核苷酸切除修复交叉互补基因1 mRNA表达与非小细胞肺癌铂类化疗患者预后的相关性

目的 探讨核苷酸切除修复交叉互补基因1(ERCC1)mRNA表达与非小细胞肺癌(NSCLC)铂类化疗患者临床病理特征的关系及其预后意义.方法 采用实时荧光定量逆转录聚合酶链反应(RT-PCR)方法,检测NSCLC石蜡包埋组织中ERCC1 mRNA的表达水平,并比较其表达水平与NSCLC铂类化疗患者临床病理特征和生存时间之间的关系.结果 61例NSCLC患者中,ERCC1 mRNA的中位表达量为0.48.ERCC1 mRNA表达与NSCLC患者临床病理特征无关.ERCC1mRNA低表达(<0.35)患者经铂类药物化疗后的无进展生存时间为14.3个月,而高表达者为8.0个月,差异有统计学意义(P=0.028).ERCC1 mRNA低表达(<0.28)患者的总生存时间为28.4个月,而高表达者为12.9个月,差异有统计学意义(P=0.0064).Cox多因素回归分析显示,ERCC1 mRNA表达水平是影响NSCLC患者预后的独立因素.结论 ERCC1 mRNA的表达水平可以作为以铂类为基础药物化疗的NSCLC患者预后的独立预测因素,ERCC1 mRNA低表达的NSCLC患者经铂类化疗后,总生存时间明显延长,为制定NSCLC个体化的化疗方案提供了重要信息.     

多药耐药基因及其表达产物对非小细胞肺癌化疗疗效影响的Meta分析

目的:应用循证医学方法评价多药耐药基因及其表达产物对非小细胞肺癌化疗疗效影响。方法:计算机检索中国学术期刊数据库(1990-2010)及MEDLINE(1990-2010),纳入有关MDR1/P-gp表对非小细胞肺癌化疗疗效影响的随机对照试验组,对纳入的文献进行质量评分,并提取有效数据进行分析。结果:共检索出相关文献176篇,经过层层筛选,有8个符合标准的研究被纳入,合计301例患者。Meta分析结果显示:MDR1/P-gp(+)与MDR1/P-gp(-)的非小细胞肺癌患者相比,MDR1/P-gp(+)可降低化疗疗效,其OR为0.16(95%CI 0.05-0.47),P=0.001,差异有统计学意义。进而对纳入的研究进行分层分析后发现,研究质量评分≥8分的研究Meta分析结果显示优势比OR=0.11(95%CI 0.02-0.78),P=0.03;研究质量评分<8分的研究Meta分析结果显示优势比OR=0.18(95%CI 0.08-0.38),P<0.00001,差异均有统计学意义。结论:目前研究表明MDR1/P-gp表达阳性患者的化疗疗效优于MDR1/P-gp表达阴性的患者。     

多药耐药基因及其表达产物对非小细胞肺癌化疗疗效影响的Meta分析

目的：应用循证医学方法评价多药耐药基因及其表达产物对非小细胞肺癌化疗疗效影响。方法：计算机检索中国学术期刊数据库（1990-2010）及MEDLINE（1990-2010）,纳入有关MDR1/P-gp表对非小细胞肺癌化疗疗效影响的随机对照试验组,对纳入的文献进行质量评分,并提取有效数据进行分析。结果：共检索出相关文献176篇,经过层层筛选,有8个符合标准的研究被纳入,合计301例患者。Meta分析结果显示：MDR1/P-gp（＋）与MDR1/P-gp（-）的非小细胞肺癌患者相比,MDR1/P-gp（＋）可降低化疗疗效,其OR为0.16（95%CI 0.05-0.47）,P=0.001,差异有统计学意义。进而对纳入的研究进行分层分析后发现,研究质量评分≥8分的研究Meta分析结果显示优势比OR=0.11（95%CI 0.02-0.78）,P=0.03;研究质量评分〈8分的研究Meta分析结果显示优势比OR=0.18（95%CI 0.08-0.38）,P〈0.00001,差异均有统计学意义。结论：目前研究表明MDR1/P-gp表达阳性患者的化疗疗效优于MDR1/P-gp表达阴性的患者。     

