Prognosis of Stage II non-small cell lung cancer according to tumor and nodal status at diagnosis

PURPOSE: To evaluate the prognostic significance of tumor and node status among patients with Stage II non-small cell lung cancer using a population-based national database. METHODS: We identified all primary cases of Stage II non-small cell lung cancer diagnosed prior to autopsy from the Surveillance, Epidemiology and End Results (SEER) registry. Lung cancer-specific survival curves were obtained for the 5254 patients who had curative surgical resection, stratifying for tumor and node status (T1-2N1M0, T3N0M0). The 12.5-year Kaplan-Meier estimator of survival was used as a measure of lung cancer cure rate. The influence of gender, age, cell type, pathologic tumor status, nodal metastasis, surgical method, and post-operative radiation therapy were evaluated using Cox regression. RESULTS: Survival was better for T1N1 cases during the first 3--4 years after diagnosis. Five-year survival for T1N1 and T3N0 cases however, was not significantly different (46% versus 48%, p=0.4) and the cure rate was somewhat higher for T3N0 cases (33% versus to 27%, p=0.10). T2N1 cases had the worst overall survival. Multivariate analysis revealed that gender, age, tumor and nodal status, and histology were independent prognostic factors. CONCLUSIONS: Among Stage II cancers, T3N0 cases have the highest cure rate and an overall survival pattern that more closely resembles T1N1 tumors. Several clinico-pathologic characteristics are significantly associated with survival and may explain some of the heterogeneity in outcomes among Stage II patients. These results suggest that T3N0 cases may be better classified as Stage IIA disease.     

Wnt3 gene expression promotes tumor progression in non-small cell lung cancer

Background

Recent studies have shown that human copper transporter 1 (hCtr1), the major copper influx transporter, is involved in the transport of platinum-based antitumor agents. We investigated the predictive and prognostic values of hCtr1, and copper efflux transporters ATP7A and ATP7B, in patients with locally advanced non-small cell lung cancer (NSCLC) receiving first-line platinum-based chemotherapy.

Methods

From 2004 to 2009, we identified 54 consecutive stage III NSCLC patients who underwent first-line platinum-based doublet chemotherapy. Immunohistochemical studies of hCtr1, ATP7A and ATP7B on the paraffin-embedded pre-treatment tumor samples were performed and correlated with chemotherapy response and survival.

Results

Overexpression of hCtr1, ATP7A and ATP7B were observed in 68%, 48% and 74% of the participants, respectively. hCtr1 overexpression was associated with better chemotherapy responses (P < 0.01); whereas ATP7A and ATP7B were not. Patients with hCtr1 overexpressing tumors had better progression-free survival (PFS) and overall survival (OS) (P = 0.01 and 0.047, respectively). In multivariate analyses for chemotherapy response and PFS, only hCtr1 overexpression emerged as a favorable independent predictive and prognostic factor (all P < 0.01).

Conclusion

This is the first report to state that hCtr1 is not only an independent predictor of platinum-based chemotherapy response but also a prognostic factor in stage III NSCLC.     

Clinical significance of VEGF-C status in tumour cells and stromal macrophages in non-small cell lung cancer patients

Recent experimental studies have revealed that tumour-associated stromal macrophages as well as tumour cells express vascular endothelial growth factor C (VEGF-C), which plays important roles in lymphangiogenesis, which is a critical factor in the progression of many malignant tumours including non-small-cell lung cancer (NSCLC). However, no clinical study on VEGF-C expression in both stromal macrophages and tumour cells has been reported, and we conducted the present study to address the issue in resected NSCLC. A total of 206 patients with completely resected pathologic stage I-IIIA NSCLC were retrospectively reviewed. Expression of VEGF-C in primary lung tumour was assessed immunohistochemically. Expression of VEGF-C in tumour cells was high in 125 patients (60.7%), and that in stromal macrophages was positive in 136 patients (71.2%). The status of VEGF-C in tumour cells or in stromal macrophages was not correlated with nodal status or angiogenesis. The 5-year survival rate of high tumoral VEGF-C patients (60.7%) was significantly lower than that of low tumoral VEGF-C patients (39.3%) (P=0.046), and a multivariate analysis confirmed that tumoral VEGF-C status was a significant and independent prognostic factor. Moreover, tumour showing high VEGF-A and VEGF-C expression in tumour cells showed the poorest prognosis (5-year survival rate, 45.1%). The status of VEGF-C in stromal macrophages was not correlated with the prognosis. In conclusion, tumoral VEGF-C status, not stromal VEGF-C status, was a significant prognostic factor in resected NSCLC.     

p53 gene mutation and protein expression in operable non-small cell lung cancer in Poland.

