EGFR与EB两项在鼻咽癌临床作用的比较及与中医证型关系初探
|
摘要
背景及目的
表皮生长因子受体(epidermal growth factor receptor, EGFR)在多种肿瘤中高表达,且与预后相关,然而,EGFR对鼻咽癌的预后价值尚存争议。本研究通过检测不同中医证型初诊鼻咽癌患者病理组织中EGFR的蛋白表达及血清中的EB两项检查,探讨EGFR与鼻咽癌临床病理特征的相关性,并比较和评价EGFR与EB两项在反映鼻咽癌分型分期中的作用,从而寻找对肿瘤的生长情况评估更有价值的实验室指标,为临床治疗及预后判断提供理论依据。同时,通过比较不同中医证型的鼻咽癌患者病理组织中EGFR的蛋白表达,以初探其与不同中医证型鼻咽癌预后的关系。
材料
收集2006年12月至2010年2月在广东省中医院住院及门诊行病理组织活检确诊为鼻咽未分化型非角化性癌的初诊鼻咽癌患者60例,同时收集病理组织活检确诊为鼻咽慢性粘膜炎的患者20例。
方法
利用免疫组织化学(IHC)二步法检测鼻咽癌及慢性鼻咽炎患者中EGFR的表达情况,免疫组织化学染色结果经Image-pro plus 6.0图像分析软件得出EGFR表达的平均光密度值(mean of optical density, MOD),并抽取外周静脉血检测EB两项检查得到其光密度值(optical density, OD),采用单因素和多因素方法分析EGFR蛋白表达量和EB两项值与临床病理特征、中医证型的关系。
结果
①在鼻咽粘膜慢性炎症组织中,EGFR在棘细胞层主要表达在细胞膜上,且随着细胞的分化的成熟而表达逐渐减少或消失,在基底层的细胞表达含量较高,且出现胞浆内有粉尘状分布。而EGFR在炎性细胞中是不表达的。EGFR在鼻咽癌细胞中均有不同程度的表达。EGFR主要在胞膜下周边的表达呈串珠状或不连续状的分布,胞浆内也可出现粗细不等、数量不一的阳性颗粒。
②鼻咽未分化型非角化性癌MOD (EGFR) (0.1075±0.0802)明显高于慢性鼻咽炎组织MOD (EGFR) (0.0608±0.0483), P=0.003;
③Ⅰ期与Ⅱ期鼻咽癌患者病理组织MOD(EGFR)之间无显著性差异(p=0.381>0.05),其他组间都存在显著性差异,并且随着临床分期的升高,MOD (EGFR)也逐渐增大。并将临床分期、性别、年龄、病程与MOD (EGFR)进行多元相关回归分析,得知MOD(EGFR)与年龄和病程无相关性,P值分别为0.088、0.073(均P>0.05),与性别存在显著负相关性(p=0.009＜0.01),即EGFR在女性鼻咽癌患者中低表达,相关系数为-0.304；与临床分期存在显著正相关性(p=0.000<0.01),即随着临床分期的升高,MOD (EGFR)有逐渐增大的趋势,相关系数为0.573；
④鼻咽癌组织EGFR的表达与T分期相关(p=0.000<0.01),T1、T2、T3之间无显著性差异,但T1、T2、T3与T4存在差异性差异。T4患者的MOD(EGFR)明显高于T1、T2、T3,而与其他病理特征无关；
⑤不同临床分期OD(VCA-IgA)、OD(EA-IgA)分别经方差分析,组间差异均无显著性,p值分别为0.408、0.068(均P>0.05)。并将临床分期、性别、年龄、病程与OD(VCA-IgA)、OD(EA-IgA)分别进行多元回归分析,差异均无统计学意义,均为P>0.05。尚不能认为OD(VCA-IgA)、OD(EA-IgA)在本实验中与临床分期、性别、年龄、病程有相关性。
⑥初诊鼻咽癌以痰浊结聚证(48.3%)及气血凝结证(38.3%)多见。痰浊结聚证与火毒困结证之间MOD (EGFR)无显著性差异(p=0.659>0.05),但气血凝结证患者MOD(EGFR)明显高于痰浊结聚证及火毒困结证患者,并且将三种中医证型的鼻咽癌患者MOD(EGFR)分别与慢性鼻咽炎比较,只有气血凝结证的鼻咽癌患者MOD (EGFR)有显著性差异(p=0.000<0.01),明显高于慢性鼻咽炎。
结论
在鼻咽癌组织中存在EGFR的高表达,EGFR蛋白表达强度随着临床分期的增高有增强的趋势,EGFR活化可能与鼻咽癌发病及进展有关,EGFR表达可能与肿瘤细胞增殖活性密切相关；EB两项检测在鼻咽癌的筛查上具有重要作用,但其与鼻咽癌在人体中的肿瘤负荷之间并无明显的量效关系,病理组织中EGFR的检测比EB两项的检测更能客观反映肿瘤在人体中的负荷,鼻咽病理组织中EGFR的免疫组化测定作为一种常规检测应用于临床具有一定的临床推广应用价值。气血凝结证鼻咽癌患者的预后可能较痰浊结聚及火毒困结证患者差。
Background and Objective
The expression of epidermal growth factor receptor(EGFR) in many kinds of tumors is strong, and is related with the prognosis, however, EGFR on the prognostic value of nasopharyngeal carcinoma (NPC) is still disputing.This study research the primary diagnosis patients of NPC in different TCM(traditional Chinese medical) syndrome type by detecting the expression of EGFR in pathological tissue and EB(epstein barr) virus in venous blood, to explore the relevance of EGFR and the clinical pathological features of nasopharyngeal carcinoma, and compare the function of determinating clinical stage in EGFR and the EB virus, thus seeks to the biochemical indicator which can appraisal the situation of tumor growth for the clinical care and the prognosis judgment. In addition, it preliminary investigated the prognostic role of NPC of TCM syndrome type by detecting the expression of EGFR in pathological tissue of patients with different TCM syndrome type.
Mater ials
Tissue was collected from patients which were first diagnosed as undifferentiated non-keratinizing NPC by biopsy(60 cases), and patients diagnosed as chronic nasopharyngitis(20 cases) admitted to Guangdong Hosiptal of TCM from December 2006 to February 2010.
