胸腔镜辅助单孔与多孔肺段切除术治疗早期NSCLC的应用价值

目的探讨胸腔镜下单孔与多孔肺段切除术对早期非小细胞肺癌(Non-small cell lung cancer,NSCLC)患者代谢反应及心肺耐力的影响。方法选取2017年6月-2022年10月南通市第一人民医院早期NSCLC患者92例,根据简单随机数字表法分为多孔组与单孔组,各46例。单孔组采取胸腔镜单孔肺段切除术,多孔组采取胸腔镜多孔肺段切除术。比较两组围术期情况、术前及术后3 d代谢反应指标[视黄醇结合蛋白(Retinol-binding protein,RBP)、转铁蛋白(Transferrin,TRF)、前白蛋白(Prealbumin,PA)]水平、心肺耐力[6 min步行距离(6 min walking distance,6MWT)、疲劳指数、呼气峰流速(Peak expiratory velocity,PEF)、第1 s用力呼气容积(Forced expiratory volume 1 s,FEV1)]和并发症发生率。结果(1)两组手术时长、淋巴结清扫数目比较,差异无统计学意义(P>0.05),单孔组术中失血量、引流量少于多孔组,引流管放置时间、住院时长短于多孔组,差异有统计学意义(P<0.05)。(2)术后3 d两组PA、TRF、RBP水平较术前下降,但单孔组PA、TRF、RBP水平高于多孔组,差异有统计学意义(P<0.05)。(3)术后3 d两组6MWT、PEF、FEV1较术前降低,疲劳指数较术前增高,但单孔组6MWT、PEF、FEV1高于多孔组,疲劳指数低于多孔组,差异有统计学意义(P<0.05)。(4)单孔组并发症发生率(4.35%)低于多孔组(17.39%),差异有统计学意义(P<0.05)。结论采取胸腔镜单孔及多孔肺段切除术治疗早期NSCLC均可取得良好效果,但单孔术式可减少失血量,对代谢状态及心肺耐力影响较小,利于机体功能及早康复,且可降低并发症发生风险。

炙甘草汤加减联合PD-1治疗晚期NSCLC(气阴两虚型)的疗效

目的:分析炙甘草汤加减联合程序性死亡受体1(programmed cell death protein-1,PD-1)治疗晚期非小细胞肺癌(nonsmall cell lung cancer,NSCLC)(气阴两虚型)的临床疗效。方法:回顾性分析2020年12月至2022年12月就诊于吉林省肿瘤医院、长春中医药大学附属医院的晚期NSCLC(气阴两虚型)患者72例,随机分为两组各36例,对照组(PD-1单抗)、治疗组(PD-1单抗联合炙甘草汤加减)。主要观察指标为免疫功能(CD3^(+)、CD3^(+)/CD4^(+)、CD3^(+)/CD8^(+))和生存质量评分(KPS),次要观察指标为客观缓解率(objective response rate,ORR)、中医症候积分、血清肿瘤标志物癌胚抗原(CEA)、神经元特异性烯醇化酶(NSE)、细胞角蛋白片段(CYFRA211)、免疫相关不良反应(胃肠毒性、肺毒性、肝毒性、甲状腺毒性)发生率。结果:治疗组在调节免疫功能CD3^(+)、CD3^(+)/CD4^(+)、CD3^(+)/CD8^(+),提高患者生存质量在T3时间点、T4时间点、降低肿瘤标志物CEA、CY211、改善中医证候咳嗽、乏力、心悸、腹泻的症状和减少免疫相关性肺炎、腹泻方面,均优于对照组(P<0.05)。两组患者客观缓解率分别为治疗组36.1%,对照组25.0%,无显著性差异(P>0.05)。结论:炙甘草汤加减联合PD-1治疗晚期NSCLC的患者,可以显著增强免疫功能,提高临床疗效,减少免疫相关不良反应且安全性较好。

