结直肠癌新辅助治疗的疗效评价及相关基因/蛋白的表达与意义
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摘要
研究背景
结直肠癌是最常见的消化系统恶性肿瘤之一,有研究表明其发病率正在逐年上升。新辅助化疗作为综合性治疗最重要的组成部分收到越来越多的关注。虽然对结直肠癌有众多的评价方法,包括广泛采用的实体瘤评价方法RECIST标准,但对结直肠癌而言,却缺乏统一的、有针对性的、行之有效的评价体系及标准。而日益成熟的分子诊断技术为我们提供了一条崭新的道路。若能找到预测新辅助治疗疗效的特异性的分子标志物,将可能对新辅助化疗的疗效评价及治疗产生深远的影响。
目的
临床研究通过对结直肠癌新辅助治疗患者临床病理等资料的分析,探讨新辅助化疗患者的特点、疗效评价、预后及相关因素。实验研究应用免疫组织化学方法,通过单因素和多因素统计分析,探讨TGOLN2和ZNF84在结直肠癌组织的表达情况及其与患者临床病理资料的关系；探讨TGOLN2、ZNF84、MMP-9、MMP-14、VEGFC、CTHRC1、 IRS-1七个蛋白在结直肠癌新辅助化疗病人前后的表达情况及其与患者基线资料和新辅助治疗疗效的关系。
对象与方法
研究纳入2003年1月至2011年6月在中日友好医院住院并符合入选条件的全部结直肠癌患者共1791例。临床研究选取其中行新辅助化疗的患者92例,通过单因素分析、配对T检验、二元非条件Logistic回归分析、Kaplan-Meier法、Cox单因素及多因素回归,探讨新辅助治疗的疗效评价指标及其对患者预后的影响。实验研究第一部分选取其中生存期大于5年或生存期小于2年的患者136例,探讨TGOLN2和ZNF84的表达情况及其与患者临床资料的关系；实验研究第二部分选取可以获得新辅助治疗前后结直肠癌病理标本的患者18例,探讨七个蛋白的在新辅助化疗前后的表达及其与新辅助治疗疗效和患者临床资料的关系。
结果
临床研究的结果提示：行新辅助化疗的患者中,临床表现缓解的占63.0%,血CEA缓解的占13.1%,原发灶大小缓解的占33.6%,浸润深度缓解的占13.0%。综合评价,按照制定的疗效评价标准,在这92例新辅助治疗的患者中,最终结果为有效的患者有63例(占68.5%),无效的为29例(占31.5%)。通过对各项评价指标灵敏度、特异度、阳性预测值、阴性预测值、正确率、约登指数、kappa值的再评价,提示浸润深度(即T分期)是其中最好的评价指标。新辅助化疗会对患者的中性粒细胞计数、红细胞计数、血红蛋白、血小板计数、谷丙转氨酶、血清肌酐、白蛋白、甘油三酯、肿瘤最大径等指标发生影响。二元Logistic回归分析提示影响新辅助化疗有效的指标包括血钠值(OR1.252,95%CI1.042-1.505,P=0.016)；血糖值(OR0.730,95%CI0.540-0.986,P=0.040)和肿瘤发病部位的不同(OR5.490,95%CI1.574-19.149,P=0.008)。Cox多因素分析提示转移淋巴结个数(RR1.340,95%CI1.058-1.697,P=0.015)可能是新辅助治疗患者预后独立的危险因素。
实验研究第一部分的结果提示：TGOLN2在结直肠癌组织中的表达高于癌旁(P<0.001),ZNF84无明显差异(P=0.825)；ZNF84的阳性表达与患者的性别(P=0.053),血压(P=0.022),血管癌栓(P=0.041)有关,Logistic回归结果提示高血压(OR5.699,95%CI1.428-22.744,P=0.014)可能为影响ZNF84表达的独立相关因素。将136例患者按照生存期大于5年或生存期小于2年分组后进行单因素分析发现,患者年龄(P=0.021)、癌组织的分化程度(P<0.001)、淋巴结转移(P<0.001)和远处转移(P<0.001)可能对预后有影响；多因素分析提示肿瘤分化程度(OR0.847、95%CI0008-0.847、P=0.036)和远处转移(OR0.033、95%C10.003-0.352、P=0.005)为影响预后的独立相关因素。
实验研究第二部分的结果提示：IRS-1(P=0.023)、TGOLN2(P=0.028)在新辅助治疗前癌组织的表达大于新辅助治疗后,ZNF84(P=0.576)、MMP-14(P=0.710)、MMP-9(P=0.151)、VEGFC (P=0.779)、CTHRC1(P=0.626)蛋白的表达无明显差异。单因素分析的结果提示,TGOLN2可能与病程的长短(P=0.017)、呼吸次数(P=0.012)以及CA199(P=0.026)相关；MMP-14可能与呼吸次数(P=0.001)、中性粒细胞计数(P=0.008)相关;CTHRC1在与红细胞计数(P=0.003)、血红蛋白(P=0.048)、血小板计数(P=0.045)、总胆红素(P=0.004)和血糖(P=0.018)相关；MMP-9可能与血钠(P=0.036)相关。
结论：92例行新辅助治疗的患者中,评价有效的患者为69例(占75.0%),浸润深度(即T分期)可能是评价新辅助化疗疗效较好的的指标；血钠、血糖和肿瘤发病部位可能是影响新辅助化疗疗效的三个独立相关因素;TGOLN2在结直肠癌组织中的表达高于癌旁(P<0.001),ZNF84无明显差异(P=0.825)；是否合并高血压可能为影响ZNF84阳性表达的独立相关因素；IRS-1和TGOLN2在新辅助化疗前的表达高于新辅助治疗后,可能作为判断新辅助化疗疗效的参考指标。
Background
Colorectal cancer is the most malignant tumors in digestive system. Neoadjuvant chemotherapy has received more and more attention, as a comprehensive treatment of tumors. Although there are so many ways to evaluate colorectal cancer, including RECIST which has widely used, there is lack of evaluation system and standards of colorectal cancer which is unified, targeted, and effective. And the increasing sophisticated molecular diagnostic technique provides us with a new way. If specific molecular markers were found to predict the efficacies of neoadjuvant therapy, it will lead far-reaching effect on evaluation and treatment of neoadjuvant chemotherapy.
Purpose
