影像学与检测血清肿瘤标志物诊断早期肺癌的实验研究
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摘要
目的
探讨经气管插管由同轴微导管超选择精确定位,灌注不同剂量的甲基胆蒽(methylcholanthrene, MCA)、二乙基亚硝胺(diethylnitrosamine, DEN)及超液化碘油混悬液,诱导犬肺癌模型,为肺癌深入研究建立新的平台。通过影像学的胸部X线平片、计算机螺旋断层扫描摄像术(spiral computed tomography,螺旋CT)、数字减影血管造影(digital substraction angiography, DSA)检查、血.清肿瘤标志物(tumor maker, TM)检测及病理检查,探讨肺癌发生发展过程中早期的影像学表现,血清肿瘤标志物的改变及病理学表现,从分子生物影像学提出早期肺癌诊断的新标准,使肺癌综合治疗的临床效果产生一个新飞跃。
材料与方法
选用30只犬龄1-3岁,体重15-20Kg的杂种犬为研究对象,雌雄均有。实验前均行疫苗接种,观察数日确定犬仍处于健康状态后随机将30只犬分为A(8只)、B(8只)、C(7只)、D(7只)四组。饲养数日观察实验犬正常,经犬前腿取静脉血3m1,室温下保存0.5-1h,离心取上层血清,进行肿瘤标志物的检测。将犬进行全身麻醉,采用改良式气管插管出同轴微导管精确定位向右肺隔叶灌注致癌药物：A、C组灌注甲基胆葸(MCA)0.25g+二乙基亚硝胺(DEN)0.38g+超液化碘油混悬3m1；B、D组灌注甲基胆葸(MCA)0.35g+二乙基亚硝胺(DEN)0.48g+超液化碘油混悬3m1。分别在第6、12个月对四组实验犬再次进行血清TM检测。同时分别行X线胸片、CT、DSA检查。C、D组实验犬在饲养12月做完上述检查后处死,取注药部位肺组织,加10%中性福尔马林液固定,石蜡包埋(切片厚度5μm)HE染色,根据标本染色情况,选取结构完整标本进行后续染色观察及统计处理。检测四组实验犬不同时期CA125、Cyfra21-1、CEA、SCC-Ag、Cal 53、DR70、NSE 7种血清TM,对所得数据进行统计处理,观察TM指标是否随时间的推移增高。在不同时期对四组实验犬进行CT和DSA支气管动脉造影(Bronchial Arteriography, BAG)检查。实验犬全身麻醉后,先进行CT检查,观察实验犬注药部位是否有可见炎性改变、肿瘤样改变。DSA检查经右侧股动脉穿刺,采用改良式Seldinger技术,行选择性BAG。穿刺成功后,经导丝置入导管鞘和C3导管,在胸主动脉近气管隆突附近以后、右、前、左的顺序寻找支气管动脉开口。当导管头有嵌顿、落空感,不再随心脏搏动而上下移动时,经导管注入少量对比剂,确定导管进入支气管动脉后,行DSA支气管动脉造影。应用高压注射器以每秒2m1的速度注入4m1对比剂,观察支气管动脉造影的表现。是否左右支气管动脉共干,支气管动脉是否增粗、变形,有无肿瘤血管及染色,是否存在其它动脉向注药部位供血。通过仔细观察DSA支气管动脉造影表现,分析在动脉期、实质期(毛细血管期)和静脉期的BAG结果,确定肿瘤的供血动脉来源、形态及肿瘤染色情况。造影结束后,肌注抗菌素预防感染。病理学检查,所有标本行HE染色,通过光镜观察灌注致癌物部位在诱发癌变过程中肺组织病理变化。采用病理图像分析系统对标本HE染色切片进行形态计量与分别计数方法。
结果
1.胸部X线平片：6个月时沉积在犬右肺膈叶的致癌物质混悬液的密度较前变淡,范围缩小,12月时大小范围进一步缩小,未见确切软组织肿块影。
2.螺旋CT平扫：6个月时所有实验犬致癌物混悬液沉积良好,注药部位支气管扩张,管壁增厚,周围可见磨玻璃密度影,邻近胸膜增厚粘连。B组2只实验犬混悬液沉积周边可见多发小叶中心结节。12月时致癌物混悬液大小范围较前缩小,其邻近胸膜仍可见增厚粘连。双肺纹理较前增多,肺野透过度不均,右肺可见多发磨玻璃密度结节影。支气管扩张更加明显,气管壁不规则增厚明显。D组1只实验犬增厚的气管周围可见不规则软组织块状密度影。B、D组各有1只实验犬可见片状肺不张。
3.DSA支气管动脉造影：所有犬支气管动脉均与肋间动脉共干。注药后6个月的支气管动脉管壁光滑,走行自然。动脉早、中、晚三期均未见异常血管及肿瘤染色影。注药后12个月,B、D组各有1只实验犬可见支气管动脉增粗,走行迂曲,并可见肿瘤样血管向右肺致癌物质混悬液灌注部位的不规则肿块供血。肿瘤染色明显,从动脉早期持续到动脉晚期。其余实验犬支气管动脉走行自然,仍未见异常新生血管及肿瘤染色影。
4.TM检测：实验犬A、C组和B、D组的CEA、Cyfra21-1、SCC、CA153、CA125、DR70、NSE7项TM浓度,灌注药物前和第6个月、第12个月,第6个月和第12个月比较,浓度差异显著,具有统计学意义(P<0.05)。A、C和B、D组灌注致癌物质混悬液的浓度不同,两种浓度对以上7种血清TM浓度影响,除Ca153,其余6项差异均无统计学意义(P>0.05)。
5.病理学检查：15只实验犬右肺注药部位及周边可见各种改变。D组形成肿块的实验犬镜下可见大量的不典型增生的细胞巢或细胞团,似“癌巢”,其内可见炎性增生细胞及不典型增生的组织细胞,周边可见出血。部分支气管上皮假复层细胞鳞状化生为柱状上皮细胞。其他实验犬分别可见急慢性肺炎改变、肺气肿改变、纤维组织增生及大量炎症细胞(主要是淋巴细胞、浆细胞和中性粒细胞)浸润。
结论
1.首次联合影像学、血清肿瘤标志物及病理学检查探讨肺癌发生发展过程中的不同表现,提出肺癌早期诊断的新标准,为提高肺癌早期诊断率,提高综合治疗效果建立新的平台。
2.提出犬早期肺癌诊断参考标准：犬CT显示肺脏有磨玻璃样改变及/或软组织肿块,DSA支气管动脉造影显示肿瘤样血管及染色,犬血清TM中Cal 25、CEA、SCC-Ag、Ca153、Cyfra21-1、NSE、DR70升高异常明显,病理学检查有不典型增生等改变时,既使犬胸部平片显示正常也高度提示为早期肺癌。
3.联合检测犬血清Ca125、CEA、SCC-Ag、Ca153、Cyfra21-1、NSE、DR70浓度,测出其正常范围为：Ca125(19.253-19.465μt/m1)、CEA(7.707-27.543ng/1)、SCC-Ag(71.519-109.351pg/m1)、Cal 53(1.397-1.711μ/m1)、Cyfra21-1(0.738-1.7221μg/1)、NSE(175.095-195.425ng/1)、DR70(0.327-0.405μg/1),为进一步深入研究血清TM对犬肺癌早期诊断提供理论依据。
4.提出诱导犬肺癌的最佳致癌物剂量为：0.35g MCA+0.48g DEN+3m1超液化碘油。
Obj iective
To evaluate the precise positioning intubation reperfusion methylcholanthrene (MCA),two diethylnitrosamine(DEN),and lipiodol suspension induced canine model of lung cancer,lung-depth studies provide new platform. Through the inspection X-ray, spiral computed tomograph digital substraction angiography, tumor maker and pathology. To disussion the relation between lung cancer and the method which is combining image science,tumor makers in serum with pathology for lung cancer, it is to find a new way for us to diagnose early lung cancer so that we can improve the clincic outcome of lung cancer.