血清CCL-20、PDGF-BB、CYFRA21-1水平对NSCLC患者靶向治疗效果的预测价值

目的分析血清趋化因子配体20(CCL-20)、血小板源性生长因子BB(PDGF-BB)、细胞角化素蛋白片段19(CYFRA21-1)对非小细胞肺癌(NSCLC)患者靶向治疗效果的预测价值。方法选取进行靶向治疗的79例中晚期NSCLC患者,均持续治疗2月,评价患者近期疗效。收集患者一般临床资料,并于治疗前后分别检测患者血清趋化因子CCL-20、PDGF-BB、CYFRA21-1水平,比较不同疗效患者间相关资料差异,分析影响疗效的因素,并利用ROC分析血清趋化因子CCL-20、PDGF-BB、CYFRA21-1水平预测近期疗效的价值。结果79例中晚期NSCLC患者均完成2个月的靶向治疗,治疗总有效率为45.57%(36/79)。有效组共36例,无效组(SD+PD)共43例,2组年龄、性别、病理类型相较无差异(P>0.05);有效组TNMⅢB期、高分化占比高于无效组(P<0.05);有效组治疗前后血清CCL-20、PDGF-BB、CYFRA21-1水平均低于无效组(P<0.05)。多因素Logistic回归分析结果显示,治疗前血清CCL-20、PDGF-BB、CYFRA21-1水平为影响疗效的独立因素(OR=9.574,10.903,11.156,P<0.05)。ROC分析结果显示,治疗前血清CCL-20、PDGF-BB、CYFRA21-1水平均具有预测临床疗效的价值(AUC=0.775,0.896,0.669,P<0.05)。结论中晚期NSCLC患者血清CCL-20、PDGF-BB、CYFRA21-1水平与靶向治疗效果有关,可作为靶向治疗近期疗效评估的辅助性指标。

凝血指标预测立体定向治疗NSCLC脑转移疗效

目的:分析凝血指标对非小细胞肺癌(non-small cell lung cancer,NSCLC)脑转移患者立体定向放射外科(stereotactic ra-dio surgery,SRS)治疗预后的预测价值。方法:回顾性收集2015年10月至2018年9月在天津市环湖医院确诊为NSCLC脑转移并行SRS治疗的512例患者临床资料,分析总体生存(overall survival,OS)率与无进展生存(progression-free survival,PFS)率,运用Cox多因素分析影响预后相关因素,并基于Cox多因素分析绘制工作特征(receiver operating characteristic,ROC)曲线,运用曲线下面积(area under the ROC curve,AUC)分析凝血指标对NSCLC脑转移行SRS治疗患者预后的预测价值。结果:1、2、3、4年的PFS分别为79.9%、69.9%、56.6%、43.2%,OS分别为93.4%、83.2%、69.9%、57.6%。吸烟、纤维蛋白原(fibrinogen,Fib)<3.22 g/L、凝血酶原时间(prothrombin time,PT)<11.69 s、D-二聚体(D-dimer,D-D)<0.51μg/L与较长的PFS率相关(P<0.05);活化部分凝血活酶时间(activated partial thromboplastin time,APTT)<21.05 s、Fib<3.22 g/L、D-D<0.51μg/mL与较长的OS率相关(P<0.05)。吸烟、Fib<3.22 g/L、D-D<0.51μg/mL与较长的PFS率显著相关(P<0.05);Fib<3.22 g/L、D-D<0.51μg/mL与较长的OS率显著相关(P<0.05)。Fib与D-D联合检测预测NSCLC脑转移患者SRS治疗预后的AUC显著高于Fib与D-D单独检测(P<0.05)。结论:凝血指标与SRS治疗的NSCLC脑转移患者预后有一定相关性,Fib与D-D为患者预后独立危险因素,可用于评估其预后,两组指标联合评估价值可能更优,具有进一步深入研究的价值。

