Musashi 2 (MSI2) expression as an independent prognostic biomarker in non-small cell lung cancer (NSCLC)

BackgroundMusashi-2 (MSI2) is a member of RNA-binding protein family that regulates mRNA translation of numerous intracellular targets and influences maintenance of stem cell identity. This study assessed MSI2 as a potential clinical biomarker in non-small cell lung cancer (NSCLC).MethodsThe current study included 40 patients with NSCLC, of whom one presented with stage 1, 14 presented with stage II, 15 presented with stage III, and 10 patients had stage IV. All patients received standard of care treatments. All patient samples were obtained before treatment started. We used immunohistochemical (IHC) approach to measure MSI2 protein expression in matching specimens of normal lung versus tumor tissues, and primary versus metastatic tumors, followed by correlative analysis in relation to clinical outcomes. In parallel, clinical correlative analysis of MSI2 mRNA expression was performed in silico using publicly available datasets (TCGA/ICGC and KM plots).ResultsMSI2 protein expression in patient samples was significantly elevated in NSCLC primary tumors versus normal lung tissue (P=0.03). MSI2 elevated expression positively correlated with a decreased progression free survival (PFS) (P=0.026) combined for all stages and with overall survival (OS) at stage IV (P=0.013). Elevated MSI2 expression on RNA level was confirmed in primary tumor versus normal tissue samples in TCGA dataset (P<0.0001), and positively correlated with decreased OS (P=0.02). No correlation was observed between MSI2 expression and age, sex, smoking, and treatment type.ConclusionsElevated MSI2 expression in primary NSCLC tumors is associated with poor prognosis and can be used as a novel potential prognostic biomarker in NSCLC patients. Future studies in an extended patient cohort are warranted.     

Distribution of Bcl-2 gene expression and its prognostic value in non-small cell lung cancer

The aim of this study was to determine the expression of Bcl-2 gene and prognostic importance of Bcl-2 expression in paraffin embedded blocks of patients diagnosed with non-small cell lung cancer (NSCLC). This study included the retrospective analysis of overall 46 patients diagnosed with NSCLC in our clinic between 1996 and 1999. In 16 (34.8%) patients, the diagnosis was made on biopsy of bronchial mucosa and in 30 (65.2%) patients, on materials obtained by surgical resection (lobectomy and pneumonectomy). We reviewed the sections 4-6 microns in size and stained with Hemotoxylin-Eosine (HE) obtained from paraffin embedded blocks and fixed by 10% formalin. These sections are transferred on to slides covered with poly-L-lysine, then de-paraffinization was made. In all cases, immunohistochemical staining with Bcl-2 antibodies was performed. Positive staining was observed in 9 (19.6%) patients, but not in 37 (80.4%) patients. Out of 32 cases with squamous cell tumor, 8 (25%) were observed to have positive staining in their sections, but 24 (75%) were not so. No staining was observed in 11 cases whose cell type was adenoma and two cases whose cell type was adenosquamos (100%). Staining was present in the section of one case with large cell (100%). Median survival time was 36.6 months in cases in which staining was observed and 6.10 months in cases in which staining was not observed, with a significant difference (p< 0.05). In conclusion, the rate of survival was higher in cases in which staining was present.     

Vascular endothelial growth factor expression in pN2 non-small cell lung cancer: lack of prognostic value

OBJECTIVE: Although several previous studies have investigated the prognostic significance of vascular endothelial growth factor (VEGF) expression in non-small cell lung (NSCL) cancer, no previous study has concentrated on NSCL cancer with pathologically abnormal mediastinal nodes (pN2). METHODOLOGY: A total of 60 patients with pN2 NSCL cancer who had undergone a complete resection with a systematic mediastinal lymph node dissection were reviewed retrospectively. Immunohistochemical examination, using antibodies against VEGF, was conducted. The prognostic significance of VEGF expression and clinicopathological factors were analysed. RESULTS: The overall 5-year survival rate was 21.7%. With respect to clinicopathological factors, single N2 involvement and skip metastasis were significantly associated with patients' survival. Expression of VEGF was found in 35/60 (58.3%) patients. VEGF expression was not related to the clinicopathological parameters examined. There was no relationship between survival rates and patients positive and negative for VEGF. Multivariate analysis showed that single N2 disease was an independent prognostic factor, while VEGF expression was not. CONCLUSIONS: Although VEGF expression might be important for tumour development and maintenance, no prognostic significance of VEGF expression in pN2 NSCL cancer was found.     

