma or squamous carcinoma were followed up for five years. The histological sections were studied for evidence of vascular invasion using an elastic van Gieson stain. The incidence of intimal fibrosis in arteries and veins was noted and the proportion with vascular invasion evaluated using a scoring system. The presence or absence of lymphatic permeation and tumour necrosis were noted. Survival data were analysed using the log rank test. RESULTS: The overall five year survival was 32%. There were 64 squamous cell carcinomas and 23 adenocarcinomas. Vascular invasion was seen in 77% of patients and lymphatic invasion in 44%. Neither the presence nor absence nor the proportion of blood vessels showing vascular invasion showed any relation to prognosis. Intimal fibrosis and tumour necrosis were unrelated to prognosis. Patients with lymphatic permeation had recurrence and died earlier than those without. CONCLUSION: The presence of arterial or venous invasion by adenocarcinoma or squamous carcinoma of the lung was unrelated to survival; lymphatic permeation was associated with poor prognosis. The two common non-small cell lung cancers behaved differently from other solid tumours, where vascular invasion was a significant factor in determination of prognosis. The presence of intimal fibrosis was unrelated to prognosis.     

Survivin expression in pre-invasive lesions and non-small cell lung carcinoma

Survivin is an inhibitor of apoptosis protein, which is overexpressed in many carcinomas, including lung carcinoma. The aim of this immunohistochemical study was to investigate the role of survivin in the early steps of lung carcinogenesis and non-small cell lung carcinomas (NSCLC), and its relationship with expression of p53 protein, a tumor suppressor gene involved in cell cycle control. In the normal bronchial epithelium, low-grade atypical adenomatous hyperplasia (AAH) and non-neoplastic lung parenchyma adjacent to tumor, survivin was found completely negative. Expression of survivin was detected in the areas of squamous metaplasia and dysplasia as well as high-grade AAH lesions adjacent to tumor. Survivin was expressed in 50 (64%) and p53 in 41 (53%) NSCLC. Survivin expression was significantly correlated with lymph node metastasis (p=0.02). There was no correlation between survivin and p53 expression. The patients with expression of survivin had significantly worse prognosis (Log-rank test, p=0.003). Multivariate Cox regression analysis showed TNM stage (p<0.001) and survivin expression (p=0.003) as independent prognostic indicators. In conclusion, survivin expression might be an early step in lung carcinogenesis. Survivin expression might also be used as a prognostic indicator predicting the worse outcome in NSCLC, and might be a novel target for the treatment of patients with preinvasive lesions of lung and NSCLC.     

Amyloid precursor protein and its phosphorylated form in non-small cell lung carcinoma

Amyloid precursor protein (APP) is a well-known to be involved in the development of Alzheimer's disease and harbors several phosphorylation sites in its cytoplasmic domain. APP has been also proposed as one of the molecules involved in cell proliferation and invasion in several human malignancies. However, the roles of APP including its phosphorylated form (p-APP) have remained largely unexplored in non-small cell lung carcinoma (NSCLC). Therefore, in this study, we first examined both APP and p-APP expressions and then explored the association between p-APP/APP status and clicopathological parameters in NSCLC. The number of APP-positive cases was 24/91 (26%) in adenocarcinomas (Ad) and 16/35 (46%) in squamous cell carcinomas (Sq), respectively. p-APP-positive cases in Ad and Sq were 28 (31%) and 17 (49%), respectively. In Ad cases, both APP and p-APP were significantly associated with clinical stages (APP and p-APP), pathologic T (p-APP), and pathologic N (APP and p-APP) of the cases examined. In Sq cases, there were no significant associations between APP status and any of the clinicopathological parameters examined with an exception of the significant correlation of p-APP with lymphatic invasion. APP status was not significantly associated with overall survival (OS) of Ad patients but a significant association was detected between p-APP-positive cases and OS of these patients (p < 0.0001). In Sq cases, both APP- (p = 0.01) and p-APP-positive (p = 0.04) groups were also significantly associated with adverse clinical outcome. These results did firstly demonstrate that APP, in particular, p-APP, is considered a potent prognostic factor for both Ad and Sq lung carcinoma patients. However, APP signaling including its phosphorylation signal are considered different between these two types of NSCC cells and further investigations are required for clarification.     

