尿中5种修饰核苷用于肺癌高危人群筛查分子标志物的可行性研究

目的：探讨尿中5种修饰核苷Pseu,mlA,mlI,mlG及m2G作为肺癌诊断分子标志的可能性。方法：应用高效液相色谱在线系统分别检测肺癌患者55例（其中包括肺鳞癌18例,肺腺癌23例与小细胞肺癌14例）与正常人30例尿中Pseu,mlA,mlI,mlG及m2G五种核苷,同时应用液相色谱法检测尿中肌酐,以两者比值表示核苷浓度;分析其与肺癌发生、病理分型及肿瘤分期之间的关系。结果：肺癌患者尿中Pseu,mlA,mlI,mlG及m2G浓度均显著高于正常人（P值均〈0．01）。小细胞癌组mlI浓度显著高于腺癌组（P=0．045）;mlA、mlI和Pseu3者联合检测对肺癌诊断的敏感性与4—5种联合检测相同,并且显著高于mlA单项检测（P=0．037）。结论：尿中Pseu,mlA,mlI,mlG及m2G可能成为肺癌诊断的分子标志物,也可能有助于肺癌病理分型。     

尿中修饰核苷在胃癌诊断中的意义

[目的]探讨尿中修饰核苷检测在胃癌诊断中的价值.[方法]应用高效液相色谱方法分别检测80名正常人与60例胃癌患者尿中Pseu、C、X、m1A、m2G和ac4C等6种核苷的水平.[结果]60例胃癌患者尿中6种核苷的平均水平明显高于正常人(P＜0.01);C与肿瘤大小呈正相关(P＜0.05):Pseu、X、m1A、m2G和ac4C与肿瘤TNM分期呈正相关(P＜0.05).[结论]尿中修饰核苷检测对胃癌的诊断有一定意义.     

尿中核苷检测在胃癌诊断中的意义

背景与目的:有研究表明,尿中修饰核苷的含量在多数恶性肿瘤患者中有明显升高。本研究拟探讨检测尿中核苷在胃癌诊断中的意义。方法:应用高效液相色谱法分别检测50名正常人与48例胃癌患者尿中15种核苷的水平,48例胃癌患者中有25例同时接受了血清CEA检测。结果:50名正常人和48例胃癌患者尿中15种核苷的平均值分别依次为:Pseu22.91±4.90,34.87±21.41;U0.34±0.32,0.62±0.82;A0.58±0.16,0.96±0.75;C0.17±0.15,0.24±0.19;m5U0.03±0.07,0.07±0.06;I0.26±0.10,0.43±0.36;m1I1.34±0.34,2.44±1.39;ac4C0.75±0.24,1.08±0.72;G0.09±0.04,0.14±0.10;X1.20±0.42,1.90±1.09;m2G0.61±0.16,1.00±0.69;m6A0.04±1.13,0.07±0.08;m1A2.26±0.56,3.71±2.21;m22G1.34±0.27,2.25±1.39;m1G0.80±0.25,1.41±0.86。胃癌患者尿中除m5U外,其余14种核苷的平均值明显高于正常人(P<0.05);次黄嘌呤与肿瘤大小,淋巴结转移正相关(P<0.05);黄嘌呤核苷与肿瘤淋巴结转移正相关(P<0.05)。以其中15种核苷浓度作为数据矢量,结合主成分分析-投影判别法区分正常人和胃癌患者,63%的胃癌患者被识别,识别率大大高于CEA检测(12%)。结论:胃癌患者尿中修饰核苷水平升高,检测尿中修饰核苷对胃癌的初筛有一定的参考意义。     

血清肿瘤标志物与肺癌的关系

目的 :探讨血清CEA、NSE、CYFRA2 1 1水平与肺癌的关系。方法 :采用电化学发光法检测 6 0例肺癌患者治疗前后血清CEA、NSE、CYFRA2 1 1水平。结果 :肺腺癌CEA水平明显高于鳞癌及小细胞癌 ,肺小细胞癌NSE水平明显高于鳞癌及腺癌 ,肺鳞癌CYFRA2 1 1水平明显高于腺癌及小细胞癌。腺癌CEA的阳性率显著高于其他类型 ,鳞癌CYFRA2 1 1的阳性率高于腺癌及小细胞癌。 3项肿瘤标志物以NSE对肺癌检出阳性率最高。治疗后CR、PR患者肿瘤标志物下降显著 ,可作为评价疗效的指标。结论 :CEA对肺腺癌的诊断价值较高 ,CYFRA2 1 1对肺鳞癌的诊断意义较大 ,NSE检测肺癌意义较大。血清 3项肿瘤标志物的水平对判断肺癌病期早晚及治疗有意义     

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.     