Pretreatment clinical prognostic factors in patients with stage IV non-small cell lung cancer (NSCLC) treated with chemotherapy

PURPOSE: We investigated the influence of potential pre-treatment clinical prognostic factors in stage IV non-small cell lung cancer (NSCLC). METHODS AND PATIENTS: A total of 285 patients were enrolled in two consecutive prospective randomised studies which compared (study 1) carboplatin and prolonged oral etoposide (group 1; n=58) with the same etoposide alone (group 2; n=59), and (study 2) carboplatin and prolonged oral etoposide (group 1; n=84) with the same carboplatin and high-dose intravenous etoposide (group 2; n=84). RESULTS: The median survival time for all 285 patients was 7 months, while 1- and 2-year survival rates were 29% and 8%, respectively. Age did not impact on outcome ( P=0.21), while female patients did significantly better than male patients ( P<0.0001). Patients with KPS 80-100 did significantly better than those with KPS 50-70 ( P<0.0001), as did patients with less pronounced weight loss ( P<0.0001) and those with only one metastatic site when compared to those having at least two metastatic sites ( P<0.0001). When evaluated regarding the metastatic site, only subcutaneous metastatic site did not influence survival. This was confirmed within univariate analyses, but when multivariate analyses were done gender, KPS, weight loss, number of metastatic sites, presence of liver metastases and presence of brain metastases independently influenced survival, while age and other metastatic locations did not. CONCLUSION: In this analysis, gender, KPS, weight loss, number of metastatic sites, presence of liver metastases and presence of brain metastases independently influenced survival in patients with stage IV NSCLC treated with CHT.     

Granulocyte growth factors in the treatment of non-small cell lung cancer (NSCLC)

Neutropenia and subsequent infections are common events that limit treatment of non-small cell lung cancer (NSCLC). Granulocyte growth factors (G- and GM-CSF) have been introduced in clinical practice and their use has yielded a reduction of the infection risk related to chemotherapy and a dose increase of drug delivery. Randomized clinical trials have shown that granulocyte colony-stimulating factors and, more recently, the longer-acting pegylated granulocyte colony-stimulating factor (pegfilgrastim) effectively reduce the incidence and severity of neutropenia and of its complications. Recommendations for the use of haematopoietic colony-stimulating factors from the American Society of Clinical Oncology (ASCO) have been published in 1994 and updated in 1996, 1997 and 2000. Recently, moreover, National Comprehensive Cancer Network (NCCN) guidelines for the myeloid growth factors in cancer treatment make available. Chemotherapy-associated myelosuppression is a major limitation of anticancer therapy also in early stage, local advanced and metastatic NSCLC. Recently, dose-dense chemotherapy has been shown to improve the outcome in early stage breast cancer and non-Hodgkin's lymphoma. However, few randomized trials have been reported on chemotherapy with or without granulocyte growth factors as primary prophylaxis in NSCLC. Presently, there is no evidence for a benefit in response rate and survival from the use of granulocyte growth factors as support of chemotherapy, in particular, for locally advanced and metastatic NSCLC. In clinical practice, the role of granulocyte growth factors for NSCLC treatment should be limited following the guidelines. An appropriate use of granulocyte growth factors may reduce the overall cost of treatment and improve the quality of life, important aims in the treatment of patients with local advanced or metastatic NSCLC. In the future, we need to identify patients who can benefit from granulocyte growth factors for optimize the schedule and doses, in advanced disease and also, after the recent positive results of adjuvant chemotherapy, in early stages. This review summarizes the present knowledge on the use of granulocyte growth factors in NSCLC.     