Material and methods
30 dogs which are half-bred,1-3 years old and 15-20 kg weigh are studied, both male and female. Before we devide them into A(eight dogs),B(eight dogs),C(seven dogs),D(seven dogs) goups in random,we give them vaccination and look after some days so that the dogs are all health.1 month later,we get 3 ml boold from the forelegs of dogs. Then we take blood serum for detecting tumor makers(TM) after boold have been kept in outer at room temperature about 0.5-1 hour. After anaesthetization,tracheal intubation by Coaxial Microcatheter precise positioning leaves to the righr lung perfusion phrenic carcinogenic substances:for go up A,B,methylcholanthrene(MCA) 0.25g + diethylnitrosamine(DEN) 0.38g+ lipiodol suspension 3 ml; for goup C,D, MCA 0.35g+DEN 0.48g+ lipiodol suspension 3 ml. Then we detect the same TMs at 6,12,18 months again. At the same time, we give each goup the X-ray,CT, DSA dynamic observation. We kill the dogs of C,D groups after raised 12 month,get the injection sites tissue, plus 10% neutral formalin-fixed, Paraffin embedded (slice thickness of 5μm) HE staining. We Choose the complete tissue structure for the subsequent observation and statistical processing. CA125、cyfra21-1、CEA、SCC-Ag、Ca153、DR70、NSE 7 have been tested so as to we can find out if they are higher. For CT, we want to observe whether inflammation or tumor change can be found at the lung of dogs. Then we give dogs selective bronchial arteriography (BAG) testing with using modified Seldinger technique, punctured across the right femoral artery under general anesthesia. After the success of puncture, we put the guide wire,catheter sheath and C3 catheter into, then we find the open placement of the bronchial artery near by thoracic aorta. When we find out the bronachila artery, inject 4 ml contrast medium with the speed of 2 ml a second in order to know that if bronchial artery and arteriae intercostals are hemitruncus,or left and right bronchial artery are hemitruncus. At the same time,we also observe the shape of bronchial artery and its size, the tumor and its artery or other artery which take blood to tumor if they can be detected. Then we analyse the outcome which we have receive from digital substraction angiography(DSA). After angiography, we give each dog some antibiotic to guard against infection. At pathology, we stain each tissue with HE staining, so we can observe the pathological changes of the lung tissue which have been injected carcinogen and account the HE section with Pathological
image analysis systems.
Results
1. X-ray:6 month later, the carcingens suspension which is perfused at right lung of dogs is thiner and smaller. They become thiner and smaller than at 6month. There is no orther changes at the lung of dogs in study.
2. CT scan:At 6 month, the carcingens suspension deposit very good and bronchus become dilatation,thickening there. Many glass-shadow can be seen surrounding them and adjacent pleura become thicker and adhesions. There are many centrilobular nodules can been seen at 2 dogs in group B. At 12 month,carcingens suspension is smaller than before and adjacen pleura are still thick and adhesioning. We can see markings at double lung of dogs are more than before and many centrilobular nodules, the degree of lung is not good. bronchus become un-regular and biger. A irregular soft tissue can been seen surround thicker bronchus at a dog in D group, two dogs (one at group B,the other at group D)have atelectasis sheet.
3. DSA:bronchial artery and intercostal arteries of all dogs are from the same trunk. At 6 month,there doesn't any abnormal at lung of dogs. At 12 month, we can find bronchial artery is thicking and running tortuos at 1 dog at each goup of B and D. there are also tumor-like blood vessels transported blood to the irregular tumor which are seen at the position of carcingens suspension at these two dogs. These tumor staining are clear and they are staining from early arterial phase lasted until late arterial. The orther bronchial artery are all normal.
4. TM detection:When we compare the concentration of CEA、Cyfra21-1、SCC、CA153、CA125、DR70、NSE of these four group at the beginning,6month, 12month,they are significant difference and statistically signidicant (P<0.05). the concentration of carcingens suspension perfused to the dogs at group A and C are different with group B and D, but they don't have different effect at the concentration of that seven TM, except Cal 53 (P>0.05)
5. Pathological detection:There are almost no pathological changes in the left of lung of 15 dogs, but in the right lung there can be seen a variety of changes around the injection site. A large number of cell nests of atypical hyperplasia or cell groups can be seen in the right lung of one dog which has tumor in the right lung at group D. These cell nest or group are like "cancer nest", the cells are inflammatory cells and dysplasia cells,with blooding around. A part of pseudostratified bronchial epithelial cells become comlumnar epithelial with a change of squamous metaplasia. We can see some changes like emphysema, fibrosis, acute and chronic pneumonia in orther dogs. A large number of inflammatory cells also can be seen in these dogs, they are main of lymphocytes, plasma cells and neutrophils.
Conclusion
1. Imaging, serum tumor markers and pathological examinations were used to analyze the different manifestations of lung cancer, to find new standard for improving early diagnosis of lung cancer and improving outcome of comprehensive treatment in lung cancer..
2. We first proposed a new reference standarad of early diagnosis of lung cancer:. When CT shows ground-glass-like changes and/or soft tissue mass in lung, DSA bronchial arteriography showed tumor-like blood vessels and staining, serum TM in Ca125, CEA, SCC-Ag, Ca153, Cyfra21-1, NSE, DR70 significantly higher than before, pathological changes had atypical hyperplasia, we can consider the early lung cancer is coming even when the chest film showed normal.
3.7 serotypes TM(Cal25, Cyfra21-1, CEA, SCC-Ag, Ca153, DR70, NSE) had been detected one time and we find out there normal range:Ca125 (19.253-19.465μ/ml), CEA(7.707-27.543ng/1), SCC-Ag (71.519-109.351pg/ml), Ca153(1.397-1.711μ/ml), Cyfra21-1(0.738-1.722μg/l), NSE(175.095-195.425ng/l) DR70 (0.327-0.405u.g/l). It can provide some value in order to study the effect of serum TM in diagnosis of lung cancer further.
