Treatment outcome for patients with primary NSCLC and synchronous solitary metastasis

Introduction

Non-small cell lung cancer (NSCLC) patients with synchronous solitary metastasis were generally considered as stage IV and believed to be incurable. Recently, growing evidence has indicated that surgical treatment may provide these patients with a survival benefit. The aim of this study was to retrospectively analyze the effectiveness of different treatments for primary tumors and solitary metastases.

Materials and methods

Patients older than 18 years with histologically confirmed stage IV NSCLC and a confirmed synchronous solitary metastasis that diagnosed within 2 months of primary NSCLC. Patients with uncontrolled massive pleural effusion were excluded. Between February 2002 and October 2010, 213 patients were considered eligible and enrolled in this cohort.

Results

The median survival time (MST) for the 213 patients was 12.6 months. Forty-five patients received primary pulmonary tumor surgery in the entire cohort. The MSTs of patients who received primary tumor resection and those who did not were 31.8 and 11.4 months (p < 0.01). The MST of the patients with solitary brain metastasis was 12.3 months. Forty-one patients who received brain surgical treatment or SRS had a MST of 15.4 months and others who only received WBRT had a MST of 11.5 months (p = 0.002). Gender, the stage of the primary tumor, PS and whether the primary tumor was removed all affected prognosis independently.

Conclusions

Aggressive local and metastasis treatments could lead to better clinical outcomes and thus provide an option for clinicians in the future management of patients with NSCLC and synchronous solitary metastasis.     

MicroRNA-328 is associated with (non-small) cell lung cancer (NSCLC) brain metastasis and mediates NSCLC migration

Brain metastasis (BM) can affect ～ 25% of nonsmall cell lung cancer (NSCLC) patients during their lifetime. Efforts to characterize patients that will develop BM have been disappointing. microRNAs (miRNAs) regulate the expression of target mRNAs. miRNAs play a role in regulating a variety of targets and, consequently, multiple pathways, which make them a powerful tool for early detection of disease, risk assessment, and prognosis. We investigated miRNAs that may serve as biomarkers to differentiate between NSCLC patients with and without BM. miRNA microarray profiling was performed on samples from clinically matched NSCLC from seven patients with BM (BM+) and six without BM (BM-). Using t-test and further qRT-PCR validation, eight miRNAs were confirmed to be significantly differentially expressed. Of these, expression of miR-328 and miR-330-3p were able to correctly classify BM+ vs. BM- patients. This classifier was used on a validation cohort (n = 15), and it correctly classified 12/15 patients. Gene expression analysis comparing A549 parental and A549 cells stably transfected to over-express miR-328 (A549-328) identified several significantly differentially expressed genes. PRKCA was one of the genes over-expressed in A549-328 cells. Additionally, A549-328 cells had significantly increased cell migration compared to A549 cells, which was significantly reduced upon PRKCA knockdown. In summary, miR-328 has a role in conferring migratory potential to NSCLC cells working in part through PRKCA and with further corroboration in additional independent cohorts, these miRNAs may be incorporated into clinical treatment decision making to stratify NSCLC patients at higher risk for developing BM.     

趋化因子受体CCR7在NSCLC与转移淋巴结中的表达关系及意义

背景与目的恶性肿瘤的靶向转移是近年来研究的热点,研究已经证实恶性肿瘤的转移是一种非随机的、有组织器官选择性的高度组织化的过程,本研究通过对趋化因子受体CCR7在非小细胞肺癌及其转移淋巴结中的表达状况进行分析,初步探讨趋化因子受体CCR7在非小细胞肺癌中的表达及其与淋巴结转移之间的关系和意义。方法用兔抗人CCR7抗体免疫组化染色检测肺腺癌17例,鳞癌17例,腺鳞癌12例,大细胞肺癌4例和转移淋巴结28例中CCR7的表达情况。阴性对照标本采用炎性假瘤5例,正常肺组织20例。结果判定在双盲法下进行,每张切片由两名病理医师分别判断。结果1.CCR7在癌组织和转移淋巴结中的表达高于正常肺组织(P<0.005);2.转移淋巴结中CCR7表达与癌组织中CCR7的表达相比无差异(P=0.177);3.CCR7在癌组织中的表达与淋巴结转移相关,淋巴结转移组高于无淋巴结转移组(P=0.016);4.随着临床分期的增加,CCR7表达有增高趋势(P=0.003)。结论CCR7蛋白主要在肺癌肿瘤细胞与转移淋巴结中表达,而在正常肺组织中未见表达,其表达水平可能与非小细胞肺癌淋巴转移有关。     

