RRM1在晚期非小细胞肺癌中的表达及其意义

目的:探讨晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)组织中核苷酸还原酶M1(RRM1)的表达水平及其与NSCLC患者病情进展及预后的关系.方法:免疫组织化学法检测60例晚期NSCLC患者肺组织中RRM1蛋白表达水平,并与患者的临床特征及预后关系进行分析.结果:RRM1的表达与性别有统计学差异(P＜0.05);与年龄、组织学类型及分期均无统计学差异(P＞0.05).在对生存期的分析中发现RRM1低表达组的中位生存期(18个月)及无疾病进展期(6个月)均明显长于高表达组(13个月,4个月)(P＜0.05),1年生存率(69.2％)及2年生存率(23.1％)均高于高表达组(58.8％,3％)(P＜0.05).结论:晚期非小细胞肺癌组织中RRM1低表达的患者比高表达患者有更长的中位生存期及无疾病进展生存期.因此,RRM1表达水平可作为晚期NSCLC的一个重要的预测预后的标志物.     

Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy.

BACKGROUND: Customizing chemotherapy on the basis of chemosentitivity prediction may improve outcome in advanced bladder cancer patients. Since DNA damaging agents are the cornerstones of therapy, we hypothesized that levels of DNA repair genes could predict survival. PATIENTS AND METHODS: Messenger RNA expression levels of excision repair cross complementing 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunit M1 (RRM1) and caveolin-1 were determined by RT-PCR in tumor DNA from 57 advanced and metastatic bladder cancer patients treated with either gemcitabine/cisplatin or gemcitabine/cisplatin/paclitaxel (Taxol). Levels were correlated with survival, time to disease progression and chemotherapy response. RESULTS: Median survival was significantly higher in patients with low ERCC1 levels (25.4 versus 15.4 months; P = 0.03) (median follow-up 19 months). A trend towards longer time to progression was observed in patients with tumors expressing low levels of all markers. Levels of RRM1, BRCA1 and caveolin-1, however, failed to predict the survival and a clear link with chemotherapy response could not be established. On multivariate analysis with pretreatment prognostic factors, ERCC1 emerged as an independent predictive factor for survival. CONCLUSION: The results of the study indicate that ERCC1 may predict survival in bladder cancer treated by platinum-based therapy.     

ASC amino-acid transporter 2 (ASCT2) as a novel prognostic marker in non-small cell lung cancer

Background:

ASC amino-acid transporter 2 (ASCT2) is a major glutamine transporter that has an essential role in tumour growth and progression. Although ASCT2 is highly expressed in various cancer cells, the clinicopathological significance of its expression in non-small cell lung cancer (NSCLC) remains unclear.

Methods:

One hundred and four patients with surgically resected NSCLC were evaluated as one institutional cohort. Tumour sections were stained by immunohistochemistry (IHC) for ASCT2, Ki-67, phospho-mTOR (mammalian target of rapamycin), and CD34 to assess the microvessel density. Two hundred and four patients with NSCLC were also validated by IHC from an independent cohort.

Results:

ASC amino-acid transporter 2 was expressed in 66% of patients, and was closely correlated with disease stage, lymphatic permeation, vascular invasion, CD98, cell proliferation, angiogenesis, and mTOR phosphorylation, particularly in patients with adenocarcinoma (AC). Moreover, two independent cohorts confirmed that ASCT2 was an independent marker for poor outcome in AC patients.

Conclusions:

ASC amino-acid transporter 2 expression has a crucial role in the metastasis of pulmonary AC, and is a potential molecular marker for predicting poor prognosis after surgery.     

CD99 is a novel prognostic stromal marker in non-small cell lung cancer

The complex interaction between cancer cells and the microenvironment plays an essential role in all stages of tumourigenesis. Despite the significance of this interplay, alterations in protein composition underlying tumour-stroma interactions are largely unknown. The aim of this study was to identify stromal proteins with clinical relevance in non-small cell lung cancer (NSCLC). A list encompassing 203 stromal candidate genes was compiled based on gene expression array data and available literature. The protein expression of these genes in human NSCLC was screened using the Human Protein Atlas. Twelve proteins were selected that showed a differential stromal staining pattern (BGN, CD99, DCN, EMILIN1, FBN1, PDGFRB, PDLIM5, POSTN, SPARC, TAGLN, TNC and VCAN). The corresponding antibodies were applied on tissue microarrays, including 190 NSCLC samples, and stromal staining was correlated with clinical parameters. Higher stromal expression of CD99 was associated with better prognosis in the univariate (p = 0.037) and multivariate (p = 0.039) analysis. The association was independent from the proportion of tumour stroma, the fraction of inflammatory cells and clinical and pathological parameters like stage, performance status and tumour histology. The prognostic impact of stromal CD99 protein expression was confirmed in an independent cohort of 240 NSCLC patients (p = 0.008). Furthermore, double-staining confocal fluorescence microscopy showed that CD99 was expressed in stromal lymphocytes as well as in cancer-associated fibroblasts. Based on a comprehensive screening strategy the membrane protein CD99 was identified as a novel stromal factor with clinical relevance. The results support the concept that stromal properties have an important impact on tumour progression.     