4. The best dose of carcinogens for induceding lung cancer at dog is 0.35g MCA, 0.48g DEN and 3 milliliter of lipiodol.
探讨经气管插管由同轴微导管超选择精确定位,灌注不同剂量的甲基胆蒽(methylcholanthrene, MCA)、二乙基亚硝胺(diethylnitrosamine, DEN)及超液化碘油混悬液,诱导犬肺癌模型,为肺癌深入研究建立新的平台。通过影像学的胸部X线平片、计算机螺旋断层扫描摄像术(spiral computed tomography,螺旋CT)、数字减影血管造影(digital substraction angiography, DSA)检查、血.清肿瘤标志物(tumor maker, TM)检测及病理检查,探讨肺癌发生发展过程中早期的影像学表现,血清肿瘤标志物的改变及病理学表现,从分子生物影像学提出早期肺癌诊断的新标准,使肺癌综合治疗的临床效果产生一个新飞跃。
材料与方法
选用30只犬龄1-3岁,体重15-20Kg的杂种犬为研究对象,雌雄均有。实验前均行疫苗接种,观察数日确定犬仍处于健康状态后随机将30只犬分为A(8只)、B(8只)、C(7只)、D(7只)四组。饲养数日观察实验犬正常,经犬前腿取静脉血3m1,室温下保存0.5-1h,离心取上层血清,进行肿瘤标志物的检测。将犬进行全身麻醉,采用改良式气管插管出同轴微导管精确定位向右肺隔叶灌注致癌药物：A、C组灌注甲基胆葸(MCA)0.25g+二乙基亚硝胺(DEN)0.38g+超液化碘油混悬3m1；B、D组灌注甲基胆葸(MCA)0.35g+二乙基亚硝胺(DEN)0.48g+超液化碘油混悬3m1。分别在第6、12个月对四组实验犬再次进行血清TM检测。同时分别行X线胸片、CT、DSA检查。C、D组实验犬在饲养12月做完上述检查后处死,取注药部位肺组织,加10%中性福尔马林液固定,石蜡包埋(切片厚度5μm)HE染色,根据标本染色情况,选取结构完整标本进行后续染色观察及统计处理。检测四组实验犬不同时期CA125、Cyfra21-1、CEA、SCC-Ag、Cal 53、DR70、NSE 7种血清TM,对所得数据进行统计处理,观察TM指标是否随时间的推移增高。在不同时期对四组实验犬进行CT和DSA支气管动脉造影(Bronchial Arteriography, BAG)检查。实验犬全身麻醉后,先进行CT检查,观察实验犬注药部位是否有可见炎性改变、肿瘤样改变。DSA检查经右侧股动脉穿刺,采用改良式Seldinger技术,行选择性BAG。穿刺成功后,经导丝置入导管鞘和C3导管,在胸主动脉近气管隆突附近以后、右、前、左的顺序寻找支气管动脉开口。当导管头有嵌顿、落空感,不再随心脏搏动而上下移动时,经导管注入少量对比剂,确定导管进入支气管动脉后,行DSA支气管动脉造影。应用高压注射器以每秒2m1的速度注入4m1对比剂,观察支气管动脉造影的表现。是否左右支气管动脉共干,支气管动脉是否增粗、变形,有无肿瘤血管及染色,是否存在其它动脉向注药部位供血。通过仔细观察DSA支气管动脉造影表现,分析在动脉期、实质期(毛细血管期)和静脉期的BAG结果,确定肿瘤的供血动脉来源、形态及肿瘤染色情况。造影结束后,肌注抗菌素预防感染。病理学检查,所有标本行HE染色,通过光镜观察灌注致癌物部位在诱发癌变过程中肺组织病理变化。采用病理图像分析系统对标本HE染色切片进行形态计量与分别计数方法。
结果
1.胸部X线平片：6个月时沉积在犬右肺膈叶的致癌物质混悬液的密度较前变淡,范围缩小,12月时大小范围进一步缩小,未见确切软组织肿块影。
2.螺旋CT平扫：6个月时所有实验犬致癌物混悬液沉积良好,注药部位支气管扩张,管壁增厚,周围可见磨玻璃密度影,邻近胸膜增厚粘连。B组2只实验犬混悬液沉积周边可见多发小叶中心结节。12月时致癌物混悬液大小范围较前缩小,其邻近胸膜仍可见增厚粘连。双肺纹理较前增多,肺野透过度不均,右肺可见多发磨玻璃密度结节影。支气管扩张更加明显,气管壁不规则增厚明显。D组1只实验犬增厚的气管周围可见不规则软组织块状密度影。B、D组各有1只实验犬可见片状肺不张。
3.DSA支气管动脉造影：所有犬支气管动脉均与肋间动脉共干。注药后6个月的支气管动脉管壁光滑,走行自然。动脉早、中、晚三期均未见异常血管及肿瘤染色影。注药后12个月,B、D组各有1只实验犬可见支气管动脉增粗,走行迂曲,并可见肿瘤样血管向右肺致癌物质混悬液灌注部位的不规则肿块供血。肿瘤染色明显,从动脉早期持续到动脉晚期。其余实验犬支气管动脉走行自然,仍未见异常新生血管及肿瘤染色影。
4.TM检测：实验犬A、C组和B、D组的CEA、Cyfra21-1、SCC、CA153、CA125、DR70、NSE7项TM浓度,灌注药物前和第6个月、第12个月,第6个月和第12个月比较,浓度差异显著,具有统计学意义(P<0.05)。A、C和B、D组灌注致癌物质混悬液的浓度不同,两种浓度对以上7种血清TM浓度影响,除Ca153,其余6项差异均无统计学意义(P>0.05)。
5.病理学检查：15只实验犬右肺注药部位及周边可见各种改变。D组形成肿块的实验犬镜下可见大量的不典型增生的细胞巢或细胞团,似“癌巢”,其内可见炎性增生细胞及不典型增生的组织细胞,周边可见出血。部分支气管上皮假复层细胞鳞状化生为柱状上皮细胞。其他实验犬分别可见急慢性肺炎改变、肺气肿改变、纤维组织增生及大量炎症细胞(主要是淋巴细胞、浆细胞和中性粒细胞)浸润。
结论
1.首次联合影像学、血清肿瘤标志物及病理学检查探讨肺癌发生发展过程中的不同表现,提出肺癌早期诊断的新标准,为提高肺癌早期诊断率,提高综合治疗效果建立新的平台。
2.提出犬早期肺癌诊断参考标准：犬CT显示肺脏有磨玻璃样改变及/或软组织肿块,DSA支气管动脉造影显示肿瘤样血管及染色,犬血清TM中Cal 25、CEA、SCC-Ag、Ca153、Cyfra21-1、NSE、DR70升高异常明显,病理学检查有不典型增生等改变时,既使犬胸部平片显示正常也高度提示为早期肺癌。
3.联合检测犬血清Ca125、CEA、SCC-Ag、Ca153、Cyfra21-1、NSE、DR70浓度,测出其正常范围为：Ca125(19.253-19.465μt/m1)、CEA(7.707-27.543ng/1)、SCC-Ag(71.519-109.351pg/m1)、Cal 53(1.397-1.711μ/m1)、Cyfra21-1(0.738-1.7221μg/1)、NSE(175.095-195.425ng/1)、DR70(0.327-0.405μg/1),为进一步深入研究血清TM对犬肺癌早期诊断提供理论依据。
4.提出诱导犬肺癌的最佳致癌物剂量为：0.35g MCA+0.48g DEN+3m1超液化碘油。
Obj iective
To evaluate the precise positioning intubation reperfusion methylcholanthrene (MCA),two diethylnitrosamine(DEN),and lipiodol suspension induced canine model of lung cancer,lung-depth studies provide new platform. Through the inspection X-ray, spiral computed tomograph digital substraction angiography, tumor maker and pathology. To disussion the relation between lung cancer and the method which is combining image science,tumor makers in serum with pathology for lung cancer, it is to find a new way for us to diagnose early lung cancer so that we can improve the clincic outcome of lung cancer.
Material and methods
30 dogs which are half-bred,1-3 years old and 15-20 kg weigh are studied, both male and female. Before we devide them into A(eight dogs),B(eight dogs),C(seven dogs),D(seven dogs) goups in random,we give them vaccination and look after some days so that the dogs are all health.1 month later,we get 3 ml boold from the forelegs of dogs. Then we take blood serum for detecting tumor makers(TM) after boold have been kept in outer at room temperature about 0.5-1 hour. After anaesthetization,tracheal intubation by Coaxial Microcatheter precise positioning leaves to the righr lung perfusion phrenic carcinogenic substances:for go up A,B,methylcholanthrene(MCA) 0.25g + diethylnitrosamine(DEN) 0.38g+ lipiodol suspension 3 ml; for goup C,D, MCA 0.35g+DEN 0.48g+ lipiodol suspension 3 ml. Then we detect the same TMs at 6,12,18 months again. At the same time, we give each goup the X-ray,CT, DSA dynamic observation. We kill the dogs of C,D groups after raised 12 month,get the injection sites tissue, plus 10% neutral formalin-fixed, Paraffin embedded (slice thickness of 5μm) HE staining. We Choose the complete tissue structure for the subsequent observation and statistical processing. CA125、cyfra21-1、CEA、SCC-Ag、Ca153、DR70、NSE 7 have been tested so as to we can find out if they are higher. For CT, we want to observe whether inflammation or tumor change can be found at the lung of dogs. Then we give dogs selective bronchial arteriography (BAG) testing with using modified Seldinger technique, punctured across the right femoral artery under general anesthesia. After the success of puncture, we put the guide wire,catheter sheath and C3 catheter into, then we find the open placement of the bronchial artery near by thoracic aorta. When we find out the bronachila artery, inject 4 ml contrast medium with the speed of 2 ml a second in order to know that if bronchial artery and arteriae intercostals are hemitruncus,or left and right bronchial artery are hemitruncus. At the same time,we also observe the shape of bronchial artery and its size, the tumor and its artery or other artery which take blood to tumor if they can be detected. Then we analyse the outcome which we have receive from digital substraction angiography(DSA). After angiography, we give each dog some antibiotic to guard against infection. At pathology, we stain each tissue with HE staining, so we can observe the pathological changes of the lung tissue which have been injected carcinogen and account the HE section with Pathological
image analysis systems.