Methods
The immunity histochemistry was used to detect the expression of EGFR in the pathological tissue of the patients of NPC and chronic nasopharyngitis, the image on the slides were analyzed with IPP6.0 software to obtain the mean of optical density(MOD) of EGFR, and to obtain the optical density(OD) of EB virus in venous blood, it analyzes the effect of EGFR protein expression and the EB check whether had relationship between the clinical stage and the prognosis or not, using the single-factor and the multi-factor method.
Results
①Expression of EGFR in chronic nasopharyngitis distributes in prickle cell layer of the nasopharyngeal epithelium, EGFR expressed mainly in the cell membrane, and cell differentiation with the expression of the mature and gradually reduced or disappeared, in the basal layer of cells expressed higher levels, and occasionally there was dust-like distribution in the cytoplasm, compared not in inflammatory cells. EGFR in NPC cells have different levels of expression. The expression of EGFR which presented the strings of beads or discrete-shaped mainly distributed in the membrane surrounding, the thickness of the cytoplasm can occur ranging from varying the number of positive thick granules;
②The MOD of EGFR of undifferentiated non-keratinizing nasopharyngeal carcinoma(0.1075±0.0802) was significantly higher than that of chronic nasopharyngitis (0.0608±0.0483), P=0.003;
③There was no significant difference between the PhaseⅠPhaseⅡpatients with NPC(p=0.381>0.05),other groups exist significant differences, and with the clinical staging increased, MOD (EGFR) also increases. And clinical stage, gender, age, the course of disease will carry on the multiple correlation regression analysis with MOD(EGFR), knew that MOD(EGFR) and the age and the course of disease hadn't relevance, P values were 0.088,0.073(P>0.05), and gender had a significant negative correlation with MOD(EGFR)(p=0.009 <0.01), namely EGFR in women with NPC was lower expression than men, correlation coefficient is-0.304;And there was a significant positive correlation with clinical stage(p=0.000<0.01), that, as the clinical stage increased, MOD (EGFR) are gradually increasing trend, The correlation coefficient is 0.573;
④There was relationship between MOD(EGFR) and T(tumour) staging(p=0.000 <0.01), while no significant differences between T1, T2, T3, but T1, T2, T3 and T4 are significant differences. The MOD (EGFR) of T4 was significantly higher than T1, T2, T3, exempt that, it has nothing.to do with other pathological features;
⑤D(VCA-IgA), OD(EA-IgA) had no significant difference between different clinical stages, analyzing by analysis of variance, p values were 0.408,0.068 (P>0.05). And there was no significant correlation between clinical stage, gender, age, course of disease and the OD (VCA-IgA), OD (EA-IgA) carrying out by multiple regression analysis, P>0.05.It still could not think that OD(VCA-IgA), OD(EA-IgA) in this experiment with clinical stage, gender, age, course of disease have the relevance by stages.