Expression of X-linked inhibitor of apoptosis as a novel prognostic marker in radically resected non-small cell lung cancer patients.

PURPOSE: To assess the pattern of expression and the prognostic value of the inhibitor of apoptosis family member X-linked inhibitor of apoptosis (XIAP; MIHA/ILP-a) in radically resected non-small cell lung cancer patients. EXPERIMENTAL DESIGN: The expression of XIAP and its relationship with overall survival was analyzed by immunohistochemistry on tumors from 144 patients with early-stage non-small cell lung cancer. In addition, the apoptotic and mitotic index, Ki-67, p53, and bcl-2 levels were also assessed. RESULTS: XIAP expression was specific for tumor cells, and the pattern was cytoplasmic. The median expression of XIAP was 20%, and when this value was used as a cutoff point for statistical analyses, 63 of the samples were considered high XIAP-expressing and 81 low XIAP-expressing. Surprisingly, high XIAP-expressing patients had a longer overall survival than the group expressing lower levels (60 versus 24 months of median survival; log rank, P = 0.01). The positive impact of XIAP expression on survival was confirmed by multivariate analysis (P = 0.026). Although no correlation was observed between XIAP expression and the apoptotic index, a significant inverse correlation was observed between XIAP, Ki-67 (P = 0.006), and mitotic index (P = 0.04). CONCLUSIONS: The unexpected inverse correlation of XIAP with proliferation markers and the absence of correlation with apoptotic index, coupled with its role as an independent positive prognostic factor for survival in radically resected NSCLC patients imply a more complex role for XIAP in tumor biology than anticipated by in vitro data.     

ERCC1、RRM1和BRCA1在非小细胞肺癌中的表达及预后意义

目的:探讨DNA修复基因家族成员ERCC1、RRM1和BRCA1在非小细胞肺癌(NSCLC)中的表达及预后意义。方法:应用实时荧光定量PCR技术对32例肺癌及16例癌旁组织中ERCC1、RRM1和BRCA1基因的mRNA进行定量检测。用非参数检验、相关分析、Kap lan-M e ier生存曲线和COX多因素回归分析进行统计分析。结果:NSCLC中ERCC1、RRM1和BRCA1在癌组织内表达量显著高于癌旁组织,且在癌内表达具有正相关性;RRM1在肺鳞癌中高于腺癌,但在不同分期中表达无差异;ERCC1和BRCA1在不同病理类型和分期中表达均无差异;RRM1和BRCA1高表达组的生存期明显长于低表达组;COX多因素回归分析示RRM1表达是影响本组患者预后的独立因素。结论:NSCLC中,ERCC1、RRM1和BRCA1在肺癌组织中的表达显著高于癌旁组织,RRM1和BRCA1高表达组的生存期长于低表达组。RRM1和BRCA1可作为判断预后的一种指标。     

GP方案治疗RRM1蛋白低表达的晚期非小细胞肺癌的疗效观察(英文)

Objective:The aim of this study was to observe the efficacy of gemcitabine combined with cisplatin(GP)in advanced non-small cell lung cancer(NSCLC)patients with low expression of ribonucleotide reductase 1(RRM1)protein using immunohistochemistry.Methods:RRM1 protein expression in tumor tissue was detected by streptavidin-peroxidase (SP)method of immunohistochemistry.GP regimen(gemcitabine 1000-1250 mg d1,d8,cisplatin 75 mg/m2)was given to advanced NSCLC patients with low expression of RRM1 protein.Results:I...     