EGFR and KRAS mutational profiling in fresh non-small cell lung cancer (NSCLC) cells

Purpose

Knowledge of tumor mutational status has become a priority for effective NSCLC-tailored treatment. NSCLC diagnosis is more often reached through biopsy; thus, there is a clear need to implement for routine tumor molecular profiling on small cytological samples. This work aims to screen and compare the EGFR and KRAS mutational prevalence in fresh tumor cells and in corresponding routinely processed samples derived from trans-thoracic fine-needle aspiration. The latter currently represents the most appropriate diagnostic procedure in case of peripheral lesions, such as adenocarcinomas, which account for almost 40 % of all NSCLCs and for the highest EGFR mutational rates.

Methods

Two hundred and forty-four patients carrying peripheral lung masses underwent CT-guided aspiration. The obtained material was split, and a part was addressed to conventional histopathological analysis while the remaining one was stored at ?20 °C. In case of confirmation of adenocarcinoma, tumor genomic DNA was extracted from both fresh and fixed material, and EGFR and KRAS sequencing was performed.

Results

We identified 136 adenocarcinomas; from 134, we could recover enough material for the study. A full match was demonstrated between EGFR/KRAS mutational prevalences through the two approaches tested. We found EGFR mutations in 13 patients (9.7 %); 7 were females and 11 never or former smokers. KRAS mutations occurred in 20 (14.9 %) patients. EGFR and KRAS mutations were mutually exclusive.

Conclusions

Mutational screening on fresh cancer cells is an achievable, safe and cost-effective procedure which might allow routinely tumor molecular profiling as powerful integration of conventional histopathological analysis.     

Molecular prognostic factors in resectable non-small cell lung cancer

Lung cancer retains the leading position in cancer-related deaths in the western countries. Non-small cell lung cancer (NSCLC) comprises more than 80% of lung cancers, and complete surgical resection of primary tumors in early-stage disease is the only potentially curative treatment. One area of intense research on early-stage NSCLC is the identification of molecular markers to complement TNM staging to fully assess the prognosis of patients and to define innovative strategies. Numerous prognostic factors have been identified in patients with early-stage NSCLC that might enable classification of such patients into different subsets corresponding to different risks of recurrence following complete resection. Most of the markers are proteins that can be detected by immunohistochemistry assays based on the antigen-antibody reaction. The present review aims at providing a panorama on classical as well as new prognostic markers. Of special interest are some molecular factors, already or currently tested from a prognostic point of view, that might also become good candidates for predicting treatment efficacy.     

Prognostic value of cyclin D1 overexpression in correlation with pRb and p53 status in non-small cell lung cancer (NSCLC)

Purpose: The aim of this study was to assess the impact of cyclin D1 overexpression (considered separately or jointly with previously assessed p53 and pRb statuses) on survival in a group of 111 surgically treated non-small cell lung cancer patients (NSCLC). Methods: Cyclin D1 accumulation was assessed immunohistochemically, with the use of monoclonal antibody (DCS-6, DakoCytomation) and the alkaline phosphatase–anti-alkaline phosphatase (APAAP) technique. Results: Overexpression of cyclin D1 was found in 55 samples (49%), whereas the altered phenotypes cyclin D1+/p53+ or cyclin D1+/pRb– were found in 23 (22%) and 9 samples (9%), respectively. Statistical analysis was performed for different cut-off values and the only significant differences were found if samples with some expression of each protein were considered positive. There was no relationship between cyclin D1 overexpression and major clinicopathological factors, including p53 expression; however, there was a direct correlation between cyclin D1 and pRb protein expression (p=0.007). Cyclin D1 accumulation did not influence patients survival. Of all possible cyclin D1/p53, cyclin D1/pRb and cyclin D1/p53/pRb phenotypes, patients with cyclin D1–/p53+ phenotype had shortened overall survival compared to other patients (p=0.027, HR=1.8). In the multivariate analysis, the only variable associated with shortened overall and disease-free survival was the stage of disease (p<0.001). Conclusions: These results suggest the lack of prognostic value of cyclin D1 overexpression in NSCLC patients.     