⑥he primary diagnosis patients of NPC formed mainly by two TCM syndrome types: phlegm syndrome (including 48.3%) and blood stasis syndrome (including 38.3%). The MOD (EGFR) of phlegm syndrome and heat-toxin syndrome had no significant difference (p=0.659> 0.05), but the MOD (EGFR) of the blood stasis syndrome was significantly higher than phlegm syndrome.By comparing MOD(EGFR) of the NPC patients of three kinds of TCM syndromes and the chronic nasopharyngitis, only MOD (EGFR) of the patients of blood stasis syndrome NPC are significantly different (p=0.000<0.01), significantly higher than that in chronic nasopharyngitis.
Conclusions
The nasopharyngeal carcinoma of TCM syndrome type of turbid phlegm and blood stasis exists high expression of EGFR, the expression of EGFR has the enhancement tendency along with the clinical stages markup, EGFR activation may be related to the pathogenesis and progression of nasopharyngeal carcinoma, EGFR expression may be closely related to proliferation of tumor cell; The EB two examinations have the influential role in NPC screening, but with nasopharyngeal carcinoma tumor burden in the human body there is no clear dose-effect relationship, histological detection of EGFR is better than the EB two examination in reflecting the tumor load in the human body, pathological tissues Immunohistochemical determination of EGFR as a routine test used in clinical application of clinical practice has a certain value. Blood stasis syndrome patients may had worse prognosis than phlegm syndrome and heat-toxin syndrome.
表皮生长因子受体(epidermal growth factor receptor, EGFR)在多种肿瘤中高表达,且与预后相关,然而,EGFR对鼻咽癌的预后价值尚存争议。本研究通过检测不同中医证型初诊鼻咽癌患者病理组织中EGFR的蛋白表达及血清中的EB两项检查,探讨EGFR与鼻咽癌临床病理特征的相关性,并比较和评价EGFR与EB两项在反映鼻咽癌分型分期中的作用,从而寻找对肿瘤的生长情况评估更有价值的实验室指标,为临床治疗及预后判断提供理论依据。同时,通过比较不同中医证型的鼻咽癌患者病理组织中EGFR的蛋白表达,以初探其与不同中医证型鼻咽癌预后的关系。
材料
收集2006年12月至2010年2月在广东省中医院住院及门诊行病理组织活检确诊为鼻咽未分化型非角化性癌的初诊鼻咽癌患者60例,同时收集病理组织活检确诊为鼻咽慢性粘膜炎的患者20例。
方法
利用免疫组织化学(IHC)二步法检测鼻咽癌及慢性鼻咽炎患者中EGFR的表达情况,免疫组织化学染色结果经Image-pro plus 6.0图像分析软件得出EGFR表达的平均光密度值(mean of optical density, MOD),并抽取外周静脉血检测EB两项检查得到其光密度值(optical density, OD),采用单因素和多因素方法分析EGFR蛋白表达量和EB两项值与临床病理特征、中医证型的关系。
结果
①在鼻咽粘膜慢性炎症组织中,EGFR在棘细胞层主要表达在细胞膜上,且随着细胞的分化的成熟而表达逐渐减少或消失,在基底层的细胞表达含量较高,且出现胞浆内有粉尘状分布。而EGFR在炎性细胞中是不表达的。EGFR在鼻咽癌细胞中均有不同程度的表达。EGFR主要在胞膜下周边的表达呈串珠状或不连续状的分布,胞浆内也可出现粗细不等、数量不一的阳性颗粒。
②鼻咽未分化型非角化性癌MOD (EGFR) (0.1075±0.0802)明显高于慢性鼻咽炎组织MOD (EGFR) (0.0608±0.0483), P=0.003;
③Ⅰ期与Ⅱ期鼻咽癌患者病理组织MOD(EGFR)之间无显著性差异(p=0.381>0.05),其他组间都存在显著性差异,并且随着临床分期的升高,MOD (EGFR)也逐渐增大。并将临床分期、性别、年龄、病程与MOD (EGFR)进行多元相关回归分析,得知MOD(EGFR)与年龄和病程无相关性,P值分别为0.088、0.073(均P>0.05),与性别存在显著负相关性(p=0.009＜0.01),即EGFR在女性鼻咽癌患者中低表达,相关系数为-0.304；与临床分期存在显著正相关性(p=0.000<0.01),即随着临床分期的升高,MOD (EGFR)有逐渐增大的趋势,相关系数为0.573；