Clinical research:we analyzed the clinical and pathological data of neoadjuvant therapy patients with colorectal cancer to explore the characteristics, efficacy evaluation, prognosis and the related factors in neoadjuvant chemotherapy patient. Experimental study:We used immunohistochemistry method and statistical analysis to explore the expression of TGOLN2and ZNF84in colorectal cancer and the relationship of clinic pathological data and to explore the expression of TGOLN2, ZNF84, MMP-9, MMP-14, VEGFC, CTHRC1and IRS-1in colorectal cancer of neoadjuvant chemotherapy patients and the relationship between the patients'base data and the effect of neoadjuvant therapy.
Methods
A total of1791colorectal cancer patients, hospitalized in China-Japan Friendship Hospital, in the period of January2003and June2011, were studied. And92patients who used the neoadjuvant chemotherapy were selected in clinical study. Univariate analysis, paired T-test, and binary non-conditional logistic regression analysis, the Kaplan-Meier method, Cox single factor and multivariate regression were used to explore the efficacy evaluation effect of neoadjuvant therapy and the impact on the prognosis of patients. On the first part of the experimental study, a total of136patients, more than the5-year survival of less than2-year old, were selected to explore the expression of TGOLN2and ZNF84and its relationship of the clinical data. The second part of the experimental study, a total of18colorectal cancer patients who can be obtained pathology specimens of before and after neoadjuvant therapy, were chosen to explore the expression of the seven relative proteins on before and after neoadjuvant chemotherapy, and the relationship of the neoadjuvant treatment efficacy and patient clinical data.
Results
Clinical research:The new adjuvant chemotherapy in patients with clinical remission accounted for63%, blood CEA remission for13.1%, primary tumor size in remission for33.6%, the depth of invasion accounted for13%.Overall merit:According to the curative effect evaluation, in these92neoadjuvant therapy patients, effective for63cases (68.5%), invalid for29patients (31.5%). The evaluation sensitivity, specificity, positive predictive value, negative predictive value, the correct rate, youden index, the re-evaluation of the kappa value, suggesting that infiltration depth (T stage) is one of the best evaluation. The neoadjuvant treatment may impact neutrophil count, red blood cell count, hemoglobin, platelet count, alanine aminotransferase, serum creatinine, albumin, triglycerides and maximum tumor size. Serum sodium (OR1.252,95%CI1.042-1.505, P=0.016); blood glucose levels (OR0.730,95%CI0.540-0.986, P=0.040) and different parts of the tumor incidence (OR5.490,95%CI1.574-19.149, P=0.008) could impact the effective of neoadjuvant treatment by using binary logistic regression analysis. Cox multivariate analysis indicated that the metastatic lymph node number (RR1.340,95%CI1.058-1.697, P=0.015) may be independent prognostic risk factors of patients with neoadjuvant therapy.
