EGFR and KRAS mutations in lung carcinomas in the Dutch population: increased EGFR mutation frequency in malignant pleural effusion of lung adenocarcinoma

Background

Frequencies of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC) have predominantly been determined in East Asian and North American populations, showing large differences between these populations. The aim of the present study was to determine the frequency of EGFR and KRAS mutations in NSCLC in the West European Dutch population in primary carcinomas and different metastatic locations.

Methods

EGFR (exons 19, 20 and 21) and KRAS (exons 2 and 3) mutation test results of NSCLC samples of patients in 13 hospitals were collected. The tests were performed on paraffin-embedded tissue or cytological material of primary and metastatic lung carcinomas.

Results

EGFR mutations were detected in 71/778 (9.1?%) tested patients; in 66/620 (10.6?%) adenocarcinomas. EGFR mutations were significantly more often detected in female than in male patients (13.4?% vs. 5.5?%, p?<?0.001). KRAS mutations were found in 277 out of 832 (33.3?%) tested patients; in 244/662 (36.9?%) adenocarcinomas. A significantly increased frequency of EGFR mutations was observed in patients with malignant pleural/pericardial effusions (26.5?%; odds ratio (OR) 2.80, 95?% confidence interval (CI) 1.22?C6.41), whereas the frequency of KRAS mutations was significantly decreased (18.8?%; OR 0.35, 95?% CI 0.14?C0.86).

Conclusions

In the investigated Dutch cohort, patients with malignant pleural/pericardial effusion of lung adenocarcinoma have an increased frequency of EGFR mutations. The overall frequency of EGFR mutations in lung adenocarcinomas in this West European population is within the frequency range of North American and South European populations, whereas KRAS mutation frequency is higher than in any population described to date.     

EGFR mutations in malignant pleural effusion of non-small cell lung cancer: a case report

EGFR mutations have been shown to correlate with the clinical responsiveness to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). The detection of EGFR mutations in non-small cell lung cancer (NSCLC) is important from the perspective of targeted anticancer therapy. We report the first case showing that the status of EGFR mutations can be successfully determined in malignant pleural effusion of NSCLC using polymerase chain reaction (PCR) technique, and correlated to the clinical responsiveness to gefitinib, an EGFR-TKI. This case demonstrated the importance of molecular cytology in the era of targeted therapy.     

HRM方法检测肺腺癌患者癌性胸水上清液EGFR基因突变的临床意义

目的:探讨应用HRM方法检测肺腺癌患者癌性胸水上清液EGFR基因突变状况及EGFR酪氨酸激酶受体抑制剂治疗的可行性。方法:收集43例肺腺癌患者癌性胸水上清液标本,提取DNA,应用HRM方法检测EGFR基因第18、19、20、21外显子突变状况。统计分析HRM方法与基因测序法检测EGFR突变率的差异。结果:43例肺腺癌患者癌性胸水上清液中,HRM法检测EGFR基因突变共17例,总突变率为39.53%,其中第19外显子突变14例,第21外显子突变3例。基因测序结果显示:EGFR突变14例,总突变率为32.56%,均为第19外显子突变。HRM方法检测第21外显子突变阳性的患者其基因测序结果均为阴性。这可能与HRM方法检测的灵敏度优于测序方法有关。两者突变率差异无统计学意义（P>0.05）。结论:对难以获取组织标本的肺腺癌患者而言,应用HRM方法检测其癌性胸水上清液,是了解其EGFR基因突变状况的可靠途径,对临床筛查靶向治疗药物具有一定的参考价值。     

非小细胞肺癌患者恶性胸腔积液中EGFR基因突变

非小细胞肺癌患者接受表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)治疗前进行EGFR检测已经成为共识.恶性胸腔积液是非小细胞肺癌(NSCLC)患者常见的临床表现,采用不同方法对胸腔积液细胞及游离核酸提取后进行EGFR检测,对预测EGFR-TKI的疗效有着良好前景.     

