Prognostic gene signatures for non-small-cell lung cancer

Resectable non-small-cell lung cancer (NSCLC) patients have poor prognosis, with 30–50% relapsing within 5 years. Current staging criteria do not fully capture the complexity of this disease. Survival could be improved by identification of those early-stage patients who are most likely to benefit from adjuvant therapy. Molecular classification by using mRNA expression profiles has led to multiple, poorly overlapping signatures. We hypothesized that differing statistical methodologies contribute to this lack of overlap. To test this hypothesis, we analyzed our previously published quantitative RT-PCR dataset with a semisupervised method. A 6-gene signature was identified and validated in 4 independent public microarray datasets that represent a range of tumor histologies and stages. This result demonstrated that at least 2 prognostic signatures can be derived from this single dataset. We next estimated the total number of prognostic signatures in this dataset with a 10-million-signature permutation study. Our 6-gene signature was among the top 0.02% of signatures with maximum verifiability, reaffirming its efficacy. Importantly, this analysis identified 1,789 unique signatures, implying that our dataset contains >500,000 verifiable prognostic signatures for NSCLC. This result appears to rationalize the observed lack of overlap among reported NSCLC prognostic signatures.     

Feasibility of postoperative adjuvant chemotherapy of cisplatin plus vinorelbine for completely resected non-small-cell lung cancer: A retrospective study in Japan

BackgroundThe efficacy of postoperative adjuvant cisplatin (CDDP)-based chemotherapy, such as the combination of CDDP and vinorelbine (VNR), has been established for surgically resected non-small-cell lung cancer (NSCLC). However, the optimal treatment schedule and dosage for CDDP and VNR are unknown. We evaluated patient compliance with and the safety of adjuvant chemotherapy of CDDP at 80 mg/m² administered on day 1 plus VNR at 25 mg/m² administered on days 1 and 8, every 3 weeks.MethodsMedical records of 100 surgically resected NSCLC patients, treated with a combination of CDDP and VNR at the Shizuoka Cancer Center between February 2006 and October 2011, were retrospectively reviewed.ResultsEighty-three (83%) patients completed the planned 4 cycles of CDDP plus VNR and 59 (59%) received the planned doses. Sixty-eight percent of the patients experienced a decreased neutrophil count (grade 3/4 toxicity); 1%, a decreased platelet count; and 4%, febrile neutropenia. No treatment-related deaths were noted in this study. Univariate analysis of the factors influencing patient compliance with this adjuvant chemotherapy showed that neither patient characteristics nor surgical procedure was significantly associated.ConclusionsOur results indicated that adjuvant chemotherapy with CDDP at 80 mg/m² administered on day 1 plus VNR at 25 mg/m² administered on days 1 and 8, every 3 weeks, was feasible for surgically resected NSCLC cases.     

Adjuvant chemotherapy for completely resected non-small cell lung cancer: a systematic review

PURPOSE: To conduct a systematic review and to evaluate the impact of postoperative adjuvant chemotherapy on the survival of patients with completely resected non-small cell lung cancer. METHODS: Relevant randomized trials and meta-analyses, published as articles or abstracts, were identified through electronic and hand searches by two reviewers. RESULTS: Seven meta-analyses and 26 randomized trials comparing surgery with or without chemotherapy met the pre-defined eligibility criteria for the review. The meta-analyses all showed a survival advantage for platinum- or UFT-based postoperative chemotherapy, although the results did not always achieve statistical significance. The results of individual trials were inconsistent, although recent trials have detected a large survival advantage with postoperative platinum-based chemotherapy. Differences in trial design, patient characteristics, disease stage, use of radiotherapy and chemotherapy regimen may explain the variation in results. CONCLUSIONS: Postoperative adjuvant platinum-based chemotherapy improves survival compared with surgery alone in completely resected non-small cell lung cancer. In patients fit for chemotherapy, the survival benefits strongly outweigh the adverse effects of the treatment.     