The first part of experimental study:Higher than that of expression of TGOLN2in colorectal cancer, Para neoplastic (P<0.001), the ZNF84no significant difference (P=0.825); of ZNF84the positive expression of the patient's gender (P=0.053), blood pressure (P=0.022).vascular tumor thrombus (P=0.041), logistic regression results suggest that hypertension (OR5.699,95%CI1.428-22.744, P=0.014) may affect ZNF84expression was independently associated factors. Univariate analysis found136patients in accordance with the survival of greater than5year survival of less than2years grouping, patient age (P=0.021), the degree of differentiation of cancer tissue (P<0.001), lymph node metastasis (P <0.001) and distant metastasis (P<0.001) may affect the prognosis; Multivariate analysis showed that the degree of tumor differentiation (OR0.847,95%CI,0008-0.847, P=0.036) and distant metastasis (OR0.033,95%CI0.003-0.352, P=0.005) for prognostic factors independently associated.
The second part of experimental study:IRS-1(P=0.023), TGOLN2(P=0.028) after neoadjuvant therapy in the neoadjuvant therapy before the cancer tissues than ZNF84(P=0.576) and MMP-14(P=0.710) and MMP-9(P=0.151), VEGFC (P=0.779), CTHRC1(P=0.626) protein expression was no significant difference. Univariate analysis, the results suggest that TGOLN2possible with the length of the course (P=0.017), respiratory rate (P=0.012) and CA199(P=0.026); MMP-14may be associated with respiratory rate (P=0.001), neutral granulocyte count (P=0.008); CTHRC1with the red blood cell count (P=0.003), hemoglobin (P=0.048), platelet count (P=0.045), total bilirubin (P=0.004) and glucose (P=0.018); MMP-9may be associated with serum sodium (P=0.036).
Conclusions
In92neoadjuvant therapy patients, the effective one with63cases (68.5%), infiltration depth (T stage) may be the better indicators to evaluate the efficacy of neoadjuvant chemotherapy. Sodium, glucose, and tumor diseased parts may be the three separate factors affecting the efficacy of neoadjuvant chemotherapy. The expression of TGOLN2in colorectal carcinoma was higher than that in adjacent (P<0.001), and the expression of ZNF84had no significant difference (P=0.825). Hypertension may be the independent factors on the positive expression of ZNF84expression. The expression of IRS-1, and TGOLN2before neoadjuvant chemotherapy was higher than that after neoadjuvant therapy, before neoadjuvant chemotherapy was higher than that of neoadjuvant therapy.And it may be used as a reference index to determine the efficacy of neoadjuvant chemotherapy
结直肠癌是最常见的消化系统恶性肿瘤之一,有研究表明其发病率正在逐年上升。新辅助化疗作为综合性治疗最重要的组成部分收到越来越多的关注。虽然对结直肠癌有众多的评价方法,包括广泛采用的实体瘤评价方法RECIST标准,但对结直肠癌而言,却缺乏统一的、有针对性的、行之有效的评价体系及标准。而日益成熟的分子诊断技术为我们提供了一条崭新的道路。若能找到预测新辅助治疗疗效的特异性的分子标志物,将可能对新辅助化疗的疗效评价及治疗产生深远的影响。