Analysis of c-myc DNA amplification in non-small cell lung carcinoma in comparison with small cell lung carcinoma using polymerase chain reaction

Previous studies of c-myc DNA amplification in lung cancer have focused primarily on analysis of small cell carcinoma or its tumor cell lines. There are few data about c-myc DNA amplification in histological types of lung cancer other than small cell carcinoma. Therefore the present study was conducted to investigate c-myc oncogene amplification in non-small cell lung carcinoma. We studied 46 lung tumor specimens for c-myc DNA amplification (15 adenocarcinomas, 15 squamous cell carcinomas, 6 large cell carcinomas, and 10 small cell carcinomas). Polymerase chain reaction, digoxigenin DNA labeling, and elecrophoresis were utilized to investigate the c-myc copy number in the lung tumor specimens. The c-myc copy number of non-small cell carcinoma ranged from 1.5 to more than 20.0 in adenocarcinoma and squamous cell carcinoma, and from 6.0 to 12.0 in large cell carcinoma. That of small cell carcinoma ranged from 1.8 to 12.0. The c-myc copy number of non-small cell carcinoma was significantly higher that than of small cell carcinoma (Wilcoxon rank sum test, Z=2.06, P=0.040). However, the differences in c-myc copy number among these four histological types were not statistically significant. Amplification of c-myc (more than 4 copies) was observed not only in small cell carcinoma but also in non-small cell carcinoma at similarly high frequency (12/15 in adenocarcinoma and squamous cell carcinoma, 6/6 in large cell carcinoma, and 9/10 in small cell carcinoma). Received: 17 October 2000 / Accepted: 7 May 2001     

Comparability of laboratory-developed and commercial PD-L1 assays in non-small cell lung carcinoma

PD-L1 expression in non-small cell lung cancer (NSCLC) is predictive of response to treatment with PD-1 and PD-L1 inhibitors. Different inhibitors have been developed with different PD-L1 assays, which use different PD-1 antibody clones on different immunohistochemistry platforms. Depending on instrument and reagent availability, laboratory-developed tests with cross-platform use of PD-L1 antibodies may have practical benefits over commercial assays. The 22C3 pharmDx Assay (referred to as 22C3 DAKO), the VENTANA PD-L1 SP263 Assay (referred to as SP263 VENTANA) and a lab-developed test using the 22C3 antibody on the VENTANA BenchMark ULTRA IHC/ISH system (referred to as 22C3 VENTANA) were performed on whole sections of 85 NSCLC surgical resections. All sections were independently scored by three pathologists using tumor proportion scores. Correlation coefficients for continuous scores in pairwise comparisons between assays ranged from 0.976 to 0.978. When using a 1% positivity threshold (dichotomous scores), the 22C3 DAKO assay and 22C3 VENTANA assays showed the greatest agreement (93% agreement, κ = 0.86, 95% CI 0.75–0.97), and the 22C3 DAKO and SP263 VENTANA assays tended to show slightly less agreement (84% agreement, κ = 0.66, 95% CI 0.50–0.82). When using a 50% positivity threshold (dichotomous scores), all pairwise comparisons showed similar agreement (96–99% agreement, κ = 0.89–0.97). Overall, there was no significant difference between assays at 1% or 50% thresholds (P = .77). These data are consistent with potential interchangeability of these assays, which may widen the scope of PD-L1 assays available to laboratories and reduce logistical barriers to testing.     

探索MAGE-A3和AKAP-4在非小细胞肺癌中的表达及意义

目的检测癌睾丸抗原（CTA）MAGE-A3、AKAP-4在非小细胞肺癌（NSCLC）的表达及意义。方法应用间接酶免疫组化技术检测MAGE-A3、AKAP-4在45例肺癌组织中的表达情况,分析其与组织类型及淋巴结转移的相关性。结果 45例标本中MAGE-A3、AKAP-4在NSCLC中的敏感度分别为62.2%和73.3%,联合两种抗原可显著提高敏感性,为91.1%（P〈0.05）;MAGE-A3、AKAP-4在鳞癌中的表达率显著高于腺癌,与性别、年龄、淋巴结有无转移不相关。结论 MAGE-A3、AKAP-4是较好的NSCLC辅助诊断指标,联合应用两种蛋白可提高诊断敏感性。     

Significance of EGFR protein expression and gene amplification in non-small cell lung carcinoma

We evaluated epidermal growth factor receptor (EGFR) protein expression by immunohistochemical analysis and EGFR gene amplification by fluorescence in situ hybridization in 199 consecutive newly diagnosed and surgically treated patients with primary non-small cell lung carcinoma (NSCLC) and correlated results with clinicopathologic findings. EGFR protein expression was more common in squamous cell carcinoma (SCC; 17 [26.2%]) than in adenocarcinoma (14 [11.1%]; (P = .0076) and more frequently associated with EGFR amplification (8 [14.5%] vs 4 [3.6%] cases; P = .0208). Poor differentiation was associated with a higher average number of EGFR gene copies per cell (mean, 4.18; P = .0322) and a higher EGFR/chromosome 7 ratio (mean, 1.84; P = .0324). N0 disease showed a higher number of EGFR gene copies (mean, 4.196; P = .0163). SCCs demonstrated a higher EGFR/chromosome 7 ratio than adenocarcinomas (mean, 1.95 vs 1.47; P = .0324), particularly T1 tumors (mean, 1.79; P = .0243). Statistical analysis failed to show correlation between outcome and EGFR protein expression and gene amplification in early NSCLC. EGFR protein expression was uncoupled from gene amplification in most cases, although good correlation occurred in a subset of SCCs.