We investigated the association of p53 abnormalities (gene mutations by DNA sequencing and protein over-expression by immunostaining) with clinical data and prognosis in 74 patients with resected non-small cell lung cancer (NSCLC). DNA analysis of exons 5-8 of the p53 gene showed 34 mutations in 74 resected primary NSCLC (45.9%). Immunohistochemical study of the p53 protein revealed that 41 of 74 (55.4%) samples had positive staining. We found strong agreement between the results of the p53 protein expression test (p53-PE) and the p53 gene mutation test (p53-M) (Cohen's kappa = 0.65, 95% CI 0.48-0.82). Joint distribution of the results (analysed using the bivariate Dale model) was mainly influenced by, histological type of tumour. A positive result for the p53-PE test significantly increased (estimated odds ratio 84.5; 95% CI 8.89-803.03) the odds of observing a positive result in the p53-M test. In the univariate analysis (log rank test), positive results in the p53-M test and the p53-PE test were significantly associated with overall survival (P < 0.001 and P = 0.005, respectively). In the multivariate analysis (Cox's proportional hazard model), a positive result for the p53-M test significantly increased relative risk for overall survival (RR 9.56; 95% CI 2.62-34.87; P < 0.001). When the result of the p53-M test was accounted for, a positive result for the p53-PE test did not offer any additional prognostic information due to the strong dependence of results of the tests. However, when the result of the p53-M test was removed from the model, a positive result for the p53-PE test became a significant unfavourable prognostic factor (P = 0.009). We conclude that p53 gene mutation and protein expression analyses are in a strong agreement. Joint distribution of the results depends mainly on histological type of tumour. When considered separately, both tests are unfavourable prognostic factors in NSCLC. When the result of the p53-M test is taken into account, the p53-PE test does not offer any additional prognostic information.     

BIRC5基因在非小细胞肺癌中的表达及与免疫细胞浸润和预后的关系

目的:通过生物信息学方法分析杆状病毒凋亡抑制蛋白5(baculoviral inhibitor of apoptosis repeat-containing protein 5,BIRC5)基因在非小细胞肺癌(non-small cell lung cancer,NSCLC)与正常组织中的表达差异,并分析其与NSCLC...     

STAT-3介导的非依赖VEGFR-2通路对NSCLC细胞放射敏感性影响的研究

目的 研究抑制STAT-3对非依赖VEGFR-2通路的NSCLC细胞放射敏感性的影响,并探讨其可能机制。 方法 采用Q-PCR及蛋白印迹法检测各组中VEGFR-2、STAT-3相关信号分子及HIF-1α、CyclinD₁ mRNA与蛋白表达变化;克隆形成实验检测各组细胞放射敏感性,流式细胞术检测细胞凋亡及周期分布。 结果 经VEGFR-2抑制剂Apatinib处理后,Calu-1细胞中VEGFR-2、STAT-3 mRNA无显著变化,HIF-1α、CyclinD₁ mRNA表达降低;联合STAT-3抑制剂S3I-201后,VEGFR-2、STAT-3及下游相关基因mRNA表达降低(F=304.54、118.99,P<0.01);VEGFR-2、STAT-3及下游相关靶蛋白磷酸化水平均降低(F=144.34、529.66,P<0.01);细胞凋亡率与G₂+M期阻滞增加,同时抑制STAT-3和VEGFR-2组更明显(F=72.37,P<0.01)。与Calu-1细胞相比,A549细胞加Apatinib抑制VEGFR-2细胞放射增敏效果有限,SER=1.39;联合S3I-201抑制STAT-3后,放射增敏效果显著,SER=1.72(t=-48.61,P=0.000)。 结论 NSCLC细胞VEGFR-2被抑制时,旁路活化的STAT-3直接和间接调控CyclinD₁表达,进而影响肺癌细胞的放射敏感性,联合抑制肺癌细胞VEGFR-2和STAT-3,具有良好的放射增敏效果。     

