健脾益肾解毒法防治胃癌复发转移作用及对凋亡信号传导的调控机制
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摘要
胃癌(gastric cancer)是威胁人类生命健康常见的恶性肿瘤之一,手术后复发转移是导致治疗失败的一个重要因素,如何减少或防止复发转移,提高生存质量,延长生存期,是目前胃癌研究领域中最迫切的课题。导师孙桂芝教授是工作在中西医结合防治肿瘤战线著名的专家,特别是在治疗以胃癌为主的消化系统肿瘤方面有其独到之处,近40年治疗肿瘤患者达50余万人次。本论文在对胃癌及肿瘤转移认识的历代大量文献梳理基础上,对导师防治胃癌复发转移方面的临床经验,用现代科学手段进行了深入挖掘,并以615小鼠前胃癌术后复发转移模型为载体,采用流式细胞技术(FCM)、TUNEL、AV-PI、Realtime RT-PCR、免疫组化(IHC)等技术,从整体-细胞-基因分子-信号传导等层次,深入探讨了健脾益肾解毒法防治胃癌术后复发转移的分子机制,从一个侧面揭示了中医药防治胃癌术后复发转移理论依据和导师临床治验的科学内涵。
一、理论研究
1 历代医家著述对后世胃癌及肿瘤转移中医治疗学具有指导意义
通过祖国医学对胃癌及肿瘤转移的认识历代文献梳理,可以看出,中医对这类病证的认识分为五个时期,(1)春秋战国以前为萌芽时期,此时虽没有具体到对于胃癌及转移的认识,但对于相关病证已有初步的认识。(2)春秋战国至东汉末年,为初步形成时期,对于胃癌相关的症状,病因与发病,诊治与预后的有了一定的认识。(3)晋、隋、唐是研究与发展时期,关于胃癌相关病证的体征上有了更深一步的描述,治疗上出现了更多的方法。(4)宋金元是充实时期,这个时期产生了诸多医学流派,也产生了很多学术观点,充实了胃癌相关病症认识。(5)明、清是一个系统与初步完善时期,出现了许多关于前人观点的系统记载的著作,不论是在理论上,还是临床运用上都达到了系统与初步完善的程度。充分挖掘祖国医学文献这一宝库,并以此为切入点,探讨现代中医胃癌转移辨证论治规律并指导临床实践,将对当代胃癌转移中医治疗学的发展具有重要意义。
2 导师孙桂芝教授防治胃癌复发转移学术经验
导师根据治病求本、扶正祛邪的指导思想,结合胃癌术后患者“本虚标实”的证候特点,(1)倡导以健脾益肾解毒为主的治疗大法,遣方用药攻补兼施;(2)
Gastric cancer is one of the common malignant tumors which threaten the life and health in our country. The postoperative recurrence and metastasis is an important factor that endangers seriously the life. How to decrease or avoid the recurrence and metastasis, and improve the quality of life, and prolong the life span, which is currently the most imminent topic on the research domain of gastric cancer. Advisor Sun Gui-zhi is one of the distinguished experts who are active on the oncoma forefront of combination of TCM with Western medicine. She has a unique approach on treating the oncoma of digestive system, especially being expert in gastric cancer. In recent 40 years, the tumor patients who she treated have reached more than 500 thousands. On the basis of combing a great deal of the ancient TCM literature relating to gastric cancer and tumor metastasis, advisor's clinical experience of the prevention and treatment gastric cancer were digged thoroughly by the modern scientific theory and technology. Meanwhile, the recurrence and metastasis of the 615 murine with forestomach carcinoma (FC) afer amputation (AMP) was adopted as animal model. And the techniques which flow cytometry (FCM)、 TUNEL、 AV-PI、 Realtime RT-PCR、 immunohistochemistry (IHC) were applied to detect the lab indexes. From the different layers of whole—cell—gene and molecule—signal conduction etc., to explore extremely the molecular mechanism of JianPi YiShen & JieDu therapy prevented and treated the postoperative recurrence and metastasis of gastric cancer. From one aspect, the reach brought to light the scientific content of which were the theories of TCM and the clinical experience of the renowned expert.Part I : Theoretical studies1. The ancient TCM literature has the far-reaching historical significance on TCM
therapeutics of gastric cancer and tumor metastasis.On the basis of combing a great deal of the ancient TCM literature relating to gastric cancer and tumor metastasis, the recognition of TCM on such species disease and syndrome was divide into five period: (1) It was the sprouting period that before the Spring & Autumn Period and Warring States Period. (2) It was the initial form period that from the Spring & Autumn Period and Warring States Period to the late years of the Eastern Han Dynasty. (3) It was the investigation and development period that the Jin, Sui and Tang Dynasties. (4) It was the substantial period