局部胸腔灌注化疗联合全身化疗对肺腺癌合并恶性胸腔积液的疗效

目的 探讨局部胸腔灌注化疗联合全身化疗对肺腺癌合并恶性胸腔积液的疗效.方法 回顾性分析85例肺腺癌合并恶性胸腔积液患者的临床资料,根据治疗方法不同将患者分为局部组(n=38)和联合组(n=47).局部组将顺铂+白细胞介素-2经胸腔置管引流后注入胸腔,联合组在局部组的基础上辅以培美曲塞全身化疗.比较两组患者恶性胸腔积液的治疗效果、治疗前后KPS评分变化以及治疗后的不良反应发生率.结果 联合组患者恶性胸腔积液的治疗有效率为93.62%,明显高于局部组的44.74%(P﹤0.01);联合组患者KPS评分改善有效率为80.85%,高于局部组的44.74%(P﹤0.05).两组患者的各种不良反应发生率比较,差异均无统计学意义(P﹥0.05).但联合组中个别患者出现白细胞减少、胸痛及胃肠道反应等3级不良反应,需及时对症治疗.结论 在顺铂+白细胞介素-2胸腔灌注化疗的基础上辅以培美曲塞全身化疗,可有效治疗肺腺癌合并恶性胸腔积液,值得临床推广.     

miRNA在肺腺癌恶性胸腔积液中的表达及临床意义

目的 检测肺腺癌恶性胸腔积液中相关的miRNA表达,探讨miRNA表达与预后的关系。方法 采用miRNA芯片技术筛选10例肺腺癌患者恶性胸腔积液miRNA表达谱,结合临床分析可能与预后有关的miRNA。采用实时荧光定量PCR（QPCR）技术检测84例肺腺癌恶性胸腔积液标本中miRNA表达,结合临床预后分析确认表达差异的miRNA。结果 在5例无进展生存期（PFS）≥5个月和5例PFS≤2个月患者中,芯片筛查显示共13种miRNAs 表达变化倍数＞2倍。在84例不同预后肺腺癌胸腔积液患者中选取miR-146a、miR-16、miR-155、miR-484、miR-134、miR-141、miR-106b和miR-93共8个miRNA进行QPCR验证,发现仅miR-93和miR-146a表达存在差异（P＜0.05）,miR-93在预后好的患者中表达升高,变化倍数为2.41倍,miR-146a在预后好的患者中表达下降,变化倍数为0.46倍。结论 miR-93在预后好的患者恶性胸腔积液中高表达,miR-146a则相反,其可能成为判断肺癌恶性胸腔积液患者预后新的分子标志物。     

EGFR突变与肺癌伴恶性胸腔积液患者生物学行为的相关性研究

目的 探讨表皮生长因子受体(EGFR)基因突变与肺癌伴恶性胸腔积液患者生物学行为之间的关系.方法 选取肺癌患者100例,其中伴恶性胸腔积液者43例作为观察组,不伴胸腔积液者57例作为对照组,观察两组患者EGFR基因突变情况.结果 观察组EGFR总突变率为72.09%,高于对照组的19.30%(P﹤0.05);观察组高分化、中分化和低分化患者的EGFR突变率分别为69.23%、71.43%和77.78%,均高于对照组高分化、中分化和低分化患者(P﹤0.05);不同性别、年龄、吸烟情况及分化程度的观察组患者EGFR基因突变率比较,差异均无统计学意义(P﹥0.05);胸腔积液与活检组织标本EGFR基因检测结果的Kappa值为0.466(P﹤0.05),一致性中等.结论 肺癌伴恶性胸腔积液患者EGFR突变率较高,但EGFR突变与肺癌伴恶性胸腔积液患者的性别、年龄、吸烟情况及分化程度无关.     

Successful management of malignant pericardial effusion with weekly paclitaxel therapy in a lung adenocarcinoma patient

A 67-year-old woman had undergone lobectomy and mediastinal lymphadenectomy on December 17, 1999, for lung adenocarcinoma. On June 29, 2001, the patient was readmitted because of acute deterioration of diabetic chronic renal failure due to cardiac dysfunction. Serum CEA level was high at 724 ng/ml. Chest X-ray and ultrasound suggested the presence of pericardial effusion, which was managed with pericardial drainage. Cytological examination revealed malignant cells (class V) in the effusion. Therefore, the patient was suffering from carcinomatous pericarditis. After the introduction of hemodialysis, the patient was treated with weekly paclitaxel therapy. Each cycle consisted of 3 weeks of therapy followed by a 1-week treatment break. Weekly paclitaxel therapy (11 infusions) brought about a normalization of the elevated CEA levels and a good control of the pericardial effusion. The patient has developed neither tumor progression nor reelevation of serum CEA levels for 12 month with no further therapy.     