Surgical adjuvant chemotherapy in non-small cell lung cancer

In two different controlled prospective randomized trials the Lung Cancer Study Group has shown that adjuvant CAP chemotherapy is effective in prolonging the disease-free survival. These studies indicate that the adjuvant chemotherapy has its effect by way of diminishing systemic recurrences and that the adjuvant therapy is more effective in non-squamous than in squamous disease. In addition, the benefit of the treatment is more apparent in patients with more advanced, though resectable, disease. It is also becoming clear that chemotherapy either alone or in combination with radiation therapy can result in relatively high response rates in patients with disease localized to the thorax. Indeed, many of these individuals can then undergo surgical resection. It remains to be determined, however, whether or not this preoperative therapy will be effective in prolonging survival. In the future it is quite likely that optimum therapy will involve the use of preoperative treatment either with chemotherapy alone or a combination of chemotherapy and radiation therapy, followed postoperatively with adjuvant chemotherapy with a non-cross resistant regimen. In addition, a major problem is brain recurrences. Indeed the brain was the most frequent site of first recurrence systemically in many of these studies. Thus, more effective therapy directed at CNS disease will have to be developed before major breakthroughs can be anticipated in the surgical adjuvant therapy of lung cancer.     

化疗前后 NLR、血小板计数对评估晚期非小细胞肺癌患者预后的价值

目的：探讨化疗前后中性粒细胞／淋巴细胞比值（NLR）、血小板计数对晚期非小细胞肺癌（NSCLC）患者预后的判断价值。方法选取河南省安阳市肿瘤医院2011年10月—2012年12月收治的70例晚期 NSCLC 患者为研究对象,收集化疗前及化疗2周期后 NLR 及血小板水平。NLR 以中位数3．43为界,分低 NLR 及高 NLR 组;血小板≥300×109／L 为血小板升高组,100×109／L ＜血小板＜300×109／L为正常组。化疗2周期后根据 NLR 变化,分为3组：①化疗前低 NLR 组;②化疗前高 NLR化疗后降为低 NLR 组;③化疗前高 NLR 化疗后仍为高 NLR 组。根据化疗前后血小板计数的变化分为3组：①化疗前血小板正常组;②化疗前血小板升高化疗后降至正常组;③化疗前血小板升高化疗后仍为升高组。对比不同组患者的临床病理特征和远期生存。结果低 NLR 组、高 NLR 组患者中位生存时间分别为16．0、12．5个月,差异有统计学意义（χ2＝3．654,P ＝0．041）。血小板正常组、升高组中位生存时间分别为14．3、10．0个月,差异有统计学意义（χ2＝5．358,P ＝0．021）。化疗前后 NLR 变化3组患者的中位生存时间分别为14．5、12．1、9．0个月,差异有统计学意义（χ2＝7．701,P ＝0．021）。血小板计数变化3组患者中位生存时间分别为14．3、13．1、10．4个月,差异有统计学意义（χ2＝12．775,P ＝0．002）。COX 多因素分析显示 NLR（RR ＝1．467,95％CI 为1．014～2．124,χ2＝4．130,P ＝0．042）、血小板（RR ＝1．631,95％CI 为1．108～2．402,χ2＝6．137,P ＝0．013）和 TNM分期（RR ＝1．380,95％CI 为1．052～1．809,χ2＝5．420,P ＝0．020）均是影响晚期 NSCLC 患者预后的独立预后因素。结论化疗前 NLR 和血小板计数与患者不良预后有关,NLR 和血小板升高,患者生存期缩短。     

Postoperative adjuvant chemotherapy for non-small cell lung cancer

Patients with completely resected non-small-cell lung cancer (NSCLC) are subjects for postoperative adjuvant treatment. Recently, several randomized trials with a large number of enrolled patients have shown that platinum-based chemotherapy has potential for improving survival among patients with completely resected NSCLC in Western countries. In Japan, uracil-tegafur was also shown to improve survival among patients with completely resected stage I adenocarcinoma. This review evaluated the role of adjuvant chemotherapy, based on the results of randomized trials and meta-analyses.     

MicroRNA expression and clinical outcomes in patients treated with adjuvant chemotherapy after complete resection of non-small cell lung carcinoma

This study determined whether expression levels of a panel of biologically relevant microRNAs can be used as prognostic or predictive biomarkers in patients who participated in the International Adjuvant Lung Cancer Trial (IALT), the largest randomized study conducted to date of adjuvant chemotherapy in patients with radically resected non-small cell lung carcinoma (NSCLC). Expression of miR-21, miR-29b, miR-34a/b/c, miR-155, and let-7a was determined by quantitative real-time PCR in formalin-fixed paraffin-embedded tumor specimens from 639 IALT patients. The prognostic and predictive values of microRNA expression for survival were studied using a Cox model, which included every factor used in the stratified randomization, clinicopathologic prognostic factors, and other factors statistically related to microRNA expression. Investigation of the expression pattern of microRNAs in situ was performed. We also analyzed the association of TP53 mutation status and miR-34a/b/c expression, epidermal growth factor receptor and KRAS mutation status, and miR-21 and Let-7a expression. Finally, the association of p16 and miR-29b expression was assessed. Overall, no significant association was found between any of the tested microRNAs and survival, with the exception of miR-21 for which a deleterious prognostic effect of lowered expression was suggested. Otherwise, no single or combinatorial microRNA expression profile predicted response to adjuvant cisplatin-based chemotherapy. Together, our results indicate that the microRNA expression patterns examined were neither predictive nor prognostic in a large patient cohort with radically resected NSCLC, randomized to receive adjuvant cisplatin-based chemotherapy versus follow-up only.     

