放射治疗联合参一胶囊治疗Ⅲ期非小细胞肺癌的临床研究

目的：探讨适形放射治疗联合参一胶囊在Ⅲ期非小细胞肺癌治疗中的临床疗效。方法：选取本院自2011 年4 月至2014 年6月经病理及影像学资料明确证实的Ⅲ期非小细胞肺癌患者60 例,随机分为两组,即对照组和治疗组。对照组行单纯适形放射治疗;治疗组在适形放射治疗的同时,给予口服参一胶囊8 周。治疗期间观察患者有无乏力症状,定期行血液学检查,完成治疗后4周行胸部CT检查。结果：治疗组出现不同程度乏力的患者数明显少于对照组,差异显著,具有统计学意义(P<0.05);定期血常规检验,治疗组出现白细胞、血红蛋白减低的患者比率明显低于对照组,差异具有统计学意义(P<0.05);两组近期治疗效果相近,差异无统计学意义(P>0.05)。结论：放射治疗联合参一胶囊治疗可以改善患者乏力状况,降低放射治疗引起的血液不良反应的发生几率。     

沙利度胺治疗中晚期非小细胞肺癌的临床观察

目的:观察沙利度胺治疗中晚期非小细胞肺癌患者的预后情况.方法:沙利度胺治疗组选取30例中晚期非小细胞肺癌患者入组研究,给予沙利度胺联合PCDE方案治疗;同时选取37例中晚期非小细胞肺癌患者作为对照组,仅使用PCDE方案治疗,分析两组患者生存率的差异.结果:沙利度胺联合PCDE方案治疗组非小细胞肺癌患者的生存率明显高于PCDE方案治疗组患者(P<0.01).结论:采用沙利度胺联合PCDE方案治疗中晚期非小细胞肺癌,可以提高非小细胞肺癌患者的生存率,值得临床推广.     

非小细胞肺癌脑转移瘤综合治疗的预后影响因素分析

目的:研究综合治疗的非小细胞肺癌(non-small cell lung cancer,NSCLC)脑转移瘤患者生存预后影响因素,为NSCLC脑转移瘤的治疗提供更多的参考依据。方法:收集83例诊断为NSCLC脑转移瘤的患者进行回顾性研究,随访后建立临床资料数据库,采用单因素分析及Cox回归模型分析不同因素对非小细胞肺癌脑转移瘤患者生存期的影响。结果:患者中位生存期为11个月,6月、12月、18月的生存率分别为79.0%、32.7%、19.4%。经单因素和多因素分析结果显示脑转移瘤的病理类型、原发灶控制情况、治疗方式、靶向治疗是NSCLC脑转移生存的独立影响预后因素。单发转移瘤中,手术联合全脑放疗(Whole brain radiotherapy,WBRT)与手术相比风险率(hazard rate,HR)为0.645(P>0.05),说明联合方式并没有在生存中获益。多发转移瘤中,手术与WBRT相结合与单纯手术对比HR=0.297(P<0.05),有统计学意义。结论:病理类型为非腺癌,原发灶未得到控制,治疗方式不当以及未应用靶向治疗是NSCLC脑转移瘤的独立危险因素。对于单发脑转移瘤患者的局部治疗,单独手术治疗可能具有更高的优势;对于多发脑转移瘤患者的局部治疗,手术与WBRT联合可能具有更多的生存获益。     