④鼻咽癌组织EGFR的表达与T分期相关(p=0.000<0.01),T1、T2、T3之间无显著性差异,但T1、T2、T3与T4存在差异性差异。T4患者的MOD(EGFR)明显高于T1、T2、T3,而与其他病理特征无关；
⑤不同临床分期OD(VCA-IgA)、OD(EA-IgA)分别经方差分析,组间差异均无显著性,p值分别为0.408、0.068(均P>0.05)。并将临床分期、性别、年龄、病程与OD(VCA-IgA)、OD(EA-IgA)分别进行多元回归分析,差异均无统计学意义,均为P>0.05。尚不能认为OD(VCA-IgA)、OD(EA-IgA)在本实验中与临床分期、性别、年龄、病程有相关性。
⑥初诊鼻咽癌以痰浊结聚证(48.3%)及气血凝结证(38.3%)多见。痰浊结聚证与火毒困结证之间MOD (EGFR)无显著性差异(p=0.659>0.05),但气血凝结证患者MOD(EGFR)明显高于痰浊结聚证及火毒困结证患者,并且将三种中医证型的鼻咽癌患者MOD(EGFR)分别与慢性鼻咽炎比较,只有气血凝结证的鼻咽癌患者MOD (EGFR)有显著性差异(p=0.000<0.01),明显高于慢性鼻咽炎。
结论
在鼻咽癌组织中存在EGFR的高表达,EGFR蛋白表达强度随着临床分期的增高有增强的趋势,EGFR活化可能与鼻咽癌发病及进展有关,EGFR表达可能与肿瘤细胞增殖活性密切相关；EB两项检测在鼻咽癌的筛查上具有重要作用,但其与鼻咽癌在人体中的肿瘤负荷之间并无明显的量效关系,病理组织中EGFR的检测比EB两项的检测更能客观反映肿瘤在人体中的负荷,鼻咽病理组织中EGFR的免疫组化测定作为一种常规检测应用于临床具有一定的临床推广应用价值。气血凝结证鼻咽癌患者的预后可能较痰浊结聚及火毒困结证患者差。
Background and Objective
The expression of epidermal growth factor receptor(EGFR) in many kinds of tumors is strong, and is related with the prognosis, however, EGFR on the prognostic value of nasopharyngeal carcinoma (NPC) is still disputing.This study research the primary diagnosis patients of NPC in different TCM(traditional Chinese medical) syndrome type by detecting the expression of EGFR in pathological tissue and EB(epstein barr) virus in venous blood, to explore the relevance of EGFR and the clinical pathological features of nasopharyngeal carcinoma, and compare the function of determinating clinical stage in EGFR and the EB virus, thus seeks to the biochemical indicator which can appraisal the situation of tumor growth for the clinical care and the prognosis judgment. In addition, it preliminary investigated the prognostic role of NPC of TCM syndrome type by detecting the expression of EGFR in pathological tissue of patients with different TCM syndrome type.
Mater ials
Tissue was collected from patients which were first diagnosed as undifferentiated non-keratinizing NPC by biopsy(60 cases), and patients diagnosed as chronic nasopharyngitis(20 cases) admitted to Guangdong Hosiptal of TCM from December 2006 to February 2010.
Methods
The immunity histochemistry was used to detect the expression of EGFR in the pathological tissue of the patients of NPC and chronic nasopharyngitis, the image on the slides were analyzed with IPP6.0 software to obtain the mean of optical density(MOD) of EGFR, and to obtain the optical density(OD) of EB virus in venous blood, it analyzes the effect of EGFR protein expression and the EB check whether had relationship between the clinical stage and the prognosis or not, using the single-factor and the multi-factor method.