中国人肺癌易感性与Cyclin D1(A870G)遗传多态性的研究

目的研究中国北方人对肺癌的易感性与Cyclin D1基因第870位核苷酸A/G(A870G)多态性的关系.方法应用PCR-SSCP方法,检测93例肺癌及122例健康对照外周血白细胞Cyclin D1(A870G)的遗传多态性.结果肺癌组与对照组Cyclin D1(A870G)A/G的等位基因频率分别为60.75%、39.25%及51.64%、48.36%,两组间分布无显著性差异(P=0.06).肺癌组与对照组的A/A、A/G及G/G基因型频率分别为38.71%、44.09%、17.20%及23.77%、55.74%、20.49%.两组间A/G及G/G基因型频率无显著性差异(P＞0.05),而肺癌组A/A基因型频率明显高于对照组(P=0.018).肺癌组与对照组A/A基因型频率的分布差异与肺癌的病理类型有关.肺鳞癌组的A/A基因型频率与对照组无显著性差异(P=0.403),而肺腺癌组的A/A基因型频率明显高于对照组(P=0.017).与A/G及G/G基因型携带者之和相比,A/A基因型携带者患肺腺癌的校正相对风险度(OR)为2.43,95%CI=1.74～4.77.结论Cyclin D1(A870G)A/A基因型是中国北方人患肺腺癌的危险因素,而肺鳞癌的易感性与Cyclin D1(A870G)多态性无关.     

肺癌患者血清和尿中假尿苷检测的临床意义

为了探讨肺癌患者血清和尿中假尿苷浓度检测的临床意义，采用高效液相色谱法测定了４１例肺癌、１５例肺内良性占位性病变、２０例肺部感染患者及５０例健康献血员血清和尿中假尿苷的浓度。肺癌患者血清、尿中假尿苷浓度分别显著高于肺内良性占位性病变、肺部感染患者和健康对照者（Ｐ均＜０．００１）。广泛型小细胞性肺癌患者的假尿苷浓度高于局限型患者，非小细胞性肺癌Ⅲ、Ⅳ期患者高于Ⅰ、Ⅱ期患者。结果提示血清和尿中假尿苷浓度的检测对肺癌的诊断及病情判断有重要价值。     

肺癌患者血清中CK19-2G2和Cyfra21-1的测定及其对肺癌的诊断价值

目的 测定肺癌患者血清中细胞角蛋白19(CK19)降解片段CK19-2G2的浓度,并评价其对肺癌的诊断价值.方法 采用CK19-2G2和Cyfr21-1的检测试剂盒,分别检测104例肺癌患者、7l例肺部炎症患者和105例健康体检者的血清标本,采用Pearson相关分析判断二者的相关性.运用受试者工作特性曲线(ROC)分析CKl9-2G2和Cyfra21-1的检测效能,并确定CK19-2G2诊断肺癌的临界值.比较CK19-2G2和Cyfra21-1诊断肺癌的灵敏度和准确率.结果 肺癌组、肺部炎症组和健康对照组血清CK19-2G2的中位浓度分别为2.87、1.02和0.01 mU/ml,肺癌组显著高于肺部炎症组和健康对照组(均P<0.01).血清CK19-2G2诊断肺癌的灵敏度(72.1%)和准确率(82.9%)均高于Cyfra21-1(分别为41.35%和73.93%,均P<0.05).CK19-2G2与Cyfra21-1的血清浓度呈正相关(r=0.543).在不同病理类型的肺癌中,肺鳞癌患者的CK19-2G2血清浓度(M=8.35)显著高于肺腺癌患者(M=1.81)和小细胞肺癌患者(M=1.65),差异均有统计学意义(P<0.05).结论 CK19-2G2是一种较好的非小细胞肺癌肿瘤标志物,对肺癌的检测性能优于Cyfra21-1,对肺鳞癌的检测可能有更高的特异性.     