新辅助化疗对局部晚期非小细胞肺癌患者术后生存质量的影响

目的:探讨新辅助化疗对局部晚期非小细胞肺癌患者术后生存质量的影响。方法:选取2011年5月至2012年5月于本院胸腔外科接受治疗的ⅢA~ⅢB期非小细胞肺癌患者240例并将其随机分成2组,即新辅助化疗组(A组)和单纯手术组(B组),每组120例。A组患者在临床确诊后接受2个周期的新辅助化疗,化疗结束2~3周后接受手术治疗;对照组患者临床确诊后直接行手术治疗。术后,两组患者均给予4周期常规放化疗。采用QLQ-C30量表对两组患者术前与术后第1、3、6个月的生存质量进行评估,并比较两组患者生存质量评分的差异。结果:术后1、3、6个月时,两组患者的各项功能分值均较术前显著升高(P0.05);术后第3、6个月,患者的总体健康状况得分较术前显著升高(P0.05);术后1个月时,A组患者的呼吸困难评分较术前明显增加(P0.05),术后第3个月后,该分值与术前比较无显著性差异;术后第1、3个月时,两组患者的疼痛评分均较术前明显升高(P0.05),但第6个月时,该评分与术前无显著性差异;术后第6个月时,两组患者的疲乏得分较术前明显降低(P0.05);术后第1、3、6个月时,两组患者的经济困难评分明显较术前升高(P0.05)。术后1、3、6个月时,A组患者的总体状况得分均显著高于B组(P0.05),呼吸困难评分和疲乏评分明显低于B组(P0.05),经济困难评分均显著高于B组(P0.05)。结论:新辅助化疗可以提高局部晚期非小细胞肺癌患者术后半年内的生存质量。     

482 例非小细胞肺癌远处转移临床特征的回顾性分析

目的：探讨不同病理类型IV 期非小细胞肺癌(NSCLC)患者远处转移的临床特征。方法：回顾性分析我科收治的482 例诊断明确IV 期NSCLC 患者的临床资料,比较不同病理类型患者各器官远处转移发生率,并进行统计学分析。结果：482 例IV 期NSCLC 患者中,鳞状细胞癌188 例(39.0%),腺癌275 例(57.1%),大细胞癌5 例(1.0%),腺鳞癌14 例(2.9%)。平均年龄55.2 岁,男女比例为2.30：1,高发年龄为40～60 岁。各器官远处转移的发生率从高到低依次为：骨217 例(45.0%),胸膜170 例(35.3%),双肺138例(28.6%),脑113 例(23.4%),肝85 例(17.6%),肾上腺33 例(6.8%),心包36 例(7.5%)。单器官转移221 例(45.9%),多器官转移261例(54.1%)。T4 期患者所占比例高达44.8%,N2+3 组患者所占比例明显高于N0+1 组患者,差异有统计学意义。单纯骨、脑、肝、肾上腺转移发生率分别为28.1%、23.9%、12.9%和15.2%。结论：NSCLC 以骨和胸膜转移最为常见,原发肿瘤情况、淋巴结转移情况与远处转移存在一定关系,多数M1b 期患者初诊时已发生全身多部位远处转移。     

非小细胞肺癌放疗所致并发症的影响因素分析

目的:分析非小细胞肺癌放疗所致并发症的影响因素.方法:选择2008年6月至2011年10月我院收治的原发非小细胞肺癌150例,所有病人接受精确放疗治疗.对各因素和并发症发生率的关系采用统计学分析.结果:本文150例病例治疗3个月后随访确认较严重的并发症16例(10.7％).单因素分析显示年龄及放射剂量与并发症相关,而病灶位置、肿瘤大小与并发症的发生无关.以上相关因素带入多因素Logistic回归模型,结果提示只有同时放射剂量指标为独立的相关因素,年龄与并发症的发生可能相关,但无显著性意义.结论:肺癌患者接受精确放疗治疗并发症与放射剂量密切相关,并发症发生于患者年龄也可能相关.放疗剂量的合理控制有助于增加放疗的安全性,这在高龄患者更尤为重要.     

榄香烯治疗非小细胞肺癌的作用机制研究进展

榄香烯注射液是从天然中草药姜科植物温郁金中提取获得的萜烯类化合物,其主要生物学活性为降低肿瘤细胞有丝分裂能力,诱导肿瘤细胞凋亡,抑制肿瘤细胞的生长,从而改善NSCLC患者的临床症状,增强患者免疫力.本文主要从杀灭癌细胞、诱导癌细胞凋亡、抑制癌细胞血管形成、增强患者免疫力等几方面综述榄香烯注射液对非小细胞肺癌的作用机制.     

