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Detection and Analysis of EGFR and KRAS Mutation with Lung Adenocarcinoma  [PDF]
Hui ZHANG, Xinjie YANG, Na QIN, Xi LI, Huiyi YANG, Jingying NONG, Jialin LV, Yuhua WU, Quan ZHANG, Xinyong ZHANG, Jinghui WANG, Lijuan ZHOU, Shucai ZHANG
- , 2015, DOI: : 10.3779/j.issn.1009-3419.2015.11.05
Abstract: Background and objective Mutations in epidermal growth factor receptor (EGFR) and KRAS are important markers in non-small cell lung cancer, which are closely related to the clinical therapeutic effect. To analysis the EGFR and KRAS gene mutation rate and its relationship with clinical features in patients with lung adenocarcinoma. Methods 395 patients with treatment na?ve lung adenocarcinoma, tumor tissue samples were available for testing. Tumor sample EGFR and KRAS mutation status were detected using mutant enriched liquidchip. Results 395 cases of lung adenocarcinoma, EGFR mutations were detected in 192 cases (48.9%), KRAS mutations were detected in 29 cases (7.8%), and the presence of EGFR and KRAS mutation were detected in 1 case (0.3%). EGFR mutations were found to occur significantly more often in female than in male patients (62.0% vs 37.1%, P<0.001) and in never smokers than in smokers (61.9% vs 30.3%, P<0.001), no significant differences were observed in age, stage and different biopsy type. KRAS mutations were not found to have statistical significance (P>0.05) in each clinical factors, only occurred in the wild type EGFR gene in patients (13.5%, 27/200) was significantly higher than that of patients with EGFR mutation (1.0%, 2/192), the difference was statistically significant (P<0.001). Conclusion In lung adenocarcinomas, EGFR mutation was higher in female and non-smoking patients, KRAS mutation only in patients with wild-type EGFR gene was higher. Before using TKI targeted therapy, EGFR and KRAS mutations should be detected.
DOK2 Inhibits EGFR-Mutated Lung Adenocarcinoma  [PDF]
Alice H. Berger, Ming Chen, Alessandro Morotti, Justyna A. Janas, Masaru Niki, Roderick T. Bronson, Barry S. Taylor, Marc Ladanyi, Linda Van Aelst, Katerina Politi, Harold E. Varmus, Pier Paolo Pandolfi
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079526
Abstract: Somatic mutations in the EGFR proto-oncogene occur in ~15% of human lung adenocarcinomas and the importance of EGFR mutations for the initiation and maintenance of lung cancer is well established from mouse models and cancer therapy trials in human lung cancer patients. Recently, we identified DOK2 as a lung adenocarcinoma tumor suppressor gene. Here we show that genomic loss of DOK2 is associated with EGFR mutations in human lung adenocarcinoma, and we hypothesized that loss of DOK2 might therefore cooperate with EGFR mutations to promote lung tumorigenesis. We tested this hypothesis using genetically engineered mouse models and find that loss of Dok2 in the mouse accelerates lung tumorigenesis initiated by oncogenic EGFR, but not that initiated by mutated Kras. Moreover, we find that DOK2 participates in a negative feedback loop that opposes mutated EGFR; EGFR mutation leads to recruitment of DOK2 to EGFR and DOK2-mediated inhibition of downstream activation of RAS. These data identify DOK2 as a tumor suppressor in EGFR-mutant lung adenocarcinoma.