肿瘤标记物和CT联检对肺癌的诊断价值

目的:探讨多种肿瘤标记物检测联合CT扫描在肺癌诊断中的价值。方法:90例肺癌和20例肺良性病变患者与20名正常人,检测其血清NSE、CEA和CYFRA21-1三项肿瘤标记物含量,同时行肺部CT扫描检查。结果:肺癌组血清三项肿瘤标记物含量均高于正常对照组和肺良性病变组,P=0·000;NSE在小细胞肺癌中高表达(36·21±19·01)μg/L,CEA在肺腺癌中高表达(50·09±25·36)μg/L,CYFRA21-1在肺鳞癌中高表达(17·72±12·05)μg/L,三项肿瘤标记物的血清浓度与肺癌病理类型有关,P=0·001;肿瘤标记物和CT扫查对肺癌分型诊断总体符合率分别为79·2%和62·5%,联合检测的总体符合率为87·8%,联合检测优于单项检测,P=0·039;三项肿瘤标记物的含量在肺癌各期间差异无统计学意义,P>0·05。结论:多种肿瘤标记物联检,可提高肺癌分型的诊断符合率,结合CT分期有助于选择针对性的治疗方案。肿瘤防治杂志,2005,12(19):1480-1482     

血清肿瘤标志物联合检测对肺癌的诊断价值

目的：探讨血清中神经元特异性烯醇化酶（NSE）、细胞角蛋白19片段（CYFRA21-1）和糖类抗原19-9（CA19-9）的水平变化对肺癌的诊断价值。方法：采用化学发光法对125例肺癌患者、80例肺良性疾病患者和80例健康人血清中的NSE、CYFRA21-1和CA19-9含量进行检测及比较。结果：肺癌组的三种血清肿瘤标志物水平均明显高于肺良性疾病患者组和正常对照组,差异均有统计学意义（P〈0.05）,其中NSE在小细胞肺癌中呈高表达,明显高于鳞癌与腺癌（P〈0.01）,CYFRA21-1在鳞癌中水平明显高于腺癌与小细胞肺癌（P〈0.01）,CA19-9在腺癌中水平明显高于其他类型肺癌（P〈0.01）。三种肿瘤标志物联合检测阳性率高达84.8%,高于单项检测。结论：三项肿瘤标志物联合检测可提高肺癌诊断的灵敏度和准确度,同时为肺癌病理分型的鉴别诊断提供依据。     

CYP 1A1 polymorphism and risk of lung cancer in relation to tobacco smoking: a case-control study in China

The impact of genetic polymorphisms in CYP1A1 on susceptibility to lung cancer has received particular interest in recent years since this enzyme plays a central role in activation of major classes of tobacco carcinogens. Several polymorphisms in the CYP1A1 locus have been identified and their genotypes appear to exhibit population frequencies that depend on ethnicity. We have assessed the role of CYP1A1 genotype in lung cancer risk in the Chinese population via a case-control study. Three polymorphisms, m1 (MSP:I), m2 (exon 7 Ile-->Val) and m4 (exon 7 Thr-->Asn), were determined by PCR-RFLP in 404 controls and 217 lung cancer cases. While no polymorphic alleles were detectable in the m4 site among our study subjects, the allele frequencies for CYP1A1 m1 and CYP1A1 m2 were found to be 35.6 and 25.6% among controls, compared with 42.6 and 34.2% among cases. Multivariate analysis showed an elevated risk for lung cancer in subjects having at least one m1 allele [odds ratio (OR) = 2.0, 95% confidence interval (CI) = 1.4-2.8] or having at least one m2 allele (OR = 1.9, 95% CI = 1.3-2.7). However, this increased risk was limited to squamous cell carcinoma (SCC), but not adenocarcinoma or other histological types of lung cancer. Stratified analysis indicated a multiplicative interaction between tobacco smoking and variant CYP1A1 m1 genotypes on the risk of SCC. The ORs of SCC for the variant CYP1A1 m1 genotype, tobacco smoking and both factors combined were 2.8, 9.1 and 29.9, respectively. When the data was stratified by the pack-year values, this joint effect was consistent and stronger among the heaviest smokers. The interaction between tobacco smoking and the variant CYP1A1 m2 genotypes followed the same pattern. Our findings support the conclusion that CYP1A1 m1 and CYP1A1 m2 polymorphisms are associated with smoking-related lung cancer risk in Chinese.     