外周血标志物检测识别免疫检查点抑制剂治疗NSCLC免疫相关毒性风险的临床观察

目的探讨外周血标志物识别免疫检查点抑制剂(ICIs)治疗晚期非小细胞肺癌(NSCLC)免疫相关毒性(irAE)风险的临床意义。方法回顾性分析2018年8月至2023年4月在右江民族医学院附属医院接受ICIs的195例晚期NSCLC患者,随访并记录irAE。比较irAE与患者临床病理特征的关系。采用Kaplan-Meier法绘制无进展生存时间(PFS)曲线,生存差异行Log-rank检验。采用Logistic多因素回归模型分析影响irAE的因素。采用受试者工作特征(ROC)曲线评价外周血标志物对irAE的诊断效能。采用R软件构建列线图。结果全组患者中位随访时间为7.91个月(1.0~45.63个月),ICIs的中位给药周期为4(1~49)个周期。57例患者发生irAE,主要包括肺炎、腹泻、脂肪酶/淀粉酶升高和皮肤反应等。irAE组患者基线NLR、PLR、MLR和LDH水平高于无irAE患者(P<0.001)。与无irAE组患者比较,发生irAE患者的ORR更高(47.37%vs.25.36%;P=0.003)。无irAE组患者的中位PFS(313天,95%CI:242~383天)略长于irAE组(235天,95%CI:199~270天),差异无统计学意义(P=0.144)。Logistic多因素回归分析显示,NLR、PLR和ICIs治疗情况是影响irAE的独立因素(P<0.05)。训练队列和验证队列的C指数接近,分别为0.71和0.75。校准曲线的拟合度较高,证实了该列线图具有较高的预测值。结论基线NLR和PLR及多线治疗ICIs可能是影响晚期NSCLC患者irAE的因素。

阿帕替尼联合埃克替尼治疗EGFR基因21号外显子L858R突变型NSCLC的临床观察

目的探究对表皮生长因子受体(EGFR)基因21号外显子L858R突变型非小细胞肺癌(NSCLC)采用阿帕替尼联合埃克替尼治疗的临床效果。方法将EGFR基因21号外显子L858R突变型NSCLC患者101例按随机数表法分为观察组(n=51)与对照组(n=50)。观察组采用阿帕替尼联合埃克替尼治疗,对照组仅采用埃克替尼治疗,治疗时间为56 d,2个周期。比较2组近期疗效、不良反应,并采用K-M生存分析曲线图分析2组远期疗效。结果观察组与对照组的客观缓解率(ORR)(74.51%vs 74.00%)与疾病控制率(DCR)(92.16%vs 94.00%)差异均无统计学意义(P>0.05);治疗期间2组未出现2级以上不良反应,观察组高血压和蛋白尿发生率分别为52.94%、50.98%,分别高于对照组的16.00%、10.00%,差异有统计学意义(P<0.05)。观察组生存率显著高于对照组(69.3%vs 43.1%),差异有统计学意义(P<0.05)。结论EGFR基因21号外显子L858R突变型NSCLC采用阿帕替尼联合埃克替尼治疗,可延长患者的无进展生存时间,不良反应的发生可接受。

Analysis and Review of Downregulated Actin Cytoskeletal Proteins in Non-Small Cell Lung Cancer

Actin, a highly conserved protein, plays a dominant role in Non-small cell lung cancer (NSCLC). Late diagnosis and the aggressive nature of NSCLC pose a significant threat. Studying the clinic pathological properties of NSCLC proteins is a potential alternative for developing treatment strategies. Towards this, 35 downregulated actin cytoskeletal proteins on NSCLC prognosis and treatment were studied by examining their protein-protein interactions, gene ontology enrichment terms, and signaling pathways. Using PubMed, various proteins in NSCLC were identified. The protein-protein interactions and functional associations of these proteins were examined using the STRING database. The focal adhesion signaling pathway was selected from all available KEGG and Wiki pathways because of its role in regulating gene expression, facilitating cell movement and reproduction, and significantly impacting NSCLC. The protein-protein interaction network of the 35 downregulated actin cytoskeleton proteins revealed that ACTG1, ACTR2, ACTR3, ANXA2, ARPC4, FLNA, TLN1, CALD1, MYL6, MYH9, MYH10, TPM1, TPM3, TPM4, PFN1, IQGAP1, MSN, and ZXY exhibited the highest number of interactions. Whereas HSPB1, CTNNA1, KRT17, KRT7, FLNB, SEPT2, and TUBA1B displayed medium interactions, while UTRN, TUBA1B, and DUSP23 had relatively fewer interactions. It was discovered that focal adhesions are critical in connecting membrane receptors with the actin cytoskeleton. In addition, protein kinases, phosphatases, and adapter proteins were identified as key signaling molecules in this process, greatly influencing cell shape, motility, and gene expression. Our analysis shows that the focal adhesion pathway plays a crucial role in NSCLC and is essential for developing effective treatment strategies and improving patient outcomes.