目的
临床研究通过对结直肠癌新辅助治疗患者临床病理等资料的分析,探讨新辅助化疗患者的特点、疗效评价、预后及相关因素。实验研究应用免疫组织化学方法,通过单因素和多因素统计分析,探讨TGOLN2和ZNF84在结直肠癌组织的表达情况及其与患者临床病理资料的关系；探讨TGOLN2、ZNF84、MMP-9、MMP-14、VEGFC、CTHRC1、 IRS-1七个蛋白在结直肠癌新辅助化疗病人前后的表达情况及其与患者基线资料和新辅助治疗疗效的关系。
对象与方法
研究纳入2003年1月至2011年6月在中日友好医院住院并符合入选条件的全部结直肠癌患者共1791例。临床研究选取其中行新辅助化疗的患者92例,通过单因素分析、配对T检验、二元非条件Logistic回归分析、Kaplan-Meier法、Cox单因素及多因素回归,探讨新辅助治疗的疗效评价指标及其对患者预后的影响。实验研究第一部分选取其中生存期大于5年或生存期小于2年的患者136例,探讨TGOLN2和ZNF84的表达情况及其与患者临床资料的关系；实验研究第二部分选取可以获得新辅助治疗前后结直肠癌病理标本的患者18例,探讨七个蛋白的在新辅助化疗前后的表达及其与新辅助治疗疗效和患者临床资料的关系。
结果
临床研究的结果提示：行新辅助化疗的患者中,临床表现缓解的占63.0%,血CEA缓解的占13.1%,原发灶大小缓解的占33.6%,浸润深度缓解的占13.0%。综合评价,按照制定的疗效评价标准,在这92例新辅助治疗的患者中,最终结果为有效的患者有63例(占68.5%),无效的为29例(占31.5%)。通过对各项评价指标灵敏度、特异度、阳性预测值、阴性预测值、正确率、约登指数、kappa值的再评价,提示浸润深度(即T分期)是其中最好的评价指标。新辅助化疗会对患者的中性粒细胞计数、红细胞计数、血红蛋白、血小板计数、谷丙转氨酶、血清肌酐、白蛋白、甘油三酯、肿瘤最大径等指标发生影响。二元Logistic回归分析提示影响新辅助化疗有效的指标包括血钠值(OR1.252,95%CI1.042-1.505,P=0.016)；血糖值(OR0.730,95%CI0.540-0.986,P=0.040)和肿瘤发病部位的不同(OR5.490,95%CI1.574-19.149,P=0.008)。Cox多因素分析提示转移淋巴结个数(RR1.340,95%CI1.058-1.697,P=0.015)可能是新辅助治疗患者预后独立的危险因素。
实验研究第一部分的结果提示：TGOLN2在结直肠癌组织中的表达高于癌旁(P<0.001),ZNF84无明显差异(P=0.825)；ZNF84的阳性表达与患者的性别(P=0.053),血压(P=0.022),血管癌栓(P=0.041)有关,Logistic回归结果提示高血压(OR5.699,95%CI1.428-22.744,P=0.014)可能为影响ZNF84表达的独立相关因素。将136例患者按照生存期大于5年或生存期小于2年分组后进行单因素分析发现,患者年龄(P=0.021)、癌组织的分化程度(P<0.001)、淋巴结转移(P<0.001)和远处转移(P<0.001)可能对预后有影响；多因素分析提示肿瘤分化程度(OR0.847、95%CI0008-0.847、P=0.036)和远处转移(OR0.033、95%C10.003-0.352、P=0.005)为影响预后的独立相关因素。
实验研究第二部分的结果提示：IRS-1(P=0.023)、TGOLN2(P=0.028)在新辅助治疗前癌组织的表达大于新辅助治疗后,ZNF84(P=0.576)、MMP-14(P=0.710)、MMP-9(P=0.151)、VEGFC (P=0.779)、CTHRC1(P=0.626)蛋白的表达无明显差异。单因素分析的结果提示,TGOLN2可能与病程的长短(P=0.017)、呼吸次数(P=0.012)以及CA199(P=0.026)相关；MMP-14可能与呼吸次数(P=0.001)、中性粒细胞计数(P=0.008)相关;CTHRC1在与红细胞计数(P=0.003)、血红蛋白(P=0.048)、血小板计数(P=0.045)、总胆红素(P=0.004)和血糖(P=0.018)相关；MMP-9可能与血钠(P=0.036)相关。
结论：92例行新辅助治疗的患者中,评价有效的患者为69例(占75.0%),浸润深度(即T分期)可能是评价新辅助化疗疗效较好的的指标；血钠、血糖和肿瘤发病部位可能是影响新辅助化疗疗效的三个独立相关因素;TGOLN2在结直肠癌组织中的表达高于癌旁(P<0.001),ZNF84无明显差异(P=0.825)；是否合并高血压可能为影响ZNF84阳性表达的独立相关因素；IRS-1和TGOLN2在新辅助化疗前的表达高于新辅助治疗后,可能作为判断新辅助化疗疗效的参考指标。
Background
Colorectal cancer is the most malignant tumors in digestive system. Neoadjuvant chemotherapy has received more and more attention, as a comprehensive treatment of tumors. Although there are so many ways to evaluate colorectal cancer, including RECIST which has widely used, there is lack of evaluation system and standards of colorectal cancer which is unified, targeted, and effective. And the increasing sophisticated molecular diagnostic technique provides us with a new way. If specific molecular markers were found to predict the efficacies of neoadjuvant therapy, it will lead far-reaching effect on evaluation and treatment of neoadjuvant chemotherapy.
