A Phase IV Efficacy Study of Formeta Plus Carboplatin as First-Line Treatment of Advanced Non-Squamous,Non-Small Cell Lung Cancer in Iran: An Affordable Price with Clinical Benefit

Background: This study performed to assess the efficacy and safety of Formeta (generic form of Pemetrexed) plusCarboplatin as first-line chemotherapy in advanced stage, non- squamous, non small cell lung cancer ( NSCLC) in Iran.Methods: This was a post marketing single-arm phase IV efficacy study of Formeta (manufactured by Oncomed.,CzechRepublic ) and Carboplatin in chemo-naive advanced non-squamous NSCLC Iranian patients. Patients received up to sixcycles of Formeta (500 mg/m2) combined with Carboplatin (area under the curve: AUC 5) every 3 weeks. The primaryendpoint was the progression free survival (PFS) and secondary endpoints were safety and overall survival (OS).Results: Fifty-two patients were enrolled between June 2014 to January 2016, and 44 patients were evaluable for bothsafety and efficacy. Partial and complete responses were achieved in 19 (36.5 %) and 2 (3.8%) patients, respectivelyas well as stable disease in 8 patients (15.3 %). Median of PFS and OS were 7.9 ± 1.1 months and 12.43±0.6 months,respectively. Anemia was the most prevalent adverse events of this regimen. Grades 3 or 4 of adverse events were notobserved in any patients. Non-hematologic and other grades of hematologic toxicities were generally mild, and therewere no treatment-related deaths. Conclusion: The combination of Formeta and Carboplatin was effective in advancednon-squamous NSCLC and can be a suitable candidate as first-line treatment in these patient’s population.     

Cell Free Tumoral DNA Versus Paraffin Block Epidermal Growth Factor Receptor Mutation Detection in Patients with Non-Small Cell Lung Cancer

Increasing knowledge about the molecular profile of tumors has led to personalized treatment for achieving better outcomes in patients with nonsmall cell lung cancer (NSCLC). Currently, finding exact somatic genomic changes of tumor has gained great importance. On the other hand, crescendoing needs to actual tumor tissue at different time points during cancer treatment may produce major discomfort for NSCLC patients. Tumor genomes can be reconstructed by information obtained from circulating cell-free deoxyribonucleic acid (cfDNA) of peripheral blood. cfDNA may be represented as a suitable alternative test  for epidermal growth factor receptor (EGFR) mutation detection in these patients. This study aimed to assess validity of cfDNA in somatic EGFR mutation identification in Iranian NSCLC cases. Methods: Somatic mutation of EGFR gene was studied in both tissue specimens and plasma. Then, mutations were detected by polymerase chain reaction(PCR) and sequencing. Results: We observed a high concordance (90%) between tissue samples and cfDNA for EGFR gene mutation.  The sensitivity, accuracy, and positive precision value were 90%, 90% and 100%, respectively. A false negative rate of 10% was also demonstrated in this study. Conclusion: We established sensitive methods for detecting EGFR gene mutation which may be very useful in clinical practice.     

厄洛替尼治疗老年晚期非小细胞肺癌的临床观察

背景与目的 非小细胞肺癌(NSCLC)约占肺癌的80%,其中70%以上为晚期患者.本文评价单药厄洛替尼治疗老年晚期非小细胞的客观疗效及毒副反应.方法 观察29例老年晚期NSCLC,口服厄洛替尼150 mg/d,记录临床疗效及毒副反应,共观察3个月,统计分析结果 .结果 29例患者均可评价疗效,总有效率为20.69%(6/29),其中CR 1例,PR 5例,SD 9例,PD14例.Ⅲ期与Ⅳ期患者有效率比较差异没有统计学意义(P=0.337).毒副反应主要为1-2级毒性反应,包括皮疹(37.93%)、腹泻(17.24%)和呕吐(6.9%).3例患者因严重毒性反应终止厄洛替尼治疗,其中1例患者口服21 d后出现典型肺纤维化.结论 单药厄洛替尼治疗老年NSCLC有较高的临床有效率,患者耐受性尚可,值得临床进一步研究.     