The expression of BTG1 is downregulated in NSCLC and possibly associated with tumor metastasis

This study aimed to analyze the expression, clinical significance of B cell translocation gene 1 (BTG1) in nonsmall cell lung cancer (NSCLC) and the biological effect in its cell line by BTG1 overexpression. Immunohistochemistry and western blot were used to analyze BTG1 protein expression in 82 cases of NSCLC and 38 cases of normal tissues to study the relationship between BTG1 expression and clinical factors. Recombinant lentiviral vector was constructed to overexpress EMP-1 and then infect NSCLC H1299 cell line. Quantitative real-time RT-PCR and western blot were used to detect the mRNA level and protein of BTG1. 3-[4,5-dimethylthiazol -2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, cell apoptosis, cell cycles, and migration and invasion assays were also conducted as to the influence of the upregulated expression of BTG1 that might be found on H1299 cells biological effect. The level of BTG1 protein expression was found to be significantly lower in NSCLC tissue than normal tissues (P?<?0.05). Decreased expression of BTG1 was significantly correlated with lymph node metastasis, clinic stage, and histological grade of patients with NSCLC (P?<?0.05). Meanwhile, loss of BTG1 expression correlated significantly with poor overall survival time by Kaplan–Meier analysis (P?<?0.05). The result of biological function show that H1299 cell transfected BTG1 had a lower survival fraction; higher percentage of the G0/G1 phases; higher cell apoptosis; significant decrease in migration and invasion; and lower CyclinD1, Bcl-2, and MMP-9 protein expression compared with H1299 cell untransfected BTG1 (P?<?0.05). BTG1 expression decreased in NSCLC and correlated significantly with lymph node metastasis; clinical stage; histological grade; poor overall survival; cell proliferation; cell cycles; cell apoptosis; and migration and invasion in NSCLC cell by regulating CyclinD1, Bcl-2, and MMP-9 protein expression, suggesting that BTG1 may play important roles as a negative regulator to NSCLC cell.     

MiR-204 inhibits human NSCLC metastasis through suppression of NUAK1

Background:

Lung cancer is a leading cause of cancer-related mortality worldwide and non-small-cell lung carcinoma (NSCLC) is responsible for almost 80% of lung cancer-related deaths. Identifying novel molecules that can repress the invasiveness and metastasis of lung cancer will facilitate the development of new antilung cancer strategies. The aim of this study is to determine the roles of NUAK1 (a downstream of Akt) and miR-204 in the invasiveness and metastasis of NSCLC and to reveal the correlation between NUAK1 and miR-204.

Methods:

The expression of NUAK1 in primary human NSCLC tissues was evaluated by immunohistochemistry. Real-time PCR was employed to measure the expression level of miR-204. The effect of NUAK1 and miR204 on the prognosis of NSCLC patients was evaluated by log-rank test. The siRNA transfection was used to manipulate the expression levels of NUAK1 and miR204 in cancer cells. Chemotaxis assay, Scratch assay, and Matrigel invasion assay were performed to evaluate the migration and invasion of cells. Cellular F-actin measurement was used to measure F-actin polymerisation in lung cancer cells. Western blot was used to detect the expression levels of corresponding proteins. The Luciferase assay and RNA immunoprecipitation were used to confirm the actual binding site of miR-204 to 3′UTR of NUAK1.

Results:

Increased expression of NUAK1 is correlated with the invasiveness and metastasis of human NSCLC. Knockdown of NUAK1 inhibited cell migration and invasion. In addition, this study showed that NUAK1 influenced mTOR phosphorylation and induced the phosphorylation of p70S6K1 and eukaryotic initiation factor 4E-binding protein1 (4E-BP1), two downstream targets of mTOR in NSCLC cells. At the same time, decreased expression of miR-204 promoted NSCLC progression and, contrarily, manipulated upregulation of miR-204-inhibited cell migration and invasion. There is clinical relevance between miR-204 downregulation and NUAK1 upregulation in human NSCLC. Furthermore, we found that miR-204 inhibited NSCLC tumour invasion by directly targeting and downregulating NUAK1 expression. Finally, our data suggested that the downregulation of miR-204 was due to hypermethylation of its promoter region.

Conclusions:

Our results indicate that NUAK1 is excessively expressed in NSCLC and plays important roles in NSCLC invasion. The miR-204 acts as a tumour suppressor by inhibiting NUAK1 expression in NSCLC. Both NUAK1 and miR-204 may serve as potential targets of NSCLC therapy.     