that from the Song Dynasty to the Jin and Yuan Dynasties. (5) It was the system and initial consummate period that the Ming and Qing Dynasties.2. Academic experience of advisor on the prevention and treatment the postoperative recurrence and metastasis of gastric cancerAccording to therapeutic principles of "concentrating treatment on the root cause" and "strengthening healthy Qi and eliminating pathogenic factors", and to combine together the syndrome characteristic of "deficiency of root and excess of branch" of which gastric cancer postoperative patients. (1) To advocate major therapeutic method mainly to JianPi YiShen & JieDu therapy. This therapy means to strengthen healthy qi and to eliminate pathogenic factors simultaneously. (2) The diagnose takes differentiation of disease as first, and the treatment regard differentiation of syndrome as principal. (3) To raise the principle of prevention and the principle of treatment were laid equally stress on. Through a long period of taking medicine, the curative effect was consolidated. (4) At the same time, to emphasize the importance of adjusting the food and the mental state.Part II: Clinical studies1. The clinical study of medicine and syndrome on advisor's prevention and treatment the recurrence and metastasis of gastric cancerTo make use of the bioinformation data mining (DM), and to take advisor's prescription and medicine as the clues, 351 pieces of the primitive prescription were carried out to analyze from multi-angles. Regularities were summarized as follow: (1) Gastric cancer was divided into six basic syndromes by Syndrome differentiation and treatment. Six elementary formulae were used commonly and respectively. They were "Decoction of four Noble Drugs", "Minor Decoction of Relieving Stuffiness in the Chest", "Pulse-activating Powder and Gypsum Decoction", "Tangerine Peel and Bamboo shaving Decoction", "Decoction of Three Kinds of Kernels", and
"Bupleurum Powder for Relieving Liver-Qi". (2) There are 214 pieces of drug in all prescriptions. According to frequency distribution, to sum up 23 pieces of drug were used the most frequently. (3) According to the drug property theory of traditional Chinese medicine, the majority drug properties were the warm and the neutral in nature. In addition to, bitter cold drug were second. (4) According to functional classification of drugs, it was the first place that a kind of the tonification drug in 61 pieces of drug which were seen the most frequently. It was the second place that a kind of the drug for heat-clearing and detoxicating and a kind of the drug for invigorating blood circulation and eliminating stasis and a kind of the drug for regulating QI flow. (5) It is the quintessence of medication that the use of a couple of drugs. (6) Not only syndrome differentiation and treatment based on TCM theory but also treatment based on differentiation of disease, furthermore, to integrate the progress of TCM on modern pharmacology research, the advisor pay attention to the multitude effects of a drug in clinical practice.2. Influence of JianPi YiShen & JieDu therapy on the quality of life(QOL) in postoperative patients of the progression gastric cancerThe study aim was to assess of the clinical efficacy of treatment for JianPi YiShen & JieDu therapy and its effect on QOL in postoperative patients of the progression gastric cancer. EORTC QLQ—C30(Chinese version 3.0) is a developed questionnaire, which was adopted to assess the effect of which prior-treatment and post-treatment of QOL in postoperative patients of the progression gastric cancer. 