Pre-radiotherapy daily exercise training in non-small cell lung cancer: A feasibility study

AimTo examine the feasibility of an individual, supervised, structured moderate-to-high intensity cycle ergometer exercise training immediately before radiotherapy in patients undergoing concomitant chemoradiotherapy for locally advanced non-small cell lung cancer (NSCLC).BackgroundLung cancer is the most common form of cancer. Despite significant advancements in therapy and supportive care it is still the leading cause of cancer-related death worldwide.Materials and methodsRandomized controlled study design; patients with NSCLC receiving concomitant chemoradiotherapy were recruited and randomly assigned to either the exercise (EXE) or the control (CON) group. Exercise training consisted of 20 min moderate-to-high intensity aerobic interval training 5 times per week (Mon–Fri) prior to radiotherapy. Secondary outcomes were assessed at baseline and after 7 weeks: peak oxygen consumption (VO_2peak), functional capacity (6MWD), pulmonary function (FEV1), psychosocial parameters (quality of life (FACT-L), anxiety and depression (HADS)) and cancer-related side effects (reported daily).ResultsFifteen patients were included. All patients completed a baseline test, while 13 patients were eligible for a posttest. The recruiting rate was 44.1% and the overall attendance rate to exercise was 90.0% with an adherence rate to full exercise participation of 88.1%. No adverse events or any unexpected reactions were observed during the exercise sessions. No significant differences were observed within or between groups from baseline to post intervention in any of the secondary outcomes.ConclusionThis study demonstrated ‘proof of principle’ that daily moderate-to-high intensity cycle ergometer exercise was feasible, safe and well tolerated among newly diagnosed patients with locally advanced NSCLC undergoing concomitant chemoradiotherapy. Larger randomized controlled trials are warranted.     

The substance P/neurokinin-1 receptor system in lung cancer: Focus on the antitumor action of neurokinin-1 receptor antagonists

The last decades have seen no significant progress in extending the survival of lung cancer patients and there is an urgent need to improve current therapies. The substance P (SP)/neurokinin-1 receptor (NK-1R) system plays an important role in the development of cancer: SP and NK-1R antagonists respectively induce cell proliferation and inhibition in human cancer cell lines. No study of the involvement of this system in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cells has been carried out in depth. Here, we demonstrate the involvement of the SP/NK-1R system in human H-69 (SCLC) and COR-L23 (NSCLC) cell lines: (1) they express isoforms of the NK-1R and mRNA for the NK-1R; (2) they overexpress the tachykinin 1 gene; (3) the NK-1R is involved in their viability; (4) SP induces their proliferation; (5) NK-1R antagonists (Aprepitant (Emend), L-733,060, L-732,138) inhibit the growth of both cell lines in a concentration-dependent manner; (6) the specific antitumor action of these antagonists against such cells occurs through the NK-1R; and (7) lung cancer cell death is due to apoptosis. We also demonstrate the presence of NK-1Rs and SP in all the human SCLC and NSCLC samples studied. Our findings indicate that the NK-1R may be a promising new target in the treatment of lung cancer and that NK-1R antagonists could be new candidate antitumor drugs in the treatment of SCLC and NSCLC.     

Strategies to develop radiomics and machine learning models for lung cancer stage and histology prediction using small data samples