Results
1. X-ray:6 month later, the carcingens suspension which is perfused at right lung of dogs is thiner and smaller. They become thiner and smaller than at 6month. There is no orther changes at the lung of dogs in study.
2. CT scan:At 6 month, the carcingens suspension deposit very good and bronchus become dilatation,thickening there. Many glass-shadow can be seen surrounding them and adjacent pleura become thicker and adhesions. There are many centrilobular nodules can been seen at 2 dogs in group B. At 12 month,carcingens suspension is smaller than before and adjacen pleura are still thick and adhesioning. We can see markings at double lung of dogs are more than before and many centrilobular nodules, the degree of lung is not good. bronchus become un-regular and biger. A irregular soft tissue can been seen surround thicker bronchus at a dog in D group, two dogs (one at group B,the other at group D)have atelectasis sheet.
3. DSA:bronchial artery and intercostal arteries of all dogs are from the same trunk. At 6 month,there doesn't any abnormal at lung of dogs. At 12 month, we can find bronchial artery is thicking and running tortuos at 1 dog at each goup of B and D. there are also tumor-like blood vessels transported blood to the irregular tumor which are seen at the position of carcingens suspension at these two dogs. These tumor staining are clear and they are staining from early arterial phase lasted until late arterial. The orther bronchial artery are all normal.
4. TM detection:When we compare the concentration of CEA、Cyfra21-1、SCC、CA153、CA125、DR70、NSE of these four group at the beginning,6month, 12month,they are significant difference and statistically signidicant (P<0.05). the concentration of carcingens suspension perfused to the dogs at group A and C are different with group B and D, but they don't have different effect at the concentration of that seven TM, except Cal 53 (P>0.05)
5. Pathological detection:There are almost no pathological changes in the left of lung of 15 dogs, but in the right lung there can be seen a variety of changes around the injection site. A large number of cell nests of atypical hyperplasia or cell groups can be seen in the right lung of one dog which has tumor in the right lung at group D. These cell nest or group are like "cancer nest", the cells are inflammatory cells and dysplasia cells,with blooding around. A part of pseudostratified bronchial epithelial cells become comlumnar epithelial with a change of squamous metaplasia. We can see some changes like emphysema, fibrosis, acute and chronic pneumonia in orther dogs. A large number of inflammatory cells also can be seen in these dogs, they are main of lymphocytes, plasma cells and neutrophils.
Conclusion
1. Imaging, serum tumor markers and pathological examinations were used to analyze the different manifestations of lung cancer, to find new standard for improving early diagnosis of lung cancer and improving outcome of comprehensive treatment in lung cancer..
2. We first proposed a new reference standarad of early diagnosis of lung cancer:. When CT shows ground-glass-like changes and/or soft tissue mass in lung, DSA bronchial arteriography showed tumor-like blood vessels and staining, serum TM in Ca125, CEA, SCC-Ag, Ca153, Cyfra21-1, NSE, DR70 significantly higher than before, pathological changes had atypical hyperplasia, we can consider the early lung cancer is coming even when the chest film showed normal.
3.7 serotypes TM(Cal25, Cyfra21-1, CEA, SCC-Ag, Ca153, DR70, NSE) had been detected one time and we find out there normal range:Ca125 (19.253-19.465μ/ml), CEA(7.707-27.543ng/1), SCC-Ag (71.519-109.351pg/ml), Ca153(1.397-1.711μ/ml), Cyfra21-1(0.738-1.722μg/l), NSE(175.095-195.425ng/l) DR70 (0.327-0.405u.g/l). It can provide some value in order to study the effect of serum TM in diagnosis of lung cancer further.
4. The best dose of carcinogens for induceding lung cancer at dog is 0.35g MCA, 0.48g DEN and 3 milliliter of lipiodol.
引文
[1]Mollberg N, Surati M, Demchuk C, Mind-mapping for lung cancer:Towards a personalized therapeutics approach[J]. Adv Ther.2011,28(3):173-194.
[2]Anthony J. Alberg, Jean G. et al. Epidemiology of Lung Cancer* ACCP Evidence-Based Clinical Practice Guidelines(2nd Edition)[J]. Chest 2007,132:29S-55S
[3]Langer C, Li S, Schiller J.et al. Randomized phase II trail of paclitaxel plus carboplatin or gemcitabine plus cisplatin Eastern Cooperative Oncology Group performance status 2 non-small cell lung cancer patients [J]. J Clin Oncol.2007,Feb 1,25(4):418-423.
[4]Lauer MS, Murthy SC, Blackstone EH, et al. Fluorodeoxyglucose uptake by positron emission tomography for diagnosis of suspectec lung cancer:impact of verification bias. Arch Intern Med.2007, Jan,22,167(2):161-165.
[5]Robert L. Keith. Chemoprevention of Lung Cancer[J]. Proc Am Thorac Soc, 2009,6:187-193
[6]Boylel P, Chapman CJ, Holdenrieder S. et al. Clinical validation of an autoantibody test for lungcancer[J]. Annals of Oncology,2011,22:383-389,.
[7]Lynch T.J, Adjei AA, Bunn PA Jr, et al. Summary statement:novel agents in the treatment of lung cancer:advances in epidermal growth factor receptor targeted agents[J]. Clin Cancer Res 2006;12:4365s-4371s.
[8]Caballero OL, Cohen D, Liu Q, et al. Loss of chromosome arms 3p and 9p and inactivation of PI 6 (INK4a) in normal ep ithelium of patients with primary lung cancer[J]. Genes Chromosomes Cancer,2006,32(2):119-125.
[9]刘勇,曹喜才,杨海贤等.犬肺癌模型的制作研究[J].中华实验外科学杂志,2003,20(suppl)：121-122.
[]0]曹喜才,刘勇,徐乃勋等.犬肺癌模型制作与支气管动脉造影[J].中华放射学杂志,2003,37(10)：877-881.
[11]Poon TC, Johnson PJ. Proteome analysis and its impact on the discovery of serological tumor markers [J]. Clin Chim Aeta,2001,313(1-2):231-239.
[12]Nawata S, Sugino N, Kato H. Squamous cell carcinomaantigen [J]. Nippon Rinsho,2005,63(Suppl8):684-686.
[13]Oremek GM, Sauer-eppel H, Bruzdziak TH. Value of tumour and imq-ammatory markers in lung cancer[J]. Anticancer Res,2007,27(4A): 1911-1915.
[14]Chi-Shing Cho W. Potentially useful biomarkers for the diagnosis treatment and prognosis of lung cancer[J]. Biom Pharm,2007,61(9):515-519.
[15]Pavicevic R, Bubanovic G, Franjevic A, et al. CYFRA21-1 in non-small cell lung cancer-standardisation and application during diagnosis[J]. Coll Antropol,2008,32(2):485-498.
[16]Green Lee RT, Marray T, Bolden S, et al. Cancer Statistics[J]. CA Cancer J. Clin,2000,50:7-9.
[17]Sone S, Li F, Yang ZG, et al. Results of three-year mass screening programme for lung cancer using mobile low-dose spiral computed tomographys canner[J]. Br. J. Cancer,2001,84:25-32.
[18]Lee J, Aronchick JM, Alavi A. Accuracy of F-18 flurodeoxyglucose po-sitron emission tomography for the evaluation of malignancy in patients presenting with new lung abnormalities:a ret rospective review[J]. Chest,2001,120(6): 1791-1797.
