Randomized Phase II Study of Preoperative Chemoradiotherapy ± Panitumumab Followed by Consolidation Chemotherapy in Potentially Operable Locally Advanced (Stage IIIa,N2+) Non–Small Cell Lung Cancer: NRG Oncology RTOG 0839

IntroductionMultimodality therapy has curative potential in locally advanced NSCLC. Mediastinal nodal sterilization (MNS) after induction chemoradiotherapy (CRT) can serve as an intermediate marker for efficacy. NRG Oncology Radiation Therapy Oncology Group (RTOG) 0229 demonstrated the feasibility and efficacy of combining full-dose radiation (61.2 Gy) with chemotherapy followed by resection and chemotherapy. On the basis of that experience and evidence that EGFR antibodies are radiosensitizing, we explored adding panitumumab to CRT followed by resection and consolidation chemotherapy in locally advanced NSCLC with a primary end point of MNS.MethodsPatients with resectable locally advanced NSCLC were eligible if deemed suitable for trimodality therapy before treatment. Surgeons were required to demonstrate expertise after CRT and adhere to specific management guidelines. Concurrent CRT consisted of weekly carboplatin (area under the curve = 2.0), paclitaxel (50 mg/m²), and 60 Gy of radiation therapy delivered in 30 fractions. There was a 2:1 randomization in favor of panitumumab at 2.5 mg/kg weekly for 6 weeks. The mediastinum was pathologically reassessed before or at the time of resection. Consolidation chemotherapy was weekly carboplatin (area under the curve = 6) and paclitaxel, 200 mg/m² every 21 days for two courses. The study was designed to detect an improvement in MNS from 52% to 72%. With use of a 0.15 one-sided type 1 error and 80% power, 97 patients were needed.ResultsThe study was opened in November 2010 and closed in August 2015 by the Data Monitoring Committee after 71 patients had been accrued for futility and excessive toxicity in the experimental arm. A total of 60 patients were eligible: 19 patients (86%) who received CRT and 29 (76%) who received CRT plus panitumumab and underwent an operation. With regard to postoperative toxicity, there were three grade 4 adverse events (13.6%) and no grade 5 adverse events (0%) among those who received CRT versus six grade 4 (15.8%) and four grade 5 adverse events (10.5%) among those who received CRT plus panitumumab. The MNS rates were 68.2% (95% confidence interval: 45.1–86.1) and 50.0% (95% confidence interval: 33.4–66.6) for CRT and CRT plus panitumumab, respectively (p = 0.95).ConclusionThe addition of panitumumab to CRT did not improve MNS. There was an unexpectedly high mortality rate in the panitumumab arm, although the relationship to panitumumab is unclear. The control arm had outcomes similar to those in NRG Oncology RTOG 0229.     

肺部占位性病变经纤支镜取材Survivin检测的意义

目的探讨新的凋亡抑制基因survivin在肺部占位性病变经纤支镜取材标本中的表达，及其临床应用价值。方法用原位杂交和免疫细胞化学的方法检测60例在经纤支镜抽吸物脱落细胞中survivin mRNA及其相应蛋白的表达。结果Survivin基因在NSCLC病例纤支镜抽吸物脱落细胞中呈高表达，survivin mRNA阳性表达与其蛋白表达呈正相关。Survivin和脱落细胞学联合检测较单用脱落细胞学检测敏感性和阴性预测值均提高。结论Survivin在非小细胞肺癌的发生发展中起重要作用，联合脱落细胞学和survivin基因分子生物学检测有助于肺癌的早期诊断。     

Low PRRX1 expression and high ZEB1 expression are significantly correlated with epithelial-mesenchymal transition and tumor angiogenesis in non-small cell lung cancer

Background:Paired related homeobox 1 (PRRX1) and zinc finger E-box binding homeobox 1 (ZEB1) have been observed to play a vital role in the epithelial-mesenchymal transition (EMT) process in different types of cancer. The microvessel density (MVD) is the most common indicator used to quantify angiogenesis. This study aimed to investigate expression of PRRX1 and ZEB1 in non-small cell lung cancer (NSCLC) and to explore associations between these factors and tumor prognosis, EMT markers and angiogenesis.Methods:Data for a total of 111 surgically resected NSCLC cases from January 2013 to December 2014 were collected. We used an immunohistochemical method to detect expression levels of PRRX1, ZEB1, and E-cadherin, and to assess MVD (marked by CD34 staining). SPSS 26.0 was employed to evaluate the connection between these factors and clinical and histopathological features, overall survival (OS) and tumor angiogenesis.Results:PRRX1 expression was obviously lower in tumor samples than in control samples. Low expression of PRRX1, which was more common in the high-MVD group than in the low-MVD group (P = .009), correlated positively with E-cadherin expression (P < .001). Additionally, we showed that ZEB1 was expressed at higher levels in tumor samples than in normal samples. High expression of ZEB1 was associated negatively with E-cadherin expression (P < .001) and positively associated with high MVD (P = .001). Based on Kaplan-Meier and multivariate survival analyses, we found that PRRX1, ZEB1, E-cadherin and the MVD had predictive value for OS in NSCLC patients.Conclusions:These findings suggest that PRRX1 and ZEB1 may serve as novel prognostic biomarkers and potential therapeutic targets.     

Association of positively selected eIF3a polymorphisms with toxicity of platinum-based chemotherapy in NSCLC patients

Aim:

Eukaryotic translation initiation factor 3 subunit A (eIF3a) plays critical roles in regulating the initiation of protein translation, and eIF3a is highly expressed in lung cancer. In this study, we investigated the association of the positively selected SNPs of eIF3a with the response to and toxicity of platinum-based chemotherapy in Chinese patients with non-small cell lung cancer (NSCLC).

