循环肿瘤细胞在非小细胞肺癌个体化诊疗中应用的研究进展

非小细胞肺癌(non-small cell lung cancer,NSCLC)是发病率及病死率最高的恶性肿瘤,确诊时大多数NSCLC患者已到疾病晚期,导致患者5年生存率低.随着肿瘤个体化治疗的进展,早期诊断以及对患者病情实时监测尤为重要.循环肿瘤细胞(circulating tumor cell,CTC)作为肿瘤血源性转移的生物学标志物之一,是“液体活检”的重要指标,可用于肿瘤患者实时动态监测.检测CTC有助于早期发现NSCLC微转移、重新确定临床分期、实时监测抗肿瘤治疗疗效、评估预后、制定个体化的治疗策略,不仅如此,对其进一步分子鉴定有助于阐明肿瘤的生物学进程及转移机制.然而,由于检测标准不统一、检测阳性率低等多种因素,现阶段CTC仍较难应用到临床工作中.本文对CTC的发展历程及其在NSCLC诊断、治疗及预后等方面的研究新近进展作一综述.     

循环肿瘤细胞检测在非小细胞肺癌中的应用

循环肿瘤细胞（CTC）是非小细胞肺癌（NSCLC）发生复发转移的重要原因。随着检测技术的不断发展,近期研究结果提示,CTC 水平不仅可以用来判断肿瘤临床分期、评估患者预后及治疗反应,还可以用于早期 NSCLC 的风险评估。另外,作为一种非侵入性的“液体活检”,CTC 检测能反映原发肿瘤的分子生物学及遗传学特征,有助于患者获得最佳的个体化治疗。     

血清肿瘤标志联合检测对非小细胞肺癌诊断价值的探讨

目的:探讨血清肿瘤标志细胞角蛋白19片段抗原(CYFRA21-1)、癌胚抗原(CEA)、神经元特异性烯醇化酶(NSE)、糖链抗原125(CA125)、胃泌素释放肽前体(ProGRP)的水平在非小细胞肺癌(NSCLC)诊断中的应用价值.方法:采用酶联免疫法(ELISA)测定120例NSCLC患者和120例肺良性病变患者的血清肿瘤标志CYFRA21-1、CEA、NSE、CA125和ProGRP的水平.结果:NSCLC组5种血清肿瘤标志的水平和阳性检测率均显著高于良性病变组,P<0.05.5种血清肿瘤标志在NSCLC诊断中的特异性较高,CYFRA21-1、CEA、NSE的敏感性较高,而CA125和ProGRP敏感性较低.5种血清肿瘤标志联合检测在NSCLC诊断中的敏感性和特异性分别为92.5%和84.2%.结论:多种肿瘤标志联合检测可以提高NSCLC诊断的敏感性,对NSCLC的早期诊断和鉴别具有重要的临床价值.     

结直肠癌外周血循环游离核酸研究进展

目的:总结国内外结直肠癌外周血循环游离核酸的研究进展.方法:应用检索NCBI生物信息学数据库及CHKD期刊全文数据库检索系统,以"外周血、游离核酸、循环核酸和结直肿瘤"等为关键字,检索2003-2008年的相关文献.共检索到英文文献74篇,中文文献38篇.通过查找全文,排除重复研究和与本研究无关的文献,最后精选纳入分析的文献41篇.结果:通过检测和分析外周血中循环游离核酸水平和特异性肿瘤基因,能有效对结直肠癌进行早期筛查、诊断、连续检测和治疗效果的评估、转移复发的预测.由于检测血循环游离核酸具有操作简便、可重复性强且微创的特点,能早期、动态、连续地对肿瘤进行诊断和检测,将具有巨大的临床应用潜力.但目前仍需要一种更可靠和敏感的检测手段.结论:通过检测和分析外周血循环游离核酸水平将有助结直肠癌的早期诊断和疗效、预后评估.其深入意义仍有待更多研究证实.     