PET在非小细胞肺癌患者术前N分期的价值

目的：探讨正电子发射断层显像（fludeoxyglu-cose positron emission tomography,FDGPET）检查在非小细胞肺癌（non-small cell lung cancer,NSCLC）术前纵隔淋巴结及肺门淋巴结癌转移方面的判定价值。方法：将术前作全身PET检查的62例非小细胞肺癌患者,行肺癌切除及淋巴结清除后得到的病理结果,与术前PET检查结果相对照,从敏感性、特异性和准确率方面得出结论。结果：PET对术前NSCLC患者纵隔淋巴结癌转移的评估中,其敏感性约为85.7%,特异性约为93.7%,准确率约为91.9%;PET对术前NSCLC患者肺门淋巴结癌转移的评估中,其敏感性约为54.2%,特异性约为89.5%,准确率约为75.8%。结论：就无创性检查而言,在NSCLC患者术前的“N”分期中,PET检查是目前最好的辅助手段,对帮助临床医师术前评估NSCLC患者的临床分期、制定治疗策略有一定的价值。     

MTA家族蛋白表达与非小细胞肺癌侵袭转移的相关性探讨

目的:探讨肿瘤转移相关基因(matastasis associated gene,MTA)家族蛋白作为非小细胞肺癌（non-small cell lung cancer,NSCLC）预后预测因子的价值,为进一步了解该基因家族与肿瘤侵袭和转移相关的分子机制提供参考。方法:应用免疫组化(SABC)检测MTA家族（MTA1、MTA2、MTA3）蛋白在54例NSCLC肿瘤组织中的表达水平,分析与NSCLC临床病理特征的关系;选取正常肺上皮细胞BEAS-2B、肺癌高转移细胞株95-D与低转移细胞株95-C,对比MTA1在其中的表达与细胞侵袭转移的相关性。结果:MTA1、MTA2和MTA3在NSCLC组织中均有较高的表达,而MTA1表达水平与淋巴结转移状态相关;细胞学实验结果显示MTA1在肿瘤细胞中高表达,而MTA1在肺癌高转移细胞95-D中的表达水平显著高于低转移细胞95-C。结论:MTA1表达水平与肿瘤侵袭、转移关系密切,可考虑作为肿瘤转移、预后预测因子。     

GP方案治疗手术后局部复发或肺内转移非小细胞肺癌的临床研究

目的观察GP方案治疗手术后局部复发或肺内转移非小细胞肺癌的疗效及毒性反应。方法对48例手术后局部复发或肺内转移病例应用GP方案化疗,给药方法:吉西他滨1000mg/m2,第1、8、15天,静脉点滴:DDP 20 mg,第1~5天,静脉点滴,28 d为一个周期,均常规化疗4个周期以上。结果CR 4例(鳞癌),PR 23例(其中鳞癌9例,腺癌14例),NC 14例,PD 5例,总有效率56.2%(其中鳞癌40.7%,腺癌76.2%)。局部复发病灶有效率58.3%(7/12),肺内多发转移结节可测病灶共238处,有效率63.9%(152/238)。结论GP方案对晚期及术后复发、转移NSCLC疗效满意,毒副反应可以耐受。     

TP及BCNU同步全脑放射治疗非小细胞肺癌脑转移的临床观察

目的:观察分析TP方案及卡莫司汀(BCNU)同步全脑放射治疗非小细胞肺癌(NSCLC)脑转移的疗效、生存率以及不良反应.方法:32例NSCLC脑转移初治患者接受TP方案.紫杉醇130 mg/m2,24 h持续静脉输注,顺铂(DDP)20 mg/m2,d1～d3,3周为1个周期;脑部放疗与TP方案同时开始,2 Gy/d,5 d/周,脑转移灶1～3个者全脑放疗40 Gy后缩野至60 Gy,脑转移灶＞3个者全脑放疗至40 Gy,放疗开始20 Gy后予BCNU80 mg/m2,d1～d3,6周为1个周期.结果:治疗后84.3%患者神经系统症状得到改善,对脑转移灶有效率为68.7%,对肺原发灶有效率为53.1%,中住总生存期(MST)11.4个月(95%CI为9.48～13.31),1、2和5年生存率分别为40.6%、18.2%和7.3%,单纯脑转移MST 13.0个月,显著高于多脏器转移9.7个月(P=0.035).常见不良反应为白细胞减少,Ⅲ～Ⅳ度发生率50.0%,经对症治疗后好转,恶心、呕吐,肌肉关节痛以Ⅰ～Ⅱ度为主.结论:TP方案及BCNU联合全脑放射治疗NSCLC脑转移的近期疗效高并延长了中位生存期,毒副反应耐受性好,可考虑作为NSCLC脑转移的治疗方案.     