Physical exercise reverses immuno-cold tumor microenvironment via inhibiting SQLE in non-small cell lung cancer

Dear Editor,Physical exercise has been shown to be associated with reduced cancer incidence and cancer-associated mortality[1,2],but the underlying mechanisms are obscure.Immunometabolic regulation has emerged as one of the most prominent mechanisms explaining the effects of exercise on cancer[1,2].Physical exercise primarily lowers blood cholesterol and triglycerides,and protects against cardiovascular diseases[3].However,whether physical exercise can modulate cholesterol metabolism in tumor cells is currently unknown.

Piperlongumine in combination with EGFR tyrosine kinase inhibitors for the treatment of lung cancer cells

Objectives:EGFR tyrosine kinase inhibitor(EGFR-TKI)therapies such as erlotinib and gefitinib are approved for the treatment of non-small cell lung cancer(NSCLC).However,the high incidence of acquired resistance to these EGFR-TKIs may preclude their effectiveness.Piperlongumine(PPL),an extract from the long pepper fruit(Piper longum),has been shown to possess anticancer properties.The purpose of the study was to investigate piperlongumine as an anticancer agent and to study a combination treatment approach with EGFR-TKIs against lung cancer cells.Methods:Anticancer efficacy of PPL,erlotinib(ERL),gefitinib(GEF),and cisplatin(CIS)were investigated in H1299 and H1975 cell lines.Cells were treated with PPL,ERL,GEF,and CIS alone,and in combination,cell viability was determined after 72 h.The mechanism of PPL-induced cytotoxicity was investigated via reactive oxygen species(ROS)induction,and apoptosis induction using acridine orange/ethidium bromide staining and flow cytometry.The effect of treatment on EGFR-mediated oncogenic signaling was investigated by immunoblotting for mitogenic and apoptotic markers.Results:PPL exhibited a potent cytotoxic effect in H1299 and H1975 cells compared to ERL,GEF,and CIS.Combination treatments of PPL with GEF and ERL showed significant reductions in cancer cells compared to control in both cell lines,which were associated with apoptotic induction,but without significant ROS induction.Compared to control,PPL with GEF significantly increased apoptotic cell death in H1975as confirmed with flow cytometry.Treatment with PPL alone and in combination induced anti-mitogenic and apoptotic responses at the molecular level.Conclusion:PPL sensitized lung cancer cells to EGFR-TKI and induced potent cytotoxic effects at low concentrations.

Predictive factors associated with gefitinib response in patients with advanced non-small-cell lung cancer(NSCLC)

Purpose： A number of different clinical characteristics have been reported to singly correlate with therapeutic activity of epidermal growth factor receptor （EGFR） tyrosine kinase inhibitors （TKIs） in advanced non-small-cell lung cancer （NSCLC）. This study aimed to identify predictive factors associated with prognostic benefits of gefitinib. Patients and methods： EGFR gene typing in 33 advanced NSCLC patients received gefitinib （250 mg/day） were analyzed with mutant-enriched PCR assay. Gefitinib response was evaluated with potential predictive factors retrospectively. Results： The overall objective response rate （ORR） and median progression-flee survival （PFS） in the 33 patients treated by gefitinib were 45.5% and 3.0 （2.0-4.0） months. The ORR and median PFS in EGFR gene mutation patients were significantly higher/longer than those in EGFR gene wild-type patients （P〈0.01）. Similarly, the ORR and median PFS in non-smoker patients were significantly higher/longer than those in smoker patients （P〈0.05, P〈0.01, respectively）. However, no difference for ORR and median PFS occurred between male and female patients. Logistic multivariate analysis showed that only EGFR mutated gene was significantly associated with the ORR （P〈0.01）. Both EGFR mutated gene and non-smoker were the major factors that contributed to PFS （P〈0.05）. Conclusions： EGFR mutated gene and non-smoker status are potential predictors for gefitinib response in NSCLC patients.