Results
①Expression of EGFR in chronic nasopharyngitis distributes in prickle cell layer of the nasopharyngeal epithelium, EGFR expressed mainly in the cell membrane, and cell differentiation with the expression of the mature and gradually reduced or disappeared, in the basal layer of cells expressed higher levels, and occasionally there was dust-like distribution in the cytoplasm, compared not in inflammatory cells. EGFR in NPC cells have different levels of expression. The expression of EGFR which presented the strings of beads or discrete-shaped mainly distributed in the membrane surrounding, the thickness of the cytoplasm can occur ranging from varying the number of positive thick granules;
②The MOD of EGFR of undifferentiated non-keratinizing nasopharyngeal carcinoma(0.1075±0.0802) was significantly higher than that of chronic nasopharyngitis (0.0608±0.0483), P=0.003;
③There was no significant difference between the PhaseⅠPhaseⅡpatients with NPC(p=0.381>0.05),other groups exist significant differences, and with the clinical staging increased, MOD (EGFR) also increases. And clinical stage, gender, age, the course of disease will carry on the multiple correlation regression analysis with MOD(EGFR), knew that MOD(EGFR) and the age and the course of disease hadn't relevance, P values were 0.088,0.073(P>0.05), and gender had a significant negative correlation with MOD(EGFR)(p=0.009 <0.01), namely EGFR in women with NPC was lower expression than men, correlation coefficient is-0.304;And there was a significant positive correlation with clinical stage(p=0.000<0.01), that, as the clinical stage increased, MOD (EGFR) are gradually increasing trend, The correlation coefficient is 0.573;
④There was relationship between MOD(EGFR) and T(tumour) staging(p=0.000 <0.01), while no significant differences between T1, T2, T3, but T1, T2, T3 and T4 are significant differences. The MOD (EGFR) of T4 was significantly higher than T1, T2, T3, exempt that, it has nothing.to do with other pathological features;
⑤D(VCA-IgA), OD(EA-IgA) had no significant difference between different clinical stages, analyzing by analysis of variance, p values were 0.408,0.068 (P>0.05). And there was no significant correlation between clinical stage, gender, age, course of disease and the OD (VCA-IgA), OD (EA-IgA) carrying out by multiple regression analysis, P>0.05.It still could not think that OD(VCA-IgA), OD(EA-IgA) in this experiment with clinical stage, gender, age, course of disease have the relevance by stages.
⑥he primary diagnosis patients of NPC formed mainly by two TCM syndrome types: phlegm syndrome (including 48.3%) and blood stasis syndrome (including 38.3%). The MOD (EGFR) of phlegm syndrome and heat-toxin syndrome had no significant difference (p=0.659> 0.05), but the MOD (EGFR) of the blood stasis syndrome was significantly higher than phlegm syndrome.By comparing MOD(EGFR) of the NPC patients of three kinds of TCM syndromes and the chronic nasopharyngitis, only MOD (EGFR) of the patients of blood stasis syndrome NPC are significantly different (p=0.000<0.01), significantly higher than that in chronic nasopharyngitis.
Conclusions
The nasopharyngeal carcinoma of TCM syndrome type of turbid phlegm and blood stasis exists high expression of EGFR, the expression of EGFR has the enhancement tendency along with the clinical stages markup, EGFR activation may be related to the pathogenesis and progression of nasopharyngeal carcinoma, EGFR expression may be closely related to proliferation of tumor cell; The EB two examinations have the influential role in NPC screening, but with nasopharyngeal carcinoma tumor burden in the human body there is no clear dose-effect relationship, histological detection of EGFR is better than the EB two examination in reflecting the tumor load in the human body, pathological tissues Immunohistochemical determination of EGFR as a routine test used in clinical application of clinical practice has a certain value. Blood stasis syndrome patients may had worse prognosis than phlegm syndrome and heat-toxin syndrome.
引文
[1]Ho, J. H. C., Lau, W. H., Kwan H. C., et al. Epstein-Barr virus-specific IgA and IgG serum antibodies in nasopharygeal carcinoma. Brit. J. Cancer.1995,34:655-659.
[2]洪明晃,郭翔等.鼻咽癌.北京：中国医药科技出版社.2003：315.
[3]洪明晃,郭翔等.鼻咽癌.北京：中国医药科技出版社.2003：16.
[4]田勇泉,孙爱华.耳鼻咽喉—头颈外科学.北京：人民卫生出版社,2005：172.
[5]Nicholson RI, Gee JMW, Harper ME. EGFR and cancer prognosis[J]. Eur J Cancer,2001,37 (4):9-15.