Milestones in the use of chemotherapy for the management of non-small cell lung cancer (NSCLC)

NSCLC, a tobacco-caused disease which is therefore highly preventable, is responsible for about 30% of all cancer deaths. Improvements in terms of survival have been overall disappointing. A major advance has been the demonstration of the value of platinum-based chemotherapy, not only for advanced disease, but also in the adjuvant and neoadjuvant settings. The favorable impact of second line therapy has been established as well.The most exciting recent development consists in the effective use of biological targeted therapies, namely the EGFR inhibitors. In selected groups of patients, these agents can be used successfully for first line or second line therapy.It is likely that other biologically targeted therapies will be developed in a near future. These progresses will lead hopefully to a more personalized and effective treatment of NSCLC.     

Clinicopathological significance and prognostic value of E-cadherin expression in non-small cell lung cancer: A protocol for systematic review and meta-analysis

Background:E-cadherin, a calcium-dependent cell adhesion molecule, as an important mediator of adhesion and signaling pathway, plays a key role in maintaining tissue integrity. However, the association of E-cadherin expression with clinicopathological features and prognostic value in non-small cell lung cancer (NSCLC) is still controversial. Therefore, the purpose of the study is to explore the clinicopathological features and prognostic value of E-cadherin expression in non-small cell lung cancer by meta-analysis.Methods:PubMed, EMBASE, Cochrane Library, and Web of Science were searched to collect the studies about expression of E-cadherin and clinicopathological features and prognosis of non-small cell lung cancer. The last search time was May 2020. Stata 15.0 software was used for statistical analysis.Results:A total of 35 studies were included, of which the results showed that high expression of E-cadherin compared with its low expression, for overall survival, HR = 0.68 (95% CI:0.64–0.73, P < .05); for disease-free survival or progression-free survival, HR = 0.54 (95% CI: 0.44–0.67); low differentiation of lung cancer compared with moderate and high differentiation, OR = 0.40 (95% CI: 0.27–0.58, P < .05); Advanced lung cancer compared with early stage, OR = 0.54 (95% CI: 0.44–0.66, P < .05); lymph node metastasis compared with non-lymph node metastasis, OR = 0.49 (95% CI: 0.31∼0.77).Conclusion:Low expression of E-cadherin is closely related to poor prognosis of patients with NSCLC, promoting tumor staging and lymph node metastasis, inhibiting tumor differentiation as well.     

VEGF及C-erbB-2蛋白在NSCLC患者肿瘤组织中的表达及意义

目的探讨血管内皮生长因子（VEGF）及表皮生长因子受体-2（C-erbB-2）表达在非小细胞肺癌（NSCLC）发病中的作用及对患者预后的影响。方法采用免疫组织化学法,对病理确诊的86例NSCLC患者肿瘤组织中VEGF及C—erbB-2蛋白表达进行检测,并与癌旁组织及正常组织进行对比;分析两种指标表达水平与肿瘤临床病理特征及患者预后的关系。结果VEGF及C-erbB-2蛋白在癌旁组织及正常组织中均无或低表达,VEGF在NSCLC肿瘤组织中阳性表达率为52．3％、与肿瘤组织学分级有关,C-erbB-2在NSCLC肿瘤组织中阳性表达率为43．0％、与肿瘤组织学类型及组织学分级有关;VEGF表达阳性及C—erbB-2表达阳性者总生存时间均显著低于阴性者,两者均为影响NSCLC患者预后的独立因素。结论VEGF和C—erbB-2表达在NSCLC发生、发展中具有重要作用,为影响预后的独立因素;临床可有针对性地使用靶向治疗药物。     