Mechanisms of Resistance to First-Line Osimertinib in Hispanic Patients With EGFR Mutant Non-Small Cell Lung Cancer (FRESTON-CLICaP)

IntroductionOsimertinib is a third generation EGFR-TKI inhibitor approved in the first-line setting for patients with advanced non-small cell lung cancer (NSCLC). Additionally, it represents the treatment of choice in patients who present with T790M mutations and evidence of relapse of the disease. Effectiveness and safety of this drug have been studied in multiple clinical trials and observational studies, however, information regarding outcomes among Hispanic patients treated with Osimertinib is scarce. The objective of this study was to examine real-world effectiveness and safety of first-line Osimertinib in a cohort of Hispanic patients with NSCLC, emphasizing post-progression outcomes.MethodsThis is a multicenter, multinational, retrospective cohort study of Hispanic patients treated with Osimertinib as first-line for EGFR-mutated NSCLC. Patients with a confirmed diagnosis of metastatic EGFR-mutated NSCLC who received Osimertinib (80mg/day until evidence of disease progression or presence of intolerable adverse effects) were identified and included. NGS was performed in tumor samples or liquid biopsies among patients who had disease progression. The primary outcome was progression-free survival, and the secondary outcome was post-progression survival.ResultsA total of 94 patients from Mexico, Argentina, Costa Rica, Colombia, Panama, Chile and the USA were included, with a median age of 59 years. Identified mutations included EGFR Exon 19 deletions and EGFR pL858R point mutations. Median progression-free survival (PFS) was 14.4 months (95%CI 12.4–18.2 months). Lung/pleura and lymph nodes were the most common sites of progression. Median post-progression survival was 7.73 months (95%CI 4.07 months-Not reached). Factors which negatively affected PFS included presence of liver metastases at diagnosis and a tumor mutational burden > 5 mut/Mb.ConclusionTreatment with first line osimertinib represents an effective and safe option for Hispanic patients with metastatic NSCLC. Liver metastases and a higher tumor mutation burden were associated with a lower PFS. Despite effectiveness, different mechanisms of resistance were identified among the patients in this cohort, including mutations which can be targeted by other therapeutic options.     

厄洛替尼治疗34例肺鳞癌患者的疗效观察

背景与目的表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhinitor, EGFR-TKI）通过影响肿瘤的信号传导来抑制肿瘤发展,它具有良好的安全性。本研究旨在观察厄洛替尼治疗肺鳞癌患者的基本情况及生存时间。方法对34例使用厄洛替尼靶向治疗的肺鳞癌患者,给予厄洛替尼150 mg每日1次口服直至病情进展或因不良反应不能耐受为止。结果截至2016年6月13日,34例患者中一线治疗患者7例,维持治疗患者6例（其中1例因严重毒性反应停药）,二线治疗患者9例（其中1例患者后续再次使用厄洛替尼）,三线治疗患者5例,三线以上治疗患者7例（其中1例患者为2次使用厄洛替尼）;确认死亡患者11例。除去1例严重不良反应的患者,口服厄洛替尼后最短疾病无进展生存时间（progression-free survival, PFS）为1个月,最长PFS为55个月,中位PFS为3.5个月。结论对于一部分晚期不能耐受化疗或拒绝化疗,并且基因状况不明的肺鳞癌患者来说,厄洛替尼有一定疗效,绝大部分患者不良反应可耐受。     

厄洛替尼二、三线治疗晚期非小细胞肺癌的临床研究

背景与目的 厄洛替尼是通过口服治疗非小细胞肺癌的靶向药物,本研究旨在探讨厄洛替尼治疗晚期非小细胞肺癌的疗效、影响因素和毒副作用.方法 对接受过1个周期以上含铂化疗方案失败的晚期非小细胞肺癌患者,每天口服150 mg厄洛替尼直至疾病进展,观察疗效、生存时间和不良事件.采用Kaplan-Meier法分析生存率,Cox模型分析影响因素.结果 2005年12月-2006年9Yl,共有48例入组厄洛替尼(erlotinib)EAP(Expanded Acess Program)项目,随访截止至2008年12月08日,中位随访时间为30个月.患者依从性为100%.症状改善中位时间为7天.部分缓解为33.4%(16/48),稳定为22.9%(11/48),进展为43.7%(21/48),有效率为33.4%(16/48),疾病控制率为56.3%(27/48).中位无进展生存时间为5个月,总的中位生存时间为8个月,1、2年无肿瘤进展生存率和总生存率分别为25%(事件36例)、8.3%(事件40例)和43.8%(死亡27例)、20.8%(死亡38例),3年总生存率为5.6%,对总牛存时间多因素分析结果 显示,功能状态为具有统计学意义预测因子.皮疹发牛率为93.7%,有1例患者由于肛周脓肿而停止厄洛替尼治疗.结论 对于化疗失败的晚期非小细胞肺癌患者,厄洛替尼是治疗的另一个选择,部分病人可获得长期疗效并安全耐受.     