[6]储大同.当代肿瘤内科治疗的新热点——细胞、分子靶向性药物的发展//秦叔逵,王健民,王杰军,主编.中国临床肿瘤学教育专辑(2001).北京：中国医药科技术版社,2001.1-5.
[7]Yamada T, Takagi M, Shioda S. Evaluation of epidermal Growth Factor Receptor in squamous cell carcinoma of the oral cavity. oral surg oral med oral pathol,1993,13:67-70.
[8]Barker FG Ⅱ, Simmons ML, Chang SM, et al. EGFR overexpression and radiation response in glioblastoma multiforme. Int J Radiat Oncol Biol Phys,2001,51 (2): 410-418.
[9]Jorissen RN, Walker F, Pouliot N, et al. Epidernal growth factor receptor: mechanisms of activation Signaling. EXP Cell Res.2003,284:31.
[10]Yarden Y, Sliwkowski M X. Untangling The ErbB Signalling Network. Nat Rev Mol Cell Biol,2001,2(2):127-137.
[11]Raben D, Bianco C, Milas L, et al. Targeted therapies and radiation for the treatment of head and neck cancer:are we making progress?. Semin in Radiat Oncol,2004,14(2):139—152.
[12]王承兴.以EGFR及其突变体为靶点的肿瘤治疗.国外医学生理病理与临床分册,2000,20(2)：137—140.
[13]C-T Kuan CJ, Wikstrand DD,et al. EGFRvⅢ as a promising target for antibody-based brain tumor therapy. Brain tumor pathol,2000,17:71-78.
[14]Kerbel RS. Tumor angiogenesis:past, present and the near future. Carcinogenesis,2000,21(3):505～515.
[15]Carmeliet P, Jani PK. Angiogenesis in cancer and other disease. Nature, 2000,407(6801):249～257.
[16]Herbst RS. Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys.2004,59(2):21—26.
[17]陈刚,林色南,等.COX-2和EGFR在鼻咽癌组织中的表达及临床意义.诊断病理学杂志,2007,14(6)：454.
[18]Bankfalvi A, Krassort M, Vegh A, et al. Deranged expression of the E-cadherin /beta-catenin complex and the epidermal growth factor receptor in the clinical evolution and progression of oral squamous cell carcinomas. J Oral Pathol Med,2002,31(8):450—457.
[19]Galizial G, Lietol E, Ferraraccio F, et al. Prognostic Significance of Epidermal Growth Factor Receptor Expression in Colon Cancer Patients Undergoing Curative Surgery. Ann Surg Oncol,2006,13(6):823—835.
[20]Umekita Y, Ohi Y, Sagara Y, Yoshida H. Co-expression of epidermal growth factor receptor and transforming growth factor-alpha predicts worse prognosis in breast-cancer patients. Int J Cancer,2000,89:484-487.
[21]Akimoto T, Hunter NR, BuchmiUer L, et al. Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas. Clin Cancer Res,1999,5:2884—2890.
[22]杨春妮,杨一兵,等.EGFR及NF-κB与鼻咽癌放射敏感性的相关性研究.临床耳鼻咽喉头颈外科学,2009.23(8)：678-681.
[23]Milas L. Mason KA. Ang KK. Epidermal growth factor receptor and its inhibition in radiotherapy:in vivo findings. Int J Radiat Biol,2003,79(7): 539—545.
[24]Harari PM. Huang S. Radiation combined with EGFR signal inhibitors:head and neck cancer focus. Semin Radiat Oncol,2006,16(1):38—44.
[25]Milas L, Akimoto T, Hunter NR, et al. Relationship between Cyclin D1 expression and poor radioresponse of murine carcinomas. Int J Radiat Oncol Biol Phys,2002,52(2):514—521.
[26]Huang SM. Harari PM. Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas:inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis. Clin Cancer Res, 2000,6(6):2166-2174.
[27]吴飞翔,赵荫农,曹骥,等.EGF和EGFR在肝细胞癌中的表达及临床意义.肿瘤研究与临床,2005,17(2)：96.
[28]徐庆中,王大亮,卢德宏,等.人脑星形细胞瘤EGF, TGF-α及其受体EGFR的表达.诊断病理学杂志,2002,9(4)：207.
[29]Kato S, Pinto M, Carvajal A, et al. Tissue factor is regulated by epidermal growth factor in normal and malignant human endometrial epithelial cells. Thromb Haemost,2005,94(2):444.