循环DNA在乳腺癌诊疗方面的研究进展

乳腺癌是全球范围女性常见的恶性肿瘤之一。目前,研究证实循环核酸检测技术能够指导临床乳腺癌的相关诊疗。循环核酸是指存在于循环系统的游离核酸,大致可分为循环DNA及循环RNA。循环DNA检测作为液体活组织检查技术,能够弥补临床指标敏感度和特异度不高的缺点,有助于乳腺癌的早期筛查诊断及监测治疗效果,并为部分患者提供一定的预后信息。笔者总结了循环DNA在乳腺癌诊断、治疗、预后方面的应用以及研究现状,以供同行参考     

血清CEA和CYFRA21-1检测与NSCLC临床诊断的相关性研究

目的: 研究血清CEA和CYFRA21-1与NSCLC临床诊断的相关性.方法: 采用电化学发光法对86例NSCLC患者和33例正常人的血清样本进行检测和分析.结果: NSCLC患者的CEA和CYFRA21-1浓度和阳性率高于正常人,二者有显著性差异(P<0.01).肺腺癌的CEA浓度高于肺鳞癌和大细胞肺癌(P<0.01),肺鳞癌的CYFRA21-1浓度高于肺腺癌和大细胞肺癌(P<0.01),CEA和CYFRA21-1联合检测对阳性率均有所提高.CEA和CYFRA21-1浓度随肿瘤分期的增加而升高.结论: 血清CEA和CYFRA21-1与NSCLC临床诊断具有明显相关性,可作为NSCLC患者临床诊断和肿瘤分期的判断指标之一.     

ctDNA在非小细胞肺癌放射治疗中的应用进展

循环肿瘤DNA（ctDNA）以其无创检测、克服肿瘤异质性等优点,已成为无创液体活检最为常用的分析指标。肺癌是全世界发病率和死亡率最高的恶性肿瘤,其中约85%为非小细胞肺癌（NSCLC）。放射治疗在NSCLC各个分期中应用广泛,其直接杀死肿瘤细胞根治癌症的同时,间接增加ctDNA释放,提高液体活检准确性。因此ctDNA在NSCLC放射治疗中的应用前景广阔。本文将对ctDNA用于NSCLC放疗患者诊断、预后评估、复发监测以及疗效预测各领域的新进展进行综述。     

ctDNA在非小细胞肺癌放射治疗中的应用进展

循环肿瘤DNA（ctDNA）以其无创检测、克服肿瘤异质性等优点,已成为无创液体活检最为常用的分析指标。肺癌是全世界发病率和死亡率最高的恶性肿瘤,其中约85%为非小细胞肺癌（NSCLC）。放射治疗在NSCLC各个分期中应用广泛,其直接杀死肿瘤细胞根治癌症的同时,间接增加ctDNA释放,提高液体活检准确性。因此ctDNA在NSCLC放射治疗中的应用前景广阔。本文将对ctDNA用于NSCLC放疗患者诊断、预后评估、复发监测以及疗效预测各领域的新进展进行综述。     

循环肿瘤DNA监测早期肺癌术后微小残留病灶的研究进展

循环肿瘤DNA(circulating tumor DNA,ctDNA)已经应用于监测转移性非小细胞肺癌（non-small cell lung cancer,NSCLC）的治疗。近来研究者开始关注ctDNA预测早期NSCLC患者根治术后微小残留病灶(minimal residual disease,MRD)的价值。全文总结目前常用的ctDNA检测方法，并介绍了其在早期肺癌术后评估MRD和复发预警方面的应用进展。     

非小细胞肺癌微转移的研究进展

肺癌是目前人类死亡率最高的恶性肿瘤,影响非小细胞肺癌(non-small cell lung cance,NSCLC)患者预后的主要因素是肿瘤的转移和复发.近年来多数学者认为手术前常规检查难以发现的微转移是引起肿瘤转移和复发的主要原因.早期发现NSCLC的微转移,可以判断有无肿瘤转移、转移的途径及其范围,对肿瘤的临床诊断、治疗及判断预后均具有重要意义.本文对非小细胞肺癌微转移的分子生物学诊断和临床意义方面的研究现况进行了回顾综述.     

Detection of microsatellite alterations in plasma DNA of non-small cell lung cancer patients: a prospect for early diagnosis.