46 patients who had been treated for three to six months were investigated. The questionnaire consists of seven functioning scales (physical, role, emotional, cognitive, social, symptom and financial impact), and the global quality of life scale. Improvement of QOL was not only the global quality of life scale but also multi-functioning scales, and especially there were the significant improvement on several scales of physical, role, emotional, social and symptom. Furthermore, by principal component analysis (PCA), above several scales belong to the first principal component of the questionnaire. The study showed postoperative patients of the progression gastric cancer must gain profit from long-term TCM treatment of JianPi YiShen & JieDu therapy. Chinese medicine therapy was essential in an ideal project of combined therapy of cancerPart HI: Experimental studies1. To establish a patient-like animal models of the recurrence and metastasis of
the 615 murine with FC afer AMP.2. JianPi YiShen & JieDu Formula (JYJF) could inhibit the regional recurrence and pulmonary metastasis (PM) of the 615 murine with FC afer AMP(recurrence tumor inhibition ratio is 63.11% and PM inhibition ratio is 27.8%). The level of recurrence and metastasis were controlled obviously, and QOL was raised and life span was prolonged (life prolong ratio is 94.44%).3. By the application of different testing apoptosis methods, it was confirmed that the key mechanism of action on JYJF which of the prevention and treatment postoperative recurrence and metastasis of gastric cancer which is to alter the apoptotic sensitivity of both T lymphocytes and tumor cells.4. Through to elevate T lymphocytic reproductive activity, JYJF can degrade T lymphocytic apoptotic activity. The Fas expression in T lymphocyte was lower, and the FasL expression in which was elevated. Thereby, JYJF can sublimate immunization surveillance capability and reduce tumour cell immune escape. The analysis of proliferation and apoptosis of T lymphocyte might play an important role on overall assessment cellular immunity of organism.5. Signal conduction disturbance of apoptosis that is one of key mechanisms of the recurrence and metastasis of tumor. JYJF induced apoptosis involved in Fas death receptor -mediated apoptotic pathway and mitochondria-mediated apoptotic pathway. JYJF induced effector caspase-3 activation and apoptosis through coaction of both apoptotic pathways.6. The possible molecular mechanism of JYJF involved in that the expression levels of Fas protein and its mRNA of tumor tissue were increased, and the expression levels of FasL protein and its mRNA were decreased, accordingly up-regulated initiator caspase-8 activation. Meanwhile, the expression levels of Bax protein and its mRNA were increased, and the ratio of Bcl-2/Bax was decreased, accordingly the expression levels of Bcl-2 protein and its mRNA were attenuated and apoptosis was inhibited. In addition to, it was observed that both the mitochondria membrane potential (Av|/m) of tumor cell and PH value of inside cell were decreased. Mitochondria-mediated apoptotic pathway enlarged efficiently apoptotic signal. These increased an experiment basis for multi-target point effect of compound recipe on TCM.