Bio-adhesio-chemo (BAC) therapy for patients with malignant pleural effusion

Eighteen patients with serious pleuritis carcinomatosa with remarkable pleural effusion were treated with a new pleurodesic therapy, and all the patients treated obtained favorable results. After removing pleural effusion, fibrinogen solution was intrapleurally instilled and then, our newly devised material, G.T.XIII and an anticancer drug, Adriamycin (ADM), were administered as chemosclerosing agents in an attempt to prevent recurrence of the effusion and also to provide locoregional antineoplastic effects. Recurrence of pleural effusion was nil in all patients treated, and subjective complaints of the patients were remarkably relieved. There were 14 patients evaluable, and all the response of these patients resulted in partial response (PR) according to the World Health Organization (WHO) criteria. Improvement of performance status (PS) was observed in 61% (11/18). Eight patients could be discharged. Three patients have remained alive. Fifteen patients died after the therapy, and their median survival was 67 days. Eight patients were autopsied. The postmortem examinations confirmed that fibrous adhesion in the pleural cavity with these materials was significant, and evidence of recurrence of pleural fluid was not seen. Topical oncolytic effects of the ADM were histologically remarkable. This pleurodesis was called "Bio-adhesio-chemo (BAC) therapy."     

K-ras and rho A mutations in malignant pleural effusion

Mutations of the Kristen ras (K-ras) gene have been implicated in the pathogenesis of human lung cancer, especially adenocarcinoma, and have been proposed to be a prognostic factor. The K-ras mutation in codon 12 is detectable even in cell-free fluids by using the enriched polymerase chain reaction (PCR) technique. On the other hand, based on experimental results, the rho A mutation in codon 14 is also proposed to be oncogenic as observed in the K-ras mutation. Malignant pleural effusion is a common complication of lung cancer. We studied the point mutation of K-ras codon 12 and rho A codon 14 using enriched PCR in specimens of pleural effusion. Forty patients with pleural effusion were enrolled in this study. The causes of pleural effusion were non-small cell lung cancer (18 cases), small cell lung cancer (6 cases), malignant mesothelioma (2 cases), metastatic lung tumor (5 cases), thymoma (1 case), malignant lymphoma (1 case), and pleuritis tuberculosa (7 cases). The K-ras mutation was detected in 4 of 14 cases with adenocarcinoma, 1 of 3 cases with squamous cell carcinoma, 1 of 1 case with large cell carcinoma, and 1 of 5 cases with metastatic lung tumor, respectively. The rho A mutation was not detected in any pleural effusion examined in this study. Our study demonstrates the usefullness of pleural effusion as a clinical specimen for a search of point mutation of oncogenes. The K-ras codon 12 mutation is readily detected in pleural effusion, and the demonstration of this mutation has potentially important implications for the diagnosis of malignant pleural effusion.     

伴恶性胸腔积液Ⅳ期NSCLC原发肿瘤三维放疗的临床分析

目的 回顾性探讨伴恶性胸腔积液Ⅳ期NSCLC原发灶三维放疗的有效性和安全性。方法 选择2007-2018年经病理诊断、初诊的伴恶性胸腔积液Ⅳ期NSCLC198例,按治疗状况分为未治疗组45例、药物治疗组57例、放疗组96例。分析放疗组和药物组近期疗效、总生存和不良反应。Kaplan-Meier法计算生存率并log-rank检验,Cox模型多因素预后分析。结果 放疗组有效率为54%、无效率为46%,显著优于药物组的25%、75%(P=0.007);1、2、3、5年总生存和中位生存期放疗组分别为47%、18%、6%、1%和12个月,显著高于药物组的15%、3%、2%、0%和5个月(P<0.001)。多因素分析显示增加原发灶放疗是延长生存的影响因素(P<0.001), ≥63Gy、4~6周期化疗有延长生存趋势(P=0.063、0.071),EGFR敏感突变者放疗联合分子靶向治疗总生存显著优于联合化疗而EGFR突变未知者(P=0.007)。增加原发灶放疗未增加明显的不良反应(P>0.05)。结论 伴恶性胸腔积液Ⅳ期NSCLC原发灶三维放疗可能延长患者总生存,增加三维放疗的不良反应可耐受。     