Purpose
Clinical research:we analyzed the clinical and pathological data of neoadjuvant therapy patients with colorectal cancer to explore the characteristics, efficacy evaluation, prognosis and the related factors in neoadjuvant chemotherapy patient. Experimental study:We used immunohistochemistry method and statistical analysis to explore the expression of TGOLN2and ZNF84in colorectal cancer and the relationship of clinic pathological data and to explore the expression of TGOLN2, ZNF84, MMP-9, MMP-14, VEGFC, CTHRC1and IRS-1in colorectal cancer of neoadjuvant chemotherapy patients and the relationship between the patients'base data and the effect of neoadjuvant therapy.
Methods
A total of1791colorectal cancer patients, hospitalized in China-Japan Friendship Hospital, in the period of January2003and June2011, were studied. And92patients who used the neoadjuvant chemotherapy were selected in clinical study. Univariate analysis, paired T-test, and binary non-conditional logistic regression analysis, the Kaplan-Meier method, Cox single factor and multivariate regression were used to explore the efficacy evaluation effect of neoadjuvant therapy and the impact on the prognosis of patients. On the first part of the experimental study, a total of136patients, more than the5-year survival of less than2-year old, were selected to explore the expression of TGOLN2and ZNF84and its relationship of the clinical data. The second part of the experimental study, a total of18colorectal cancer patients who can be obtained pathology specimens of before and after neoadjuvant therapy, were chosen to explore the expression of the seven relative proteins on before and after neoadjuvant chemotherapy, and the relationship of the neoadjuvant treatment efficacy and patient clinical data.
Results
Clinical research:The new adjuvant chemotherapy in patients with clinical remission accounted for63%, blood CEA remission for13.1%, primary tumor size in remission for33.6%, the depth of invasion accounted for13%.Overall merit:According to the curative effect evaluation, in these92neoadjuvant therapy patients, effective for63cases (68.5%), invalid for29patients (31.5%). The evaluation sensitivity, specificity, positive predictive value, negative predictive value, the correct rate, youden index, the re-evaluation of the kappa value, suggesting that infiltration depth (T stage) is one of the best evaluation. The neoadjuvant treatment may impact neutrophil count, red blood cell count, hemoglobin, platelet count, alanine aminotransferase, serum creatinine, albumin, triglycerides and maximum tumor size. Serum sodium (OR1.252,95%CI1.042-1.505, P=0.016); blood glucose levels (OR0.730,95%CI0.540-0.986, P=0.040) and different parts of the tumor incidence (OR5.490,95%CI1.574-19.149, P=0.008) could impact the effective of neoadjuvant treatment by using binary logistic regression analysis. Cox multivariate analysis indicated that the metastatic lymph node number (RR1.340,95%CI1.058-1.697, P=0.015) may be independent prognostic risk factors of patients with neoadjuvant therapy.
The first part of experimental study:Higher than that of expression of TGOLN2in colorectal cancer, Para neoplastic (P<0.001), the ZNF84no significant difference (P=0.825); of ZNF84the positive expression of the patient's gender (P=0.053), blood pressure (P=0.022).vascular tumor thrombus (P=0.041), logistic regression results suggest that hypertension (OR5.699,95%CI1.428-22.744, P=0.014) may affect ZNF84expression was independently associated factors. Univariate analysis found136patients in accordance with the survival of greater than5year survival of less than2years grouping, patient age (P=0.021), the degree of differentiation of cancer tissue (P<0.001), lymph node metastasis (P <0.001) and distant metastasis (P<0.001) may affect the prognosis; Multivariate analysis showed that the degree of tumor differentiation (OR0.847,95%CI,0008-0.847, P=0.036) and distant metastasis (OR0.033,95%CI0.003-0.352, P=0.005) for prognostic factors independently associated.