A novel set of DNA methylation markers in urine sediments for sensitive/specific detection of bladder cancer.

PURPOSE: This study aims to provide a better set of DNA methylation markers in urine sediments for sensitive and specific detection of bladder cancer. EXPERIMENTAL DESIGN: Fifty-nine tumor-associated genes were profiled in three bladder cancer cell lines, a small cohort of cancer biopsies and urine sediments by methylation-specific PCR. Twenty-one candidate genes were then profiled in urine sediments from 132 bladder cancer patients (8 cases for stage 0a; 68 cases for stage I; 50 cases for stage II; 4 cases for stages III; and 2 cases for stage IV), 23 age-matched patients with noncancerous urinary lesions, 6 neurologic diseases, and 7 healthy volunteers. RESULTS: Despite six incidences of four genes reported in 3 of 23 noncancerous urinary lesion patients analyzed, cancer-specific hypermethylation in urine sediments were reported for 15 genes (P < 0.05). Methylation assessment of an 11-gene set (SALL3, CFTR, ABCC6, HPR1, RASSF1A, MT1A, RUNX3, ITGA4, BCL2, ALX4, MYOD1, DRM, CDH13, BMP3B, CCNA1, RPRM, MINT1, and BRCA1) confirmed the existing diagnosis of 121 among 132 bladder cancer cases (sensitivity, 91.7%) with 87% accuracy. Significantly, more than 75% of stage 0a and 88% of stage I disease were detected, indicating its value in the early diagnosis of bladder cancer. Interestingly, the cluster of reported methylation markers used in the U.S. bladder cancers is distinctly different from that identified in this study, suggesting a possible epigenetic disparity between the American and Chinese cases. CONCLUSIONS: Methylation profiling of an 11-gene set in urine sediments provides a sensitive and specific detection of bladder cancer.     

Association of genetic variants of O6-methylguanine-DNA methyltransferase with risk of lung cancer in non-Hispanic Whites.

O6-methylguanine, a methylated damage lesion in DNA, correlates with spontaneous G:C --> A:T transition mutations and leads to activation of oncogene K-ras or dysfunction of the tumor suppressor gene p53. O6-methylguanine-DNA methyltransferase (MGMT) is critical for repairing damage to the O6-position of guanine. Therefore, we tested our hypothesis that genetic variants of MGMT are associated with increased lung cancer risk in a Caucasian population of 1,121 lung cancer patients and 1,163 matched cancer-free controls. We genotyped four potentially functional single nucleotide polymorphisms (SNPs) of MGMT: exon 3 codon 84C --> T (L84F), exon 5 codon 143A --> G (I143V), and two promoter SNPs 135G --> T and 485C --> A. The allele frequency distributions of the SNPs of codon 84C --> T and the promoter 135G --> T in the cases were borderline different from that in the controls. After defining the minor allele (T for codon 84C --> T and G for codon 143A --> G) as the variant allele, we categorized the MGMT genotypes as either 0 variants (84CC-143AA) or 1-4 variants. Compared with 0 variants, those with 1-4 variants showed a statistically significantly increased risk of lung cancer (P = 0.040). Further stratification analysis showed that this increased risk was more pronounced in women, current smokers, and non-small cell lung cancer. We did not find any association between the MGMT promoter SNPs and lung cancer risk. Our findings suggest that non-synonymous SNPs in MGMT are associated with modestly increased risk of lung cancer in Caucasians and need to be further investigated.     