血清总胆红素与非小细胞肺癌临床相关性的初步分析

  目的  研究血清总胆红素（total bilirubin,TBIL）与非小细胞肺癌（non-small cell lung cancer,NSCLC）患者临床病理特征以及炎症细胞之间的关系,探讨血清TBIL对NSCLC患者治疗的指导意义以及预后价值。  方法  回顾性分析2017年3月至2020年12月于上海中医药大学附属市中医医院就诊的NSCLC患者332例,收集患者临床资料,并通过电话、门诊复诊等方式进行随访,采用Logistic回归分析进行单因素分析,采用Kaplan-Meier生存曲线进行生存分析。  结果  NSCLC患者血清TBIL水平在不同性别中存在差异,男性高于女性（P<0.05）,但在不同年龄、有无吸烟史及患病时间中无显著性差异（P>0.05）;在不同淋巴浸润程度、是否存在远处转移和不同肿瘤分期中,血清TBIL表达存在显著性差异（P<0.05）。Logistic回归分析发现TBIL、白蛋白、谷草转氨酶水平与患者预后具有显著相关性（P<0.05）;当女性患者TBIL>9.85 μmol/L时,患者无病生存期相比TBIL≤9.85 μmol/L时延长,男性患者TBIL水平与无病生存期无明显相关性（P>0.05）。根据TBIL水平将患者分为高水平和低水平组,男性患者淋巴细胞比例在TBIL高水平组较高,中性粒细胞淋巴细胞比值（neutrophil- lymphocyte ratio,NLR）在高水平组较低;女性患者淋巴细胞比例在高水平组较高,NLR、CD3、CD4细胞比例在高水平组较低（P<0.05）。  结论  血清TBIL在NSCLC早期患者中的表达水平高于进展期患者,有望成为NSCLC的治疗指导依据;TBIL与中性粒细胞和NLR之间可能存在协同作用,共同在肺癌免疫调节中发挥抗肿瘤作用。      

非小细胞肺癌组织中VEGF-C及其受体VEGFR-3的表达与淋巴结转移的关系

 目的　研究血管内皮生长因子C（VEGF-C）及VEGF受体-3（VEGFR-3）在人类非小细胞肺癌（NSCLC）组织中的表达,并探讨其与淋巴转移之间的关系。方法　对60例NSCLC患者术后标本行VEGF-C、VEGFR-3免疫组织化学（SP法）检测,计数阳性率,并结合临床和病理资料进行分析。结果　60例NSCLC组织中VEGF-C阳性表达率为68.3 %（41／60）,VEGFR-3阳性表达率为53.3 %（32／60）,VEGF-C的表达与肺癌分化程度呈负相关（P＝0.004）,VEGF-C、VEGFR-3的表达与淋巴结转移呈正相关（P＝0.009）,肺癌组织中VEGF-C与VEGFR-3的表达亦相关（r＝0.27）。结论　NSCLC组织中VEGF-C、VEGFR-3的表达与肿瘤细胞的淋巴结转移相关。VEGF-C是促使肿瘤组织内淋巴管形成,促进肺癌淋巴结转移的重要原因。     

JAM-C promotes lymphangiogenesis and nodal metastasis in non-small cell lung cancer

This study aims to investigate lymphatic metastasis-related genes in non-small cell lung carcinomas (NSCLC). NSCLC tissue was analyzed for expression of junctional adhesion molecule-C (JAM-C) protein. Our data revealed novel associations between JAM-C overexpression in primary tumors and lymphatic microvessel density (LMVD), lymph node metastasis, and poorer overall survival and recurrence-free survival. We used the highly metastatic human lung adenocarcinoma cell line Anip973 and its parental line AGZY83-a, which has a low metastatic capacity, in vivo and vitro. We found that JAM-C played an important role in different metastasis capacity of lymph node. JAM-C affected tumor growth, LNM, JAM-C, VEGF-C, vasculature, and ERK1/2 phosphorylation (p-ERK1/2). β1 integrin was involved in lymph node metastasis. Moreover, JAM-C knockdown in highly metastatic Anip973 decreased cell migration in scratch-wound assays. The JAM-C knockdown in Anip973 cells and JAM-C cDNA in AGZY83-a cells regulated the vascular endothelial growth factor C (VEGF-C) expression. Immunofluorescence showed that blocked VEGF-C expression in JAM-C shRNA Anip973 cells were restored after JAM-C treatment. JAM-C-induced VEGF-C in JAM-C cDNA AGZY83-a cells was also effectively inhibited by treatment with an antibody specifically against JAM-C. Use of media from Anip973 cells, AGZY83-a, and A549cells lung cancer cells that overexpressed or downregulated JAM-C was demonstrated to affect activity of VEGF-C-induced β1 integrin subunit or ERK activity in human dermal lymphatic endothelial cells (HDLEC) treated with VEGF-C or inhibitory antibody to JAM-C. Overall, these results indicate that JAM-C could mediate metastasis as it contributes to VEGF-C expression in cancer cells. JAM-C affects β1and ERK activation in HDLEC, thus promoting lymphangiogenesis and nodal metastasis. Our findings indicate that JAM-C may be a therapeutic target for preventing and treating lymphatic metastases.     