The second part of experimental study:IRS-1(P=0.023), TGOLN2(P=0.028) after neoadjuvant therapy in the neoadjuvant therapy before the cancer tissues than ZNF84(P=0.576) and MMP-14(P=0.710) and MMP-9(P=0.151), VEGFC (P=0.779), CTHRC1(P=0.626) protein expression was no significant difference. Univariate analysis, the results suggest that TGOLN2possible with the length of the course (P=0.017), respiratory rate (P=0.012) and CA199(P=0.026); MMP-14may be associated with respiratory rate (P=0.001), neutral granulocyte count (P=0.008); CTHRC1with the red blood cell count (P=0.003), hemoglobin (P=0.048), platelet count (P=0.045), total bilirubin (P=0.004) and glucose (P=0.018); MMP-9may be associated with serum sodium (P=0.036).
Conclusions
In92neoadjuvant therapy patients, the effective one with63cases (68.5%), infiltration depth (T stage) may be the better indicators to evaluate the efficacy of neoadjuvant chemotherapy. Sodium, glucose, and tumor diseased parts may be the three separate factors affecting the efficacy of neoadjuvant chemotherapy. The expression of TGOLN2in colorectal carcinoma was higher than that in adjacent (P<0.001), and the expression of ZNF84had no significant difference (P=0.825). Hypertension may be the independent factors on the positive expression of ZNF84expression. The expression of IRS-1, and TGOLN2before neoadjuvant chemotherapy was higher than that after neoadjuvant therapy, before neoadjuvant chemotherapy was higher than that of neoadjuvant therapy.And it may be used as a reference index to determine the efficacy of neoadjuvant chemotherapy
引文
[1]Parking DM, Bray F, Ferlay J. Global encer statistics.2002[J]. CA Cancer J Clin,2005, 55(2):74-108
[2]郑树、蔡善荣.中国人大肠癌的流行病学研究[J].中德临床肿瘤学杂志(英文版),2003,2(2)：72-75
[3]曹洋、刘展华、陈志坚.陈锐深教授治疗大肠癌的经验[J].中医药学刊,2005,23(10)：1750-1751
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[8]何立丽.孙桂芝教授治疗大肠癌经验[J],辽宁中医药大：学学报,2009,11(4)：97-99
[9]赵海燕.郭勇教授中西医结合治疗大肠癌的经验[J].中国医药导报,2010,7(10)：138-139
[10]周岱翰.临床中医肿瘤学[M].北京：人民卫生出版社.2004,166-174
[11]任锡祥、周雍明、侯炜.103例大肠癌中西结合治疗疗效分析[J].世界中西医结合杂志,2010,5(8)：703-705
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[24]金哲秀.针灸两步法治疗大肠癌27例临床分析[J].上海中医药杂志,2003,37(5)：4
[25]舒涛、邱剑峰、袁亮等.李国栋运用中药干预大肠癌术后经验介绍[J].中医药信息杂志,2009,16(4)：80-81
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[9]金懋林.消化道恶性肿瘤化学治疗[M].北京：北京大学医学出版社,2007.3
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[12]Barone C,Nuzzo G,Cassano A,et al.Final analysis of colorectal cancer patients treated with irinotecan and 5-fluorouracil plus folinic acid neoadjuvant chemotherapy for unresectable liver Metastases[J]. Br J Cancer,2007,97(8):1035-1039
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[1]Parkin DM, Bray F, Ferlay J. Global encer statisties [J]. Cancer J Clin,2005,55(2): 74-108
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[1]Parkin DM, Bray F, Ferlay J. Global encer statisties [J]. CA Cancer J Clin,2005,55(2): 74-108