Predictive models based on radiomics and machine-learning (ML) need large and annotated datasets for training, often difficult to collect. We designed an operative pipeline for model training to exploit data already available to the scientific community. The aim of this work was to explore the capability of radiomic features in predicting tumor histology and stage in patients with non-small cell lung cancer (NSCLC).We analyzed the radiotherapy planning thoracic CT scans of a proprietary sample of 47 subjects (L-RT) and integrated this dataset with a publicly available set of 130 patients from the MAASTRO NSCLC collection (Lung1). We implemented intra- and inter-sample cross-validation strategies (CV) for evaluating the ML predictive model performances with not so large datasets.We carried out two classification tasks: histology classification (3 classes) and overall stage classification (two classes: stage I and II). In the first task, the best performance was obtained by a Random Forest classifier, once the analysis has been restricted to stage I and II tumors of the Lung1 and L-RT merged dataset (AUC = 0.72 ± 0.11). For the overall stage classification, the best results were obtained when training on Lung1 and testing of L-RT dataset (AUC = 0.72 ± 0.04 for Random Forest and AUC = 0.84 ± 0.03 for linear-kernel Support Vector Machine).According to the classification task to be accomplished and to the heterogeneity of the available dataset(s), different CV strategies have to be explored and compared to make a robust assessment of the potential of a predictive model based on radiomics and ML.     

p16和Ki67在非小细胞肺癌组织中的表达及其与预后的关系

目的探讨p16和Ki67在非小细胞肺癌（non-small cell lung cancer,NSCLC）中的表达,研究它们对NSCLC患者预后的影响及其与临床及病理因素之间的关系。方法收集NSCLC术后标本160例及正常肺组织20例（对照组）,应用免疫组化法检测NSCLC组织和正常肺组织中p16和Ki67的表达。结果在NSCLC组织和正常肺组织中,p16和Ki67的阳性表达率分别为23.8%、82.5%和90%、5%,差异有统计学意义（P〈0.05）。多因素分析：PTNM分期、淋巴结转移、p16及Ki67的表达是影响NSCLC根治术后患者预后的独立因素（P〈0.05）;p16阳性组与阴性组5年生存率分别为55.3%和18.0%,差异有统计学意义（P〈0.05）;Ki67阳性组与阴性组5年生存率分别为23.5%和42.9%,差异有统计学意义（P〈0.05）,p16和Ki67表达呈负相关（P〈0.05）。结论 p16和Ki67参与了NSCLC的发生发展,p16和Ki67的表达水平与NSCLC的发展及预后有一定的关系。     

Generation of ribozyme-adenoviral vector against K-ras mutant human lung cancer cells

ras mutations represent one of the most common oncogenetic lesions in human non-small cell lung cancer (NSCLC) and adversely affect the survival of patients afflicted with this disease. ras-directed gene therapy in the past employed primarily antisense oligonucleotides (AS-ODN) or expression vectors (such as a viral vector construct) that deliver the antisense sequence to inactivate the mutant oncogene message. These approaches produced minimal toxicity, and yet were limited in efficacy. Ribozymes present a viable alternative in antisense therapy by virtue of their renewable catalytic capability for site-specific RNA cleavage. We recently produced an adenoviral vector with a hammerhead ribozyme transgene (KRbz) that is specific for the K-ras codon 12 mutant sequence GUU, given the considerations that (a) in the United States, approx 30% of human NSCLCs express K-ras oncogene mutations, nearly all of which reside in codon 12; (b) anti-K-ras, anti-H, as well as anti-N-ras hammerhead ribozymes are potent growth inhibitors in various human cancers tested; and (c) in vitro and animal model studies suggest that ribozymes directed at oncogene (K- and H-ras C-fos, BCR-ABL) or human immunodeficiency viral gene messages are more effective than their antisense counterpart. This article describes the techniques involved in the production of the KRbz-adenoviral vector that is specific for the K-ras mutation GTT, and summarizes its in vivo antitumor effect against NSCLC xenografts expressing the relevant K-ras mutation in athymic mice.     

Curcumin inhibits interferon-alpha induced NF-kappaB and COX-2 in human A549 non-small cell lung cancer cells

The A549 cells, non-small cell lung cancer cell line from human, were resistant to interferon (IFN)-alpha treatment. The IFN-alpha-treated A549 cells showed increase in protein expression levels of NF-kappaB and COX-2. IFN-alpha induced NF-kappaB binding activity within 30 min and this increased binding activity was markedly suppressed with inclusion of curcumin. Curcumin also inhibited IFN-alpha-induced COX-2 expression in A549 cells. Within 10 min, IFN-alpha rapidly induced the binding activity of a gamma-(32)P-labeled consensus GAS oligonucleotide probe, which was profoundly reversed by curcumin. Taken together, IFN-alpha-induced activations of NF-kappaB and COX-2 were inhibited by the addition of curcumin in A549 cells.     

