Synergistic effects of pemetrexed and amrubicin in non-small cell lung cancer cell lines: Potential for combination therapy

The purpose is to examine the synergistic effect of pemetrexed (PEM) and amrubicin (AMR) on the proliferation of lung cancer cell lines. In vitro, dose-dependent synergistic effects of concurrent PEM and AMRol, which is an active metabolite of AMR were observed in A549 and H460 cells. In real-time RT-qPCR analysis and western blotting, expression of the target enzymes of PEM were suppressed in cells treated with amrubicinol alone. In vivo, AMR/PEM treatment also showed synergistic antitumor activity both in A549-bearing and H520-bearing mice. PEM and AMR work synergistically to inhibit the proliferation of several different lung cancer cell lines.     

The role of thymidylate synthase in non-small cell lung cancer treated with pemetrexed continuation maintenance therapy

Pemetrexed continuation maintenance therapy has been proven to be beneficial for patients with advanced non-squamous non-small cell lung cancer (NSCLC). However, the eligibility criteria for maintenance treatment are too simple. This study sought to evaluate thymidylate synthase (TS) as a predicting biomarker for pemetrexed continuation maintenance treatment in NSCLC. Specimens were collected from 87 patients treated with pemetrexed continuation maintenance therapy before and after four-cycle induction chemotherapy. Real-time quantitative PCR was used to detect TS expression in tissues. The TS expression level was correlated with characteristic clinical data, radiographic response, progression-free time (PFS) and overall survival (OS). Low total TS expression (<8.47) was associated with improved PFS (median: 4.7 months vs. 3.5 months, p = 0.034) and improved OS (time from random assignment: 16.4 months vs. 11.7 months, p = 0.026; time from induction: 19.7 months vs. 14.8 months, p = 0.022). Our results indicate that in NSCLC patients treated with pemetrexed continuation maintenance therapy, low TS expression is associated with improved PFS and OS.     

含培美曲塞方案治疗非小细胞肺癌疗效与胸苷酸合成酶基因多态性的相关性研究

目的 探讨含培美曲塞方案治疗晚期非鳞型非小细胞肺癌（NSCLC）的疗效及其与胸苷酸合成酶基因（TYMS）多态性的关系。方法67例晚期非鳞型NSCLC患者接受培美曲塞单药或联合铂类治疗,具体用药为：培美曲塞500mg／m2静滴,第1天;顺铂75mg／m2或卡铂AUC=5静滴,第1天,21天为1周期。取患者外周静脉血白细胞提取DNA,采用PCR及PCR RFLP法检测TYMS基因5’-非翻译区（UTR）重复序列多态性和3’-UTR缺失／插入多态性,并分析其与疗效的关系。结果 67例患者均可评价疗效,有效率为28.4％,疾病控制率为76.1％;中位无进展生存期为3.5个月。TYMS基因5’-UTR重复序列多态性基因型和3’-UTR缺失／插入多态性基因型与含培美曲塞方案治疗的有效率和疾病控制率均无关。结论 TYMS基因5’-UTR串联重复序列多态性与3’-UTR缺失／插入序列多态性基因型与含培美曲塞方案治疗晚期非鳞型NSCLC的疗效无关, TYMS基因多态性能否预测含培美曲塞方案的疗效尚需进一步研究证实。     

培美曲塞治疗晚期非小细胞肺癌近期疗效分析

目的　观察培美曲塞治疗５０例晚期非小细胞肺癌（ＮＳＣＬＣ）患者的疗效和毒副反应。方法　收集２００６年６月至２０１０年４月接受培美曲塞化疗的５０例ＮＳＣＬＣ患者,分为单药组１３例和联合组３７例。单药组：培美曲塞５００ｍｇ／ｍ２ｄ１,ｑ３ｗ。联合组：培美曲塞５００ｍｇ／ｍ２ｄ１,卡铂（ＡＵＣ＝５）ｄ１,或顺铂２５ｍｇ／ｍ２ｄ１～ｄ３,或奈达铂８０ｍｇ／ｍ２ｄ１,ｑ３ｗ。所有患者接受至少２个周期化疗。近期疗效评价采用ＲＥＣＩＳＴ１.０标准,毒副反应评价按照ＷＨＯ毒性评定标准。生活质量评价参照孙燕提出的生活质量（ＱＯＬ）评分表。结果　５０例患者均可评价疗效,完全缓解（ＣＲ）２例,部分缓解（ＰＲ）７例,稳定（ＳＤ）２２例,进展（ＰＤ）１９例,有效率（ＲＲ）１８.０％,疾病控制率（ＤＣＲ）６２.０％。生活质量改善率达５８.０％。主要毒性反应为１～２级骨髓抑制和胃肠道反应,经对症处理后不影响化疗进行。结论　以培美曲塞为主的化疗方案治疗晚期ＮＳＣＬＣ疗效较好,可明显改善患者生活质量,且毒性反应轻,易于耐受。     