Frequent EGFR mutations in brain metastases of lung adenocarcinoma

Lung adenocarcinomas often metastasize to the brain, and the prognosis of patients with brain metastases is still very poor. The epidermal growth factor receptor (EGFR) gene is mutated in a considerable fraction of primary lung adenocarcinomas, in particular those with drastic response to EGFR tyrosine kinase inhibitors. The present study was designed to elucidate the prevalence of EGFR mutations in brain metastases and the timing of their occurrence during cancer progression. EGFR mutations were detected in 12 of 19 metastatic lung adenocarcinomas to the brain (63%). This frequency was higher than those in previous studies for EGFR mutations at various stages of lung adenocarcinoma in East Asia, including Japan (i.e., 20-55%). In 6 cases with EGFR mutations, the corresponding primary lung tumors were also examined for the mutations, and in all of them, the same types of EGFR mutations were detected also in the primary tumors. In 2 of them, second metastatic brain tumors in addition to the first ones were also available for analysis, and the same types of EGFR mutations were detected in both the first and second ones in both cases. These results indicate that EGFR mutations are present frequently in brain metastases and occur preceding brain metastasis. These findings will be highly informative for treatment of metastatic lung adenocarcinoma to the brain.     

Bevacizumab plus chemotherapy for advanced non-squamous non-small-cell lung cancer with malignant pleural effusion

Purpose

The presence of malignant pleural effusion (MPE) indicates a poorer prognosis for patients with non-small-cell lung cancer (NSCLC) and impairs their quality of life. Because vascular endothelial growth factor (VEGF) is the key mediator MPE production, we evaluated the efficacy and safety of chemotherapy plus bevacizumab, an anti-VEGF antibody, in non-squamous NSCLC patients with MPE, especially regarding the control of pleural effusions.

Methods

From November 1, 2009 to September 30, 2011, medical charts of 13 consecutive patients with MPE who received bevacizumab plus chemotherapy as the initial or secondary treatment were retrospectively analyzed.

Results

Of the 13 patients, 6 did not undergo pleurodesis, 3 were unsuccessfully treated by pleurodesis, 2 had encapsulated pleural effusion, and 2 had no re-expansion of the lung. Twelve patients (92.3 %) achieved MPE control lasting >8 weeks following bevacizumab plus chemotherapy. Five of 10 patients with measurable lesions had confirmed partial responses. Of 3 patients without measurable lesions, one had confirmed CR. Median progression-free survival time without re-accumulation of MPE was 312 days. Grade 3 or 4 neutropenia, thrombocytopenia, hypertension, or proteinuria was observed in 2, 2, 1, or 1 patient, respectively.

Conclusions

This is the first study to report that bevacizumab plus chemotherapy is highly effective for the management of MPE in non-squamous NSCLC patients. Prospective clinical trials are warranted to investigate the efficacy of bevacizumab for MPE.     

胸腔镜对恶性胸腔积液的诊治探讨

目的探讨胸腔镜对恶性胸腔积液的诊治优势.方法对27例恶性胸腔积液患者在胸腔镜辅助下行胸膜活检、固定术.结果所有患者的诊断都得到明确,无一例胸水控制失败,复发5例,术后复张性肺水肿1例.结论胸腔镜对恶性胸腔积液具有良好的诊断价值,且在其辅助下行胸膜固定术有创伤小、效果好等优点.     