[19]Demura Y, Tsuchida T, Ishizaki T, et al.18 F-FDG accumulation with PET for differentiation between benign and malignant lesions in the thorax [J]. J Nucl Med,2003,44(4):540-548.
[20]Marom EM, Sarvis S, Herndon JE, et al. T1 lung cancers:sensitivity of diagnosis with fluorodeocyglucose PET[J]. Radiology,2002,223(2):453-459.
[21]Guilbaud N, Kraus-Berthier L, Meyer-Losic F, et al. New approaches in experimental cancerology:in search of therapeutic model s[J]. Bull Cancer. 2001 Jan;88(1):75-84.
[22]Schneider P, Kampfer S, Loddenkemper C, et al. Chemoembolization of the lung improves tumor control in a rat model[J]. Clin Cancer Res.2002 Jul;8(7):2463-2468.
[23]Nobel TA, Perk K. Bronchiolo-alveolar cell carcinoma. Animal model: pulmonary adenomatosis of sheep, pulmonary carcinoma of sheep, pulmonary carcinoma of sheep (Jaagsiekte)[J]. Am J Pathol.1978 Mar;90(3):783-786.
[24]Milne EN, Zerhouni EA. Blood supply of pulmonary metastases[J]. J Thorac Imaging.1987 Oct;2(4):15-23.
[25]Vincent C. Daniel, Luigi Marchionni, Jared S. Hierman, et al. A Primary Xenograft Model of Small-Cell Lung Cancer Reveals Irreversible Chang-es in Gene Expression Imposed by Culture In vitro [J].Cancer Res 2009; 69:3364-3373.
[26]Ping Yang, Mark S. Allen, Marie C. Aubry. et al. Clinical Features of 5,628 Primary Lung Cancer Patients Experience at Mayo Clinic From 1997 to 2003[J]. Chest 2005;128;452-462.
[27]Nobel TA, Perk K, Bronchiolo-alveolar cell carcinoma Animal model: pulmonary adenomatosis of sheep,pulmonary carcinoma of sheep (Jaagsiekte)[J]. Am J Pathol,1978,90:783-786.
[28]Griffiths DJ, Martineau HM, Cousens C. Pathology and pathogenesis of ovine pulmonary adenocarcinoma[J]. J Comp Pathol.2010 May; 142(4):260-83.
[29]Enchev S.Bronchoalveolar cancer or pulmonary adenomatosis (Jaagsiekte) of sheep. Neoplasma.1970; 17(4):415-25.
[30]师路,刘伦旭.医学影像学在肺癌筛查和早期诊断中的应用进展[J].华西医学,2008,23(14)：932-933.
[31]Soda H, Tomita H, Kohno S, et al. Limitation of annual screening chest radiography for the diagnosis of lung cancer. A retrospective study [J]. Cancer, 1993,72(8):2341-2346.
[32]Zhang S, Chen W, Wang W, et al. The best scan parameters for low dose CT scan in early lung cancer screening[J]. Zhongguo Yi Liao Qi Xie Za Zhi. 2010,34(6):421-423.
[33]Hensehke CI, Yankelevitz DF, Libby DM, et al. Survival of patients with stage I lung cancer detected on CT screening[J]. N Engl J Med,2006,355: 1763-1771.
[34]Stefan D, Dag W, Didderich S, et al. Screening for Early Lung Cancer with Low-Dose Spiral CT:Prevalence in 817 Asymptomatic Smokers[J]. Radiology,2002,222 (3):773-781.
[35]Funami Y。 Okuyama K. Shimada Y, et al. Anatomic study of the bronchial arteries wllh special reference to their preservation during the radical dissection of the uppermediastinum lymph nodes [J]. Surgery,1996,119(1): 67-75.
[36]Marshall TJ, Jackson JE. Vascular intervention in the thorax:bronchial artery embolization for hemoptysis [J]. European Radiology,1997,7:1221-1227.
[37]Me Lean RH, Parandian BB, Nam MH. Pericardial tamponade:an unusual complication of lobeetomy for lung cancer[J]. Ann Thorac sury,1999,67(2): 545-546.
[38]单鸿,主编.临床介入诊疗学[M].广州：广东科技出版社,1997.77-86.
[39]Viamonte M. Angiographic evaluation of lung neoplasms [J]. Radio] Clin North Am,1965,3(3):529-542.
[40]Milne EN,Circulation of primary and metastatic pulmonary neoplasma apostmorem microarteriographic study [J]. AJR,1967,100(26):603-619.
[41]董伟华,肖湘生,李惠民,等.支气管动脉和肺动脉多层螺旋CT血管造影对肺癌血供的研究[J].中华放射学杂志,2003,37(7)：612-614.
[42]Pavicevic R, Bubanovic G, Franjevic A, et al. CYFRA21-1 in non-small cell lung cancer-standardisation and application during diagnosis [J]. Coll Antropol,2008,32(2):485-498.
[43]Ruibal A, Nunez M I, Rodrguez 1, et al. Cytosolic levels of neu ronspecific enolase in squamous cell carcinomas of the lung [J]. In J Biol Markers,2003, 18(3):188-194.
[44]Li CS, Cheng BC, Ge W, et al. Clinical value of CYFRA21-1, NSE, CA15-3, CA19-9 and CA125 assay in the elderly patients with pleura] effusions[J]. Int J Clin Pract.2007,61(3):444-448.
[45]Shltrit D, Zingennan B, Shitrit AB, et al. Diagnostic value of CYFRA21-1, CEA, CA19-9, CA15-3 and CA125 assays in pleural effusions:analysis of 116 cases and review of the literature[J]. Onclogist,2005,10(7):501-507.
[1]吴在德,吴肇汉主编.外科学.第6版.北京：人民卫生出版社,2003,356
[2]李玉林主编.病理学.第6版.北京：人民卫生出版社,2004,183
[3]张波,钟理.肺癌肿瘤标志物筛选的进展[J].河北医药,2008,30(12)：1958-1960
[4]Ruibal A, Nunez M I, Rodrguez J, et al. Cytosolic levels of neu-ronspecific enolase in squamous cell carcinomas of the lung [J]. In J Biol Markers,2003, 18(3):188-194.
[5]黄芳,王小莉,杨莲,等.胸水和血清中CEA、CYFRA21-1、TPS联合检测对良恶性胸水及肺癌的诊断价值[J].细胞与分子免疫学杂志,2008,24(4)：370-372
[6]吴勤如,何凤屏,何惠玲,等.血清癌胚抗原、细胞角蛋白19片段、神经元特异性烯醇化酶联合检测对肺癌的诊断价值[J].国际检验医学杂志,2009,30(7)：627-629
[7]Buccheri G, Ferrigno D. Identifying patients at risk of early postoperative recurrence of lung cancer:a new use of the old CEA test[J]. Ann ThomC surg, 2003,75(3):973-980.
[8]Mizuguchi S, Nishiyama N, Lwata T, etal. Clinical value of serum cytokeratin 19 fragment and sialyl-lewis x in non-small cell lung cancer[J]. Ann Thorac Surg,2007,83(1):216-221.
[9]Buccheri G, Torchio P, Ferrigno D. Clinical equivalence of two Cytokertin markers in non small cell lung cancer:a study of tissue poly peptide antigen and cytokeratin 19 fragments [J]. Chest, 2003,124(2):622626.
[10]Pavicevic R, Bubanovic G, Franjevic A, et al. CYFRA21-1 in non-small cell lung cancer-standardisation and application during diagnosis[J]. Coll Antropol,2008,32(2):485-498.
[11]杨昊,张帆,赵理.血清肿瘤标志物联合检测对肺癌的诊断价值[J].医学临床研究,2009,26(12),2316-2321.