A major problem in lung cancer is the lack of clinically useful tests for early diagnosis and screening of an asymptomatic population by non-invasive diagnostic procedures. Recent studies have demonstrated the possibility to detect genetic alterations in plasma or serum DNA from patients with various cancers. However, these data rely on small series of aggressive tumors with advanced-stage disease. To determine whether genetic changes in plasma are also detectable in patients with limited disease and thereby potentially useful for early detection, we looked for microsatellite instability (allele shift) and loss of heterozygosity in plasma DNA of 87 stage I-III non-small cell lung cancers and 14 controls. Combining two markers with a high rate of instability (D21S1245) and loss of heterozygosity (FHIT locus), a microsatellite alteration was observed in 49 of 87 (56%) non-small cell lung cancer tumors and in 35 of 87 (40%) plasma samples. Thirty of 49 (61%) of the cases showing tumor alterations also displayed a change in plasma DNA; in addition, 5 patients displayed alterations in plasma samples only. None of the control individuals had genetic changes in plasma. No association was found between the frequency of microsatellite alterations in plasma and tumor stage or histology. Of interest, plasma DNA abnormalities were detectable in 43% of pathological stage I cases and in 45% of tumors up to 2 cm in maximum diameter. These findings highlight new prospects for early tumor detection by noninvasive screening procedures based on the analysis of genetic changes in plasma.     

肺癌筛查方法现状

肺癌是目前恶性肿瘤死亡的首要原因,早期诊断对肺癌的预后至关重要。研究显示低剂量计算机断层扫描（computed tomography, CT）筛查可以使肺癌的死亡率下降。但其存在的问题不可忽视,如过高的假阳性率、过度诊断、辐射效应等。作为一种肿瘤无创筛查方法,血液相关肿瘤标志物的检测,在肺癌早期诊断中显示出良好的敏感性和特异性。如何利用现有的筛查手段,建立肺癌筛查综合模式,需要更多大规模的临床研究。     

The Impact of Genetic Markers on the Diagnosis of Lung Cancer: A Current Perspective

Lung cancer is the leading worldwide source of cancer-related death. It is acknowledged that prognosis and treatment outcomes in lung cancer might be improved by increasing the effectiveness of early-stage diagnosis. Several recently published studies have produced intriguing results regarding the detection of biomarkers in tumor samples, but also in easily accessible specimens such as sputum, plasma, and exhaled breath condensate. This review presents advances in genetic diagnostics of lung cancer, with particular reference to the clinical usefulness of individual biomarkers, specimens, and methods. The adequacy of their sensitivity and specificity for cancer screening and early detection is discussed in detail.     

Identification of the methylation of p14ARF promoter as a novel non-invasive biomarker for early detection of lung cancer

Background

Recent diagnostic procedure advances have greatly improved early lung cancer detection. However, the invasive, unpleasant and inconvenient nature of current diagnostic procedures limits their application. There is a great need of novel non-invasive biomarkers for early lung cancer diagnosis. In the present study, we intend to determine whether the blood signatures of p14ARF promoter methylation are suitable for early detection of lung cancer.

Methods

The study aimed to assess the probability of p14ARF promoter methylation in plasma samples to detect early lung cancer using nested methylation-specific PCR in the training set consisted of tumor tissues and paired blood. Besides, we were further to discuss the difference in time to progression between methylation and unmethylation of p14ARF promoter using univariate and multivariate analysis.

Results

The methylation of p14ARF promoter was detected in 33.6 % of tumor tissues, and 12.1 and 25.2 % in distant-cancer mucosa and matched plasma, respectively, and our study has also demonstrated the positive correlation between them by Pearson’s test (r = 0.300). The tumor-free survival time of the unmethylation of p14ARF promoter is significantly longer than that of the methylation of p14ARF promoter in tumor tissues (χ ² = 7.149, P = 0.008).

Conclusion

The methylation of p14ARF promoter in plasma samples has strong potential as a novel non-invasive biomarker for early detection of lung cancer, and the methylation of p14ARF promoter was considered as prognostic factor in our study.     