Clinical Biomarkers and Prognosis in Taiwan Residents Patients with Non-Small Cell Lung Cancer (NSCLC)

Introduction: Lung cancer is the leading cause of cancer death worldwide with poor survival rates. However, the prognostic factors for survival of patients with lung cancer are not well-established. In this study, we examined the impact of routine laboratory biomarkers and traditional factors on survival of patients with non-small cell lung cancer (NSCLC). Method: Secondary data analysis was conducted from a retrospective study of 404 patients with newly diag-nosed lung cancer in 2005-2007 in Taiwan. There were eight routine laboratory biomarkers and eight traditional factors investigated in the analyses. Cox proportional hazards model was used to assess the hazard ratios for the association between risk factors and patient overall survival. The Kaplan-Meier method was used to compare survival curves for each prognostic indicator. Results: High WBC counts (HR = 1.798, 95%CI: 1.225 - 2.639), low Hgb level (HR = 1.437, 95%CI: 1.085 - 1.903), and low serum albumin level (HR = 2.049, 95%CI: 1.376 - 3.052) were significant laboratory prognostic biomarkers for poor NSCLC survival. Additionally we confirmed the traditional prognostic factors for poor overall survival among NSCLC patients, including older age, comorbidity conditions, advanced cancer stage, and non-surgical treatment. Conclusions: This study identified three available laboratory biomarkers, high WBC counts, low Hgb level, and low serum albumin level, to be significant prognostic factors for poorer overall survival in NSCLC patients. Further prognostic evaluation studies are warranted to compare different ethnic groups on the prognostic values of these clinical parameters in NSCLC survival outcomes. These identified prognostic biomarkers should be included in early risk screening of hospitalized lung cancer patient population.

Single nucleotide polymorphisms of MAGE-A3 gene and its clinical implications in Chinese patients with non-small cell lung cancer(NSCLC)

Background： Available study revealed advanced tumors have a higher expression rate of MAGE-A3 gene which has a lot of single nucleotide polymorphism（SNP） loci with polymorphisms. This study aimed to analyze the allele frequency of SNP loci in MAGE-A3 gene and investigate the relationship between MAGE-A3 gene polymorphisms and clinical factors.Methods： Tumor samples of a cohort of 191 NSCLC patients were collected. EGFR m RNA expression were detected by q RT-PCR. SNPs in whole length of MAGE-A3 gene were detected by direct sequencing. Frequencies of the SNPs were correlated to gene expression, mutation status of EGFR and clinical factors.Results： Sequencing analysis confirmed that allele frequencies of genotypes on SNP loci rs5970360, rs5925210, rs5970361, rs5925211 and rs35123853 were CC（0.681）/CT（0.319）, CC（0.660）/CG（0.340）, CC（0.681）/CA（0.319）, AA（0.984）/AT（0.016） and GG（1.000）/GA（0.000）, respectively, which were different from the frequencies and genotypes of MAGE-A3 in SNP database. Chi-square tests showed the EGFR mR NA expression level had significant correlation with the genotypes of SNP loci rs5970360 and rs5925210. But all frequencies of each MAGE-A3 SNPs were not found significantly different between EGFR mutant and wild type patients. MAGE-A3 gene polymorphisms had no significant effects on survival of NSCLC patients.Conclusions： Chinese patients with NSCLC had different SNP patterns of MAGE-A3 in comparison with those in international SNP database. These MAGE-A3 SNP loci might have not prognostic significance. MAGE-A3 SNP loci rs5970360 and rs5925210 might be predictive for EGFR m RNA expression levels and helpful to the selection of patients for epidermal growth factor receptor（EGFR） targeted immunotherapy.