CCR7上调MMP-9表达促进非小细胞肺癌转移

背景与目的 趋化因子激素受体(CC chemokine receptor 7,CCR7)与非小细胞肺癌(non-small celllung cancer,NSCLC)的淋巴结转移密切相关,但CCR7促进其淋巴结转移的机制尚不明了.本研究通过观察CCR7和MMP.9在NSCLC组织中的表达和相互关系.探讨CCR7促进NSCLC淋巴结转移的机制.方法 应用免疫组织化学染色(SP法)检测90例NSCLC组织中CCR7、MMP-9的表达;将BEI细胞经趋化因子CCLl9处理24 hA,应用RT-PCR和Western blot方法检测MMP-9 mRNA和蛋白表达水平.结果 免疫组织化学结果显示:CCR7主要表达于癌细胞胞质和(或)胞膜,MMP-9主要表达于癌细胞胞质,NSCLC中CCR7、MMP.9阳性表达率分别为70%(63/90)和65.5%(59/90),X2检验显示CCR7和MMP-9表达与NSCLC的临床病理分期(P=0.003,P=0.001)和淋巴结转移(P=0.0042 P=0.003)密切相关,而与年龄、组织学类型、分化程度无关(P>0.05).此外,CCR7和MMP-9表达正相关(r=0.342,P=0.001).CCL21处理组BEI细胞后MMP-9 mRNA和蛋白水平均上调(P<0.05).结论 CCR7和MMP-9表达与NSCLC侵袭转移密切相关,CCL19/CCR7通过上调NSCLC中MMP-9表达促进其转移.     

Mitochondrial translocation of EGFR regulates mitochondria dynamics and promotes metastasis in NSCLC

Dysfunction of the mitochondria is well-known for being associated with cancer progression. In the present study, we analyzed the mitochondria proteomics of lung cancer cell lines with different invasion abilities and found that EGFR is highly expressed in the mitochondria of highly invasive non-small-cell lung cancer (NSCLC) cells. EGF induces the mitochondrial translocation of EGFR; further, it leads to mitochondrial fission and redistribution in the lamellipodia, upregulates cellular ATP production, and enhances motility in vitro and in vivo. Moreover, EGFR can regulate mitochondrial dynamics by interacting with Mfn1 and disturbing Mfn1 polymerization. Overexpression of Mfn1 reverses the phenotypes resulting from EGFR mitochondrial translocation. We show that the mitochondrial EGFR expressions are higher in paired samples of the metastatic lymph node as compared with primary lung tumor and are inversely correlated with the overall survival in NSCLC patients. Therefore, our results demonstrate that besides the canonical role of EGFR as a receptor tyrosine, the mitochondrial translocation of EGFR may enhance cancer invasion and metastasis through regulating mitochondria dynamics.     

非小细胞肺癌外周血抗Hu抗体水平与远处转移的相关性

目的：检测非小细胞肺癌（non-small cell lung cancer,NSCLC）患者外周血抗Hu抗体水平与健康志愿者抗Hu抗体水平进行比较,并分析其与肿瘤转移部位和多种临床病理变量间的关系。方法： 收集济南军区总医院肿瘤科2013年6月至2013年12月NSCLC患者外周血清标本75例,同时收集成年健康志愿者外周血清标本100例（除外肿瘤及神经系统疾病史）作为阴性对照,按照酶联免疫吸附试验原理,检测175例血清抗Hu抗体表达。纳入研究的变量主要包括：75例NSCLC患者的性别、年龄、组织类型、核分化级别、EGFR突变状态、肿瘤标志物（CEA、CY21-1和NSE）水平及远处转移部位（脑转移、骨转移及其他部位转移）。结果： 肺癌患者外周血抗Hu抗体水平\[（40.00±35.76) ng/ml\]显著高于健康人群\[（16.40±819) ng/ml, P=0.000\]。75例患者中有62.67%（47/75）抗Hu抗体高水平表达,37.33%(28/75)呈低表达。外周血抗Hu抗体水平与患者脑转移（P=0.015）显著相关;81.81%（9/11）的脑转移患者检测到高水平的抗Hu抗体,但仅仅50.00%（32/64）的非脑转移患者检测到高水平的抗Hu抗体;抗Hu抗体水平与患者性别、年龄、组织类型、分期、EGFR突变、CEA水平、CY21-1、NSE、骨转移及其他部位转移无关（P>0.05）。多变量回归分析显示,外周血中抗Hu抗体水平是预测脑转移的独立变量（P=0.015）。结论：非小细胞肺癌患者外周血中抗Hu抗体呈高水平,与脑转移显著相关。抗Hu抗体在非小细胞肺癌脑转移中的作用机制尚需进一步明确。     