Overexpression of dihydrodiol dehydrogenase as a prognostic marker of non-small cell lung cancer

By using mRNA differential display to examine specimens of non-small cell lung cancer (NSCLC), we have identified overexpression of dihydrodiol dehydrogenase (DDH) that was not detected in the corresponding normal lung tissue. Normally DDH is associated with catalysis of polycyclic aromatic hydrocarbons (PAHs) in the liver; in NSCLC cells, DDH expression would implicate an association with disease progression. In this study we investigated the prognostic significance of DDH expression in patients with NSCLC. By using immunohistochemistry, we measured DDH expression in 381 patients with NSCLC. The relationship between DDH expression and clinicopathological parameters (age, gender, smoking history, mitotic index, histological type, stage, cell differentiation, and lymphovascular invasion) was analyzed by chi2 analysis. Survival curves were plotted with the method of Kaplan-Meier, and statistical difference of survivals between different groups was compared by a log-rank test. Our results showed that DDH overexpression could be detected in 317 (83.2%) of 381 pathological sections and in 77.9% (60 of 77) of metastatic lymph nodes. Expression of DDH was confirmed by immunoblotting. Compared with patients with DDH overexpression in tumors, patients with low DDH expression had significantly lower incidence of early tumor recurrence and distant organ metastasis (46.7 versus 29.7%; P = 0.045). Interestingly, survival was also significantly better in patients with low DDH expression than in those with DDH overexpression (P = 0.0017). Using univariate analysis, we correlated three important factors, DDH overexpression, tumor stages, and gender, with poor prognosis for NSCLC patients. Nevertheless, biological function and involvement of DDH in the disease progression of NSCLC require additional studies.     

Excision-repair-cross-complement-1 protein as a prognostic factor in patients with advanced non-small cell lung cancer treated with platinum-based first-line chemotherapy

Excision-repair-cross-complement-1 (ERCC1) protein expression in tumor cells has been associated with resistance to platinum compounds, the backbone of treatment in NSCLC. In the current study the impact of the tumoral ERCC1 protein expression on the outcome of patients with advanced stage NSCLC treated with platinum-based chemotherapy, was investigated. Ninety-four patients with inoperable stage III–IV NSCLC, treated with platinum-based first-line chemotherapy, were retrospectively analyzed. Pretreatment tumor samples were analyzed for ERCC1 protein expression using immunohistochemistry. Response to treatment, time to tumor progression (TTP), and overall survival (OS) were correlated with patients’ clinicopathological characteristics and ERCC1 protein expression on tumor cells. ERCC1 protein low expression was detected in 39 (41.5%) patients and did not correlate with patients’ clinicopathological characteristics or response to chemotherapy. However, ERCC1 protein low expression showed a trend for better disease control rate (p = 0.059), longer TTP (5.3 vs. 3.2 months; p = 0.051) and significantly longer OS (18.7 vs. 9.7 months; p = 0.009). ERCC1 could have a role in refining prognosis and thus individualizing chemotherapy for advanced stage NSCLC.     

RRM1与BRCA1在晚期非小细胞肺癌患者中的表达及与吉西他滨联合卡铂化疗预后的相关性

目的探讨RRM1与BRCA1在晚期非小细胞肺癌患者中的表达及与吉西他滨联合卡铂化疗预后的相关性。方法选取2014年1月至2015年1月间新疆医科大学第一附属医院收治的54例非小细胞肺癌患者,均采用吉西他滨联合卡铂化疗方案。化疗前检测肿瘤组织及外周血中BRCA1与RRM1的表达水平,分析肿瘤组织中的BRCA1和RRM1表达与吉西他滨联合卡铂化疗预后之间是否存在相关性。结果肿瘤组织中的RRM1和BRCA1含量均显著高于外周血;RRM1与BRCA1在肺癌组织中的表达间比较,差异无统计学意义(P>0.05)。患者中位总生存时间为15.6个月,其中1年生存率为61.1%,2年生存率为9.3%。RRM1低表达组患者的中位总生存时间为18.2个月,高表达组为13.7个月,差异有统计学意义(P<0.05)。BRCA1低表达组患者中位总生存时间为14.3个月,高表达组为13.9个月,差异无统计学意义(P>0.05)。结论肿瘤组织内的RRM1表达水平或可作为预测非小细胞肺癌患者吉西他滨联合卡铂治疗后预后的因子,对今后临床制订个体化的治疗方案具有重要的指导意义。     

MRP2 and GSTP1 polymorphisms and chemotherapy response in advanced non-small cell lung cancer

Purpose

The level of drug metabolism and drug transport is correlated with the sensitivity of cancer cells towards platinum-based chemotherapy. We hypothesize that genetic polymorphisms in metabolising enzymes gene GSTP1 (glutathione S-transferase P1), and MRP2 (multidrug resistance-associated protein 2) (ABCC2), which result in inter-individual differences in metabolism and drug disposition, may predict clinical response to platinum agents in advanced non-small cell lung cancer (NSCLC) patients.