Prognostic factors before and after recurrence of resected non-small cell lung cancer

BackgroundThe post-surgical follow-up strategy in non-small cell lung cancer (NSCLC) is still controversial. Data on factors that affect the interval between surgery and recurrence or predict survival after recurrence in NSCLC patients are still limited.MethodsFrom a group of 775 NSCLC patients who consecutively underwent curative surgery, 133 patients showing recurrence were retrospectively analyzed.ResultsRecurrence was most often seen in smokers and patients with advanced stage disease. In patients experiencing relapse, the 1- and 2-year recurrence rates were 58% and 84%, respectively. A multivariate analysis showed that patients who underwent limited surgery, had non-adenocarcinoma disease, or had metastatic lymph node involvement showed early recurrence (p-values: <0.01, 0.04, and 0.04, respectively). Among all relapsed patients, the 2-year overall survival rate after recurrence was 37%. A multivariate analysis demonstrated that patients with lymph node metastasis at the time of surgery and patients who experienced early recurrence were significantly more likely to have a shorter survival time after recurrence (hazard ratio, 1.73; p=0.03; hazard ratio, 2.56; p<0.001, respectively).ConclusionsPatients who are node-positive, show non-adenocarcinoma disease, and/or undergo limited surgery should receive careful follow-up during the first year after surgery for NSCLC. The present data provide additional information about postoperative recurrence in NSCLC patients.     

Interobserver and intraobserver variability of standardized uptake value measurements in non-small-cell lung cancer

OBJECTIVES: To assess interobserver and intraobserver variabilities in measuring the maximal standardized uptake value (SUV) of non-small-cell lung cancer. METHODS: Positron emission tomography-computed tomography examinations of 20 consecutive patients referred for initial evaluation of newly diagnosed non-small-cell lung cancer were retrospectively reviewed by 5 experienced positron emission tomography-computed tomography readers, who independently measured the maximal SUV/body weight of the primary tumors. Interobserver and intraobserver variabilities were assessed by using 4 statistical methods: correlation, regression analysis, Bland-Altman analysis, and analysis of variance. The SUV measurements derived in the study were compared with the SUV measurements documented in the original reports using correlation and regression analysis. The percentages of tumors whose retrospective SUV measurements were more than 20% different and more than 25% different from those in the original report were assessed. RESULTS: Both interobserver and intraobserver SUV measurements were highly reproducible. Pearson correlation coefficients were greater than 0.95 and 0.94, respectively. Good interobserver and intraobserver agreement was shown with regression analysis (F test P value >0.05), the Bland-Altman analysis, and analysis of variance (F test P value >0.95). The mean original SUV was much less than the mean study SUV (P<0.05). The study SUV differed from the SUV of the original report by more than 20% in 50% of the tumors, and by more than 25% in 45% of the tumors. CONCLUSIONS: There was excellent interobserver and intraobserver agreement in SUVs measured in the study environment but poor agreement between study SUVs and those documented in original reports, which can affect treatment decisions substantially.     

Meis1 regulates proliferation of non-small-cell lung cancer cells

As one of the most common cancers, lung cancer remains to be a major public health problem. Non-small-cell lung adenocarcinoma cancer exhibits higher resistance to chemotherapy than small cell lung cancer, which requires novel strategies. To further understand underlying mechanisms for non-small-cell lung adenocarcinoma cancer cell proliferation, we explored the role of Meis1 in non-small-cell lung adenocarcinoma cancer cells. The results show that Meis1 inhibits non-small-cell lung cancer (NSCLC) cell proliferation. Specific knockdown of Meis1 resulted in strengthened proliferative ability of non-small-cell lung adenocarcinoma cancer cells. Cell cycle analysis indicated that DNA synthesis was increased when Meis1 was down-regulated specifically. As well as histone H3 phosphorylation, which is indicative of mitosis. More importantly, forced Meis1 expression repressed the proliferation of non-small-cell lung adenocarcinoma cancer cell. These data demonstrated Meis1 limits the proliferation of non-small-cell lung adenocarcinoma cancer cell and could potentially represent a therapeutic strategy that may control non-small-cell lung adenocarcinoma cancer cell proliferation.     