Optimizing the use of adjuvant chemotherapy in non-small cell lung cancer patients with comorbidities

Veterans with locoregional non-small cell lung cancer (NSCLC) may benefit from adjuvant chemotherapy. However, comorbidities and other factors may impact the harms and benefits of this treatment. Here, we identified the optimal indications for adjuvant chemotherapy in Veterans with NSCLC, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), and/or coronary artery disease (CAD). We used data from randomized controlled trials (RCTs) and Veterans Administration (VA) databases to enhance a simulation model. Then, we conducted in-silico RCTs comparing adjuvant chemotherapy vs observation among Veterans with stage II-IIIA NSCLC. Among Veterans without COPD or CKD, adjuvant chemotherapy was the optimal strategy regardless of the presence or absence of CAD except for patients >70 years with squamous cell carcinoma. Conversely, most veterans without COPD but with CKD were optimally managed with observation. Veterans with COPD but without CKD, benefited from adjuvant chemotherapy if they were ≤70 years with stage II-IIIA adenocarcinoma or <60 years with stage II-IIIA squamous cell carcinoma. Adjuvant chemotherapy was only beneficial for Veterans with both COPD and CKD among stage II-IIIA adenocarcinoma <60 years of age. Veterans with stages II-IIIA squamous cell carcinoma, COPD, and CKD were optimally managed with observation. Many Veterans with comorbidities are optimally managed with observation post-surgical resection. However, we also identified several groups of Veterans whom the benefits of adjuvant chemotherapy outweighed the risks of early toxicity. Our findings could inform patient-provider discussions and potentially reduce physicians’ uncertainty about the role of adjuvant chemotherapy in this population.     

螺旋断层放疗治疗转移性非小细胞肺癌的预后分析

目的 探讨转移性非小细胞肺癌（NSCLC）患者接受螺旋断层放疗后的预后情况及其影响因素。方法 对本院2011年6月至2013年2月采用螺旋断层放疗技术治疗的51例转移性NSCLC患者的临床资料进行回顾性分析。所有靶区的中位放疗剂量为42.5 Gy（30～62 Gy）,单次放疗的中位剂量2 Gy（1.8～3 Gy）。应用Kaplan-Meier法计算生存率,Log-rank检验比较组间的生存差异,Cox风险比例回归模型分析影响预后的各种因素。结果 所有患者随访时间均超过1年。51例转移性NSCLC患者的中位生存时间为19.3个月,1年生存率为64.7％。单因素分析显示,KPS评分高、病理类型为腺癌、放疗前接受过化疗、无肝转移和所有病灶计划靶区体积（PTV）≤1300 cm³是NSCLC患者预后良好的影响因素（P＜0.05）;Cox多因素分析显示KPS评分、放疗前是否化疗和所有病灶PTV是转移性NSCLC患者采用螺旋断层放疗的独立预后因素。结论 转移性NSCLC采用螺旋断层放疗对延长患者的生存时间及改善预后可能有重要意义。     

Topoisomerase II alpha expression and the benefit of adjuvant chemotherapy for postoperative patients with non-small cell lung cancer

Background  

Adjuvant chemotherapy has been shown to improve survival rates of postoperative patients with non-small cell lung cancer (NSCLC). Biomarkers could help select an appropriate chemotherapy for NSCLC patients or predict the efficacy of chemotherapy. The objective of this study was to explore the possible prognostic and predictive role of topoisomerase II alpha (TopIIα) expression level in postoperative NSCLC patients who received adjuvant chemotherapy.     