不同放化疗模式治疗中晚期非小细胞肺癌的疗效分析

目的:探讨同步和序贯放疗联合不同化疗方案对治疗中晚期非小细胞肺癌近期疗效、远期生存及毒性反应的影响。方法:将45例III-IV期非小细胞肺癌患者随机归入两组,同步放化疗组22例;序贯放化疗组23例。全组病例依据病情分别选择艾素和顺铂、吉西他滨和顺铂、长春瑞滨和顺铂或培美曲塞和顺铂方案化疗。比较两组近期疗效、远期生存率及毒性反应。结果:同步组近期有效率为81.8%高于序贯组73.9%,但无统计学差异(P0.05);两组均有随放疗剂量增加有效率升高趋势。NP和TP方案两组近期疗效相近(P0.05)。同步组和序贯组1年生存率分别为90.9%和86.9%(P0.05);2年生存率分别为72.7%和52.2%(P0.05)。毒性反应主要为骨髓抑制、放射性食管炎和肺炎。同步组毒副反应发生率高于序贯组,但无统计学差异(P0.05)。结论:同步放化疗治疗中晚期非小细胞肺癌近期疗效及远期生存率有优于序贯放化疗的趋势,但毒副反应发生相对增多。联合治疗模式下,分期越早,患者远期生存时间越长。近期疗效有随放疗剂量增高而提高趋势,但放疗剂量、病理类型、化疗方案等对患者远期生存无明显统计学差异。     

化疗联合放疗治疗非小细胞肺癌疗效观察

目的:研究化疗联合放疗治疗非小细胞肺癌的临床疗效及毒副作用.方法:58例非小细胞肺癌患者随机分为观察组与对照组两组各29例,观察组患者采用化疗联合放疗治疗,对照组患者只采用化疗治疗.观察比较两组患者的临床疗效、1,2,3年生存率及毒副作用.结果:观察组患者的有效率(79.3％)明显高于对照组(41.4％),两组相比差异有统计学意义(P＜0.05).观察组患者1,2,3年生存率均高于对照组,两组相比差异有统计学意义(P＜0.05,P＜0.01).两组患者的Ⅱ-Ⅳ级白细胞减少率,Ⅲ-Ⅳ级血红蛋白减少率,Ⅲ-Ⅳ级消化系统反应无显著差别,两组相比差异均无统计学意义(P＞0.05).结论:相对于单纯化疗,化疗联合放疗治疗非小细胞肺癌临床效果更好,毒副作用并未加重,可以显著提高患者生存率,值得临床推广应用.     

非小细胞肺癌靶向治疗的临床前研究进展

针对表皮生长因子受体（EGFR）和血管生成（angiogenesis）信号通路的靶向治疗已经在晚期非小细胞肺癌的治疗上取得成功,但由于抗药性的存在,大多数晚期患者的生存时间仍然提高有限。继发性的EGFR T790M突变和原癌基因肝细胞生长因子受体（MET）的扩增被鉴定为两种主要的抗药机制。最近转化生长因子-β（TGF-β）/白介素-6信号通路被报道能介导选择性和适应性地对erlotinib的抗药。另一方面,Kras突变所致肺癌的靶向治疗方面也取得了一些进展。双重抑制磷脂酰肌醇3-激酶（PI3K）和促分裂素原活化蛋白激酶激酶（MEK）信号通路可导致Kras突变肿瘤的显著消退,联合抑制SRC、PI3K和MEK可使丝氨酸/苏氨酸蛋白激酶11（Lkb1）缺失,Kras突变的肺癌小鼠的肿瘤明显消退,抑制核因子-κB（NF-κB）信号通路导致p53缺失,Kras突变的肿瘤发展显著减慢。这些发现都为发展非小细胞肺癌患者的靶向治疗提供了有力的支持。     

Online Survival Analysis Software to Assess the Prognostic Value of Biomarkers Using Transcriptomic Data in Non-Small-Cell Lung Cancer