培美曲塞维持治疗晚期非小细胞肺癌临床疗效的Meta分析

目的 本研究对培美曲塞维持治疗晚期非小细胞肺癌的临床疗效进行Meta分析。方法 计算机检索Cochrane、Pubmed、Web of science、Embase、临床试验等数据库,同时追溯参考文献。收集培美曲塞维持治疗和最佳支持治疗(Best supportive care,BSC)对非小细胞肺癌相关指标进行随机对照试验(Randomized controlled trial,RCT),根据Cochrane系统评价手册5.3质量评价标准评价,采用Stata 12.0软件和Revman5.3进行Meta分析及GRADEpro软件进行证据的评级。结果 共纳入3篇随机对照试验,共1257名研究对象,Meta分析结果显示,与BSC相比培美曲塞可以延长无进展生存期(Pogression free survival,PFS)(HR=0.55,95%CI:0.48~0.64),以及总生存期(Overall survival,OS)(HR=0.76,95%CI:0.65~0.88),但客观缓解率(Objective response rate,ORR)无统计学意义(RR=0.97,95%CI:0.86~1.10)。结论 与BSC相比,培美曲塞组可明显延长非小细胞肺癌的无进展生存期、总生存期,但在客观缓解率上影响并不显著。     

甘露糖对6个人非小细胞肺癌细胞系放射敏感性影响

目的 探讨甘露糖对6个人非小细胞肺癌细胞系放射敏感性的影响及其可能机制。方法 采用Western blot检测磷酸甘露糖异构酶在6个肺癌细胞系中的表达。利用MTT法观察甘露糖对肺癌细胞系的增殖抑制作用;分别给予对照组、甘露糖组0、2、4、6、8、10Gy照射,采用平板克隆形成实验检测甘露糖对6个肺癌细胞放射敏感性的影响;流式细胞术检测对照组、甘露糖组、照射组及联合组细胞的凋亡情况。结果 6个肺癌细胞系中磷酸甘露糖异构酶表达量各不相同,其中A549细胞表达量最高,H460细胞表达量最低。11.1mmol/L甘露糖对A549、H460细胞系抑制作用相同,随着甘露糖浓度增加,对H460细胞系抑制作用更显著。采用11.1mmol/L的甘露糖可明显增加H460细胞系放射敏感性及细胞凋亡率,而对A549细胞系放射敏感性和凋亡率影响不大。结论 在磷酸甘露糖异构酶高表达的6个肺癌细胞系中,甘露糖可增强部分肿瘤细胞的放射敏感性。     

Role of pemetrexed in non-small cell lung cancer

Pemetrexed was approved for the treatment of relapsed or chemotherapy refractory non-small cell lung cancer patients, as it produced similar response and survival outcomes and less toxicity as compared to taxotere. Pemetrexed in combination with platinum analogs or with gemcitabine or vinorelbine, produce equivalent responses and overall survival results compared to combinations of platinum analogs with other drugs. The role of bevacizumab and the inhibitors of epithelial growth factor receptor also should be evaluated in selected patients with NSCLC treated with pemetrexed combinations. Further increases in drug dose may be possible using transfer of drug resistance genes in hematopoietic stem cells.     

局部晚期非鳞非小细胞肺癌同步放化疗两种方案比较研究

目的 比较两种方案治疗局部晚期非鳞非小细胞肺癌副反应及近期疗效。方法 回顾2009年3月—2013年1月42例局部晚期非鳞非小细胞肺癌患者,所有患者均接受同步放化疗,A组放疗同步培美曲塞+顺铂化疗,B组放疗同步多西他赛+顺铂化疗,比较A、B两组患者副反应及近期疗效。结果 A组28例患者,B组14例患者,两组副反应比较,血液毒性:白细胞减少、中性粒细胞减少、血色素降低、血小板减少无统计学差异(P＞0.05)。非血液毒性:放射性肺损伤发生率、咳嗽发生率B组明显高于A组,有统计学差异(P＜0.05)。而其他非血液毒性:肝功能损伤、肾功能损伤、发热、呼吸困难、放射性食管炎、乏力、体重下降、消化道反应、皮肤反应均无统计学差异(P＞0.05)。近期疗效:A、B两组有效率分别为75%及71.43%,无统计学差异(P＞0.05)。结论 放疗同步培美曲塞+顺铂化疗与同步多西他塞+顺铂化疗的两组疗效无显著差异,但培美曲塞在治疗局部晚期非鳞非小细胞肺癌副反应方面存在一定优势。     