[30]LEMOINE N R, HUGHES C M, GULLICK W J, et al. Abnormalities of the EGF receptor system in human thyroid neo-plasia. Int J Cancer,1991,49 (4):558-561.
[31]孙迪文,项锋钢,梁超群.肺癌VEGF和MMP2的表达与临床病理特征的关系.青岛大学医学院学报,2004,40(1)：44-46.
[32]Ravindranath N, Wion D, Brachet P, et al. Epidermal growth factor modulates the expression of vascular endothelial growth factor in the human prostate. J Androl,2001,22(3):432-443.
[33]Thomas SM, Grandis JR. Pharmacokinetic and pharmacodynamic properties of EGFR inhibitors under clinical investigation. Cancer Treat Rev,2004, 30(3):255-268.
[34]Cohen EE, Rosen F, StadlerWM, et al. Phase II Trial of ZD1839 in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck. J Clin Oncol, 2003,21:1980-1987.
[35]Gao LB, Wei YS, et al. No association between epidermal growth factor and epidermal growth factor receptor polymorphisms and nasopharyngeal carcinoma. Cancer Genet Cytogenet,2008,185(2):69-73.
[36]张哲洋,程光华.鼻息肉患者血清EGF含量变化的观察.放射免疫学杂志,2008,21(1)：453-455.
[37]胡连生,李凡成等.中医耳鼻咽喉科学.北京：中国中医药出版社,2004：293-294.
[38]刘书静,田道法等.鼻咽癌患者初诊中医证型与病灶颅内侵犯潜力的相关性.中国中西医结合杂志,2006,26(12)：1086-1089.
[39]刘宇龙,徐凯等.鼻咽癌中医证型与TNM分期相关性的研究.四川中医,2005,23(9)： 90-91.
[40]潘艳东,黎静等.Ki67, VEGF和EGFR的表达与鼻咽癌临床分期及分化程度的关系.广东医学,2009,30(7)：1095-1097.
[2]洪明晃,郭翔等.鼻咽癌.北京：中国医药科技出版社.2003：315.
[3]洪明晃,郭翔等.鼻咽癌.北京：中国医药科技出版社.2003：16.
[4]田勇泉,孙爱华.耳鼻咽喉—头颈外科学.北京：人民卫生出版社,2005：172.
[5]Nicholson RI, Gee JMW, Harper ME. EGFR and cancer prognosis[J]. Eur J Cancer,2001,37 (4):9-15.
[6]储大同.当代肿瘤内科治疗的新热点——细胞、分子靶向性药物的发展//秦叔逵,王健民,王杰军,主编.中国临床肿瘤学教育专辑(2001).北京：中国医药科技术版社,2001.1-5.
[7]Yamada T, Takagi M, Shioda S. Evaluation of epidermal Growth Factor Receptor in squamous cell carcinoma of the oral cavity. oral surg oral med oral pathol,1993,13:67-70.
[8]Barker FG Ⅱ, Simmons ML, Chang SM, et al. EGFR overexpression and radiation response in glioblastoma multiforme. Int J Radiat Oncol Biol Phys,2001,51 (2): 410-418.
[9]Jorissen RN, Walker F, Pouliot N, et al. Epidernal growth factor receptor: mechanisms of activation Signaling. EXP Cell Res.2003,284:31.
[10]Yarden Y, Sliwkowski M X. Untangling The ErbB Signalling Network. Nat Rev Mol Cell Biol,2001,2(2):127-137.
[11]Raben D, Bianco C, Milas L, et al. Targeted therapies and radiation for the treatment of head and neck cancer:are we making progress?. Semin in Radiat Oncol,2004,14(2):139—152.
[12]王承兴.以EGFR及其突变体为靶点的肿瘤治疗.国外医学生理病理与临床分册,2000,20(2)：137—140.
[13]C-T Kuan CJ, Wikstrand DD,et al. EGFRvⅢ as a promising target for antibody-based brain tumor therapy. Brain tumor pathol,2000,17:71-78.
[14]Kerbel RS. Tumor angiogenesis:past, present and the near future. Carcinogenesis,2000,21(3):505～515.
[15]Carmeliet P, Jani PK. Angiogenesis in cancer and other disease. Nature, 2000,407(6801):249～257.
[16]Herbst RS. Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys.2004,59(2):21—26.
[17]陈刚,林色南,等.COX-2和EGFR在鼻咽癌组织中的表达及临床意义.诊断病理学杂志,2007,14(6)：454.