一、理论研究
1 历代医家著述对后世胃癌及肿瘤转移中医治疗学具有指导意义
通过祖国医学对胃癌及肿瘤转移的认识历代文献梳理,可以看出,中医对这类病证的认识分为五个时期,(1)春秋战国以前为萌芽时期,此时虽没有具体到对于胃癌及转移的认识,但对于相关病证已有初步的认识。(2)春秋战国至东汉末年,为初步形成时期,对于胃癌相关的症状,病因与发病,诊治与预后的有了一定的认识。(3)晋、隋、唐是研究与发展时期,关于胃癌相关病证的体征上有了更深一步的描述,治疗上出现了更多的方法。(4)宋金元是充实时期,这个时期产生了诸多医学流派,也产生了很多学术观点,充实了胃癌相关病症认识。(5)明、清是一个系统与初步完善时期,出现了许多关于前人观点的系统记载的著作,不论是在理论上,还是临床运用上都达到了系统与初步完善的程度。充分挖掘祖国医学文献这一宝库,并以此为切入点,探讨现代中医胃癌转移辨证论治规律并指导临床实践,将对当代胃癌转移中医治疗学的发展具有重要意义。
2 导师孙桂芝教授防治胃癌复发转移学术经验
导师根据治病求本、扶正祛邪的指导思想,结合胃癌术后患者“本虚标实”的证候特点,(1)倡导以健脾益肾解毒为主的治疗大法,遣方用药攻补兼施;(2)
Gastric cancer is one of the common malignant tumors which threaten the life and health in our country. The postoperative recurrence and metastasis is an important factor that endangers seriously the life. How to decrease or avoid the recurrence and metastasis, and improve the quality of life, and prolong the life span, which is currently the most imminent topic on the research domain of gastric cancer. Advisor Sun Gui-zhi is one of the distinguished experts who are active on the oncoma forefront of combination of TCM with Western medicine. She has a unique approach on treating the oncoma of digestive system, especially being expert in gastric cancer. In recent 40 years, the tumor patients who she treated have reached more than 500 thousands. On the basis of combing a great deal of the ancient TCM literature relating to gastric cancer and tumor metastasis, advisor's clinical experience of the prevention and treatment gastric cancer were digged thoroughly by the modern scientific theory and technology. Meanwhile, the recurrence and metastasis of the 615 murine with forestomach carcinoma (FC) afer amputation (AMP) was adopted as animal model. And the techniques which flow cytometry (FCM)、 TUNEL、 AV-PI、 Realtime RT-PCR、 immunohistochemistry (IHC) were applied to detect the lab indexes. From the different layers of whole—cell—gene and molecule—signal conduction etc., to explore extremely the molecular mechanism of JianPi YiShen & JieDu therapy prevented and treated the postoperative recurrence and metastasis of gastric cancer. From one aspect, the reach brought to light the scientific content of which were the theories of TCM and the clinical experience of the renowned expert.Part I : Theoretical studies1. The ancient TCM literature has the far-reaching historical significance on TCM
therapeutics of gastric cancer and tumor metastasis.On the basis of combing a great deal of the ancient TCM literature relating to gastric cancer and tumor metastasis, the recognition of TCM on such species disease and syndrome was divide into five period: (1) It was the sprouting period that before the Spring & Autumn Period and Warring States Period. (2) It was the initial form period that from the Spring & Autumn Period and Warring States Period to the late years of the Eastern Han Dynasty. (3) It was the investigation and development period that the Jin, Sui and Tang Dynasties. (4) It was the substantial period that from the Song Dynasty to the Jin and Yuan Dynasties. (5) It was the system and initial consummate period that the Ming and Qing Dynasties.2. Academic experience of advisor on the prevention and treatment the postoperative recurrence and metastasis of gastric cancerAccording to therapeutic principles of "concentrating treatment on the root cause" and "strengthening healthy Qi and eliminating pathogenic factors", and to combine together the syndrome characteristic of "deficiency of root and excess of branch" of which gastric cancer postoperative patients. (1) To advocate major therapeutic method mainly to JianPi YiShen & JieDu therapy. This therapy means to strengthen healthy qi and to eliminate pathogenic factors simultaneously. (2) The diagnose takes differentiation of disease as first, and the treatment regard differentiation of syndrome as principal. (3) To raise the principle of prevention and the principle of treatment were laid equally stress on. Through a long period of taking medicine, the curative effect was consolidated. (4) At the same time, to emphasize the importance of adjusting the food and the mental state.Part II: Clinical studies1. The clinical study of medicine and syndrome on advisor's prevention and treatment the recurrence and metastasis of gastric cancerTo make use of the bioinformation data mining (DM), and to take advisor's prescription and medicine as the clues, 351 pieces of the primitive prescription were carried out to analyze from multi-angles. Regularities were summarized as follow: (1) Gastric cancer was divided into six basic syndromes by Syndrome differentiation and treatment. Six elementary formulae were used commonly and respectively. They were "Decoction of four Noble Drugs", "Minor Decoction of Relieving Stuffiness in the Chest", "Pulse-activating Powder and Gypsum Decoction", "Tangerine Peel and Bamboo shaving Decoction", "Decoction of Three Kinds of Kernels", and