In the last decade, optimized treatment for non-small cell lung cancer had lead to improved prognosis, but the overall survival is still very short. To further understand the molecular basis of the disease we have to identify biomarkers related to survival. Here we present the development of an online tool suitable for the real-time meta-analysis of published lung cancer microarray datasets to identify biomarkers related to survival. We searched the caBIG, GEO and TCGA repositories to identify samples with published gene expression data and survival information. Univariate and multivariate Cox regression analysis, Kaplan-Meier survival plot with hazard ratio and logrank P value are calculated and plotted in R. The complete analysis tool can be accessed online at: www.kmplot.com/lung. All together 1,715 samples of ten independent datasets were integrated into the system. As a demonstration, we used the tool to validate 21 previously published survival associated biomarkers. Of these, survival was best predicted by CDK1 (p<1E-16), CD24 (p<1E-16) and CADM1 (p = 7E-12) in adenocarcinomas and by CCNE1 (p = 2.3E-09) and VEGF (p = 3.3E-10) in all NSCLC patients. Additional genes significantly correlated to survival include RAD51, CDKN2A, OPN, EZH2, ANXA3, ADAM28 and ERCC1. In summary, we established an integrated database and an online tool capable of uni- and multivariate analysis for in silico validation of new biomarker candidates in non-small cell lung cancer.     

Serum Level of CC-Chemokine Ligand 18 Is Increased in Patients with Non-Small-Cell Lung Cancer and Correlates with Survival Time in Adenocarcinomas

CC-chemokine ligand 18 (CCL18) is mainly expressed by alternatively activated macrophages and DCs and plays an important role in lung fibrosis, arthritis and other diseases. Here CCL18 was measured in sera of 31 healthy volunteers and 170 patients with lung cancer and correlated these data with histology, tumor stage and clinical parameters. Mean CCL18 serum level of the patients with non-small-cell lung cancer was 150(857) ng/ml vs. 32(61) ng/ml in the healthy control group. Patient groups differ significantly according their histology (adenocarcinoma 143(528) ng/ml vs squamous cell carcinoma 187(857) ng/ml, p<0.02). In addition, we found a significant difference between patients with lower versus higher T-stage (p<0.003). Receiver operating characteristic (ROC) analyses revealed a cutoff point of 83 ng/ml (area under the curve (AUC): 0.968; p<0.0001) to discriminate between healthy controls and non-small-cell lung cancer patients. ROC analyses to discriminate between patients, who died because of cancer related death and those who died for other reasons did not lead to a valid AUC. To stratify the tumor patients, a criterion value plot was performed leading to a point of equal sensitivity and specificity (54%) of 162 ng/ml. Patients with a CCL18 serum level higher than 160 ng/ml had a mean survival time of 623 days. In contrast, those in patients with a baseline level between 83 ng/ml and 160 ng/ml the mean survival time was 984 days (p<0.005). Survival-analysis revealed in adenocarcinoma a mean survival of 1152 days in the group below 83 ng/ml. In the median group the mean survival time was 788 days and in the group with the highest levels the mean survival time was 388 days (p<0.001). In contrast, we found no correlation between the FEV1 and the CCL18 baseline level. In conclusion, in patients suffering from adenocarcinoma increased serum CCL18 levels predict a diminished survival time.     

MicroRNA-143 Inhibits Migration and Invasion of Human Non-Small-Cell Lung Cancer and Its Relative Mechanism

Background: MicroRNAs (miRNAs) play important roles in many biological processes, including cancer development. Among those miRNAs, miR-143 shows tumor-suppressive activity in some human cancers. However, the function and mechanism of miR-143 in lung cancer cells remains unknown. Here we explored the role of miR-143 in lung cancer. Results: According to qRT-PCR, we found that miR-143 was notably down-regulated in 19 NSCLC tissues and 5 cell lines. In vitro experiments showed us that miR-143 could significantly suppress the migration and invasion of NSCLC cell lines while it had no effects on the growth of NSCLC cell lines, and in vivo metastasis assay showed the same results. Finally, we found that the mechanism of miR-143 inhibiting the migration and invasion of NSCLC might be through targeting CD44v3. Conclusions: The up-regulated miR-143 in lung cancer could significantly inhibit cell migration and invasion, and this might work through targeting CD44v3, which was newly identified by us.     