Methods

Totally 113 patients with advanced NSCLC were routinely treated with platinum-based chemotherapy, and clinical response was evaluated after four cycles. MRP2 C-24T (?24C>T), MRP2 Val417Ile (1249G>A), MRP2 Ile1324Ile (3972C>T), and GSTP1 Ile105Val (342A>G) genotype were determined by gene-chip method (a 3-D (three dimensions) polyacrylamide gel-based DNA microarray method) using DNA samples isolated from peripheral blood collected before treatment. Pearson Chi-square test and Fisher’s exact test were performed to measure the differences of the chemotherapeutic efficacy among variant genotype. The odds ratios and 95% confidence intervals were computed by logistic regression.

Results

The C→T change of MRP2 C-24T and the A→G change of GSTP1 Ile105Val polymorphism significantly increased platinum-based chemotherapy response.

Conclusion

The polymorphic status of MRP2 C-24T and GSTP1 Ile105Val might be the predictive markers for the treatment response of advanced NSCLC patients. The DNA microarray-based method is accurate, high throughput and inexpensive, suitable for single-nucleotide polymorphism genotyping in a large number of individuals.     

State-of-the-art chemotherapy for advanced non-small cell lung cancer

The treatment of advanced non-small cell lung cancer (NSCLC) has continued to evolve over recent years. We have moved from an era of therapeutic nihilism to optimism, largely because of the advent of the newer cytotoxic agents developed in the 1990s that have complemented the platinum compounds for treatment of advanced NSCLC. Doublet chemotherapy combinations have become the current standard of care for patients with advanced NSCLC who have a good performance status. For patients with poor performance status and the elderly, single-agent chemotherapy results in modest improvements in survival. Prolongation of survival and improved quality of life have also been shown with second-line chemotherapy for patients who are either refractory to or relapse following first-line chemotherapy. Noncytotoxic, molecularly targeted agents currently under various phases of development for the treatment of lung cancer will serve as the cornerstones for further innovations in the treatment of NSCLC.     

Docetaxel and cisplatin as second-line chemotherapy for advanced non-small cell lung cancer

AIMS AND BACKGROUND: Docetaxel and cisplatin are both active against non-small cell lung cancer (NSCLC). This pilot study evaluated the efficacy and toxicity of docetaxel and cisplatin as second-line chemotherapy for patients with advanced NSCLC. PATIENTS AND METHODS: Eleven patients with advanced NSCLC who had no response to platinum-based treatment or had recurrence after a partial response were enrolled (2 stage III B, 9 stage IV; 8 men, 3 women). Median age was 58 years (range, 40 to 74 years). Seven patients had an Eastern Cooperative Oncology Group performance status of 0, and four had a performance status of 1. Four weeks or more after the end of previous therapy, all 11 patients received docetaxel 60 mg/m2 and cisplatin 80 mg/m2 on day 1 every four weeks. RESULTS: Two patients (18.2%) achieved a partial response,five (45.4%) patients had stable disease, and four (36.4%) patients showed progressive disease after initiation of second-line therapy. Median survival was 277 days. Median time to disease progression was 101 days, and the one-year survival rate was 36.4%. Hematological toxicities were moderate. Grade 3 and 4 leukocytopenia and neutropenia were observed in five (45.4%) patients. Grade 3 anemia occurred in one (9 .1%) patient. No severe non-hematological toxicities were observed except grade 3 nausea in two (18.2%) patients. CONCLUSIONS: The regimen of docetaxel and cisplatin has reasonable efficacy with moderate toxicity as second-line chemotherapy for patients with previously treated, advanced NSCLC.     

Non-cisplatin based chemotherapy in advanced non-small cell lung cancer

Platinum-based, especially cisplatin-based chemotherapy is still the backbone of combination chemotherapy for advanced non-small cell lung cancer (NSCLC). Several combinations of cisplatin-or carboplatin-based chemotherapy are widely used in the treatment of advanced NSCLC. However, cisplatin is associated with considerable toxicity and large amount of fluid infusion that may lead to reluctance on the part of both physicians and patients to accept cisplatin-based chemotherapy for incurable NSCLC. Carboplatin has also been a widely used agent in the treatment of NSCLC instead of cisplatin. However, it is controversial whether carboplatin has the same activity as cisplatin or not. Several reports showed that carboplatin was not superior but almost equal to cisplatin in terms of survival. Third generation agents have been developed in the past decades including gemcitabine, paclitaxel, docetaxel, vinorelbine and irinotecan. All of them have promising levels of anti-tumor activity for NSCLC and the development of non-platinum-based chemotherapy was expected. Several randomized trials and meta-analysis have compared platinum-based combination chemotherapy with non-platinum chemotherapy based on various combinations of these third generation agents. The analysis of these trials indicated that non-platinum based chemotherapy was not superior to platinum-based chemotherapy for survival time but less toxicity. Third-generation-based non-platinum combinations are still treatment options for advanced NSCLC patients who are not eligible for platinum-based chemotherapy.     