"Bupleurum Powder for Relieving Liver-Qi". (2) There are 214 pieces of drug in all prescriptions. According to frequency distribution, to sum up 23 pieces of drug were used the most frequently. (3) According to the drug property theory of traditional Chinese medicine, the majority drug properties were the warm and the neutral in nature. In addition to, bitter cold drug were second. (4) According to functional classification of drugs, it was the first place that a kind of the tonification drug in 61 pieces of drug which were seen the most frequently. It was the second place that a kind of the drug for heat-clearing and detoxicating and a kind of the drug for invigorating blood circulation and eliminating stasis and a kind of the drug for regulating QI flow. (5) It is the quintessence of medication that the use of a couple of drugs. (6) Not only syndrome differentiation and treatment based on TCM theory but also treatment based on differentiation of disease, furthermore, to integrate the progress of TCM on modern pharmacology research, the advisor pay attention to the multitude effects of a drug in clinical practice.2. Influence of JianPi YiShen & JieDu therapy on the quality of life(QOL) in postoperative patients of the progression gastric cancerThe study aim was to assess of the clinical efficacy of treatment for JianPi YiShen & JieDu therapy and its effect on QOL in postoperative patients of the progression gastric cancer. EORTC QLQ—C30(Chinese version 3.0) is a developed questionnaire, which was adopted to assess the effect of which prior-treatment and post-treatment of QOL in postoperative patients of the progression gastric cancer. 46 patients who had been treated for three to six months were investigated. The questionnaire consists of seven functioning scales (physical, role, emotional, cognitive, social, symptom and financial impact), and the global quality of life scale. Improvement of QOL was not only the global quality of life scale but also multi-functioning scales, and especially there were the significant improvement on several scales of physical, role, emotional, social and symptom. Furthermore, by principal component analysis (PCA), above several scales belong to the first principal component of the questionnaire. The study showed postoperative patients of the progression gastric cancer must gain profit from long-term TCM treatment of JianPi YiShen & JieDu therapy. Chinese medicine therapy was essential in an ideal project of combined therapy of cancerPart HI: Experimental studies1. To establish a patient-like animal models of the recurrence and metastasis of
the 615 murine with FC afer AMP.2. JianPi YiShen & JieDu Formula (JYJF) could inhibit the regional recurrence and pulmonary metastasis (PM) of the 615 murine with FC afer AMP(recurrence tumor inhibition ratio is 63.11% and PM inhibition ratio is 27.8%). The level of recurrence and metastasis were controlled obviously, and QOL was raised and life span was prolonged (life prolong ratio is 94.44%).3. By the application of different testing apoptosis methods, it was confirmed that the key mechanism of action on JYJF which of the prevention and treatment postoperative recurrence and metastasis of gastric cancer which is to alter the apoptotic sensitivity of both T lymphocytes and tumor cells.4. Through to elevate T lymphocytic reproductive activity, JYJF can degrade T lymphocytic apoptotic activity. The Fas expression in T lymphocyte was lower, and the FasL expression in which was elevated. Thereby, JYJF can sublimate immunization surveillance capability and reduce tumour cell immune escape. The analysis of proliferation and apoptosis of T lymphocyte might play an important role on overall assessment cellular immunity of organism.5. Signal conduction disturbance of apoptosis that is one of key mechanisms of the recurrence and metastasis of tumor. JYJF induced apoptosis involved in Fas death receptor -mediated apoptotic pathway and mitochondria-mediated apoptotic pathway. JYJF induced effector caspase-3 activation and apoptosis through coaction of both apoptotic pathways.6. The possible molecular mechanism of JYJF involved in that the expression levels of Fas protein and its mRNA of tumor tissue were increased, and the expression levels of FasL protein and its mRNA were decreased, accordingly up-regulated initiator caspase-8 activation. Meanwhile, the expression levels of Bax protein and its mRNA were increased, and the ratio of Bcl-2/Bax was decreased, accordingly the expression levels of Bcl-2 protein and its mRNA were attenuated and apoptosis was inhibited. In addition to, it was observed that both the mitochondria membrane potential (Av|/m) of tumor cell and PH value of inside cell were decreased. Mitochondria-mediated apoptotic pathway enlarged efficiently apoptotic signal. These increased an experiment basis for multi-target point effect of compound recipe on TCM.