[18]Bankfalvi A, Krassort M, Vegh A, et al. Deranged expression of the E-cadherin /beta-catenin complex and the epidermal growth factor receptor in the clinical evolution and progression of oral squamous cell carcinomas. J Oral Pathol Med,2002,31(8):450—457.
[19]Galizial G, Lietol E, Ferraraccio F, et al. Prognostic Significance of Epidermal Growth Factor Receptor Expression in Colon Cancer Patients Undergoing Curative Surgery. Ann Surg Oncol,2006,13(6):823—835.
[20]Umekita Y, Ohi Y, Sagara Y, Yoshida H. Co-expression of epidermal growth factor receptor and transforming growth factor-alpha predicts worse prognosis in breast-cancer patients. Int J Cancer,2000,89:484-487.
[21]Akimoto T, Hunter NR, BuchmiUer L, et al. Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas. Clin Cancer Res,1999,5:2884—2890.
[22]杨春妮,杨一兵,等.EGFR及NF-κB与鼻咽癌放射敏感性的相关性研究.临床耳鼻咽喉头颈外科学,2009.23(8)：678-681.
[23]Milas L. Mason KA. Ang KK. Epidermal growth factor receptor and its inhibition in radiotherapy:in vivo findings. Int J Radiat Biol,2003,79(7): 539—545.
[24]Harari PM. Huang S. Radiation combined with EGFR signal inhibitors:head and neck cancer focus. Semin Radiat Oncol,2006,16(1):38—44.
[25]Milas L, Akimoto T, Hunter NR, et al. Relationship between Cyclin D1 expression and poor radioresponse of murine carcinomas. Int J Radiat Oncol Biol Phys,2002,52(2):514—521.
[26]Huang SM. Harari PM. Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas:inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis. Clin Cancer Res, 2000,6(6):2166-2174.
[27]吴飞翔,赵荫农,曹骥,等.EGF和EGFR在肝细胞癌中的表达及临床意义.肿瘤研究与临床,2005,17(2)：96.
[28]徐庆中,王大亮,卢德宏,等.人脑星形细胞瘤EGF, TGF-α及其受体EGFR的表达.诊断病理学杂志,2002,9(4)：207.
[29]Kato S, Pinto M, Carvajal A, et al. Tissue factor is regulated by epidermal growth factor in normal and malignant human endometrial epithelial cells. Thromb Haemost,2005,94(2):444.
[30]LEMOINE N R, HUGHES C M, GULLICK W J, et al. Abnormalities of the EGF receptor system in human thyroid neo-plasia. Int J Cancer,1991,49 (4):558-561.
[31]孙迪文,项锋钢,梁超群.肺癌VEGF和MMP2的表达与临床病理特征的关系.青岛大学医学院学报,2004,40(1)：44-46.
[32]Ravindranath N, Wion D, Brachet P, et al. Epidermal growth factor modulates the expression of vascular endothelial growth factor in the human prostate. J Androl,2001,22(3):432-443.
[33]Thomas SM, Grandis JR. Pharmacokinetic and pharmacodynamic properties of EGFR inhibitors under clinical investigation. Cancer Treat Rev,2004, 30(3):255-268.
[34]Cohen EE, Rosen F, StadlerWM, et al. Phase II Trial of ZD1839 in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck. J Clin Oncol, 2003,21:1980-1987.
[35]Gao LB, Wei YS, et al. No association between epidermal growth factor and epidermal growth factor receptor polymorphisms and nasopharyngeal carcinoma. Cancer Genet Cytogenet,2008,185(2):69-73.
[36]张哲洋,程光华.鼻息肉患者血清EGF含量变化的观察.放射免疫学杂志,2008,21(1)：453-455.
[37]胡连生,李凡成等.中医耳鼻咽喉科学.北京：中国中医药出版社,2004：293-294.
[38]刘书静,田道法等.鼻咽癌患者初诊中医证型与病灶颅内侵犯潜力的相关性.中国中西医结合杂志,2006,26(12)：1086-1089.
[39]刘宇龙,徐凯等.鼻咽癌中医证型与TNM分期相关性的研究.四川中医,2005,23(9)： 90-91.
[40]潘艳东,黎静等.Ki67, VEGF和EGFR的表达与鼻咽癌临床分期及分化程度的关系.广东医学,2009,30(7)：1095-1097.