肺腺癌合并恶性胸腔积液患者血管生成素-2与胸腔积液局部控制及预后的关系

目的 探讨胸腔积液及血清中血管生成素-2（Ang-2）与肺腺癌合并恶性胸腔积液（MPE）患者胸腔积液局部控制及预后的关系。方法 收集肺腺癌合并MPE患者的胸腔积液及血液标本,采用ELISA法测定胸腔积液和血清中Ang-2水平,分析其与临床病理特征、胸腔积液局部控制情况及预后的关系。结果 胸腔积液和血清Ang-2水平分别为（26.67±8.82）pg／ml和（361.18±97.58） pg／ml。采用ROC曲线分析,当截断值为25.57 pg／ml时,胸腔积液Ang-2水平预测胸腔积液局部控制情况效能为最佳。Logistic回归分析显示胸腔积液Ang-2水平是胸腔积液局部控制情况的独立因素（OR=5.65,95%CI：2.40～16.78,P<0.001）。Cox多因素分析表明胸腔积液Ang-2水平（HR=1.15, 95%CI：1.01～1.32） 及胸腔积液局部控制情况（HR=0.42,95%CI：0.19～0.89）是影响肺癌合并MPE患者生存预后的独立因素。血清Ang-2水平与胸腔积液局部控制情况及预后无关（P＞0.05）。结论 胸腔积液Ang-2水平可作为肺腺癌合并MPE患者预测胸腔积液局部控制及判断预后的分子标志物,具有重要的临床应用价值。     

肺癌胸膜全肺切除术的围术期处理

目的：总结对于肺癌伴胸膜转移和恶性胸水行胸膜全肺切除手术的围术期处理经验。方法：1988年1月～2003年1月对21例肺癌伴胸膜转移和恶性胸水患者行胸膜全肺切除术。肺部原发病灶位于左肺8例,右肺13例。病理分类：鳞状细胞癌1例,腺癌12例,腺鳞癌2例,肺泡细胞癌6例。结果：术后呼吸机机械通气支持12例,平均支持时间4．5小时。无围手术期死亡,无支气管胸膜瘘、脓胸、大出血等严重并发症。随访已死亡16例,生存期为5～34个月,其余5例患者随访24～29个月仍生存,全组中位生存时间18个月。结论：加强围术期处理,对常见并发症重点防范、早期治疗,是降低手术风险、促进此类患者康复的关键。     

沙培林联合羟基喜树碱腔内给药治疗恶性胸腔积液

目的：为观察沙培林联合羟基喜树碱腔内给药治疗恶腔积液患的治疗。方法：60例恶性胸腔积液患采用胸腔穿刺，使用比利时生产的贝朗可分裂中心静脉导管置入胸腔、接负压瓶持续闭式引流排胸液。并随机分成两组，治疗组采用沙培林联合羟基喜树碱治疗（30例），第一周2次，每隔3天一次，由引流管注入生理盐40ml加羟基喜树碱30mg，第2周连续3天注入沙培林5KE/次、10KE/次、10KE/次，对照组单用羟基喜树碱治疗（30例），每一周2次，每隔3天一次，由引流管注入生理盐水40ml加羟基喜树碱30mg。结果：治疗组有效率90%[CR11例（37%） PR16例（53%）]，对照组有效率67%[CR8例（27%） PR12例（40例）]。经论：沙培林联合羟基喜树碱腔内注射治疗恶性胸腔积液优于单用羟基喜树碱，而胸腔穿刺置管引流创伤轻微，无倒流污染，引流通畅彻底，避免胸膜多房性包裹粘连的形成以至带来后续治疗困难，可防止医源性感染及气胸等并发症。     

综合治疗非小细胞肺癌并恶性胸水疗效观察

目的 探讨非小细胞肺癌并恶性胸水的综合治疗方法.方法 采用博来霉素加力尔凡胸腔灌注并原发灶及纵隔转移之淋巴结外照射.2001年2月至2002年2月治疗非小细胞肺癌并恶性胸水30例,均由病理证实,采用DF方案化疗两个周期后行博来霉素加力尔凡胸腔灌注.其中腺癌8例,鳞癌 15例,鳞腺癌7例.生活质量水平评分60～70分14例,50～60分16例.结果 胸水全部消失21例,胸水残留500 ml以下3例,残留1000 ml以下6例.原发灶CR 21例,PR 5例,SD 3例,PD 1例.坚持3年随访,其中21例均存活36个月并无胸水复发及远地转移,6例死于全身多脏器转移.3例骨髓抑制,白细胞3.0×109/L左右,不时靠重组人粒巨细胞集落刺激因子或口服中成药维持.结论 非小细胞肺癌DF方案化疗两周期后博来霉素加力尔凡胸腔灌注后并外照射是综合治疗非小细胞肺癌合并恶性胸水的很好治疗方法.