Prognostic value of S-100 immunostaining in tumour cells of non-small cell lung cancer

S-100 protein expression is present in various malignant tissues, yet its prognostic relevance is debatable. The aim was to assess in non-small cell lung cancer (NSCLC) patients' prognostic value of S-100 protein considered alone or in relation with other variables. Tumour samples taken from 86 NSCLC patients during resection were assayed for S-100 protein expression with the use of polyclonal DAKO ZO311 antibody. S-100 expression was found in 32 cases (37%). Positive staining was not correlated with clinical characteristics including age, sex, pathology type of tumour, stage and cigarette smoking. There was a tendency for simultaneous expression of S-100 and P53 protein (p=0.06). A median survival rate for the entire group was 2.3 years (95% CI, 0.9-3.6 years). The median and 5-year survival of patients with positive staining for S-100 protein was 1.5 years and 25%, respectively, compared with 3.0 years and 35%, respectively, in the S-100 negative group (p=0.17). In the final model of a multivariate analysis, S-100 protein expression in tumour cells was associated with significantly decreased survival (p=0.005). S-100 protein expression in tumour cells seems to be an independent predictor of poor prognosis in NSCLC patients.     

P42 Ebp1 functions as a tumor suppressor in non-small cell lung cancer

Although the short isoform of ErbB3-binding protein 1 (Ebp1), p42 has been considered to be a potent tumor suppressor in a number of human cancers, whether p42 suppresses tumorigenesis of lung cancer cells has never been clarified. In the current study we investigated the tumor suppressor role of p42 in non-small cell lung cancer cells. Our data suggest that the expression level of p42 is inversely correlated with the cancerous properties of NSCLC cells and that ectopic expression of p42 is sufficient to inhibit cell proliferation, anchorage-independent growth, and invasion as well as tumor growth in vivo. Interestingly, p42 suppresses Akt activation and overexpression of a constitutively active form of Akt restores the tumorigenic activity of A549 cells that is ablated by exogenous p42 expression. Thus, we propose that p42 Ebp1 functions as a potent tumor suppressor of NSCLC through interruption of Akt signaling. [BMB Reports 2015; 48(3): 159-165]     

Prognostic value of S-100 immunostaining in tumour cells of non-small cell lung cancer

S-100 protein expression is present in various malignant tissues, yet its prognostic relevance is debatable. The aim was to assess in non-small cell lung cancer (NSCLC) patients’ prognostic value of S-100 protein considered alone or in relation with other variables. Tumour samples taken from 86 NSCLC patients during resection were assayed for S-100 protein expression with the use of polyclonal DAKO ZO311 antibody. S-100 expression was found in 32 cases (37%). Positive staining was not correlated with clinical characteristics including age, sex, pathology type of tumour, stage and cigarette smoking. There was a tendency for simultaneous expression of S-100 and P53 protein (p=0.06). A median survival rate for the entire group was 2.3 years (95% CI, 0.9–3.6 years). The median and 5-year survival of patients with positive staining for S-100 protein was 1.5 years and 25%, respectively, compared with 3.0 years and 35%, respectively, in the S-100 negative group (p=0.17). In the final model of a multivariate analysis, S-100 protein expression in tumour cells was associated with significantly decreased survival (p=0.005). S-100 protein expression in tumour cells seems to be an independent predictor of poor prognosis in NSCLC patients.     