[12]Lai R S,Chen C C,Lee P C,etal.Evaluation of cytokeration 19 fragment(CYFRA 21-1) as a tumaor marker in malignant pleural effusion [J].Jpn J Clinoncol,2003,29(9):421-423
[13]Seemann M D, Einerl T, Furst H, etal. An evaluation of the tumor Markers,carcinoembryonic antigen(CEA), cytokeratin marker(C YF-RA21-1) and neuron-specific enolase(NSE) in the differe-ntiation of malignant from benign solitary pulmonary lesions[J]. Lung Cancer,1999,26(3):149.
[14]任丽芬,陈名声,张志平,等.神经元特异性烯醇化酶对小细胞肺癌诊断的临床价值[J].现代肿瘤医学,2009,17(12)：2335-2337.
[15]Plebani M, Basso D. Clinical evalution of,seven tumor market in lung cancer diagnosis:Can any combination impove the results[J].Bri J Cancer,2005,72 (1):170-173.
[16]杨静.血.清NSE和CEA含量及其比值对小细胞肺癌的诊断价值[J].广东医学,2010,31(14)：1834-1835.
[17]Petrovic M,Tomic I,Plavec G,etal. Neuron specific enolase tissue expressiun as a prognostic factor in advanced non-small cell lung cancer[J]. J Buon,2008,13(1):93-96.
[18]Nunez GR, Ito C, Del Giglio A. Increased serum CA125 levels in patients with lung cancer post thoracotomy[J]. South MedJ,2009,102(4):427—428
[19]毛正道,韦国桢,殷小伟.探讨肿瘤标记物CY211、NSE、CEA及CAl25在肺癌诊断中的意义[J].实用临床医药杂志.2010,14(3)：18-21.
[20]Diez M, Torres A, Pollan M, et al. Prognostic significance Of serum CA125 antigen assay in patients with non-small cell lung cancer[J]. Cane2er.2003,73:1368.
[21]Kagohashi K,Satoh H,Kurishima K,et al. Squamous cell carcinom a antigen in lung cancer and nonmalignant respiratory diseases [J]. Lung,2008,186(5): 323—326.
[22]周扬,高静,贾兴旺,向荣,等.鳞癌相关抗原在鳞癌及相关I良性疾病中的临床意义[J].标记免疫分析与临床,2010,17(3)：137-140.
[23]Nishi N, Miyazaki M, Tsuji K, el al. Squamous cell carcinoma related antigen(SCC-Ag)in children with acute asthma[J]. Ann Allergy Asthma Immunol,2005,94:391-397
[24]Shltrit D, Zingennan B, Shitrit AB, et al. Diagnostic value of CYFRA21-1, CEA, CA19-9, CA15-3, and CA125 assays in pleural effusi-ons.-analysis of 116 cases and review of the literature [J]. Onclogist.2005,10(7):501-507.
[25]温丹萍,肖东,殷伟强,等.血清CEA、CA125及CA153联合检测对肺癌诊断临床价值的探讨[J].临床和实验医学杂志,2010,9(7)：490-491.
[26]Porcel JM,Vives M,Esquerda A,et al.Use of a panel tumor markers (carcinoembryonic antigen,cancer antigen 125,carbohydrate antigen 15-3,and cytokeratin 19fragments) in pleural fluid for the differdential diagnosis of benign and malignant effusions[J]. Chest,2004,126 (6):1757-1763.
[27]Lee JH,Chang JH,Diagnostic utility of serum and pleural fluid car-cinoembryonic antigen, neuron-specific enolase,and cytokeratin 19 fragments in patients with effusions from primary lung cancer.Chest,2005,128(4): 2298-2303.
[28]Szekaneez E,Szucs G,Szekaneez z,etal. Tumor-associated Antigens in Systemic Sclerosis and Systemic Lupus Erythematosus Associa- tions with Organ Manifestations, Immunolaboratory Markers and Disease Activity Indices[J]. J Autoimmun,2008,31(4):372-376.
[29]Justice G,Guerrero R,Rounds D,et al.Ring Shaped Particle:A new tumor marker more accurate than either CA153 or CEA for monitoring breast cancer. ASCO Proc,1992,11(1):124—131.
[30]WuD, Zhou X, Yang G, et al. Clinical performance of the AMDL DR-70TM immunoassay kit for cancer detection[J].J 1998.19(1):63-72.
[31]李启英.血清DR-70对肺癌诊断的临床意义[J].四川肿瘤防治,2000,13(2)：79-80
[32]Lei Min,Junwei,Cao,Zhi Qiao,等. Application of DR-70TM and CA50 Immunoassay for Lung Cancer[J]. Amino Acids & biotic Resources 2002, 24(2):69～70.
[33]Kopfstein L,Veikkola T, Djonov VG, et al. Distinc roles of vascular endothelial growth factor-D in lymphangiogenesis and metastasis [J]. Am J Pathol,2007,174(4):1348-1350.
[34]Tamura M, Ohta Y, Nakamura H, et al. Diagnostic value of plasma vascular endothelial growth factor as a tumor marker in patients with non-small cell lungcancer[J]. Int J Biol Markers,2002,17(4):275-297.
[35]Saglam D A,Ursavas A, Karadg M, et al. The evaluation to relationship between serum vascular endothelial growth factot(VEGF)level met-astases and other tumor markers in patients with lung cancer [J]. Tuberk Toraks, 2008,56(1):50-55.
[36]Stefaoup D, Coussia AC, Arkoumani E, et al. Expression of vascular endothelial growth factor and the adhesion molecule E cadherin in nonsmall cell lung cancer[J]. Antieaneer Res,2003,23:4715—4720.
[37]Weryflska B, Kosacka M, Golecki M, et al. VEGF in the cancer anorexia—cachexia syndrome in patients with lung cancer[J]. Pneumonol Alergol pol,2006,74(2):186-190.
[38]Shingyoji M,Ando S,Nishimura H,et al.VEGF in patients with no- n-small cell lung cancer during combination chemotherapy of car- boplatin and paclitaxel[J].Anticancer Res,2009,29(7):2635—2639.
[39]Roskoski R.J. Vascular endothelial growth factor(VEGF) signaling in tumor progression [J]. Crit Rev Oneol Hematol,2007,62(3):179-182.
[40]林志国VEGF、COX-2和NF-KB在非小细胞肺癌中的表达及其意义.齐齐哈尔医学院学报[J1].2010,31(11)：1695-1697.
[2]Anthony J. Alberg, Jean G. et al. Epidemiology of Lung Cancer* ACCP Evidence-Based Clinical Practice Guidelines(2nd Edition)[J]. Chest 2007,132:29S-55S
[3]Langer C, Li S, Schiller J.et al. Randomized phase II trail of paclitaxel plus carboplatin or gemcitabine plus cisplatin Eastern Cooperative Oncology Group performance status 2 non-small cell lung cancer patients [J]. J Clin Oncol.2007,Feb 1,25(4):418-423.
[4]Lauer MS, Murthy SC, Blackstone EH, et al. Fluorodeoxyglucose uptake by positron emission tomography for diagnosis of suspectec lung cancer:impact of verification bias. Arch Intern Med.2007, Jan,22,167(2):161-165.
[5]Robert L. Keith. Chemoprevention of Lung Cancer[J]. Proc Am Thorac Soc, 2009,6:187-193
[6]Boylel P, Chapman CJ, Holdenrieder S. et al. Clinical validation of an autoantibody test for lungcancer[J]. Annals of Oncology,2011,22:383-389,.
[7]Lynch T.J, Adjei AA, Bunn PA Jr, et al. Summary statement:novel agents in the treatment of lung cancer:advances in epidermal growth factor receptor targeted agents[J]. Clin Cancer Res 2006;12:4365s-4371s.
[8]Caballero OL, Cohen D, Liu Q, et al. Loss of chromosome arms 3p and 9p and inactivation of PI 6 (INK4a) in normal ep ithelium of patients with primary lung cancer[J]. Genes Chromosomes Cancer,2006,32(2):119-125.
[9]刘勇,曹喜才,杨海贤等.犬肺癌模型的制作研究[J].中华实验外科学杂志,2003,20(suppl)：121-122.