Prognostic Significance of Circulating Tumor Cells in Non-Small-Cell Lung Cancer Patients: A Meta-Analysis

Background

The prognostic significance of circulating tumor cells (CTCs) detected in patients with non-small-cell lung cancer (NSCLC) is still inconsistent. We aimed to assess the prognostic relevance of CTCs using a meta-analysis.

Methods

We searched PubMed, Web of Science and EMBASE for relevant studies that assessed the prognostic relevance of CTCs in NSCLC. Statistical analyses were conducted to calculate the summary incidence, odds ratio, relative risks (RRs) and 95% confidence intervals (CIs) using fixed or random-effects models according to the heterogeneity of included studies.

Results

A total of 20 studies, comprising 1576 patients, met the inclusion criteria. In identified studies, CTCs were not correlated with histology (adenocarcinoma vs squamous cell carcinoma) (odds ratio [OR]  =  0.88; 95% confidence interval [CI]: 0.59–1.33; Z = –0.61; P = 0.545). However, pooled analyses showed that CTCs were associated with lymph node metastasis (OR = 2.06; 95% CI: 1.18–3.62; Z = 2.20; P = 0.027) and tumor stage (OR  = 1.95; 95% CI: 1.08–3.54; Z = 2.53; P = 0.011). Moreover, CTCs were significantly associated with shorter overall survival (relative risk [RR]  = 2.19; 95% CI: 1.53–3.12; Z = 4.32; P<0.0001) and progression-free/disease-free survival (RR  = 2.14; 95% CI: 1.36–3.38; Z = 3.28; P<0.0001).

Conclusion

The presence of CTCs indicates a poor prognosis in patients with NSCLC. Further well-designed prospective studies are required to explore the clinical applications of CTCs in lung cancer.     

Methylation Profile of Several Tumor Suppressor Genes in Non-Small-Cell Lung Cancer

Multiplex methylation-sensitive PCR was employed in studying the methylation of CpG islands in the RB1, p16/CDKN2A, p15/CDKN2B, p14/ARF, CDH1, HIC1, and N33 5 regions in non-small cell lung cancer (51 tumors). Methylation was observed for the two suppressor genes involved in controlling the cell cycle through the Cdk–Rb–E2F signaling pathway, RB1 (10/51, 19%) and p16 (20/51, 39%). The highest methylation frequencies were established for CDH1 (72%) and HIC1 (82%). The CpG islands of p14 and p15 proved to be nonmethylated. At least one gene was methylated in 90% (46/51) tumors and no gene, in 10% (5/51) tumors. In addition, the genes were tested for methylation in peripheral blood lymphocytes of healthy subjects. Methylation frequency significantly differed between tumors and normal cells in the case of RB1, p16, CDH1, HIC1, and N33. Gene methylation frequency was tested for association with histological type of the tumor and stage of tumor progression. Methylation index of a panel of tumor suppressor genes was established for groups of tumors varying in clinical and morphological parameters.     

Single Circulating-Tumor-Cell-Targeted Sequencing to Identify Somatic Variants in Liquid Biopsies in Non-Small-Cell Lung Cancer Patients