Clinical Observation of Translating to Small Cell Lung Cancer Following Treatment with EGFR-Tyrosine Kinase Inhibitors in Lung Adenocarcinoma  [PDF]
Shuping XUE, Tingting YU, Yan ZHANG, Li SHAN
- , 2015, DOI: : 10.3779/j.issn.1009-3419.2015.10.10
Abstract: In recent years, the chemotherapy of non-small cell lung cancer (NSCLC) has almost been reached a platform stage, and there is no obvious progress in terms of response rate (RR) and overall survival (OS); With the great development of molecular biology, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has good therapeutic effect on the NSCLC. But, almost all patients of EGFR-mutant lung cancers develop drug resistance to these agents. This paper reported a case of a 49-year-old woman with lung adenocarcinoma who had EGFR mutant (19-DEL) treated with EGFR-TKIs. After disease progression, histological examination of a secondary biopsy specimen revealed small cell lung cancer (SCLC) had transformed to SCLC treatment. Through the analysis of the process and effect of her therapy, the following is a summary of the relevant mechanism.
Management of EGFR-Mutant Non-Small Cell Lung Cancer: Focus on Gefitinib
Yoichi Naito,Koichi Goto
Clinical Medicine : Therapeutics , 2009,
Abstract: Gefitinib is a first generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), and EGFR TKIs, such as gefitinib and erlotinib, have yielded dramatic and durable responses in approximately 75% of of non-small cell lung cancer (NSCLC) patients whose tumor has an activating EGFR mutation. EGFR mutations are found in approximately 10%–15% of lung cancers in Caucasians, and they are more frequent in female patients, patients with adenocarcinoma, patients who are never- smokers or have a history of light-smoking, and patients with Asian ethnicity. Recent phase III trials comparing gefitinib with standard chemotherapy have demonstrated a similar survival benefit of gefitinib in patients with NSCLC and improved quality of life both in a first-line setting (IPASS; comparing gefitinib with carboplatin/paclitaxel) and a previously-treated setting (INTEREST; comparing gefitinib with docetaxel). Subset analyses of the data obtained in these studies showed that in patients with EGFR-mutant NSCLC gefitinib yielded a higher response rate, longer progression-free survival, and similar overall survival than standard cytotoxic chemotherapy did. The toxicity of EGFR TKIs is generally milder than that of standard cytotoxic chemotherapy. This review focuses on gefitinib, and issues in the management of EGFR-mutant NSCLC are discussed.
EGFR Mutation Status in Uighur Lung Adenocarcinoma Patients  [cached]
Li SHAN,Yan ZHANG,Feng ZHAO,Limou ZHENG
Chinese Journal of Lung Cancer , 2013, DOI: 10.3779/j.issn.1009-3419.2013.02.04
Abstract: Background and objective Epidermal growth factor receptor (EGFR), a transmembrane protein, is a member of the tyrosine kinase family. Gefitinib, an EGFR tyrosine-kinase inhibitors, has shown a high response rate in the treatment of lung cancer in patients with EGFR mutation. However, significant differences in EGFR mutations exist among different ethnic groups. The aim of this study is to investigate the prevalence of EGFR mutations in Uighur lung adenocarcinoma patients by using a rapid and sensitive detection method and to analyze EGFR mutation differences compared with Han lung adenocarcinoma patients. Methods We examined lung adenocarcinoma tissues from 138 patients, including 68 Uighur lung adenocarcinoma patients and 70 Han lung adenocarcinoma patients, for EGFR mutations in exons 18, 19, 20, and 21 by using the amplification refractory mutation system (ARMS) PCR method. The mutation differences between Uighur and Han lung adenocarcinoma were compared by using the chi-square test method. Results EGFR mutations were detected in 43 (31.2%) of the 138 lung adenocarcinoma patients. EGFR mutations were detected in 11 (16.2%) of the 68 Uighur lung adenocarcinoma patients and in 32 (45.7%) of the 70 Han lung adenocarcinoma patients. Significant differences were observed in the EGFR mutations between Uighur lung adenocarcinoma patients and Han lung adenocarcinoma patients (P<0.001). Conclusion Our results indicate that the EGFR mutation in Uighur lung adenocarcinoma patients (16.2%) is significantly lower than that in Han lung adenocarcinoma patients (45.7%).