Axl-altered microRNAs regulate tumorigenicity and gefitinib resistance in lung cancer

The involvement of Axl kinase in non-small cell lung cancer''s (NSCLC) acquired resistance to tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib has been identified recently, but the mechanism by which Axl contributes to TKI resistance is largely unknown. MicroRNAs (miRNAs) repress gene expression and their critical role in tumorigenesis has been implicated. To investigate the role of miRNAs in the Axl-mediated acquired gefitinib resistance, we examined the Axl-mediated miRNA changes in gefitinib-resistant lung cancers. A panel of Axl kinase-altered miRNAs was identified. In this study, we validate and report that miR-374a and miR-548b modulated by Axl have essential roles in cell cycle arrest, gefitinib-induced apoptosis, epithelial-to-mesenchymal transition, migration and tumorigenesis of gefitinib-resistant lung cancer cells in vitro and in vivo by targeting Wnt5a and CCNB1 genes, respectively. Of clinical significance, high expression of Axl and miR-374a and low expression of miR-548b are associated with poor disease-free survival postoperatively. These findings indicate that the modulation of specific miRNAs may provide a therapeutic target to treat or reverse gefitinib resistance in NSCLC with high expression of Axl in the future.     

TKI治疗晚期tPd,细胞肺癌患者免疫功能的变化及意义

目的：通过观察晚期非小细胞肺癌患者TKI治疗前后外周血IgG、[gM、IgA、C3、c4、C-反应蛋白及CD3＋、CD4＋、CD8＋、CD4＋／CD8＋细胞的表达变化,探讨TKI治疗对晚期非小细胞肺癌患者免疫功能的影响及意义。方法：检测TKI组30例非小细胞肺癌患者TKI治疗前、治疗一个月后外周血IgG、IgM、IgA、C3、C4、C-反应蛋白及CD3＋、CD4＋,CD8＋、CD4＋／CD8＋细胞表达水平,分析表达变化及与疗效的关系。30例非小细胞肺癌患者作为对照组。结果：治疗前,TKI组与对照组IgG、IgM、IgA、C3、C4、c＋反应蛋白水平基本正常,但CD4＋细胞数量减低、CD4＋／CD8＋比值较低、CD8＋细胞数量增高,两组相比IgG、IgM、IgA、C3、C4、C-反应蛋白、CD3＋、CD4＋．CD8＋、CD4＋／CD8‘差异均无统计学意义（P〉0．05）;TKI治疗一个月后,TKI组与对照组IgG、IgM、IgA、C3、C4、C-反应蛋白水平无明显变化,而CD4＋细胞数量增多、CD4＋／CD8＋较前增高,CD8＋细胞数量较前减低,两组相比CD3＋、IgG、IgM、IgA、C3、C4、c-反应蛋白差异无统计学意义（P〉0．05）,而CD4＋．CD4＋／CD8＋、CD8＋差异有统计学意义（P〈O．01）。结论：TKI治疗后,晚期非小细胞肺癌患者细胞免疫功能得到改善,体现在CD4＋,CD8＋细胞数量的变化上,且TKI治疗的疗效可通过比较外周血CD4＋、CD4＋／CD8＋、cD8＋细胞表达变化体现。     

p53 gene status modulates the chemosensitivity of non-small cell lung cancer cells