Non-small-cell lung cancer (NSCLC) accounts for most cancer-related deaths worldwide. Liquid biopsy by a blood draw to detect circulating tumor cells (CTCs) is a tool for molecular profiling of cancer using single-cell and next-generation sequencing (NGS) technologies. The aim of the study was to identify somatic variants in single CTCs isolated from NSCLC patients by targeted NGS. Thirty-one subjects (20 NSCLC patients, 11 smokers without cancer) were enrolled for blood draws (7.5 mL). CTCs were identified by immunofluorescence, individually retrieved, and DNA-extracted. Targeted NGS was performed to detect somatic variants (single-nucleotide variants (SNVs) and insertions/deletions (Indels)) across 65 oncogenes and tumor suppressor genes. Cancer-associated variants were classified using OncoKB database. NSCLC patients had significantly higher CTC counts than control smokers (p = 0.0132; Mann–Whitney test). Analyzing 23 CTCs and 13 white blood cells across seven patients revealed a total of 644 somatic variants that occurred in all CTCs within the same subject, ranging from 1 to 137 per patient. The highest number of variants detected in ≥1 CTC within a patient was 441. A total of 18/65 (27.7%) genes were highly mutated. Mutations with oncogenic impact were identified in functional domains of seven oncogenes/tumor suppressor genes (NF1, PTCH1, TP53, SMARCB1, SMAD4, KRAS, and ERBB2). Single CTC-targeted NGS detects heterogeneous and shared mutational signatures within and between NSCLC patients. CTC single-cell genomics have potential for integration in NSCLC precision oncology.     

Molecular Markers of Various Stages of Non-Small-Cell Lung Cancer

Studies performed in the recent decade in the Laboratory of the Regulation of Cell and Virus Oncogenes associated structural and functional defects of several oncogenes and tumor suppressor genes with various stages of non-small-cell lung cancer. High risk of lung cancer was established for carriers of rare alleles of the Hras1 minisatellite, the hypermethylated p16 ^INK4A promoter, and microsatellite defects in chromosome regions 3p12, 3p14.2, 3p22–24, 3p21, 3p25, 9p21, and 17p13. Analysis of the Hras1 minisatellite and microsatellites located in two minimal deletion overlap regions of 1p36 was shown to allow a more reliable prognosis in lung cancer. The results testified again that panels of molecular markers are useful for individual risk assessment, early and differential diagnosis, and prognosis in cancer.     

The Association between COX-2 Polymorphisms and Hematologic Toxicity in Patients with Advanced Non-Small-Cell Lung Cancer Treated with Platinum-Based Chemotherapy

Background and Objective

Overexpression of COX-2 is proved to contribute to tumor promotion and carcinogenesis through stimulating cell proliferation, inhibiting apoptosis and enhancing the invasiveness of cancer cells. Apoptosis-related molecules are potential predictive markers for survival and toxicity in platinum treatment. This study aimed at investigating the association between COX-2 polymorphisms and the occurrence of grade 3 or 4 toxicity in advanced non–small cell lung cancer patients treated with platinum-based chemotherapy.

Materials and Methods

Two hundred and twelve patients with inoperable stage IIIB-IV NSCLC received first-line chemotherapy between 2007 and 2009 were recruited in this study. Four functional COX-2 polymorphisms were genotyped by PCR-based restriction fragment length polymorphism (RFLP) methods.

Results

The incidence of grade 3 or 4 hematologic toxicity was significantly higher in G allele carriers of the COX-2 rs689466 (−1195G/A) polymorphism compared with wild-type homozygotes AA (P value = 0.008; odds ratio, 2.47; 95% confidence internal, 1.26–4.84) and the significance still existed after the Bonferroni correction. Statistically significant difference was also found in grade 3 or 4 leukopenia (P value = 0.010; OR = 2.82; 95%CI = 1.28–6.20). No other significant association was observed between genotype and toxicity in the study. The haplotype analysis showed that the haplotype AGG was associated with a reduced risk of grade 3 or 4 hematologic and leukopenia toxicity (P value = 0.009; OR = 0.59; 95%CI = 0.39–0.88 and P value = 0.025; OR = 0.61; 95%CI = 0.39–0.94, respectively) while the haplotype GGG was associated with an increased risk of grade 3 or 4 hematologic and leukopenia toxicity (P value = 0.009; OR = 1.71; 95%CI = 1.14–2.56 and P value = 0.025; OR = 1.65; 95%CI  = 1.06–2.57, respectively).

Conclusion

This investigation for the first time suggested that polymorphism in COX-2 rs689466 may be a potent bio-marker in predicting severe hematologic toxicity in NSCLC patients after platinum-based chemotherapy.