Circulating MicroRNAs in Relation to EGFR Status and Survival of Lung Adenocarcinoma in Female Non-Smokers  [PDF]
Huan Zhang, Yuliang Su, Fangxiu Xu, Jinyu Kong, Herbert Yu, Biyun Qian
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0081408
Abstract: Objectives Lung adenocarcinoma is considered a unique disease for Asian female non-smokers. We investigated whether plasma microRNA (miRNA) expression profiles are different by the EGFR status and are associated with survival outcomes of the patients. Methods Using real-time RT-PCR, we analyzed the expression of 20 miRNAs in the plasma of 105 female patients with lung adenocarcinoma. Kaplan-Meier survival analysis and Cox proportional hazards regression were performed to determine the association between miRNA expression and overall survival. Time dependent receiver operating characteristic (ROC) analysis was also performed. Results In the 20 miRNAs, miR-122 were found differently expressed between wild and mutant EGFR carriers (P=0.018). Advanced disease stage and tumor metastasis were independently associated with poor prognosis of patients with lung adenocarcinoma (P=0.010 and 1.0×10-4). Plasma levels of miR-195 and miR-122 expression were also associated with overall survival in the patients, especially in those with advanced stage (HR=0.23, 95%CI:0.07-0.84; and HR=0.22, 95%CI:0.06-0.77) and EGFR mutation (HR=0.27, 95%CI:0.08-0.96; and HR=0.23, 95%CI=0.06-0.81). Moreover, a model including miR-195, miR-122 may predict survival outcomes of female patients with lung adenocarcinoma (AUC=0.707). Conclusions Circulating miR-195 and miR-122 may have prognostic values in predicting the overall survival as well as predicting EGFR mutation status in non-smoking female patients with lung adenocarcinoma. Measuring plasma levels of miR-195 and miR-122 may especially be useful in EGFR mutant patients with lung adenocarcinoma.
A case of lung adenocarcinoma harboring EGFR mutation and EML4-ALK fusion gene  [cached]
Tanaka Hisashi,Hayashi Akihito,Morimoto Takeshi,Taima Kageaki
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-558
Abstract: Background Lung cancer is the leading cause of cancer-related death worldwide. Epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitor (TKI) is used for the patients with EGFR-mutant lung cancer. Recently, phase III studies in the patients with EGFR-mutant demonstrated that EGFR-TKI monotherapy improved progression-free survival compared with platinum-doublet chemotherapy. The echinoderm microtubule-associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion oncogene represents one of the newest molecular targets in non-small cell lung cancer (NSCLC). Patients who harbor EML4-ALK fusions have been associated with a lack of EGFR or KRAS mutations. Case presentation We report a 39-year-old patient diagnosed as adenocarcinoma harboring EGFR mutation and EML4-ALK fusion gene. We treated this patient with erlotinib as the third line therapy, but no clinical benefit was obtained. Conclusion We experienced a rare case with EGFR mutation and EML4-ALK. Any clinical benefit using EGFR-TKI was not obtained in our case. The therapeutic choice for the patients with more than one driver mutations is unclear. We needs further understanding of the lung cancer molecular biology and the biomarker infomation.