Co-expression of survivin, c-erbB2, and cyclooxygenase-2 (COX-2): prognostic value and survival of endometrial cancer patients

Aim  

The purpose of this study was to investigate the co-expression of survivin, c-erbB2, and COX-2 in endometrial cancer tissues and evaluate its prognostic significance in endometrial cancer     

非小细胞肺癌差异基因的筛选及预后分析

目的利用生物信息学方法分析非小细胞肺癌(NSCLC)基因表达谱芯片,筛选差异基因,分析其与预后的关系。方法从GEO数据库下载芯片数据(GSE19804、GSE27262、GSE18842),利用GEO2R软件筛选差异基因,通过基因本体(GO)和京都基因与基因组百科全书(KEGG)进行差异基因的功能及通路富集分析,用STRING数据库构建蛋白-蛋白相互作用网络,Cytoscape筛选出核心基因。Kaplan-Meier plotter数据库进行预后分析,采用实时荧光定量PCR(QPCR)检测目的基因在NSCLC组织中的表达。结果共筛选出401个差异表达基因,GO分析结果表明差异基因主要参与血管生成、细胞粘附、调节细胞增殖等生物学过程。通过Cytoscape软件筛选出29个核心基因。预后分析显示ASPM低表达患者的总生存期较高表达患者明显延长。QPCR显示ASPM在NSCLC组织中高表达,差异有统计学意义。结论ASPM在NSCLC组织中高表达,与患者的预后相关,可能是NSCLC潜在的治疗靶点。     

癌胚抗原信使核糖核酸在非小细胞肺癌组织中的表达

目的　探讨癌胚抗原信使核糖核酸 (CEA- m RNA)在非小细胞肺癌 (NSCL C)组织中的表达与临床的关系。方法　对 74例 NSCL C肺癌组织与 38例肺癌组织边缘的正常组织对照 ,采用反转录套式聚合酶链反应(RT- NP- PCR)技术检测 CEA- m RNA。结果　肺癌组织表达 CEA- m RNA的阳性表达率为 87.8% ,明显高于非肺癌组织 (P<0 .0 1) ,但其阳性表达与性别、年龄、临床分期、分化程度和病理类型无关 (P>0 .0 5 )。结论　检测 CEA-m RNA对肺癌的诊断具有重要的临床意义。     

Prognostic value of COX-2 expression in patients with non-small cell lung cancer: a systematic review and meta-analysis

Background

Cyclooxygenase-2 (COX-2) has been implicated in tumorigenesis and metastasis, and it presumably mediates the proliferation of endothelial cells and promotes vascular permeability. However, the prognostic value of COX-2 overexpression in patients with non-small cell lung cancer (NSCLC) remains controversial.

Methods

A systematic review of eligible studies with meta-analysis was performed to quantitatively review the correlation of COX-2 overexpression with survival in patients with NSCLC.

Results

We conducted a final analysis of 1,892 patients from 16 studies. The studies were categorized by histology, disease stage, patient race and laboratory techniques used. Combined hazard ratios (HR) suggested that COX-2 overexpression was not associated with a significant impact on survival, the HR (95% CI) was 0.90 (95% CI: 0.76-1.04) overall, 0.99 (0.71-1.26) in Asian patients, 0.87 (0.71-1.03) in non-Asian patients, 0.63 (0.33-0.93) in adenocarcinoma, 1.42 (1.02-1.81) in stage I NSCLC, 0.83 (0.72-1.08) in NSCLC by IHC, 3.28 (1.48-5.13) in NSCLC by RT-PCR.

Conclusions

COX-2 overexpression seems to have no significant impact on survival of NSCLC patients. However, the statistically significant was found in stage I NSCLC, suggesting that COX-2 expression could be useful at early stages to distinguish those with a worse prognosis.KEY WORDS : Cyclooxygenase-2 (COX-2), prognosis, lung cancer, meta-analysis