[2]ZhengS. Recent study on colorectal cancer in China:early detection and novel related gene[J]. Cahin Med J (Engl),1997,110(4):309-310
[3]Jemal A, Murray T, Samules A, Ghafoor A, Ward E, Thun MJ, Cancer statistics[J]. CA Cancer J Clin,2003,53(1):5-26
[4]Kim IJ, Lim SB, Kang HC, Chang HJ, Ahn SA, Park HW, Jang SG etc. Microarray gene expression profiling for predicting compelet response to preoperative chemoradiotherapy in patients with advanced cancer[J]. Dis Colon Rectum,2007,50(9):1342-1353
[5]Gao C, Wang AY, Han YJ. Microwave antigen retrieval blocks endogenous peroxidase activity in immunohistochemistry[J]. Appl Immunohistochem Mol Morphol,2008,16(4):39
[6]Gao C, Wang AY. Significance of increased apoptosis and Bax expression in human small intestinal adenocarcinoma[J]. J Histochem Cytochem,2009,57(12):48-1139
[7]Gao C, Guo WJ, Wang AY. Significance of decreased apoptosis, role of Bid expression and Bcl-Xl/Bid ratio in human jejunal stromal tumors[J]. APMIS,2012,120(3):81-171
[8]Deschoolmeester V, Baay M, Specenier P, Lardon F, Vermorken JB. A review of the most promising biomarkers in colorectal cancer:one step closer to targeted therapy [J]. Oncologist, 2010,15(7):699-731
[9]Lu AT, Salpeter SR, Reeve AE, Eschrich S, Johnston PG, Barrier AJ, Bertucci F, Buckley NS, Salpeter EE, Lin AY. Gene expression profiles as predictors of poor outcomes in stage Ⅱ colorectal cancer:A systematic review and meta-analysis[J]. Clin Colorectal Cancer,2009, 8(4):207-214
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[11]Theodoropoulos G, W iseWE, Padmanabhan A, T-level down staging and complete pathologic response after p reoperat ive chemorad-iation for advanced rectal cancer result in decreased recurren ce and improved d isease free survival [J]. D is Colon Rectum,2002,45(7): 895-903
[12]John E,N iederbuber MD Neoadjuvant therapy [J]. Ann Surg,2003,229 (3):309-312
[2]郑树、蔡善荣.中国人大肠癌的流行病学研究[J].中德临床肿瘤学杂志(英文版),2003,2(2)：72-75
[3]曹洋、刘展华、陈志坚.陈锐深教授治疗大肠癌的经验[J].中医药学刊,2005,23(10)：1750-1751
[4]王小宁、霍介格.中医治疗大肠癌思路与方法研讨[J].中国中医基础医学杂志,2007,13(9)：681-692
[5]余莉芳、李勇.上海名老中医治疗消化病经验精粹[M].北京：中国中医药出版社,2007,75-90
[6]张宇翔.张东岳教授治疗肛管直肠癌的学术经验[J].中医药管理杂志,2006,14(2)：56-58
[7]陈四清.周仲瑛教授从瘤毒辨治肿瘤经验[J].新中医,2004,36(2)：7-9
[8]何立丽.孙桂芝教授治疗大肠癌经验[J],辽宁中医药大：学学报,2009,11(4)：97-99
[9]赵海燕.郭勇教授中西医结合治疗大肠癌的经验[J].中国医药导报,2010,7(10)：138-139
[10]周岱翰.临床中医肿瘤学[M].北京：人民卫生出版社.2004,166-174
[11]任锡祥、周雍明、侯炜.103例大肠癌中西结合治疗疗效分析[J].世界中西医结合杂志,2010,5(8)：703-705
[12]王晓戎,张宏等.基于现代文献的大肠癌中医证候及病机研究[J].中国中医急症,2009,14(2)：56
[13]Kapiteijn E, PutterH, Van de VeldecJ. Impact of the introduction and training of total mesorectal excision on reculrence and survival in rectal cancer in the NetIlleddand8[J]. Br J surs,2002,89(9):1142-1149
[14]Liang YC, Qing SH, Ding WX, Total mesorectal excision versus conventional radical srgery for rectal cancer:a Meta-analysis [J]. Chin J Gastrointoinl Surg,2007,10(1):43-48.