棘皮动物微管相关蛋白4-间变型淋巴瘤激酶融合基因在非小细胞肺癌靶向治疗中的作用

肺癌是全球发病率及病死率高的恶性肿瘤[1],我国肺癌的发病率与病死率也呈明显上升趋势,世界卫生组织预测,至2025年我国肺癌患者将达到100万,成为世界第一肺癌大国.近年来,非小细胞肺癌(nonsmall-cell lung cancer,NSCLC)靶向治疗优势明显,而且针对特定的靶点开展个体化治疗也已成为现实,因此寻找新的靶点成为研究的重点.     

Immunohistochemical findings in resected lung cancer]

The relationship between histological type and immunohistological findings was studied in total 141 cases of resected lung cancer. Adenocarcinoma was cytologically subtyped according to the ultrastructural findings. Immunohistochemical staining was performed on paraffin-embedding tissue using the avidin-biotin-peroxidase complex method for carcinoembryonic antigen (CEA), keratin, secretory component (SC), neuron specific enolase (NSE), lysozyme (Ly) and lactoferrin (La). Adenocarcinoma stained strongly positive with antibody against CEA and SC. There was no statistical difference among the different subtypes of adenocarcinoma, but in the cases of clara cell type, CEA staining was less intense and in goblet cell type, the intensity of SC staining was great. Goblet cell type characteristically stained positively with anti-Ly antibody, and Ly was a specific marker for differentiating adenocarcinoma of goblet cell type. La was positive not only in bronchial gland cell type, but also in other subtypes in adenocarcinoma. Squamous cell carcinoma showed more intense staining with anti-keratin antibody than other histological types. Small cell carcinoma extensively stained with anti-NSE antibody, but some of the other histological types also stained positively. NSE was a relatively good marker for small cell carcinoma but was not specific. It is concluded that immunohistochemical examination is a useful method for differentiation of different histological types of lung cancer.     

Clinical adjustability of radiological tools in patients with surgically resected cT1N0-staged non-small-cell lung cancer from the long-term survival evaluation

BackgroundVarious radiological tools have been introduced to determine the malignancy or prognosis of lung carcinomas. We retrospectively summarized the clinical outcomes to evaluate whether radiological tools such as consolidation-to-tumor ratio (CTR), tumor disappearance ratio (TDR), and mediastinal diameter (MD) are suitable for surgically resected non-small-cell lung cancer (NSCLC).MethodsThis retrospective study included 260 patients (128 men and 132 women; median age, 64 years) with cT1N0-staged NSCLC who underwent thoracotomy. Disease-free survival (DFS) and overall survival (OS) outcomes were analyzed using the Kaplan-Meier method and Cox proportional hazards model.ResultsWhen the adjusted hazard ratios (HRs) with reference to cT1a/1 mi were calculated, significant differences were observed in cT1b and cT1c for DFS (P=0.04 and P<0.01, respectively) and in cT1c for OS (P=0.01). For HRs with reference to CTR (≤0.5), a significant difference was only observed in CTR (>0.5) for DFS (P=0.01). For HRs with reference to TDR (≤25%), significant differences were observed in TDR (>75%) for DFS (P=0.02) and OS (P=0.02). For HRs with reference to MD (≤5 mm), significant differences were observed in 6–20 mm (P=0.04) and >20 mm (P=0.02) for DFS and in >20 mm (P=0.02) for OS.ConclusionsAll radiological tools revealed significant correlations with prognosis in the patients with cT1N0-staged NSCLCs. We recommend the use of MD in a clinical context. However, further investigation of this issue is needed.     