大分割容积旋转调强放疗与常规分割动态调强放疗治疗老年NSCLC的近期疗效观察

目的比较大分割容积旋转调强放疗与常规分割动态调强放疗治疗老年非小细胞肺癌(NSCLC)的近期疗效和不良反应。方法选择2020年1月至2021年9月南部战区海军第一医院肿瘤放疗科收治的66例老年NSCLC患者为研究对象,按随机数表法分为研究组和对照组各33例,研究组患者开展大分割容积旋转调强放射治疗,对照组患者实施常规分割动态调强放射治疗,两组共治疗4周。比较两组患者治疗4周后的疗效、不良反应和危及器官的受量;比较两组患者治疗前及治疗4周后的肿瘤标志物[癌胚抗原(CEA)、糖抗原125(CA125)]、T淋巴细胞亚群[T淋巴细胞(CD3^(+))、辅助性T细胞(CD4^(+))、细胞毒性T细胞(CD8^(+))、CD4^(+)/CD8^(+)]、血小板-淋巴细胞比值(PLR)和中性粒细胞-淋巴细胞比值(NLR)。结果研究组患者的治疗总有效率为84.85%,明显高于对照组的60.61%,差异有统计学意义(P<0.05);研究组患者的总不良反应发生率为12.12%,明显低于对照组的36.36%,危及心脏、肺部、脊髓的受量明显低于对照组,差异均有统计学意义(P<0.05);治疗前,两组患者的肿瘤标志物、T淋巴细胞亚群、PLR、NLR比较差异均无统计学意义(P>0.05);治疗后,研究组患者的CEA、CA125、PLR、NLR、CD3^(+)、CD4^(+)、CD4^(+)/CD8^(+)明显低于对照组,但CD8^(+)明显高于对照组,差异均有统计学意义(P<0.05)。结论与常规分割动态调强放疗治疗比较,大分割容积旋转调强放射治疗老年NSCLC的效果更好,其不仅能够改善肿瘤标志物,减少不良反应,减轻炎性反应及免疫抑制,同时还能降低危及器官的受量,值得临床推广应用。

Non-platinum doublets versus single agents in non-small cell lung cancer （NSCLC） patients with elderly age and/or poor performance status： a meta-analysis

Objective： The aim of the study was to compare the efficacies and toxicities of non-platinum doublets （doublets group） with a non-platinum single agent （single-agent group） in previously untreated advanced non-small cell lung cancer （NSCLC） patients with elderly age and/or poor performance status （PS）. Methods： The PubMed database was screened. Subsequently, the hazard ratios （HRs） for overall survival （OS） and progression-free survival （PFS）, relative risks （RRs） for overall response rate （ORR） and one-year survival, and odds ratios （ORs） for the different types of toxicities were pooled using the Review Manager 5.0 package. Results： This study comprised of 1427 patients enrolled in four randomized controlled trials. The pooled HR showed that the doublet group could increase ORR （P = 0.002） with no heterogeneity （P = 0.64）, and might improve OS （P = 0.01 / P = 0.06） with heterogeneity （P 0.001）. There was no significant difference in PFS （P = 0.16） and one-year survival （P = 0.25） between two treatment groups. The doublet group led to more grade 3/4 neutropenia and thrombocytopenia than the single-agent group （P = 0.02 and P = 0.000, respectively）. The incidences of grade 3/4 anemia, vomiting, mucositis, constipation, diarrhea, neurotoxicity, allergy, and fatigue between the two treatment groups were insignificant. Conclusion： Except for neutropenia and thrombocytopenia, the non-platinum doublets could increase ORR, and might improve OS for NSCLC patients with elderly age and/or poor PS without addition of more side effects; however, the doublets showed an increased rate of neutropenia and thrombocytopenia. The addition of doublets may not improve PFS and one-year survival.