Current treatment landscape for oligometastatic non-small cell lung cancer

The management of patients with advanced non-small cell lung carcinoma (NSCLC) has undergone major changes in recent years. On the one hand, improved sensitivity of diagnostic tests, both radiological and endoscopic, has altered the way patients are staged. On the other hand, the arrival of new drugs with antitumoral activity, such as targeted therapies or immunotherapy, has changed the prognosis of patients, improving disease control and prolonging survival. Finally, the development of radiotherapy and surgical and interventional radiology techniques means that radical ablative treatments can be performed on metastases in any location in the body. All of these advances have impacted the treatment of patients with advanced lung cancer, especially in a subgroup of these patients in which all of these treatment modalities converge. This poses a challenge for physicians who must decide upon the best treatment strategy for each patient, without solid evidence for one optimal mode of treatment in this patient population. The aim of this article is to review, from a practical and multidisciplinary perspective, published evidence on the management of oligometastatic NSCLC patients. We evaluate the different alternatives for radical ablative treatments, the role of primary tumor resection or radiation, the impact of systemic treatments, and the therapeutic sequence. In short, the present document aims to provide clinicians with a practical guide for the treatment of oligometastatic patients in routine clinical practice.     

Oncogene addiction in non-small cell lung cancer: Focus on ROS1 inhibition

Detection of molecular aberrations driving the biology and the clinical behavior of advanced non-small cell lung cancer (NSCLC) allows the adoption of specific therapeutic strategies dramatically impacting disease courses. Among these, ROS1 rearrangements are present in 1–2% of lung adenocarcinomas. Thanks to similarities between ALK and ROS1 oncogenes, lessons inferred from ALK can be applied to ROS1-positive NSCLC; nevertheless, disparities exist between diseases mastered by these two fusion genes. In the absence of more common genetic alterations detected in NSCLC (e.g. EGFR and KRAS mutations, ALK gene fusions), seeking for ROS1 rearrangements is crucial. Dedicated molecular diagnostics should be standardized, hopefully relying upon practical and efficient algorithms, comprehending immunohistochemistry and fluorescence in situ hybridisation. The major clinical impact exerted by crizotinib represents the main reason for which not even a sole ROS1-positive tumor should be undetected. The recent approval of the inhibitor by both American and European health agencies would hopefully boost the widespread testing for ROS1, eventually increasing the absolute number of positive cases, potential further source of information regarding molecular and clinical resistance. In vitro and clinical evidence have already been generated concerning crizotinib resistance and strategies to maintain patients under specific driver-inhibition are being successfully developed. Gathering data concerning diagnostics, preclinical evidence, clinical practice and ongoing studies, the present review depicts the current scenario of ROS1 inhibition in NSCLC.     

重组人血管内皮抑素联合培美曲塞治疗复治进展期非小细胞肺癌的临床观察

目的　观察和比较重组人血管内皮抑素（恩度）联合培美曲塞与单药培美曲塞治疗晚期复治的非小细胞肺癌（ＮＳＣＬＣ）的近期疗效及毒副反应。方法　３２例均已确诊并有远处转移的复治的晚期ＮＳＣＬＣ患者,其中恩度联合培美曲塞组１２例,培美曲塞单药组２０例,按照ＲＥＳＩＳＴ标准每周期评价化疗疗效和ＷＨＯ标准每周期评价毒性。结果　恩度联合培美曲塞组共完成３５个周期,平均２.９个周期。ＲＲ３例（２５.０％）,ＣＢＲ９例（７５.０％）。培美曲塞单药组共完成５５个周期,平均２.７个周期。ＲＲ４例（２０.０％）,ＣＢＲ１２例（６０.０％）。两组比较,ＲＲ率差异无统计学意义（Ｐ＞０.０５）,ＣＢＲ率差异有统计学意义（Ｐ＜０.０５）。毒副反应主要为骨髓抑制、胃肠道反应,均未达到３级及以上,可以耐受。结论　恩度联合培美曲塞治疗复治晚期ＮＳＣＬＣ具有较好的近期疗效,且毒性反应轻,耐受性好,值得临床进一步应用。     