[15]曾庆华、汤恢焕、李宜雄.鸦胆子油乳剂对大肠癌细胞影响的实验研究[J].中国现代医学杂志,2003,13(15)：19-20
[16]谢鑫灵.陈培丰诊治肠癌临床经验[J].浙江中西医结合杂志.2011,22(3)：146-148
[17]郑玉玲、王新杰.肠达顺灌肠液治疗湿热蕴结型大肠癌的临床研究[J].河南中医,2002,22(1)：12-24
[18]刘树梅.中医治疗肠癌26例疗效观察[J].光明中医.2010,25(9)：1644-1645
[19]刘静安、张悦红.脾肾方治疗大肠癌术后化疗副反应96例总结[J].湖南中医杂志,2000,16(2)：9-10
[20]顾缨,韩颖盈,郑坚等.胃肠安治疗大肠癌临床分析[J].辽宁中医药大学学报,2006,8(5)：5-6
[21]郭志雄.扶正抑癌汤在大肠癌术后治疗中的作用观察[J].中国中西医结合外科杂志,1999,5(1)：10-13
[22]周留勇、尤建良、单珍珠等.中药赵氏微调三号方治疗大肠癌临床与实验研究[J].中华中医药杂志.2009,24(1)：34-37
[23]穆立新、姜军作、范杰华等.针灸治疗大肠癌术后30例疗效观察[J].大连大学学报,2006,27(6)：100-101
[24]金哲秀.针灸两步法治疗大肠癌27例临床分析[J].上海中医药杂志,2003,37(5)：4
[25]舒涛、邱剑峰、袁亮等.李国栋运用中药干预大肠癌术后经验介绍[J].中医药信息杂志,2009,16(4)：80-81
[1]Jemal A.Siegel R. Ward E Cancer statistics[M],2007, (1):30
[2]万德森.结直肠癌流行趋势及其对策[J].癌症,2009,28：897-902
[3]李立.结直肠癌外科应用技术的规范与创新(一)[J].中国普外基础与临床杂志,2006,13(1)：106
[4]季加孚.结直肠癌肝转移的治疗策略[J].中国实用外科杂志,2004,24(7)：398-400
[5]Bengtsson G,Carlsson G,Hafstrom L. Natural history of patients with untreated liver metastases from colorectal cancer[J]. Am J Surg,1981,141:586-589
[6]Scheele J,Altendorf-Hofmann A,Grude T. Resection of colorectal liver Metastases.What prognostic factors determines patient selection? [J]. Chirurg,2001,72(5):547-560
[7]Kato T,Yasui K,Hirai T. Therapeutic results for hepatic Metastasis of colorectal cancer with special reference to effectiveness of hepatectomy:analysis of prognostic factors for 763 cases recorded at 18 institutions[J]. Dis Colon Rectum,2003,46(10):22-31
[8]Scheele J,Stang R,Altendorf-Hofmann A. Resection of colorectal metastases[J]. World J Surg,1995,191:59-71
[9]金懋林.消化道恶性肿瘤化学治疗[M].北京：北京大学医学出版社,2007.3
[10]Harms BA, Gracbow L, Niederbuber JE. Colon and rectum.In:Abeloff MD, Armitage JO, Lichter. Clinical Oncology 2ed. Singapore:Harcourt Asia Churchill Livingstone,2001,1646.
[11]刘朝晖,陈跃宇.低位直肠癌保肛手术现状及进展[J].中国医师进修杂志,2009,32(26)：76-77
[12]Barone C,Nuzzo G,Cassano A,et al.Final analysis of colorectal cancer patients treated with irinotecan and 5-fluorouracil plus folinic acid neoadjuvant chemotherapy for unresectable liver Metastases[J]. Br J Cancer,2007,97(8):1035-1039
[13]Glynne-Jones R,Sebag-Montefiore D, McDonald A.Preliminary phase II SOCRATES study results:capecitabine(CAP) combined with oxaliplatin(OX) and preoperative radiation(RT) in patients(pts) with locally advanced rectal cancer(LARC) [J]. Porc Am Soc Clin Oncol,2004,23:35-75
[14]Saltz LB, Cox JV, Blanke C,et al.Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer Irinotecan Study Group[J]. N Engl J Med,2000,343:905-914.
[15]Douillard JY, Cunningham D, Roth AD, et al.Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer:a multicentre randomised trial [J]. Lancet,2000,355:1041-1047
[16]Fuchs CS, Marshal Jl, Mitchell E,et al.A randomized,controlled trial of irinotecan plus infusional,bolus,or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancenresults from the BICC-C study[J]. J Clin Oncol,2007,25:4779-4786
[17]Nordlinger B, Benoist S.Benefits and risks of neoadjuvant therapy for liver metastases [J]. J Clin Oncol,2006,24(31):4954-4955
[18]Ho WM, Ma B, Mok T. Liver resection after irinotecan,5-fluorouracil, and folinic acid for patients with unresectable colorectal liver metastases:a multicenter phase Ⅱ study by the Cancer Therapeutic Research Group[J]. Med Oncol,2005,22:303-312
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