人类第9号染色体微卫星改变与非小细胞肺癌发生及转移的关系

目的 探讨人类第９号染色体短臂（９ｐ）上微卫星改变与肺癌发生及转移的相关性。方法 应用聚合酶链反应（ＰＣＲ）结合微卫星银染分析方法检测３２例非小细胞肺癌（ＮＳＣＬＣ）组织中两个微卫星标志物ＩＦＮＡ和Ｄ９Ｓ１７１的改变。结果 ３２例ＮＳＣＬＣ患者中,１４例（４３．８％）出现了微卫星标志物改变。其中伴有淋巴结转移的肺癌组织微中微卫星改变检出率为６４．７％,不伴转移的肺癌组织中微卫星改变检出率为２０％,     

局部晚期非小细胞肺癌三维适形放疗同步化疗的临床观察

为了评价三维适形放疗同步紫杉醇+顺铂化疗治疗局部晚期非小细胞肺癌(NSCLC)的疗效和放射反应,对收治的65例不能手术的Ⅲ期NSCLC患者进行三维适形放疗加同步化疗,化疗方案全部采用PC方案:紫杉醇75 mg/m2,d1、d8静脉滴入;顺铂30 mg/m2、d1～d3静脉滴入,每21 d为1个周期.放疗设备采用西门子直线加速器,6 MV-X线,CT模拟定位,放疗中位剂量60 Gy,6周完成.靶区为原发肿瘤及受侵的纵隔淋巴结区,放射治疗结束后2个月评价疗效.CR 8例(12.3%),PR 45例(69.2%),无变化12例(18.5%),总有效率(CR+PR)81.5%.1年生存率72.3%(47/65).急性毒副反应主要是骨髓抑制、放射性食管炎和放射性肺炎,以1～2级为主,7例(10.8%)出现3级骨髓抑制.晚期毒副反应均为1～2级放射性肺炎.初步研究结果提示,三维适形放疗结合紫杉醇+顺铂化疗治疗局部晚期NSCLC耐受性较好,均可完成治疗计划,短期疗效好,远期疗效有待进一步观察.     

非小细胞肺癌淋巴结切除数量及转移状况对预后影响的研究

目的：分析非小细胞肺癌（non-small cell lung cancer，NSCLC）淋巴结（1ymph node，LN）切除数量及不同LN转移状况对预后的影响。方法：对接受手术同时切除LN的1575例肺癌患者，分析LN切除数量以及LN转移范围、数量和转移率。结果：LN切除数量影响预后，N0期患者切除7～13个LN者5年生存率优于≤6和≥13个LN者，P值分别为0．001和0．021；N1、N2患者切除LN〉12个者5年生存率优于≤6和≥13个LN者，P值分别为0．000和0．003；N0期患者5年生存率优于N1、N2患者，P=0．000；N，期和“跳跃式”N2期患者5年生存率优于“连续式”N2期患者，P值分别为0．003和0．002；单站LN转移者5年生存率明显优于多站LN转移者，P=0．000；转移LN数为1、2个者5年生存率明显优于〉2个者，P=0．000；LN转移率分为〈25％、25％～50％、50％～75％及≥75％，生存期依次降低。结论：LN切除数量影响NSCLC预后，一般术中应切除7～13个LN；LN转移范围、数量及转移率均影响NSCLC的术后生存期。     

非小细胞肺癌淋巴结切除数量及转移状况对预后影响的研究

目的:分析非小细胞肺癌(non-small cell lung cancer,NSCLC)淋巴结(lymph node,LN)切除数量及不同LN转移状况对预后的影响。方法:对接受手术同时切除LN的1575例肺癌患者,分析LN切除数量以及LN转移范围、数量和转移率。结果:LN切除数量影响预后,N0期患者切除7~13个LN者5年生存率优于≤6和≥13个LN者,P值分别为0.001和0.021;N1、N2患者切除LN>12个者5年生存率优于≤6和≥13个LN者,P值分别为0.000和0.003;N0期患者5年生存率优于N1、N2患者,P=0.000;N1期和"跳跃式"N2期患者5年生存率优于"连续式"N2期患者,P值分别为0.003和0.002;单站LN转移者5年生存率明显优于多站LN转移者,P=0.000;转移LN数为1、2个者5年生存率明显优于>2个者,P=0.000;LN转移率分为<25%、25%~50%、50%~75%及≥75%,生存期依次降低。结论:LN切除数量影响NSCLC预后,一般术中应切除7~13个LN;LN转移范围、数量及转移率均影响NSCLC的术后生存期。