[]0]曹喜才,刘勇,徐乃勋等.犬肺癌模型制作与支气管动脉造影[J].中华放射学杂志,2003,37(10)：877-881.
[11]Poon TC, Johnson PJ. Proteome analysis and its impact on the discovery of serological tumor markers [J]. Clin Chim Aeta,2001,313(1-2):231-239.
[12]Nawata S, Sugino N, Kato H. Squamous cell carcinomaantigen [J]. Nippon Rinsho,2005,63(Suppl8):684-686.
[13]Oremek GM, Sauer-eppel H, Bruzdziak TH. Value of tumour and imq-ammatory markers in lung cancer[J]. Anticancer Res,2007,27(4A): 1911-1915.
[14]Chi-Shing Cho W. Potentially useful biomarkers for the diagnosis treatment and prognosis of lung cancer[J]. Biom Pharm,2007,61(9):515-519.
[15]Pavicevic R, Bubanovic G, Franjevic A, et al. CYFRA21-1 in non-small cell lung cancer-standardisation and application during diagnosis[J]. Coll Antropol,2008,32(2):485-498.
[16]Green Lee RT, Marray T, Bolden S, et al. Cancer Statistics[J]. CA Cancer J. Clin,2000,50:7-9.
[17]Sone S, Li F, Yang ZG, et al. Results of three-year mass screening programme for lung cancer using mobile low-dose spiral computed tomographys canner[J]. Br. J. Cancer,2001,84:25-32.
[18]Lee J, Aronchick JM, Alavi A. Accuracy of F-18 flurodeoxyglucose po-sitron emission tomography for the evaluation of malignancy in patients presenting with new lung abnormalities:a ret rospective review[J]. Chest,2001,120(6): 1791-1797.
[19]Demura Y, Tsuchida T, Ishizaki T, et al.18 F-FDG accumulation with PET for differentiation between benign and malignant lesions in the thorax [J]. J Nucl Med,2003,44(4):540-548.
[20]Marom EM, Sarvis S, Herndon JE, et al. T1 lung cancers:sensitivity of diagnosis with fluorodeocyglucose PET[J]. Radiology,2002,223(2):453-459.
[21]Guilbaud N, Kraus-Berthier L, Meyer-Losic F, et al. New approaches in experimental cancerology:in search of therapeutic model s[J]. Bull Cancer. 2001 Jan;88(1):75-84.
[22]Schneider P, Kampfer S, Loddenkemper C, et al. Chemoembolization of the lung improves tumor control in a rat model[J]. Clin Cancer Res.2002 Jul;8(7):2463-2468.
[23]Nobel TA, Perk K. Bronchiolo-alveolar cell carcinoma. Animal model: pulmonary adenomatosis of sheep, pulmonary carcinoma of sheep, pulmonary carcinoma of sheep (Jaagsiekte)[J]. Am J Pathol.1978 Mar;90(3):783-786.
[24]Milne EN, Zerhouni EA. Blood supply of pulmonary metastases[J]. J Thorac Imaging.1987 Oct;2(4):15-23.
[25]Vincent C. Daniel, Luigi Marchionni, Jared S. Hierman, et al. A Primary Xenograft Model of Small-Cell Lung Cancer Reveals Irreversible Chang-es in Gene Expression Imposed by Culture In vitro [J].Cancer Res 2009; 69:3364-3373.
[26]Ping Yang, Mark S. Allen, Marie C. Aubry. et al. Clinical Features of 5,628 Primary Lung Cancer Patients Experience at Mayo Clinic From 1997 to 2003[J]. Chest 2005;128;452-462.
[27]Nobel TA, Perk K, Bronchiolo-alveolar cell carcinoma Animal model: pulmonary adenomatosis of sheep,pulmonary carcinoma of sheep (Jaagsiekte)[J]. Am J Pathol,1978,90:783-786.
[28]Griffiths DJ, Martineau HM, Cousens C. Pathology and pathogenesis of ovine pulmonary adenocarcinoma[J]. J Comp Pathol.2010 May; 142(4):260-83.
[29]Enchev S.Bronchoalveolar cancer or pulmonary adenomatosis (Jaagsiekte) of sheep. Neoplasma.1970; 17(4):415-25.
[30]师路,刘伦旭.医学影像学在肺癌筛查和早期诊断中的应用进展[J].华西医学,2008,23(14)：932-933.
[31]Soda H, Tomita H, Kohno S, et al. Limitation of annual screening chest radiography for the diagnosis of lung cancer. A retrospective study [J]. Cancer, 1993,72(8):2341-2346.
[32]Zhang S, Chen W, Wang W, et al. The best scan parameters for low dose CT scan in early lung cancer screening[J]. Zhongguo Yi Liao Qi Xie Za Zhi. 2010,34(6):421-423.
[33]Hensehke CI, Yankelevitz DF, Libby DM, et al. Survival of patients with stage I lung cancer detected on CT screening[J]. N Engl J Med,2006,355: 1763-1771.
[34]Stefan D, Dag W, Didderich S, et al. Screening for Early Lung Cancer with Low-Dose Spiral CT:Prevalence in 817 Asymptomatic Smokers[J]. Radiology,2002,222 (3):773-781.
[35]Funami Y。 Okuyama K. Shimada Y, et al. Anatomic study of the bronchial arteries wllh special reference to their preservation during the radical dissection of the uppermediastinum lymph nodes [J]. Surgery,1996,119(1): 67-75.
[36]Marshall TJ, Jackson JE. Vascular intervention in the thorax:bronchial artery embolization for hemoptysis [J]. European Radiology,1997,7:1221-1227.
[37]Me Lean RH, Parandian BB, Nam MH. Pericardial tamponade:an unusual complication of lobeetomy for lung cancer[J]. Ann Thorac sury,1999,67(2): 545-546.
[38]单鸿,主编.临床介入诊疗学[M].广州：广东科技出版社,1997.77-86.
[39]Viamonte M. Angiographic evaluation of lung neoplasms [J]. Radio] Clin North Am,1965,3(3):529-542.
[40]Milne EN,Circulation of primary and metastatic pulmonary neoplasma apostmorem microarteriographic study [J]. AJR,1967,100(26):603-619.
[41]董伟华,肖湘生,李惠民,等.支气管动脉和肺动脉多层螺旋CT血管造影对肺癌血供的研究[J].中华放射学杂志,2003,37(7)：612-614.
[42]Pavicevic R, Bubanovic G, Franjevic A, et al. CYFRA21-1 in non-small cell lung cancer-standardisation and application during diagnosis [J]. Coll Antropol,2008,32(2):485-498.
[43]Ruibal A, Nunez M I, Rodrguez 1, et al. Cytosolic levels of neu ronspecific enolase in squamous cell carcinomas of the lung [J]. In J Biol Markers,2003, 18(3):188-194.
[44]Li CS, Cheng BC, Ge W, et al. Clinical value of CYFRA21-1, NSE, CA15-3, CA19-9 and CA125 assay in the elderly patients with pleura] effusions[J]. Int J Clin Pract.2007,61(3):444-448.
[45]Shltrit D, Zingennan B, Shitrit AB, et al. Diagnostic value of CYFRA21-1, CEA, CA19-9, CA15-3 and CA125 assays in pleural effusions:analysis of 116 cases and review of the literature[J]. Onclogist,2005,10(7):501-507.
[1]吴在德,吴肇汉主编.外科学.第6版.北京：人民卫生出版社,2003,356
[2]李玉林主编.病理学.第6版.北京：人民卫生出版社,2004,183
[3]张波,钟理.肺癌肿瘤标志物筛选的进展[J].河北医药,2008,30(12)：1958-1960
[4]Ruibal A, Nunez M I, Rodrguez J, et al. Cytosolic levels of neu-ronspecific enolase in squamous cell carcinomas of the lung [J]. In J Biol Markers,2003, 18(3):188-194.