非小细胞肺癌组织中ABCG4表达与耐药的相关性研究

目的 检测ABCG4 mRNA和蛋白在非小细胞肺癌（NSCLC）组织中的表达,分析其表达与病理类型及NSCLC细胞耐药的相关性,为研究其耐药机制提供理论基础。方法 采用免疫组化染色、RT-PCR及Western blotting检测ABCG4在NSCLC组织中的表达;MTT法检测NSCLC对化疗药物的敏感性,分析药物敏感性与ABCG4 mRNA和蛋白表达的相关性。结果 ABCG4蛋白阳性主要定位于细胞膜和胞质,其在NSCLC组织中的阳性表达率为73.9%（68/92）,而在30例癌旁正常肺组织中几乎不表达。ABCG4蛋白在肺鳞癌和肺腺癌中的阳性表达率分别为67.3%和81.4％,差异无统计学意义（P＞0.05）。环磷酰胺、吉西他滨、多柔比星、紫杉醇和顺铂在NSCLC组织中的药物敏感程度与其相应组织中ABCG4蛋白阳性表达有关（rs均＞0.3,P均＜0.05）;除紫杉醇外,环磷酰胺、吉西他滨、多柔比星和顺铂在NSCLC组织中的药物敏感程度与其相应组织中ABCG4 mRNA表达量有关（P均＜0.05）。结论 ABCG4在肺鳞癌、肺腺癌中高表达,其表达程度与NSCLC部分化疗药物耐药有关,为进一步研究ABCG4在NSCLC中的表达及可能耐药机制提供实验依据。     

非小细胞肺癌E GF R基因突变的表现及其与肿瘤标记物的相关性

目的：探讨非小细胞肺癌（NSCLC）EGFR基因突变位点状态,分析其与血清肿瘤标记物NSE、CEA、CYFRA21－1、TSGF间的关系。方法：回顾性分析240例NSCLC患者组织标本中EGFR不同位点基因突变状态,分析基因突变率与患者性别、年龄、吸烟史和组织分型间的关系及NSCLC患者19、21突变位点与肿瘤标记物NSE、CEA、CYFRA21－1、TSGF的相关性。结果：240例标本突变135例,18号外显子突变2例（1．5％）;19号外显子突变47例（34．8％）;20号外显子突变7例（5．2％）;21号外显子突变71例（52．6％）;双突变8例（5．9％）。EGFR突变主要发生在19、21号外显子上,其中19号外显子突变与组织分型有关（P＜0．05）,与年龄、性别、吸烟史无关（P＞0．05）;21号外显子突变与组织分型、吸烟史、性别有关（P＜0．05）,与年龄无关（P＞0．05）。EGFR突变组肿瘤标志物NSE、CEA、CYFRA21－1、TSGF的表达水平与未突变组之间差异无统计学意义（P＞0．05）,19、21号外显子突变的肿瘤标记物NSE、CEA、CYFRA21－1、TSGF之间的差异也无统计学意义（P＞0．05）。结论：NSCLC的EGFR突变中19、21号外显子突变率显著高于其他类型,这对于指导临床合理应用EGFR－TKIs药物治疗有重要的意义。而肿瘤标记物NSE、CEA、CYFRA21－1、TSGF在突变组与未突变组之间、19和21号外显子突变之间的差异均无统计学意义。因此,血清肿瘤标记物可能不足以作为评估EGFR突变的指标。     

Relationship between tumor size and disease stage in non-small cell lung cancer

Background  

Whether tumor size and stage distribution are correlated remains controversial. The objective is to assess the relationship between tumor size and disease stage distribution in non-small cell lung cancer (NSCLC).