This study examined the effects of p53 gene status on DNA damage-induced cell death and chemosensitivity to various chemotherapeutic agents in non-small cell lung cancer (NSCLC) cells. A mutant p53 gene was introduced into cells carrying the wild-type p53 gene and also vice versa to introduce the wild-type p53 gene into cells carrying the mutant p53 gene. Chemosensitivity and DNA damage-induced apoptosis in these cells were then examined. This study included five cell lines, NCI-H1437, NCI-H727, NCI-H441 and NCI-H1299 which carry a mutant p53 gene and NCI-H460 which carries a wild-type p53 gene. Mutant p53-carrying cells were transfected with the wild-type p53 gene, while mutant p53 genes were introduced into NCI-H460 cells. These p53 genes were individually mutated at amino acid residues 143, 175, 248 and 273. The representative cell line NCI-H1437 cells transfected with wild-type p53 gene (H1437/wtp53) showed a dramatic increase in susceptibility to three anticancer agents (7-fold to cisplatin, 21-fold to etoposide, and 20-fold to camptothecin) compared to untransfected or neotransfected H1437 cells. An increase in chemosensitivity was also observed in wild-type p53 transfectants of H727, H441, H1299 cells. The results of chemosensitivity were consistent with the observations on apoptotic cell death. H1437/wtp53 cells, but not H1437 parental cells, exhibited a characteristic feature of apoptotic cell death that generated oligonucleosomal-sized DNA fragments. In contrast, loss of chemosensitivity and lack of p53-mediated DNA degradation in response to anticancer agents were observed in H460 cells transfected with mutant p53. These observations suggest that the increase in chemosensitivity was attributable to wild-type p53 mediation of the process of apoptosis. In addition, our results also suggest that p53 gene status modulates the extent of chemosensitivity and the induction of apoptosis by different anticancer agents in NSCLC cells.     

Vasoactive intestinal polypeptide binds with high affinity to non-small cell lung cancer cells and elevates cyclic AMP levels

Vasoactive intestinal polypeptide (VIP) receptors were characterized on non-small cell lung cancer (NSCLC) cells. ¹²⁵I-VIP bound specifically to membranes derived from 6 NSCLC cell lines. Specific ¹²⁵I-VIP was time dependent and a linear function of EPLC-65H membrane concentration. ¹²⁵I-VIP bound with high (K_d=0.2 nM) and moderate (K_d=39 nM) affinity to two classes of sites. Pharmacology studies indicated that the order of peptide potency was VIP > rGHRH > PHI = helodermin > secretin > glucagon. Also VIP elevated the cAMP levels 10-fold using cell line ADLC-5M2. These data indicate that functional VIP receptors are present on NSCLC cells.     

Gene therapy for lung cancer

Lung cancer continues to be the largest killer of Americans due to cancer. Although progress has been made, with advances in chemotherapy, the majority of patients diagnosed with lung cancer ultimately succumb to the disease. A better understanding of the molecular pathogenesis of lung cancer is demonstrating how alterations in oncogenes and tumor suppressor genes control lung cancer initiation, growth, and survival. In this article, attempts to target molecular alterations in lung cancer using gene therapy techniques are reviewed. These include introducing suicide genes into tumor cells, replacement of defective tumor suppressor genes, inactivating oncogenes, and immunotherapy-based approaches using gene therapy technology. The major barrier for these techniques continues to be the inability to specifically target tumor cells while sparing normal cells. Nonetheless, these approaches are likely to yield important biologic and clinical data which will further the progress of lung cancer treatment.     

稀土磁疗对开胸术后机体免疫功能及疼痛的影响

目的:研究稀土磁治疗床对食管癌、肺癌手术患者术后机体免疫力及切口疼痛的影响。方法:选食管癌患者37例,肺癌23例,采集手术前及稀土磁治疗床治疗后患者静脉血,检测T细胞亚群CD3 、CD4 、CD8 、CD4 /CD8 比值和NK细胞的比例变化,检查手术切口疼痛的恢复情况。结果:术后给予稀土磁治疗床治疗后与手术前相比较CD3 、CD4 、NK、CD4 /CD8 细胞有显著提高(P<0.05),也高于对照组术后的T细胞亚群水平(P<0.05)。结论:稀土磁治疗床可提高食管癌、肺癌患者术后的机体免疫力,减轻疼痛,有利于患者术后恢复。     

Rab11-FIP2 suppressed tumor growth via regulation of PGK1 ubiquitination in non-small cell lung cancer