培美曲塞单药与联合用药治疗复发晚期非小细胞肺癌的临床观察

目的　观察培美曲塞单药或联合铂类二线治疗复发晚期非小细胞肺癌（ＮＳＣＬＣ）的疗效及毒副反应。方法 回顾性分析７２例复治晚期ＮＳＣＬＣ患者,其中应用培美曲塞单药治疗２７例,培美曲塞联合铂类药物治疗４５例。培美曲塞单药组：培美曲塞５００ｍｇ／ｍ２静滴,第１天。联合组：培美曲塞５００ｍｇ／ｍ２静滴,第１天;顺铂２５ｍｇ／ｍ２静滴,第１～３天;或卡铂３００ｍｇ／ｍ２,静滴,第１天。两组均２１天为１周期。比较两组疾病控制率（ＤＣＲ）、无进展生存期（ＰＦＳ）、总生存期（ＯＳ）和１年生存率,并对老年患者（≥６０岁）及病理类型分别作亚组分析。结果　７２例患者均可评价疗效及毒副反应,无ＣＲ病例,获ＰＲ１１例,ＳＤ３４例,ＰＤ２７例。单药组与联合组的ＤＣＲ（５５.６％ ｖｓ．６６.７％）、中位ＰＦＳ（２.８个月ｖｓ．３.6个月）、中位ＯＳ（１１.９个月ｖｓ．９.６个月）和１年生存率（３２.０％ ｖｓ．２４.０％）差异均无统计学意义。两组主要毒副反应为骨髓抑制和胃肠道反应,差异均无统计学意义。在老年患者亚组分析中,单药组与联合组的ＤＣＲ（６１.１％ ｖｓ．７５.０％）、中位ＰＦＳ（２.８个月ｖｓ．３.４个月）、中位ＯＳ（１０.３个月ｖｓ．７.２个月）和１年生存率（３１.０％ ｖｓ．３９.０％）差异均无统计学意义;但在毒副反应方面,联合组的白细胞减少和胃肠道反应均显著高于单药组。病理亚组中,非鳞癌组的ＤＣＲ（７００％ ｖｓ．４５.５％）和１年生存率（３４.０％ ｖｓ．１５.０％）均高于鳞癌组（Ｐ＜０.０５）,但两组的中位ＰＦＳ（３.６个月ｖｓ．２.５个月）和中位ＯＳ（１１.１个月ｖｓ．９.４个月）均无明显差异（Ｐ＞０.０５）。结论　培美曲塞单药或联合铂类方案用于复发晚期ＮＳＣＬＣ的疗效和毒副反应均无显著差异,在疗效方面可能对非鳞癌具有一定的优势。与联合组比较,培美曲塞单药组对于≥６０岁老年患者的安全性更高。     

Thymidylate synthase and dihydrofolate reductase expression in non-small cell lung carcinoma: the association with treatment efficacy of pemetrexed

Thymidylate synthase (TS) and dihydrofolate reductase (DHFR) are target enzymes of inhibition by pemetrexed, an antifolate for treatment of advanced non-small-cell lung cancer (NSCLC). This study is to evaluate the association of TS and DHFR expressions and the treatment efficacy of pemetrexed in NSCLC patients. From January 2006 to October 2008, patients with advanced NSCLC treated with pemetrexed after prior chemotherapy were included. The TS and DHFR expressions in tumor tissues were examined by immunohistochemistry and evaluated by a semiquantitative histologic score (H-score). The H-score was derived from the degrees of intensity of tumor cells multiplied by the percentage of positive neoplastic cells. The medical records were reviewed and analyzed with respect to patients’ characteristics, histology types, treatment responses and survivals. Among 268 NSCLC patients treated with pemetrexed, 49 had tumor specimens available for TS and DHFR evaluation. The TS expression was positively correlated with DHFR expression (r² = 0.11, p = 0.02). Patients with low TS (≤150) expression had a longer median progression-free survival (PFS) than those with high TS (>150) expression (4.8 vs. 3.4 months; p = 0.01). Patients with low DHFR expression (≤120) also had a longer median PFS than patients with high DHFR expression (>120), which was not statistically significant (5.8 vs. 3.6 months; p = 0.33). In patients with adenocarcinoma, the low TS patient group also had a longer median PFS and a longer median overall survival (OS) as compared with patients with high TS expression (PFS, 4.8 vs. 3.8 months, p = 0.03; OS, 21.4 vs. 10.0 months, p = 0.03). Nevertheless, the association of DHFR expression level and median PFS as well as OS were not statistically significant. TS expression, rather than DHFR, may be an important predictive factor for treatment efficacy of pemetrexed in NSCLC patients.     