疫情防控常态下肺癌早筛的现状及进展

肺癌是我国发病率最高的恶性肿瘤。早发现早鉴别出有症状的肺癌患者和及时从高危人群中筛选出无症状患者需要多方面配合。目前,尽管已经联合影像学、血清学、基因组学、蛋白质组学等手段对可疑肺癌进行筛查,但仍存在漏诊、误诊等问题。同时,新型冠状病毒肺炎(corona virus disease 2019, COVID-19)流行病的蔓延给肺癌早筛带来了新的挑战。在疫情防控常态化下,肺癌早筛工作应该做出相应改变:提高人群防癌控癌意识、加强就诊流程管理、提高肿瘤检出效率、优化检测技术并合理利用互联网和大数据平台。联合多种筛查方法建立一种理想的肺癌早筛模式,保证疫情防控常态下肺癌早筛工作既精简又高效。     

Impact of low-dose CT on lung cancer screening

Despite advances in therapy, the prognosis of lung cancer remains dismal due to the fact that most cases of lung cancer are diagnosed at advanced stages, when the chance of cure is poor. In cases detected at early stages prognosis is better. Unfortunately, early lung cancer usually causes no symptoms and is, consequently, rarely diagnosed. Therefore, screening for early asymptomatic lung cancer with diagnostic procedures appears promising particularly as risk factors for lung cancer are well known (cigarette smoking, occupational asbestos exposure and others) and screening could, therefore, focus on these risk groups. In the past, screening trials using analysis of sputum cytology and to some extent chest radiography have failed to demonstrate a reduction in lung-cancer mortality with screening, probably due to insufficient sensitivity of these tests for early lung cancer. During the last decade the introduction of spiral computed tomography (CT) has provided a technique with a much higher sensitivity for small lung cancers. Feasibility studies using low-radiation-dose CT demonstrated a high proportion of non-small-cell lung cancer at the initial examination (prevalence) with decreasing numbers of detected cancers at follow-up (incidence). The proportion of early-stage tumors was high both at prevalence and incidence examinations. The rate of invasive procedures for benign lesions was low; most indeterminate lesions could be classified with non-invasive diagnostic approaches. The proportion of interval cancers (cancers diagnosed by symptoms between two screening CT scans) was low. As, however, these one-arm feasibility trials are not appropriate to assess a potential mortality reduction through CT screening, prospective randomised multicenter trials were recently initiated in several countries to analyse the effect of CT screening on lung-cancer mortality.     

Peroxiredoxins and tropomyosins as plasma biomarkers for lung cancer and asbestos exposure

The prognosis of lung cancer is poor due to late diagnosis, the lack of established screening programs, and the paucity of early biomarkers for high-risk populations. Plasma proteome analysis was used to identify novel biomarkers for diagnosing lung cancer, and to unravel the mechanisms of underlying pathogenesis. Plasma proteins obtained from asbestos-exposed lung cancer cases detected by CT screening, asbestos-exposed subjects, clinical lung cancer patients, and healthy tobacco smokers, 5-6 cases in each group, were separated by two-dimensional gel electrophoresis, and identified with tandem mass spectrometry (LC-MS/MS). Nine proteins were selected for immunological confirmation in a test or validation set of plasma samples from an additional 49 clinical lung cancer cases, 66 asbestos-exposed patients, and 107 healthy tobacco smokers. Twenty-eight unique proteins were differentially expressed between the four study groups (p<0.05). Peroxiredoxin 1 (PRX1) was detected as a novel plasma marker for lung cancer (p=0.001). We also confirmed the previously found association of serum amyloid A with lung cancer (p<0.001). High plasma levels of tropomyosin 4 (TPM4: p<0.001) and peroxiredoxins 1 and 2 (PRX2: p<0.001) correlated with asbestos exposure or a diagnosis of asbestosis. PRX1 and PRX2 exhibited an inverse correlation with tobacco smoking (p<0.001). Plasma peroxiredoxins 1 and 2, and tropomyosin 4 were shown to associate with asbestos-exposure, and peroxiredoxin 1 with lung cancer. High plasma levels of peroxiredoxin 1 may result from genetic damage caused by reactive oxygen species. This study has identified several biomarkers worthy of further investigation in lung cancer and asbestos-related diseases.     