非小细胞肺癌组织ERCC1和RRM1基因表达及其对预后影响探讨

目的比较非小细胞肺癌（non-small cell lung cancer,NSCLC）患者原发灶与转移淋巴结中切除修复交叉互补基因1（excision repair cross-complementation group1,ERCC1）和核糖核苷酸还原酶M1亚基（ribonucleotidereductase subunit M1,RRM1）表达情况,探讨ERCC1和RRM1表达状态与NSCLC患者治疗效果及预后的关系,为NSCLC患者的合理治疗提供依据。方法选取山东省肿瘤医院外科六病区2008-08-01-2012-08-31行手术切除且术后病理确诊为NSCLCⅡA-ⅢA期的患者106例,所有患者术前均未接受任何针对肿瘤的治疗措施,均釆用免疫组化技术测定组织中ERCC1和RRM1表达状况,术后均采用长春瑞滨联合顺铂（NP方案）进行辅助化疗,并进行临床随访。结果 NSCLC癌组织及转移淋巴结中RRM1阴性表达患者中位无疾病进展时间分别为23.1和24.7个月,显著优于RRM1阳性表达患者的16.4和19.1个月,两组比较差异有统计学意义,P值分别为0.007和0.026;而ERCC1阴性表达患者中位无疾病生存期为17.5个月,与ERCC1阳性表达患者的19.4个月比较,差异无统计学意义,P=0.59。原发灶和淋巴结转移灶中ERCC1和RRM1的表达水平差异无统计学意义,P〉0.05。不同性别、分期及病理类型的NSCLC患者ERCC1及RRM1表达水平差异均无统计学意义,P〉0.05。结论 NSCLC患者癌组织及转移淋巴结中,RRM1基因表达情况可作为NP方案术后辅助化疗预后的重要指标。     

非小细胞肺癌吉西他滨方案化疗相关耐药标志物RRM1的研究进展

化疗是治疗非小细胞肺癌的主要手段,但是由于耐药的存在,使化疗疗效大大降低.研究表明一些基因表达水平是影响某些化疗药物疗效的重要因素.现对非小细胞肺癌常用化疗药物吉西他滨相关耐药标志物RRM1近年来国内外的研究进展做一综述.     

RRM1基因多态性与非小细胞肺癌患者血清铂类化疗敏感的相关性分析

目的:观察RRM1亚基基因多态性对预测非小细胞肺癌(non-small cell lung cancer,NSCLC)患者以铂类为基础的化疗方案的敏感性和化疗毒性的临床价值.方法:用PCR-RFLP技术检测214例NSCLC患者RRM1启动子基因型.所有患者均经以铂类为基础的化疗方案治疗.结果:214例NSCLC病例中,RR37C/C、C/A和A/A基因型分别为11 6例(54.46%)、87例(40.85%)和10例(4.69%),化疗有效率分别为44.83%(52/116)、45.98%(40/87)和30.00%(3/10),差异无统计学意义(P=0.629),调整OR值为0.68(95%CI:0.16～2.85);RR524 C/C、C/T和T/T基因型分别为25例(11.68%)、89例(41.59%)和100例(46.73%),化疗有效率分别为24.00%(6/25)、51.69%(46/87)和43.00%(43/100),差异有统计学意义(P=0.046),C/T+T/T基因组的有效率显著高于C/C基因组,P=0.008.携带RR524T等位基因型者的化疗敏感性是RR524C/C基因型患者的2.7倍,调整OR=2.70(95%CI为0.98～7.41).化疗后总有效率(完全缓解+部分缓解)为44.4%.RR37A/A基因型患者化疗相关的血转氨酶升高显著高于C/C、C/A基因型者,P=0.02.结论:RRM1基因RR524基因型多态性可影响以铂类为基础的化疗方案治疗肺癌的敏感性,RRM1基因检测对指导NSCLC的化疗、预测疗效具有较高的临床价值.