非小细胞肺癌中p53蛋白表达及其临床意义

目的：为探讨非小细胞肺癌中p53蛋白表达与肺癌组织学类型、分化程度和淋巴结转移的关系。方法：应用免疫级化技术（ABC法），以p53单克隆抗体检测53例非小细胞肺癌组织中p53基因的表达，组织经微波抗原修复后进行免疫染色。结果采用X2检验。结果：p53蛋白在53例非小细胞肺癌中表达阳性率为64．2％，p53蛋白表达与非小细胞肺癌的组织学类型无关（P＞0.05）；与肺鳞癌分化程度有关（P＜0.01）；肺腺癌中与淋巴结转移有关（p＜0.05）。结论：p53基因的表达异常与不同类型的肺癌发生发展相关，提示P53基因在肺癌的形成、分化和转移过程中起不同的调节作用，p53蛋白过度表达则预后差，检测p53蛋白对判断非小细胞肺癌预后具有应用价值。     

Pneumonitis in Non-Small Cell Lung Cancer Patients Receiving Atezolizumab Post Chemo-Radiation

Objective: The use of Durvalumab following chemoradiotherapy in patients with stage III NSCLC, considerably increased PFS (progression free survival) and OS (overall survival). Unfortunately, Durvalumab is currently not reimbursed for this indication in Lebanon so far. We have used Atezolizumab on a series of patients to the similar mechanism of action. We report in this paper the incidence of pneumonitis using this approach. Methods: We selected from our lung cancer registry, a group of patients diagnosed with stage III NSCLC, who received Atezolizumab (Tecentriq) as consolidation therapy following concurrent chemoradiation therapy. We specifically look at the incidence and severity of pneumonitis based on Common Toxicity Criteria and Adverse Events (CTCAE). Finally, we analyzed patient and tumor characteristics looking for predictive markers for pneumonitis. Result: Of the 14 patients who met our selection criteria, 8 developed pneumonitis and 6 did not. Age, gender and smoking status did not affect the probability of having pneumonitis, with p-values of 0.98,1 and 0.86 respectively. The impact of having PDL-1 status on pneumonitis could not be assessed due to our small sample size. The mean onset of pneumonitis after completion of chemoradiotherapy is 3.62 and after starting Atezolizumab is 2.45 months. Conclusion: The administration of Atezolizumab carries a significant risk of developing pneumonitis following chemoradiation therapy for NSCLC. The presence of certain factors and tumor characteristics might affect the chances of having pneumonitis. However due to our small sample size, definitive conclusions could not be drawn.     

非小细胞肺癌的DNA表达谱(英文)

作为新一代基因诊断技术,DNA芯片已广泛应用于肺癌分子分类、基因表达和分子通路的病理变异分析、预后及转移监测、个体化治疗和药物开发等.基于技术差异、不同患者人群和生物多样性等因素,目前DNA芯片发展的主要障碍为缺乏机械性、可靠性和可重复性.冀望借着更好的标准化和分析手段,利用高维数据分析方法来减少噪音,未来DNA芯片技术或能实际应用于肺癌的个体化诊疗.     

厄洛替尼治疗晚期非小细胞肺癌的临床观察

目的观察厄洛替尼治疗晚期非小细胞肺癌的疗效及不良反应。方法32例经放、化疗治疗失败的非小细胞肺癌患者,其中6例肿瘤局限于胸腔内,26例已有远处转移,厄洛替尼剂量为每天150mg,口服,每天1次,直到肿瘤进展或因不良反应不能耐受而中止治疗。结果32例患者中,完全缓解1例,部分缓解9例,稳定13例,进展9例,全组有效率为31.3%,疾病控制率为71.9%,中位生存期7.8月,1年生存率为45.3%。主要不良反应是皮疹和腹泻,不需要特殊处理。结论厄洛替尼对放、化疗失败的晚期非小细胞肺癌有较好的治疗效果,且不良反应轻。     

Involvement of FoxM1 in Non-Small Cell Lung Cancer Recurrence

Background: Predictive biomarkers for lung cancer recurrence after curative tumor resection remainunclear. This study set out to assess the role of FoxM1 in the recurrence of non-small cell lung cancer. Methods:Immunohistochemistry for FoxM1 expression was performed on paraffin-embedded tumor tissues from 165NSCLC patients. Association of FoxM1 expression with clinicopathological parameters and disease free survivalwere evaluated. Results: Our results indicated FoxM1 expression to be significantly associated with poorer tissuedifferentiation (P =0.03), higher TNM stage (P <0.01), lymph node metastasis (P <0.01), advanced tumor stage(P <0.01), and poorer disease free survival (P <0.01). Multivariable analysis showed that FoxM1 expressionincreased the hazard of recurrence (hazard ratio= 1.96, 95% CI, 1.04-3.17, P <0.05), indicating that FoxM1is an independent and significant predictor of lung cancer recurrence. Conclusion: Therefore, FoxM1 is anindependent risk factor for recurrence of NSCLC. Elevated FoxM1 expression could be used as an indicator ofpoor disease free survival.     