Influence of Different Therapies on EGFR Mutants by Circulating Cell-free DNA of Lung Adenocarcinoma and Prognosis  [PDF]
Fei SU, Ke ZHENG, Yiyun FU, Qian WU, Yuan TANG, Weiya WANG, Lili JIANG
- , 2018, DOI: : 10.3779/j.issn.1009-3419.2018.05.06
Abstract: Background and objective Epidermal growth factor receptor (EGFR) gene mutation is closely related to the EGFR-TKI target treatment and prognosis of lung adenocarcinoma patients. The mutation status of EGFR is limited by tissue detection. The purpose of this study was to investigate the difference of EGFR mutants in plasmacirculating cell-free DNA (cfDNA) obtained from patients with non-small cell lung cancer (NSCLC) in three groups: pre-therapy, after traditional chemotherapy and targeted therapy. The aim of this study was to analyze whether the plasma cfDNA could effectively determine the EGFR mutations and monitor the drug resistant gene T790M, as well as its prognostic prediction value in patients with targeted therapy. Methods ARMS (amplification refractory mutation system)-PCR was used to detect EGFR mutations in 107 (50 of pre-therapy, 29 after traditional chemotherapy and 28 after targeted therapy) cases of paired plasma and tumor tissue specimens, followed by comparing their concordance. The sensitivity, specificity and the prognostic value of plasma cfDNA detection were also observed. Results The total rate of EGFR mutation was 56% (60/107) in all plasma samples and 77.6% (83/107) in corresponding tumor tissues. Completely the same mutants and wild-type EGFR were found in 68.2% cases of paired specimens. The sensitivity of plasma cfDNA detection was 72.3% and the specificity was up to 100%. Patients were sub-categorized according to therapy. The results showed that the highest consistent rate of cfDNA and tumor tissues was found in the group of pre-therapy (74%, 37/50). Whereas, the lowest consistent rate was observed in the targeted therapy group (57.1%, 16/28). It indicated that the targeted treatment could change the EGFR status in plasma cfDNA. Further analyses on inconsistent cases in this group revealed that 50% of them were compound EGFR mutations with T790M. Thereby, it suggested that targeted therapy might induce the emergence of drug resistance gene T790M. This speculation was confirmed by survival analyses. Based on plasma cfDNA results, patients with T790M mutant had significantly worse progression-free survival (PFS) and overall survival (OS). Conclusion For EGFR testing, ARMS-PCR on plasma cfDNA is a promising methodology with the highest specificity and effective sensitivity. It is useful for EGFR testing in patients before treatment, especially the late-stage patients. Simultaneously, plasma cfDNA could be used to monitor the drug resistant mutation, T790M status and predict prognosis after targeted therapy.?
The Study on Gene Amplification of EGFR in Bronchioloalveolar Carcinoma and Conventional Adenocarcinoma of the Lung  [PDF]
Xin SONG,Zhigang SONG,Yali LV,Mei ZHONG
Chinese Journal of Lung Cancer , 2009,
Abstract: Background and objective Patients with adenocarcinoma of the lung have disproportionately response to the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). The aim of this study is to analyze the difference of EGFR gene amplification in bronchioloalveolar carcinoma (BAC), adenocarcinma mixed subtype and conventional adenocarcinoma of the lung and provide some information to clinical therapies. Methods Lung cancer cases were collected and reviewed from the archives of the Department of Pathology, Chinese PLA General Hospital during the time period from 2004 to 2006. The definite diagnosis of BAC based on 2004 WHO classification of lung tumors was made by two pathologists. Fluorescence in situ hybridization (FISH) was performed to detect EGFR gene amplification in pure BAC, adenocarcinma mixed subtype and conventional adenocarcinoma. Results Conventional adenocarcinoma had higher EGFR amplification compared with pure BAC and adenocarcinma mixed subtype (χ2=11.632, P<0.05). EGFR gene amplification was found in 45.45% of conventional adenocarcinoma, 14.81% in pure BACs, and 22.58% in adenocarcinma mixed subtype. EGFR gene amplification was observed as scattered signals in most cases. Conclusion EGFR gene amplification was seen more frequently in the invasive components than in BAC. EGFR gene amplification might be associated with the development of adenocarcinoma of the lung.
Primary adenocarcinoma of ureter mimicking pyelonephritis  [cached]
Punia R. P. S,Mundi Irneet,Arora Komal,Dalal Ashwani
Urology Annals , 2010,
Abstract: Tumors of the ureter are rare. We present a case of primary mucinous adenocarcinoma of the ureter diagnosed as chronic pyelonephritis preoperatively. This tumor is postulated to arise from metaplastic glandular mucosa in response to chronic irritation of the urothelium.
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