Methods:

SNP data for eIF3a locus were downloaded from HapMap database. For each SNP, haplotype, LD profile and population differentiation were analyzed. The long-range haplotype (LRH) test was employed to identify positively selected SNPs of eIF3a. A total of 325 NSCLC patients were enrolled and genotyped for these SNPs.

Results:

Five positively selected (rs1409314, rs4752219, rs4752220, rs7091672 and rs10510050) and 5 non-positively selected SNPs (rs10886342, rs11198804, rs2275112, rs10787899 and rs4752269) were identified in the LRH test. However, none of them was correlated with the platinum-based chemotherapy response. In contrast, 4 of the positively selected SNPs (rs1409314, rs4752219, rs4752220 and rs7091672) were significantly correlated with the toxicities tested (neutropenia, anemia, thrombocytopenia, emesis and hepatotoxicity). In addition, rs10510050 was significantly correlated with thrombocytopenia, emesis and hepatotoxicity. None of the 5 non-positively selected SNPs was correlated with the 5 toxicities.

Conclusion:

The positively selected SNPs of eIF3a are significantly correlated with platinum-based chemotherapy toxicities in Chinese NSCLC patients.     

小细胞和非小细胞肺癌晚期患者CD3~+ CD4~+及CD3~+ CD8~+T淋巴细胞亚群的差异

目的:探索小细胞和非小细胞肺癌晚期患者CD3+CD4+及CD3+CD8+T淋巴细胞亚群是否存在差异,并为治疗提供参考。方法:选取肺癌晚期患者共65例,其中包括小细胞肺癌14例,非小细胞肺癌51例以及20例健康对照。用流式细胞仪检测研究对象外周血淋巴细胞表面CD3+CD4+及CD3+CD8+的表达情况。结果:CD3+CD4+T细胞所占比例无论是小细胞还是非小细胞肺癌晚期的患者都较健康对照显著降低;CD3+CD8+T细胞所占比例在肺癌晚期的患者较健康对照并无显著变化;CD4+/CD8+比值在小细胞肺癌晚期患者较健康对照显著下降。结论:无论是小细胞还是非小细胞肺癌晚期的患者CD3+CD4+T细胞的水平较健康人都显著降低,说明肺癌晚期患者细胞免疫功能严重受损。     

还原型谷胱甘肽减轻NSCLC放射性肺损伤的临床观察

目的　观察还原型谷胱甘肽对减轻 NSCL C患者放射性肺损伤的作用。方法　 174例 NSCL C患者随机分为治疗组和对照组。治疗组放疗同时加用还原型谷胱甘肽 ;对照组单纯放疗。结果　 174例患者全部完成放疗计划 ,有效率 (CR+PR)治疗组为 89.7% ;对照组为 92 .0 %。急性放射性肺炎和肺纤维化的发生率治疗组为 9.2 %和 36 .8% ,对照组为 2 1.8%和 5 4 .0 % (P<0 .0 5 )。结论　还原型谷胱甘肽可以减轻 NSCL C患者放射性肺损伤     

金复康口服液对吉非替尼耐药人肺腺癌PC9/R的增敏作用和机制研究

目的 研究金复康口服液对人肺腺癌PC9细胞及耐药PC9/R细胞的吉非替尼增敏作用及机制。方法 金复康口服液20 mg/mL联合不同浓度的吉非替尼（40、20、10、5、2 μmol/L）作用于PC9/R细胞,CCK-8法检测细胞增殖;培养PC9、PC9/R细胞,分为对照组、金复康口服液组、吉非替尼组、联合用药组,流式细胞术检测PC9、PC9/R细胞周期和凋亡。在BALB/c裸鼠右前肢腋窝皮下接种PC9/R细胞建立裸鼠移植瘤模型,观察金复康口服液联合吉非替尼的体内抑瘤作用;对AKT、p-AKT、PTEN、PDCD4蛋白表达的影响和对miRNA-21表达的影响。结果 与吉非替尼（2、5、10、20 μmol/L）组比较,吉非替尼（2、5、10、20 μmol/L）+金复康口服液（20 mg/mL）组的PC9/R细胞抑制率显著增加（P<0.01）;与吉非替尼组比较,联合用药可以通过显著增加早期凋亡细胞比例诱导PC9及PC9/R细胞凋亡,并使PC9、PC9/R细胞停滞在DNA合成前期,从而抑制细胞增殖,差异均具有统计学意义。体内实验表明,与吉非替尼组比较,联合用药显著抑制裸鼠PC9/R移植瘤的生长（P<0.05）,且能显著降低裸鼠PC9/R组织p-AKT表达（P<0.05）,增强PTEN、PDCD4的表达（P<0.05）,联合用药组裸鼠PC9/R瘤组织miRNA-21的表达显著降低（P<0.05）。结论 金复康口服液能提高人肺腺癌PC9/R细胞对吉非替尼的敏感性,其作用的可能机制为通过降低miRNA-21的表达从而增强PTEN、PDCD4的表达以抑制AKT通路活性。     

Association of IL-8 gene polymorphisms with non small cell lung cancer in Tunisia: A case control study

Interleukin 8 (IL-8), is a proinflammatory chemokine, has been reported to have angiogenic activity and to be responsible for tumor-associated angiogenesis in several cancers. In this study, we aimed to study the (IL-8) gene polymorphism in relation with risk development of non small cell lung cancer in Tunisian patient. Two single nucleotide polymorphisms (−251T/A [rs4073], +781C/T [rs2227306]) of the IL-8 gene were screened in 170 patients with NSCLC and 225 healthy controls by PCR–RFLP.