[5]黄芳,王小莉,杨莲,等.胸水和血清中CEA、CYFRA21-1、TPS联合检测对良恶性胸水及肺癌的诊断价值[J].细胞与分子免疫学杂志,2008,24(4)：370-372
[6]吴勤如,何凤屏,何惠玲,等.血清癌胚抗原、细胞角蛋白19片段、神经元特异性烯醇化酶联合检测对肺癌的诊断价值[J].国际检验医学杂志,2009,30(7)：627-629
[7]Buccheri G, Ferrigno D. Identifying patients at risk of early postoperative recurrence of lung cancer:a new use of the old CEA test[J]. Ann ThomC surg, 2003,75(3):973-980.
[8]Mizuguchi S, Nishiyama N, Lwata T, etal. Clinical value of serum cytokeratin 19 fragment and sialyl-lewis x in non-small cell lung cancer[J]. Ann Thorac Surg,2007,83(1):216-221.
[9]Buccheri G, Torchio P, Ferrigno D. Clinical equivalence of two Cytokertin markers in non small cell lung cancer:a study of tissue poly peptide antigen and cytokeratin 19 fragments [J]. Chest, 2003,124(2):622626.
[10]Pavicevic R, Bubanovic G, Franjevic A, et al. CYFRA21-1 in non-small cell lung cancer-standardisation and application during diagnosis[J]. Coll Antropol,2008,32(2):485-498.
[11]杨昊,张帆,赵理.血清肿瘤标志物联合检测对肺癌的诊断价值[J].医学临床研究,2009,26(12),2316-2321.
[12]Lai R S,Chen C C,Lee P C,etal.Evaluation of cytokeration 19 fragment(CYFRA 21-1) as a tumaor marker in malignant pleural effusion [J].Jpn J Clinoncol,2003,29(9):421-423
[13]Seemann M D, Einerl T, Furst H, etal. An evaluation of the tumor Markers,carcinoembryonic antigen(CEA), cytokeratin marker(C YF-RA21-1) and neuron-specific enolase(NSE) in the differe-ntiation of malignant from benign solitary pulmonary lesions[J]. Lung Cancer,1999,26(3):149.
[14]任丽芬,陈名声,张志平,等.神经元特异性烯醇化酶对小细胞肺癌诊断的临床价值[J].现代肿瘤医学,2009,17(12)：2335-2337.
[15]Plebani M, Basso D. Clinical evalution of,seven tumor market in lung cancer diagnosis:Can any combination impove the results[J].Bri J Cancer,2005,72 (1):170-173.
[16]杨静.血.清NSE和CEA含量及其比值对小细胞肺癌的诊断价值[J].广东医学,2010,31(14)：1834-1835.
[17]Petrovic M,Tomic I,Plavec G,etal. Neuron specific enolase tissue expressiun as a prognostic factor in advanced non-small cell lung cancer[J]. J Buon,2008,13(1):93-96.
[18]Nunez GR, Ito C, Del Giglio A. Increased serum CA125 levels in patients with lung cancer post thoracotomy[J]. South MedJ,2009,102(4):427—428
[19]毛正道,韦国桢,殷小伟.探讨肿瘤标记物CY211、NSE、CEA及CAl25在肺癌诊断中的意义[J].实用临床医药杂志.2010,14(3)：18-21.
[20]Diez M, Torres A, Pollan M, et al. Prognostic significance Of serum CA125 antigen assay in patients with non-small cell lung cancer[J]. Cane2er.2003,73:1368.
[21]Kagohashi K,Satoh H,Kurishima K,et al. Squamous cell carcinom a antigen in lung cancer and nonmalignant respiratory diseases [J]. Lung,2008,186(5): 323—326.
[22]周扬,高静,贾兴旺,向荣,等.鳞癌相关抗原在鳞癌及相关I良性疾病中的临床意义[J].标记免疫分析与临床,2010,17(3)：137-140.
[23]Nishi N, Miyazaki M, Tsuji K, el al. Squamous cell carcinoma related antigen(SCC-Ag)in children with acute asthma[J]. Ann Allergy Asthma Immunol,2005,94:391-397
[24]Shltrit D, Zingennan B, Shitrit AB, et al. Diagnostic value of CYFRA21-1, CEA, CA19-9, CA15-3, and CA125 assays in pleural effusi-ons.-analysis of 116 cases and review of the literature [J]. Onclogist.2005,10(7):501-507.
[25]温丹萍,肖东,殷伟强,等.血清CEA、CA125及CA153联合检测对肺癌诊断临床价值的探讨[J].临床和实验医学杂志,2010,9(7)：490-491.
[26]Porcel JM,Vives M,Esquerda A,et al.Use of a panel tumor markers (carcinoembryonic antigen,cancer antigen 125,carbohydrate antigen 15-3,and cytokeratin 19fragments) in pleural fluid for the differdential diagnosis of benign and malignant effusions[J]. Chest,2004,126 (6):1757-1763.
[27]Lee JH,Chang JH,Diagnostic utility of serum and pleural fluid car-cinoembryonic antigen, neuron-specific enolase,and cytokeratin 19 fragments in patients with effusions from primary lung cancer.Chest,2005,128(4): 2298-2303.
[28]Szekaneez E,Szucs G,Szekaneez z,etal. Tumor-associated Antigens in Systemic Sclerosis and Systemic Lupus Erythematosus Associa- tions with Organ Manifestations, Immunolaboratory Markers and Disease Activity Indices[J]. J Autoimmun,2008,31(4):372-376.
[29]Justice G,Guerrero R,Rounds D,et al.Ring Shaped Particle:A new tumor marker more accurate than either CA153 or CEA for monitoring breast cancer. ASCO Proc,1992,11(1):124—131.
[30]WuD, Zhou X, Yang G, et al. Clinical performance of the AMDL DR-70TM immunoassay kit for cancer detection[J].J 1998.19(1):63-72.
[31]李启英.血清DR-70对肺癌诊断的临床意义[J].四川肿瘤防治,2000,13(2)：79-80
[32]Lei Min,Junwei,Cao,Zhi Qiao,等. Application of DR-70TM and CA50 Immunoassay for Lung Cancer[J]. Amino Acids & biotic Resources 2002, 24(2):69～70.
[33]Kopfstein L,Veikkola T, Djonov VG, et al. Distinc roles of vascular endothelial growth factor-D in lymphangiogenesis and metastasis [J]. Am J Pathol,2007,174(4):1348-1350.
[34]Tamura M, Ohta Y, Nakamura H, et al. Diagnostic value of plasma vascular endothelial growth factor as a tumor marker in patients with non-small cell lungcancer[J]. Int J Biol Markers,2002,17(4):275-297.
[35]Saglam D A,Ursavas A, Karadg M, et al. The evaluation to relationship between serum vascular endothelial growth factot(VEGF)level met-astases and other tumor markers in patients with lung cancer [J]. Tuberk Toraks, 2008,56(1):50-55.
[36]Stefaoup D, Coussia AC, Arkoumani E, et al. Expression of vascular endothelial growth factor and the adhesion molecule E cadherin in nonsmall cell lung cancer[J]. Antieaneer Res,2003,23:4715—4720.
[37]Weryflska B, Kosacka M, Golecki M, et al. VEGF in the cancer anorexia—cachexia syndrome in patients with lung cancer[J]. Pneumonol Alergol pol,2006,74(2):186-190.
[38]Shingyoji M,Ando S,Nishimura H,et al.VEGF in patients with no- n-small cell lung cancer during combination chemotherapy of car- boplatin and paclitaxel[J].Anticancer Res,2009,29(7):2635—2639.
[39]Roskoski R.J. Vascular endothelial growth factor(VEGF) signaling in tumor progression [J]. Crit Rev Oneol Hematol,2007,62(3):179-182.
[40]林志国VEGF、COX-2和NF-KB在非小细胞肺癌中的表达及其意义.齐齐哈尔医学院学报[J1].2010,31(11)：1695-1697.