非小细胞肺癌预后影响因素分析

目的:探讨非小细胞肺癌(NSCLC)患者的预后相关因素。方法:对2005年6月-2006年6月我院收治的162例非小细胞肺癌患者的临床、病理资料进行回顾性研究,采用Kaplan-Meier和COX回归方法分析评价各因素对预后的影响。结果:单因素分析表明KPS评分、手术与否、临床分期、治疗状况及治疗前血小板(PLT)、癌胚抗原(CEA)和神经元特异性烯醇化酶(NSE)的水平与NSCLC患者的预后有关。多因素分析表明,临床分期、治疗状况、血小板及血清癌胚抗原的水平是独立的预后影响因素。临床分期Ⅳ期、未治疗、PLT>300×109/L、CEA>5.0μg/L时,相对危险度(RR)分别为5.524、16.096、3.563、2.607。结论:治疗前血小板、血清CEA的水平、临床分期及治疗情况是NSCLC患者独立的预后影响因素。     

Heat shock protein 70 as a predictive marker for platinum-based adjuvant chemotherapy in patients with resected non-small cell lung cancer

Objectives

Although adjuvant platinum-based chemotherapy improves survival in completely resected non-small cell lung cancer (NSCLC), its effect is limited. We evaluated whether the expression of heat shock protein 70 (Hsp70) is associated with clinical outcomes in patients with completely resected NSCLC who were treated with or without adjuvant platinum-based chemotherapy.

Patients and methods

Patients who underwent curative resection for NSCLC and diagnosed as stage IIA through IIIA were included. Immunohistochemical staining for Hsp70 was performed on surgical specimens and survival rates were compared by Hsp70 expression and adjuvant platinum-based chemotherapy.

Results

Of 327 enrolled patients, Hsp70 expression was positive in 220 (67.3%). For patients who did not receive adjuvant chemotherapy, Hsp70 expression did not significantly affect survival. However, for patients who received adjuvant chemotherapy, those with Hsp70-positive tumors had a longer disease-free survival outcome than cases with Hsp70-negative tumors (not reached vs. 27.3 months; P = 0.002), although there was no significant difference in overall survival (97.0 vs. 58.9 months, P = 0.080). In the adjuvant chemotherapy group, multivariate modeling showed that patients with Hsp70-postitive tumors had a lower risk of recurrence and death after adjusting for age, sex, performance status, pathologic stage, and histological type (disease-free survival: adjusted hazard ratio, 0.537; 95% CI, 0.362–0.796; P = 0.002; overall survival: adjusted hazard ratio, 0.663; 95% CI, 0.419–1.051; P = 0.080).

Conclusion

Hsp70 is a positive predictive factor in completely resected NSCLC with received platinum-based adjuvant chemotherapy.     

Prognostic value of xanthine oxidoreductase expression in patients with non-small cell lung cancer

Background

Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in the purine metabolism pathway. Lack of XOR expression is associated with unfavorable clinical outcomes. The objective of this study was to correlate XOR expression with prognosis in surgically resected non-small cell lung cancer (NSCLC).

Methods

Immunohistochemical staining was performed on deparaffinized specimens from 82 patients with stage I-IV NSCLC using a polyclonal anti-XOR rabbit antibody. Cytoplasmic XOR staining was scored on frequency and intensity scales from 0 to 4 with low expression defined as 0-1 and high expression defined as ≥2-4. XOR immunostaining was correlated with clinical characteristics and outcomes and analyzed using Kaplan-Meier and Cox proportional hazard methods.

Results

Positive XOR expression was observed in 53/82 cases (65%). Patients with high XOR frequency had a longer median survival of 3053 days (95% CI: 2190-3916) vs. 592 days (95% CI: 492-692 days) for patients with low XOR frequency, p = 0.0089, HR 0.47. Neither XOR intensity nor the overall score of XOR frequency multiplied by XOR intensity demonstrated any significant association with survival. Surgical resection was performed on 61 patients of which 34 (56%) received adjuvant chemotherapy. Patients who received adjuvant chemotherapy with low XOR expression, 15/34 (44%) had a shortened median survival compared with patients who received adjuvant chemotherapy with high XOR expression (543 days vs. 2023 days, respectively, p = 0.007 and HR = 0.33).

Conclusion

Low XOR expression was associated with shortened survival and also conferred a worse prognosis for patients with NSCLC who received adjuvant chemotherapy. Further studies of the XOR pathway are warranted to validate and mechanistically explain these outcomes.     