表皮生长因子受体少见突变型非小细胞肺癌临床病理特征及治疗分析

  目的  分析非小细胞肺癌患者表皮生长因子受体（epidermal growth factor receptor,EGFR）少见突变型的临床病理参数及EGFR-TKIs治疗的初步疗效。  方法  收集2012年1月至2016年4月新疆医科大学附属肿瘤医院经病理证实的29例非小细胞肺癌携带少见EGFR突变患者临床病理资料,分析少见突变型的临床病理特征及与EGFR-TKIs疗效之间的关系。  结果  在29例少见突变患者中,最常见的远处转移器官依次为同侧/对侧肺组织、骨、脑、肝、肾上腺,最常见的淋巴结转移依次为肺门淋巴结、锁骨上/下淋巴结、颈根部淋巴结及纵隔淋巴结。少见突变中单突变16例,L861Q 5例,G719X 5例,20ins 4例,S768I 2例。双突变型11例,S768I及20ins突变4例,L858R及S768I双突变1例,19Del及T790M双突变1例,L861Q及G719X双突变2例,19Del及S768I突变1例,20ins及G719X突变1例,T790M及G719X突变1例。三突变2例,L858R、L861Q及G719X突变1例,S768I、20ins及G719X突变1例。一线EGFR-TKIs治疗客观缓解率（objective response rate,ORR）43.75%,疾病控制率（disease control rate,DCR）50.00%,中位无疾病进展生存期（median progression-free survival,mPFS）5.50个月。二线EGFR-TKIs治疗ORR为28.57%,DCR为42.85%,mPFS为4.00个月。三线EGFR-TKIs治疗ORR为33.33%,DCR为50.00%,mPFS为2.67个月。  结论  EGFR少见突变对EGFRTKIs治疗的有效率及生存时间存在较大个体差异,EGFR少见突变患者的ORR及PFS均较经典突变患者低,部分高于野生型。对少见突变患者,EGFR-TKIs治疗一线疗效略优于二、三线,但无显著性差异。      

Polymorphisms of dopamine receptor/transporter genes and risk of non-small cell lung cancer

BACKGROUND: The dopaminergic pathway may be of interest in assessing risk of non-small cell lung cancer (NSCLC). Dopamine receptors are expressed in alveolar epithelial cells and human lung tumours, and dopamine inhibits both cell proliferation in vitro and growth of lung tumour xenografts in nude mice. Moreover, dopamine selectively inhibits the vascular permeability and angiogenic activity of vascular endothelial growth factor (VPF/VEGF). The bioavailability of dopamine is regulated by dopamine receptors D2 (DRD2), D4 (DRD4) and dopamine transporter 1 (DAT1/SLC6A3) genes. METHODS: We have analysed 10 single nucleotide polymorphisms in DRD2, DRD4 and DAT1/SLC6A3 genes in relation to lung cancer risk in a case-control study of smoking subjects. The study subjects were 413 healthy individuals from general population and 335 NSCLC cases. Both cases and controls were Caucasians of Norwegian origin. RESULTS: We demonstrate that DRD2 polymorphisms -141Cdel, 3208G>T, TaqIB; DRD4 -521C>T and DAT1/SLC6A3 -1476T>G are associated with a two- to five-fold increased NSCLC risk. The variant alleles of DRD2 1412A>G and 960C>G had protective effects. CONCLUSION: The dopamine receptor/transport gene polymorphisms are associated with the risk of NSCLC among smokers. The data show that the polymorphisms resulting in lower dopamine bioavailability were associated with increased risk of NSCLC.     

A phase I study of alpha-galactosylceramide (KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer.

PURPOSE: Human Valpha24 natural killer T (NKT) cells bearing an invariant Valpha24JalphaQ antigen receptor, the counterpart of murine Valpha14 NKT cells, are activated by a specific ligand, alpha-galactosylceramide (alphaGalCer, KRN7000), in a CD1d-dependent manner. I.v. administration of alphaGalCer-pulsed dendritic cells (DC) induces significant activation and expansion of Valpha14 NKT cells in the lung and resulting potent antitumor activities in mouse tumor metastatic models. We did a phase I dose escalation study with alphaGalCer-pulsed DCs in lung cancer patients. EXPERIMENTAL DESIGN: Patients with advanced non-small cell lung cancer or recurrent lung cancer received i.v. injections of alphaGalCer-pulsed DCs (level 1: 5 x 10(7)/m(2); level 2: 2.5 x 10(8)/m(2); and level 3: 1 x 10(9)/m(2)) to test the safety, feasibility, and clinical response. Immunomonitoring was also done in all completed cases. RESULTS: Eleven patients were enrolled in this study. No severe adverse events were observed during this study in any patient. After the first and second injection of alphaGalCer-pulsed DCs, dramatic increase in peripheral blood Valpha24 NKT cells was observed in one case and significant responses were seen in two cases receiving the level 3 dose. No patient was found to meet the criteria for partial or complete responses, whereas two cases in the level 3 group remained unchanged for more than a year with good quality of life. CONCLUSIONS: In this clinical trial, alphaGalCer-pulsed DC administration was well tolerated and could be safely done even in patients with advanced disease.