重组人血管内皮抑素靶向治疗晚期非小细胞肺癌的临床研究

背景与目的 晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)化疗处于瓶颈,抗血管靶向治疗逐渐显示优势.本文研究重组人血管内皮抑素(rh-Endostin,恩度YH-16)联合化疗靶向治疗晚期非小细胞肺癌的临床疗效、毒性反应和对生活质量的影响.方法 62例晚期非小细胞肺癌患者随机分为2组:血管内皮抑素组32例采用重组人血管内皮抑素加一线化疗方案,对照组30例仅选用一线化疗方案.2个周期后评价近期临床有效率、临床受益率以及生活质量的改善程度,同时观察毒副作用.结果 血管内皮抑素组临床有效率为46.87%,临床受益率为81.25%,而对照组分别为26.66%和53.33%.两组有效率尚不具有统计学意义(χ2=1.912,P=0.166),但两组受益率差异明显,具有统计学意义(χ2=4.3185,P=0.0377).对照组和血管内皮抑素组进行治疗后生活质最(QoL)均有所改善,血管内皮抑素组则更为明显,二者相比差异具有统计学意义(χ2=11.233,P=0.008).治疗后患者所发生的毒性反应为恶心、呕吐,骨髓抑制,周围神经毒性,主要为化疗所致的副反应,两组在这些方面差异尤统计学意义(P>0.05).血管内皮抑素组有3例感觉心前胸不适,出现心电图改变,表现为ST-T轻微下移,给予对症.冶疗后消失,但两组比较差异无统计学意义(χ2=1.2701,P=0.2597).结论 血管内皮抑素未增加化疗的毒副作用,临床应用安全,耐受性良好;血管内皮抑素联合化疗药物对晚期NSCLC具有较好的疗效,尤其在改善病人生存质量方面具有优势.     

肺癌纵隔淋巴结合理廓清范围的临床探讨

目的：探讨非小细胞肺癌(NSCLC)纵隔淋巴结转移方式。方法：回顾性研究1989年1月—1999年1月，淋巴结廓清术后病理证实的纵隔淋巴结转移(pN2)137例。分析临床病理因素与pN2的关系．应用Logistic回归分析判定纵隔淋巴结CT扫描阴性时(cN0-1)pN2有意义的预测指标；总结不同位置肺癌纵隔淋巴结转移的方式。结果：NSCLC无论病理类型和临床状态如何，均有纵隔淋巴结转移发生。纵隔淋巴结增大(cN2)和cT2或cT3腺癌患者转移的发生率较高(65．0％，75．0％)。纵隔淋巴结转移多为区域性(80．9％)，跨区域纵隔淋巴结转移多数伴有隆凸下淋巴结受累。结论：对NSCLC应行纵隔淋巴结廓清，尤其对cN2和cT3、cT3腺癌。多数患者单独廓清区域纵隔淋巴结即可达到目的。建议手术中对肺门和隆凸下淋巴结冰冻病理检查，无转移时可不必廓清非区域纵隔淋巴结。     

70岁以上老年人非小细胞肺癌的生存研究

背景与目的随着全球的老龄化,老年人疾病受到越来越广泛的关注。肺癌是典型的老年人疾病,大约三分之一的非小细胞肺癌患者年龄超过70岁。国际上文献大多数也以70岁作为老年人肺癌的划分界限。本文的目的是研究70岁以上老年人非小细胞肺癌的生存状况,分析影响其预后的因素。方法回顾性研究148例70岁以上老年人非小细胞肺癌患者的临床资料,利用SPSS13.0统计软件COX回归模型分析性别、年龄、吸烟、症状、病理类型、分期、ECOG状态评分、合并症、手术、放疗、化疗等11个预后因素对生存期的影响。结果随访5-168个月,死亡119例,存活率19.6%。1、2、3、5年生存率分别为43.2%、19.0%、9.5%、5.4%,中位生存期9.29个月。COX回归多因素分析显示,影响预后的独立因素是:临床分期(P=0.002)、ECOG评分(P=0.000)、病灶手术切除(P=0.012)和原发灶放疗(P=0.012)。结论临床分期早及身体状态好的老年非小细胞肺癌患者生存时间长,病灶切除手术及原发灶放疗可以延长其生存期。     