PD-L1 protein expression assessed by immunohistochemistry is neither prognostic nor predictive of benefit from adjuvant chemotherapy in resected non-small cell lung cancer

BackgroundThe expression of programmed death (PD) ligand 1 (PD-L1) protein expression assessed by immunohistochemistry (IHC) has been correlated with response and survival benefit from anti-PD-1/PD-L1 immune checkpoint inhibitor therapies in advanced non-small cell lung carcinoma (NSCLC). The efficacy of several agents appears correlated with PD-L1 expression. It remains controversial whether PD-L1 is prognostic in NSCLC. We assessed the prognostic value of PD-L1 IHC and its predictive role for adjuvant chemotherapy in early stage NSCLC.Patients and methodsTumor sections from three pivotal adjuvant chemotherapy trials (IALT, JBR.10, CALGB 9633) using the E1L3N antibody were studied in this pooled analysis. PD-L1 staining intensity and percentage in both tumor cells (TCs) and immune cells (ICs) were scored by two pathologists. The average or consensus PD-L1 expression levels across intensities and/or percent cells stained were correlated with clinicopathological and molecular features, patient survivals and potential benefit of adjuvant chemotherapy.ResultsResults from 982 patients were available for analysis. Considering staining at any intensities for overall PD-L1 expression, 314 (32.0%), 204 (20.8%) and 141 (14.3%) tumor samples were positive for PD-L1 staining on TCs using cut-offs at ≥1%, ≥10% and ≥25%, respectively. For PD-L1 expressing ICs, 380 (38.7%), 308 (31.4%) and 148 (15.1%) were positive at ≥ 1%, ≥10% and 25% cut-offs, respectively. Positive PD-L1 was correlated with squamous histology, intense lymphocytic infiltrate, andKRAS but not withTP53 mutation.EGFR mutated tumors showed statistically non-significant lower PD-L1 expression. PD-L1 expression was neither prognostic with these cut-offs nor other exploratory cut-offs, nor were predictive for survival benefit from adjuvant chemotherapy.ConclusionsPD-L1 IHC is not a prognostic factor in early stage NSCLC patients. It is also not predictive for adjuvant chemotherapy benefit in these patients.     

Ⅳ期NSCLC化疗同期三维放疗的预后再分析

目的 进一步分析Ⅳ期NSCLC化疗同期三维放疗的预后因素。方法 对2003—2010年前瞻性入组201例Ⅳ期NSCLC患者重新进行预后评价,包括依据放疗剂量>36 Gy的159例OS的影响因素分析,以及120例PFS的影响因素分析。化疗以铂类为基础的两药联合方案,中位周期数4个。原发肿瘤中位放疗剂量63 Gy。Kaplan-Meier法计算生存率并Logrank检验,Cox模型预后多因素分析时间从最长的3年延长至5年。结果 全组201例1、2、3、5年OS及中位生存期分别为40.1%、17.3%、10.2%、5.1%及10个月。近期疗效中CR、PR、SD、PD分别为7.5%、66.0%、19.5%、6.9%,其中位生存期分别为19、13、8、6个月(P=0.000)。化疗4~5周期同期≥63 Gy与<63 Gy患者1、2、3、5年PFS和中位生存期分别为77.4%、36.2%、27.2%、15.9%和20个月与32.6%、21.7%、0%、0%和9个月(P=0.002)。4~5周期化疗、疗后KPS稳定或增加、GTV<175 cm³为OS影响因素(P=0.035、0.000、0.008)。原发肿瘤三维放疗≥63 Gy对PFS的影响接近有统计学意义(P=0.051)。结论 Ⅳ期NSCLC 4~5个周期化疗同期三维放疗≥63 Gy三维放疗使PFS、OS明显延长。     

非小细胞肺癌中EGFR、VEGF和COX-2表达的预后意义

目的：探讨EGFR、VEGF和COX-2这三种与肿瘤血管生成相关的蛋白在非小细胞肺癌（NSCLC）中的表达与临床病理特征和预后的关系。方法：将88例NSCLC及10例正常肺组织标本制作成组织芯片，应用免疫组化S—P法检测EGFR、VEGF和COX-2的表达，并与临床病理特征及预后进行比较分析。结果：EG-FR、VEGF和COX-2在NSCLC标本中的阳性表达率分别为46．6％、67．0％和71．6％，而三者在10例正常肺组织中表达均为阴性。EGFR表达与各种临床病理参数均无关（P〉0．05），VEGF在女性病人中表达升高（P=0．035），COX-2在女性、不吸烟者、腺癌和淋巴结转移阳性者中表达升高（P值分别为0．005，0．027，0．001和0．003）。EGFR和VEGF、VEGF和COX-2之间呈正相关关系（γ=0．267，P=0．012和γ=0．416，P=0．000），而EGFR和COX-2之间无相关性（P=0．441）。生存分析显示EGFR和VEGF表达与生存期无关（P=0．110和P=0．773），而COX-2阳性表达者生存期短（P=0．014）。多因素分析显示EGFR、VEGF和COX-2表达不是影响预后的独立危险因素。结论：EGFR、VEGF和COX-2在NSCLC中表达升高且存在正相关关系，可能在肿瘤血管形成过程中起协同作用。COX-2阳性表达者生存期短，可能在预后判定中有重要作用。