Mounting evidence has shown that the Rab11-FIP2 has critical roles in cancer cell growth. However, the clinical significance of Rab11-FIP2 in Non-small cell lung cancer (NSCLC) remains to be fully elucidated. In this study, we investigated the expression of Rab11-FIP2 using immunohistochemistry in 150 patients with NSCLC. We found that its expression level in NSCLC was much lower than that in the corresponding adjacent normal tissues. The DNA methylation data revealed that Rab11-FIP2 were significantly hypermethylated in NSCLC. The methylation level in the gene body was negatively correlated with the expression level of Rab11-FIP2 in NSCLC. Furthermore, enforced expression of Rab11-FIP2 dramatically reduced cancer cell proliferation and tumorigenesis, indicating a tumor suppressor role of PGK1 in NSCLC progression. Mechanistic investigations showed that Rab11-FIP2 interacted with the glycolytic kinase PGK1 and promoted its ubiquitination in NSCLC cells, leading to inactivation of the oncogenic AKT/mTOR signaling pathway. Overall, our data indicate that reduced expression of Rab11-FIP2 by DNA hypermethylation plays an important role in NSCLC tumor growth.     

血清肿瘤标志物检测对晚期非小细胞肺癌靶向治疗的预后分析

目的：探究检测血清肿瘤标志物对预测晚期非小细胞肺癌靶向治疗预后的影响。方法：选取2010年4月至2012年12我院收治的晚期非小细胞肺癌患者70例,均予以吉非替尼进行治疗,检测治疗前及治疗后2个月肿瘤标志物癌胚抗原CEA、角蛋白19的可溶性片段（CYFRA21—1）、癌抗原125（CA125）的表达水平,观察其表达水平与患者疗效之间的关系。结果：治疗后,患者完全缓解1例,部分缓解37例,疾病稳定19例,疾病进展13例,有效率为54．3％。治疗后,治疗有效的患者CEA、CA125明显比治疗前降低,结果具有统计学意义（P〈0．05）;而疾病稳定、疾病进展的患者治疗后CEA、CA125与治疗前比却无明显差异（P〉0．05）。治疗有效与疾病稳定的患者治疗后CYFRA21．1有明显降低,但与治疗前比却无明显差异（P〉0．05）;而疾病进展患者的CYFRA21—1却明显升高,与治疗前比有显著差异（P〈0．05）。而治疗前,治疗有效的患者血清中CEA、CA125比疾病稳定、疾病进展的患者明显较高,结果具有统计学意义（P〈0．05）;疾病稳定患者的CEA、CA125与疾病进展患者的相比,治疗有效的患者CYFRA21-1与疾病稳定、疾病进展的相比,结果均不具有统计学意义（P〉0．05）。结论：治疗前CEA、CA125浓度较高则治疗效果不错．治疗后效果较好则CEA、CA125浓度较低,效果不好则CYFRA21-1浓度较高。利用血清肿瘤标志物可显著反映肿瘤靶向药物治疗的预后情况,为临床判断其治疗效果提供依据。     

转录因子Hey1在非小细胞肺癌中的表达及临床意义

目的检测Hey1与Notch1在非小细胞肺癌组织中的表达,探讨Hey1在非小细胞肺癌中的表达与Notch1的表达、各临床病理特征之间的关系。方法制作组织芯片,采用免疫组织化学染色检测Notch1和Hey1在246例非小细胞肺癌组织及相应117例癌旁正常肺组织中的表达,应用SPSS 21.0进行统计分析。结果 Notch1在肺鳞癌、肺腺癌和癌旁正常肺组织的阳性率分别为78.8%,28.9%和30.8%,Hey1在肺鳞癌、肺腺癌和癌旁正常肺组织中的阳性率分别为79.7%,23.4%和33.3%;肺鳞癌患者Notch1阳性表达与TNM分期和淋巴结转移情况呈正相关;肺鳞癌患者Hey1阳性表达与TNM分期呈正相关,与肿瘤分化程度呈负相关;Spearman相关分析显示,肺鳞癌和肺腺癌组织中Notch1表达与Hey1表达具有显著的正相关关系。结论 Hey1和Notch1与肺鳞癌的恶性程度密切相关,可能是肺鳞癌发生、发展的重要参与因子。