Expressions and significance of Survivin,MDR1 and MRP in non-small cell lung cancer (NSCLC)

Objective： To investigate the expressions and significance of Survivin, MDR1 and MRP in non-small cell lung cancer （NSCLC）. Methods： Immunohistochemical staining was used to detect the expressions of Survivin, MDR1 and MRP. The correlation between the results was assessed and the impact of Survivin on prognoses was also examined. Results： Survivin was expressed in 78% tissues from NSCLC patients but not found in tissues from control patients （P 〈 0.05）. The expression of Survivin was related to the tissue differentiation stage and lymph nodes metastasis of lung cancer. The mean survival time was shorter in patients with Survivin-expression than those who not. There was a significant correlation between MDR1 and Survivin （P 〈 0.05）, whereas no close correlation was found between MRP and Survivin. Conclusion： （1） Survivin is of critical importance in the development of NSCLC, thus may provide an novel therapeutic target for lung cancer; （2） MDR1 and MRP present in tissues from lung cancer synergistically with Survivin, which might be involved in turnout resistance.

TERT基因在非小细胞肺癌易感性及预后中的研究进展

肺癌是世界上最常见的恶性肿瘤之一,具有很高的死亡率,85%的肺癌患者组织学类型为非小细胞肺癌(non-small cell lung cancer,NSCLC)。非小细胞肺癌的预后较差,与诊断晚、复发风险高、药物耐药等有关。端粒酶是细胞存活的关键酶,它能维持细胞端粒的长度,使细胞具有无限增殖和永生化的潜能。端粒酶逆转录酶(TERT基因编码)是端粒酶的催化亚基,能激活端粒酶,为细胞提供癌变的可能。TERT启动子突变被证明是激活端粒酶的一种新的遗传机制,并存在于多种人类肿瘤中。端粒酶激活和端粒损伤与人类肺癌的发生有关,且TERT基因多态性与非小细胞肺癌的易感性及预后有关。本文总结了TERT启动子突变及TERT多态性在非小细胞肺癌中的研究,以及它对非小细胞肺癌预后的影响及靶向治疗前景。

Integrated A nalysis of CircRN A-miRNA-mRNA Network Reveals Potential Prognostic Biomarkers for Radiotherapy in Non-small Cell Lung Cancer(NSCLC)

CIRT(carbon ion radiotherapy)is considered to be one of the effective treatment modalities against NSCLC.However,limited clinical CIRT facilities are unable to meet all patients'demands.

赛沃替尼治疗MET基因突变非小细胞肺癌的药物浓度与疗效和不良反应的关系

目的:探讨药物浓度与疗效和不良反应之间的关系,了解赛沃替尼治疗MET14外显子跳跃突变晚期非小细胞肺癌患者的疗效和安全性。方法:回顾性分析2018年4月至2019年9月北京大学肿瘤医院收治的携带MET14外显子跳跃突变,并且接受赛沃替尼治疗的16例局部晚期或转移性非小细胞肺癌患者的临床资料及其血浆药物浓度,评估赛沃替尼治疗的疗效和安全性,分析药物浓度与疗效及不良反应的相关性。随访患者的无进展生存期(progression-free survival,PFS)和总生存期(overall survival,OS),采用Kaplan-Meier法计算中位PFS和OS。结果:16例患者中男性9例(56.3%),年龄范围51~84岁。肺癌病理类型包括:腺癌11例,肉瘤样癌5例,鳞癌1例。赛沃替尼的客观缓解率为50.0%(8/16),疾病控制率达到87.5%(14/16)。评效达到部分缓解患者和未达到者相比,赛沃替尼的药物谷浓度分别为77.2 ng/mL和146.7 ng/mL(P=0.06)。治疗中出现过2级以上不良反应的患者和仅出现过1级不良反应者,其药物谷浓度分别为116.5 ng/mL和93.2 ng/mL(P=0.59)。所有患者的中位PFS为8.5个月,中位OS为14.1个月。结论:赛沃替尼治疗MET基因突变非小细胞肺癌的效果较好,不良反应可耐受。常规用药剂量下,赛沃替尼的血浆药物谷浓度与疗效可能存在一定负相关,但药物浓度与不良反应的程度无明显相关性。