Genetic abnormalities in plasma DNA of patients with lung cancer and other respiratory diseases

The detection of tumour-associated genetic alterations in plasma DNA has been proposed as a simple method for the early diagnosis of lung cancer and for identifying individuals at high risk of lung cancer who might be included in screening or chemoprevention programmes. To evaluate the practicality of this approach, we screened a panel of 16 plasma DNA markers in a lung cancer population to identify those with the highest genetic alteration rate. These were then used to study plasma DNA in 206 hospital outpatients with lung cancer and other respiratory diseases. Plasma and lymphocyte DNA were isolated from blood samples collected from hospital outpatients. Polymerase chain reaction was carried out with 16 microsatellite markers covering chromosomal regions 3p, 8p, 9p, 13q and 17p, using DNA from 32 lung cancer patients. The 3 markers most commonly affected were selected for use in a larger study of 86 lung cancer patients and 120 patients with other respiratory diseases. In the pilot study, 3 primer pairs (D3S1300, D3S1560, D8S201) together detected genetic alterations in plasma DNA in 60% of lung cancer patients. In the larger study, significantly higher genetic alteration rates were observed in lung cancer patients than in patients with other respiratory diseases for the two markers D3S1560 and D8S201. The overall genetic alteration rate was 69% in the lung cancer patients and 42% in the patients with other respiratory diseases (p < 0.001). Analysis of plasma and lymphocyte DNA to detect genetic alterations typical of lung cancer is possible in large studies. The genetic alteration rate we found in lung cancer patients was comparable with other studies. Although the genetic alteration rate was significantly higher in the lung cancer than the respiratory disease patients, it did not have good positive predictive value in this population. Longitudinal studies are required to determine whether genetic changes in plasma DNA of non-cancer patients indicate a high risk of later lung cancer.     

Lung cancer epigenetics and genetics

Lung cancer is the leading cause of cancer-related death and thus a major health problem. The efficiency of current treatment modalities for lung cancer depends strongly on the time of diagnosis, with better chances of survival if a tumor has been detected at an early stage. Thus, there is an urgent need for rapid and efficient early detection methods. Biomarkers represent a possible alternative to current, rather expensive, screening tools such as spiral computer tomography (CT), or may allow the identification of high risk groups for whom screening would be cost efficient. Although most lung cancers are the consequence of smoking, a substantial fraction of molecular-epidemiological studies point to high-prevalence, low-penetrance genetic polymorphisms as modifiers of environmental lung cancer risk. In the past the genomics field has also made significant advances in identifying genetic lesions that can now be harvested with the goal of identifying novel biomarkers for lung cancer. Furthermore, the importance of epigenetic changes that occur during lung cancer development has been reported, but has been underestimated in the past. Novel high-throughput, quantitative assays for the detection of DNA methylation or histone tail modifications are now applied, to search for alterations in the lung cancer genome and will identify novel cancer-related genes that may become attractive targets for treatment, provide new insight into the biology of lung cancers, and could also become useful biomarkers for the early detection of lung cancer in sputum, or may be used as prognostic markers. Thus, an integrative approach in lung cancer research combining epidemiological, genetic and epigenetic information becomes an important concept for the future.     

无创液体组织活检技术在结直肠癌筛查中的研究进展

结直肠癌（colorectal cancer,CRC）是最常见的消化道恶性肿瘤,早期筛查与干预是降低其发病率和死亡率的有效措施。无创液体组织活检技术与传统的结肠镜检查相比,具有操作简便、成本低、并发症少、依从性高的优点,能带来更好的社会效益,是目前CRC筛查技术的研究热点与突破点。近年来,随着多组学研究技术的发展,粪便及外周血基因组、蛋白质组、微生物组检测等均被证实了在肠癌筛查中的应用潜力,许多可用于肠癌早筛的生物标志物被发现,进而涌现出大量的CRC无创性筛查的新方法。本文结合国内外文献报道,综合现有的CRC无创性早期诊断的技术,探讨其应用价值,以期为进一步的肠癌早筛研究提供理论依据。