蛞蝓对人肺鳞癌、肺腺癌细胞抑癌作用初探

 在对肺鳞癌、乳腺癌、原发性肝癌、直肠癌手术切除标本和肺腺癌胸膜侵犯胸水中的癌细胞进行双层琼脂克隆培养和药敏试验的同时, 进行3H－胸腺嘧啶掺入试验(3H-TdR), 结果显示蛞蝓对肺鳞癌、肺腺癌细胞有明显的抑制作用:对肺鳞癌细胞的3H－TdR摄入抑制率93.08%, 与顺铂(93.33%相当；对肺腺癌克隆集落抑制率65.24%, 3H-TdR摄入抑制率46.21%, 比顺铂的34.77%和15.23%显著增高, 这一结果, 为今后进一步研究蛞蝓的抗癌作用提供了体外抑瘤的实验依据。     

培美曲塞联合卡铂治疗晚期非鳞型非小细胞肺癌的临床观察

【摘要】目的 探讨培美曲塞联合卡铂治疗晚期非鳞型非小细胞肺癌（NSCLC）的疗效及毒副反应。方法收集55例经病理组织学或细胞学确诊的晚期非鳞型NSCLC患者,接受培美曲塞联合卡铂方案化疗：培美曲塞500mg／m² 静滴,d₁;卡铂AUC=5静滴,d₁或d₂,21天为1周期。每例患者均治疗2个周期以上,观察疗效和毒副反应。结果55例患者均可评价疗效,获CR 4例,PR 14例,SD 20例,PD 17例,有效率为32.7％（18／55）,疾病控制率为69.1％（38／55）;中位无进展生存时间为5.5个月（95％CI：4.4～6.6个月）。亚组分析显示,ECOG评分0～1分者较2分者和初治患者较复治者的近期疗效好（P＜.05）。主要毒副反应包括骨髓抑制、胃肠道反应、乏力和周围神经毒性,以1～2级为主。结论 培美曲塞联合卡铂方案治疗晚期非鳞型NSCLC疗效确切,毒副反应发生率低,耐受较好。     

Thymidylate synthase and dihydropyrimidine dehydrogenase expression levels are associated with response to S-1 plus carboplatin in advanced non-small cell lung cancer

S-1 is an oral fluoropyrimidine derivative that is active against non-small cell lung cancer (NSCLC). Development of S-1 combination chemotherapy for advanced NSCLC is under way. Given the importance of designing therapeutic strategies based on specific tumor biology, we have evaluated the relation between immunohistochemical expression levels of thymidylate synthase (TS), orotate phosphoribosyltransferase (OPRT), or dihydropyrimidine dehydrogenase (DPD) and the response to treatment with S-1 plus carboplatin in patients with advanced NSCLC. Chemotherapy-naïve patients with advanced (stage IIIB or IV) NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ function, and archival tumor tissue were assigned to receive S-1-carboplatin (n = 22). The predictive or prognostic relevance of the molecular markers was also examined by their evaluation in patients treated with paclitaxel plus carboplatin (n = 25). Expression levels of TS, OPRT, or DPD in tumor specimens did not differ significantly between patients treated with S-1-carboplatin and those treated with paclitaxel-carboplatin. A low expression level of TS or of DPD was associated with a better response and longer survival in patients treated with S-1-carboplatin but not in those treated with paclitaxel-carboplatin. Tumor expression levels of TS and DPD are predictive of response to S-1-carboplatin chemotherapy in patients with advanced NSCLC.     