miR-218-5p靶向PDE7A调节人非小细胞肺癌A549细胞的糖酵解

目的:探究miR-218-5p靶向磷酸二酯酶7A(PDE7A)调节人非小细胞肺癌(NSCLC)A549细胞糖酵解过程的机制。方法:常规培养A549细胞,用Lipo3000将miR-218-5pmimic、mimic-NC、PDE7A过表达质粒(PDE7A-oe)和PDE7A对照质粒(PDE7A-NC)转染A549细胞,记为miR-218-5pmimic组、mimic-NC组、PDE7A-oe组和PDE7A-NC组。qPCR法验证转染效率,WB法检测糖酵解关键酶蛋白的表达,葡萄糖测定法和乳酸生成测定法检测各转染组A549细胞中2脱氧葡萄糖和乳酸含量,双萤光素酶报告基因实验验证miR-218-5p与PDE7A靶向结合关系,用TCGA数据库数据分析PDE7AmRNA在肺癌组织中的表达水平。结果:在A549细胞中成功地过表达了miR-218-5p(P<0.01)。过表达miR-218-5p均能显著抑制A549细胞中PDE7A、HK2、PKM2蛋白的表达(均P<0.01)、葡萄糖摄取量和乳酸生成量(均P<0.01)。过表达PDE7A均可显著促进A549细胞中PDE7A、HK2、PKM2蛋白的表达(均P<0.01),以及葡萄糖摄取量和乳酸生成量(均P<0.01)。A549细胞中miR-218-5p可与PDE7AmRNA的3´-UTR直接结合。数据库数据分析结果显示,PDE7AmRNA在肺鳞状细胞癌组织中呈高表达(P<0.01)。结论:miR-218-5p靶向PDE7A调控A549细胞中HK2和PKM2的表达水平,进而抑制糖酵解过程,miR-218-5p/PDE7A可能是NSCLC临床诊断和治疗的潜在靶点。

Biological insights in non-small cell lung cancer

Lung oncogenesis relies on intracellular cysteine to overcome oxidative stress.Several tumor types,including non-small cell lung cancer(NSCLC),upregulate the system x-c cystine/glutamate antiporter(xCT)through overexpression of the cystine transporter SLC7A11,thus sustaining intracellular cysteine levels to support glutathione synthesis.Nuclear factor erythroid 2-related factor 2(NRF2)serves as a master regulator of oxidative stress resistance by regulating SLC7A11,whereas Kelch-like ECH-associated protein(KEAP1)acts as a cytoplasmic repressor of the oxidative responsive transcription factor NRF2.Mutations in KEAP1/NRF2 and p53 induce SLC7A11 activation in NSCLC.Extracellular cystine is crucial in supplying the intracellular cysteine levels necessary to combat oxidative stress.Disruptions in cystine availability lead to iron-dependent lipid peroxidation,thus resulting in a type of cell death called ferroptosis.Pharmacologic inhibitors of xCT(either SLC7A11 or GPX4)induce ferroptosis of NSCLC cells and other tumor types.When cystine uptake is impaired,the intracellular cysteine pool can be sustained by the transsulfuration pathway,which is catalyzed by cystathionine-B-synthase(CBS)and cystathionine g-lyase(CSE).The involvement of exogenous cysteine/cystine and the transsulfuration pathway in the cysteine pool and downstream metabolites results in compromised CD8^(+)T cell function and evasion of immunotherapy,diminishing immune response and potentially reducing the effectiveness of immunotherapeutic interventions.Pyroptosis is a previously unrecognized form of regulated cell death.In NSCLCs driven by EGFR,ALK,or KRAS,selective inhibitors induce pyroptotic cell death as well as apoptosis.After targeted therapy,the mitochondrial intrinsic apoptotic pathway is activated,thus leading to the cleavage and activation of caspase-3.Consequently,gasdermin E is activated,thus leading to permeabilization of the cytoplasmic membrane and cell-lytic pyroptosis(indicated by characteristic cell membrane ballooning).Breakthroughs in KRAS G12C allele-specific inhibitors and potential mechanisms of resistance are also discussed herein.