BCRP基因在非小细胞肺癌组织和非癌肺组织中的表达及意义

目的：F是一步研究从人类乳腺癌细胞株（MCF-7/AdrVp)中克隆出对蒽环类抗癌药耐药的BCRP基因在非癌肺组织及非小细胞肺癌组织中的表达。方法：从术后即刻获得的正常肺组织和有省略的非小细胞肺癌组织新鲜标本中及时提取细胞总RNA,通过RT-PCR及PCR法获得并扩增BCRP基因的cDNA产物,再经凝胶电泳分离BCRP基因cDNA带,然后再通过转膜技术把这些BCRP基因cDNA产物转移到杂交膜上,用Southern blot杂交技术检测BCRP基因的表达程度。结果：细胞总RNA分别从8个只有肺癌组织标本和12对同时获取的肺癌组织及非癌肺组织标本中成功提取,然后用变性凝胶电泳鉴定提取RNA的质量,其中4例标本因术中缺血时间太长,或有坏死炎症或术前放化疗等原因,所提RNA有降解而放弃进一步的检测,通过RT-PCR及PCR方法从16例可用标本中获得并扩增BCRP基因的cDNA产物,再通过转膜及Southern blot杂交技术,最终发现BCRP基因在正常肺组织中均有不同程度的表达（10/10）,而在非小细胞肺癌组织标本中只有一半病人的标本有不同程度的表达（8/16）。结论：BCRP基因可能是一个在非癌肺组织中常规表达的基因,而在部分病人的肺癌组织中可能此基因有缺失或被抑制。因此,在部分非小细胞肺癌患者中如用蒽环类抗癌药（如阿霉素,柔红霉素等）化疗时,可能会诱导BCRP基因的过度表达而产生对此类药物的耐药现象。     

Natural Interferon-Alpha Alone and in Combination with Conventional Therapies in Non-Small Cell Lung Cancer

Fourteen previously untreated patients with non-small cell lung cancer (NSCLC) were treated with natural interferon-alpha (IFN) in combination with conventional therapies. The planned dose of IFN was 6 × 10⁶ IU/d.i.m. 5 days a week for 12 weeks. After 12 weeks of IFN monotherapy patients with M0 disease underwent twice-daily fractionated radiotherapy (RT), 55 Gy/4F/30d, while IFN continued. Patients with M1 disease received 3 cycles of chemotherapy (CT) concomittantly with IFN. CT consisted of cisplatinum (P) 90 mg/m² i.v. on days 1, 28, and 56 and of vindesine (VDS) 3 mg/m² i.v. once a week 5 times and every other week thereafter for up to 8 courses. Thirteen patients were evaluable for response and toxicity. There were 9 patients with epidermoid, 3 with adeno- and one with large cell carcinoma. In 12 of 13 patients, the disease remained stable for 1 month during IFN monotherapy and one acheived a minimal response, which lasted 4 weeks. Of seven patients who completed the 12-week course of IFN monotherapy, 4 achieved stable disease (SD) and 3 had progressive disease. Three patients received RT and one received CT in combination with IFN as their subsequent treatment. There were 3 partial responses (2/3 after RT + IFN, 1/1 after CT + IFN), and 1 SD. Fatigue and weight loss were the most severe side-effects during IFN monotherapy. The combination of IFNs with conventional therapies might be clinically useful. We recommend further testing in larger studies.     

Quality of Life During Chemotherapy in Non-Small Cell Lung Cancer Patients

To evaluate the usefulness of chemotherapy in non-small cell lung cancer, objective response, length of remission and survival have been considered the main yardsticks. Subjective improvement and gain in Karnofsky performance status have attracted very little attention. Thirty-one patients with stages III and IV underwent combination chemotherapy with high-dose cisplatin, and were assessed with categorical scales and 100 mm visual analogue scales used by patients themselves to report on several symptoms of their illness. After chemotherapy 17 of 19 patients (89%) gained weight; 20 presented anorexia, 10 of those (50%) improved; 15 had pain, 7 of those (47%) were alleviated; cough was reported in 22, in 10 (45%) it was ameliorated; hemoptysis disappeared in 10 of 11 patients (91 %); of the 9 patients who had dyspnea, 7 improved (78%); and astenia was attenuated in 8 of 16 patients (50%). Quality of life was reported improved in 75% of those patients who had considered themselves seriously affected prior to the treatment. When compared with Karnofsky performance status, no relationship was found (r=0.31). It is concluded that, apart from the objective response achieved, a significant proportion of patients did benefit from treatment as demonstrated by a marked relief of symptoms.