复治晚期非小细胞肺癌EGFR-TKI治疗失败后培美曲塞与多西他赛挽救性化疗的疗效比较

目的 比较复治晚期非小细胞肺癌（NSCLC）表皮生长因子受体 酪氨酸激酶抑制剂（EGFR TKI）治疗失败后用培美曲塞或多西他赛挽救性化疗的疗效及毒副反应。方法120例复治晚期NSCLC患者于EGFR-TKI治疗失败后分别接受培美曲塞（500mg／m2,d1）或多西他赛（75mg／m2,d1）的挽救性化疗,均21天为1周期。记录并比较两者的疗效和预后。结果培美曲塞组和多西他赛组的有效率（RR）分别为13.4％和5.3％（P=0.307）,疾病控制率（DCR）分别为58.5％和42.1％（P=0.093）,中位无进展生存期（PFS）分别为2.83个月和2.10个月（P=0.862）,中位总生存期（OS）分别为8.40个月和9.10个月（P=0.527）。EGFR-TKI治疗有效和挽救性化疗前行为状态评分（PS）≤1者的中位PFS较长。培美曲塞组1～4级中性粒细胞减少的发生率低于多西他赛组,分别为41.5％和65.8％（P=0.013）。在非血液学毒性方面两组差异均无统计学意义（P＞0.05）。结论 复治晚期NSCLC TKI治疗失败后用培美曲塞或多西他赛挽救性化疗,部分患者仍可以获益,两组疗效相当,且大部分患者能够耐受化疗的毒副反应。对于EGFR-TKI治疗有效、挽救性化疗前PS评分较好的患者,有可能从挽救性化疗中获益更大。     

Establishment and comparative characterization of novel squamous cell non-small cell lung cancer cell lines and their corresponding tumor tissue

Background

Cell lines play an important role for studying tumor biology and novel therapeutic agents. Particularly in pulmonary squamous cell carcinoma (SCC) the availability of cell lines is limited and knowledge about their representativeness for corresponding tumor tissue is scanty.

Materials and methods

We established three novel SCC cell lines from fresh tumor tissue of 28 donors, including 8 SCC. Two cell lines were derived from different localizations of the same donor, i.e. primary tumor and lymph node metastasis. This represents a so far unique combination in lung cancer. The genotypes, gene expression profiles and mutational status of epidermal growth factor receptor (EGF-R) and Kirsten rat sarcoma (k-ras) of the cell lines and their corresponding tumor tissue were analyzed and compared. Moreover, the molecular characteristics were related to functional properties of the cell lines. Those comprised proliferation, motility and chemosensitivity. The cell lines were authenticated by single tandem repeat DNA typing. Tumorigenicity was analyzed in a murine xenograft model.

Results

Comparative genomic hybridization and multiplex fluorescence in situ hybridization revealed essential genetic similarities between the cell lines and their corresponding tumor tissue, but indicated also some genetic evolution and clonal selection. EGF-R or k-ras mutations were not detected. Gene expression profiling showed various differences between tumor tissue and cell lines affecting gene clusters associated with immune response, adhesion, proliferation, differentiation and angiogenesis. However, there were also common gene expression patterns reflecting the relationship between cell lines and their corresponding tumor tissue. Moreover, the molecular characteristics of the tumor tissue and the descendent cell line were associated with functional properties of the latter. All cell lines showed a unique, heterozygous human DNA profile and one cell line displayed rapid tumor formation in mice.

Conclusions

Here, we demonstrate that cell lines represent a useful in vitro system for studying basic mechanisms in lung cancer, but cover only distinct molecular characteristics of the original tumor. Moreover, we present three novel, comprehensively characterized SCC cell lines.     

肺癌神经内分泌分化与术后生存关系探讨

目的 探讨非小细胞肺癌神经内分泌(NSCLC—NE)分化与患者手术后生存关系。方法 收集1997年4月至1999年4月98例肺癌手术切除病理标本，采用免疫组化标记特异性烯醇化酶(NSE)及突触素(SY)，并按强弱区分为“ 、 、 ”。对同一手术病例标本采用电镜观察特异性NE颗粒。术后病例随访36月，最长60月。采用Cox多因素风险模型分析NSCLC-NE分化与患者术后生存的关系。结果 91例为非小细胞肺癌。非小细胞肺癌NF阳性表达率为63．7％(58/91)，其中NSE阳性表达54例(59．3％)，SY阳性表达22例(24．1％)，电镜观察NE持异性颗粒30例(33．0%)。结合免疫组化和电镜观察，NSCLC-NE分化44例(48．4％)。Cox模型多因素分析结果表明NSCLC-NE分化者术后生存时间明显缩短(P=0.048)。术后生存与肺癌细胞分化程度(P=0．006)、病理分期(P=0．001)、NE表达强弱(P=0．054)有密切关系。结论 NSCLC-NE分化与肿瘤细胞分化和患者术后生存有关。采用NE标志物标记肿瘤，并观察其强弱改变．对术后评估具有较重要的参考意义，可作为为临床判断患者预后指标之一。