Targeted therapy in advanced non-small-cell lung cancer

Molecularly targeted therapies have recently expanded the options available for patients with advanced non-small-cell lung cancer (NSCLC). Two cancer cell pathways in particular have been exploited, the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathway. The former has emerged as a key regulator of cancer cell proliferation and invasion, and several EGFR inhibitors have been developed. Erlotinib, a small-molecule inhibitor of the EGFR intracellular tyrosine kinase, has been found to improve survival compared with placebo in previously treated patients with advanced NSCLC and is Food and Drug Administration (FDA)-approved in this setting. Clinical and molecular predictors of response to erlotinib, such as a history of never smoking and EGFR gene mutation or amplification, are presently being evaluated to select patients for earlier therapy with erlotinib. Additional EGFR inhibitors are also being examined in randomized trials. The VEGF pathway, a key mediator of angiogenesis, has become an attractive target in multiple malignancies, including lung cancer. Bevacizumab, a monoclonal antibody to VEGF, received FDA approval for use in advanced non-squamous-cell NSCLC in 2006 after a phase III trial reported a significant survival advantage when bevacizumab was added to standard first-line chemotherapy. Small-molecule inhibitors of the VEGF receptor tyrosine kinase, such as sunitinib and sorafenib, have also shown promise in phase II trials and are being further investigated in phase III studies. Because preclinical data suggest a synergistic effect when VEGF and EGFR inhibitors are combined, the concurrent use of erlotinib and bevacizumab has additionally been evaluated in a phase II trial, with encouraging early results suggesting at least equivalent activity to standard salvage chemotherapy, with less toxicity. Several other novel agents are being examined, including inhibitors of histone deacteylases and the 26S proteosome. Research efforts are currently focusing on tailoring such therapies according to predictive clinical and molecular markers.     

非小细胞肺癌分子靶向治疗药物的研究进展

分子靶向治疗是肺癌治疗的新方法.分子靶向治疗药物包括表皮生长因子受体抑制药、肿瘤新生血管生成抑制药和凋亡诱导药等.与传统细胞毒性化疗药物相比,分子靶向治疗能更特异地作用于肿瘤而毒副反应显著减少.虽然目前多数分子靶向治疗药物对肺癌的疗效不佳,但是厄罗替尼、贝伐单抗等对某些非小细胞肺癌(NSCLC)患者的良好疗效展示了这一研究领域的美好前景.本文对近年来NSCLC分子靶向治疗药物的研究进展作一综述.     

18F- FDG最大摄取值在判断非小细胞肺癌手术患者预后中的作用

目的 探讨18氟-脱氧葡萄糖(18F- FDG)最大摄取值(SUV)在判断可手术切除非小细胞肺癌(NSCLC)手术患者预后中的价值.方法 对82例NSCLC患者的术前SUV值(以11为分界点)与术后2 a无瘤生存率(DES)、总生存率的相关性进行回顾性分析.结果 TNM Ⅰ期和Ⅱ期术前原发灶SUV高值组术后DES显著低于低值组,Ⅰ期SUV高值组总生存时间显著短于低值组.结论 SUV测定在筛选TNM各期高危NSCLC患者及指导辅助治疗中有重要价值.     

Molecular pathology of non-small-cell lung cancer

The molecular basis of lung carcinogenesis must be understood more fully and exploited to enhance survival rates of patients suffering from lung cancer. In this review we will discuss the major molecular alterations that occur in lung cancer. Emphasis is placed on alterations that occur early during carcinogenesis since they might be relevant for future screening programs. Finally we will shortly review new approaches that are used to study the molecular pathology of lung cancer and how they can be applied in a clinical setting.     

18F-脱氧葡萄糖正电子发射体层摄影对非小细胞肺癌疗效的监测作用

胸部CT或其他解剖成像模式测量的肿瘤体积变化不能客观地评价疗效,因为肿瘤组织是由不同的恶性细胞、间质和炎症细胞组成,各种成分的修复不同步且不完全,即使在非小细胞肺癌(non-small cell lung cancer,NSCLC)治愈后,仍然残留纤维化闭块.另外,肺不张、放射性肺炎以及后期的纤维化均影响治疗前后原发病灶的界定,这导致了影像学随访最佳时间的不确定性并可导致一些新发病灶不能及时发现,使患者因此失去了治疗的机会.相反,治疗后肿块缓慢缩小可能导致治疗期不必要的延长,或者误认为是对初期治疗疗效差而采用更激进的疗法.