引文
1.周际昌主编.实用肿瘤内科学(第2版).北京:人民卫生出版社,2005,187-198
2.孙燕,周际昌主编.临床肿瘤内科手册(第4版).北京:人民卫生出版社,2003,328-336
3.罗荣城,韩焕兴主编.肿瘤综合治疗新进展.北京:人民军医出版社,2003,4-9
4.陈峻青.胃癌根治术后复发形式和方法的选择.中国实用外科杂志,1995,15(12):709-710
5. Yoo CH, Noh SH, Shin DW, et al. Recurrence following curative resection for gastric carcinoma. Br J Snrg, 2002, 87(2): 236-242
6. Oki E, Maehara Y, Tokunaga E, et al. Detection of disseminated cancer cells in bone marrow of gastric cancer using real time quantitative reverse transcriptase polymerase chain reaction. Cancer Lett, 2002, 188(1-2): 191-198
7. Matsumoto M, Natsugoe S, Ishigami S, et al. Lymph node micrometastasis and lymphatic mapping determined by reverse transciptase-polymerase chain reaction in pN0 gastric carcinoma. Surgery, 2002, 131 (6):630-635.
8. Kudoh, A., Daikoku, T., Sugaya, Y, et al. Quantitative detection of micrometastases in the lymph nodes of gastric cancer patients with real-time RT-PCR:a comparative study with immunohistochemistry.Int J Cancer,2003, 105(1): 136-143
9. Okada Y, Fujiwara Y, Yamamoto H, et al.Genetic detection of lymph node micrometastases in patients with gastric carcinoma by multiple-marker reverse transcriptase-polymerase chain reaction assay. Cancer,2001,92(8):2056-2064
10. Sumikura S, Ishigami S, Natsugoe S, et al. Disseminated cancer cells in the blood and expression of sialylated antigen in gastric cancer. Cancer Lett 2003, 200(1):77-83
11. Majima T, Ichikura T, Takayama E, et al. Detecting circulating cancer cells using reverse transcriptase-polymerase chain reaction for cytokeratin mRNA in peripheral blood from patients with gastric cancer. Jpn J Clin Oncol, 2000, 30(11):499-503
12. Ikeguchi M, Ohro S, Maeda Y, et al. Detection of cancer cells in the peripheral blood of gastric cancer patients. Int J Mol Med, 2003, 11 (2):217-221.
13. Noh YH, Kim JA, Lim GR, et al.Detection of circulating tumor cells in patients with gastrointestinal tract cancer using RT-PCR and its clinical implications. Exp Mol Med, 2001, 33(1):8-14
14. Wang Z, Zhang X, Xu H, et al.Detection of peritoneal micrometastasis by reverse transcriptase-polymerase chain reaction for heparanase mRNA and cytology in peritoneal wash samples.J Surg Oncol,2005, 90(2):59-65
15. Vogel P, Ruschoff J, Kummel S, et al. Prognostic value of microscopic peritoneal dissemination: comparison between colon and gastric cancer. Dis Colon Rectum, 2000, 43(1):92-100
16. Ueno H, Yoshida K, Hirai T, et al. Quantitative detection of carcinoembryonic antigen messenger RNA in the peritoneal cavity of gastric cancer patients by real-time quantitative reverse transcription polymerase chain reaction. Anticancer Res, 2003, 23(2C): 1701-1708
17. Kodera Y, Nakanishi H, Ito S, et al. Detection of Disseminated Cancer Cells in Linitis Plastica-type Gastric Carcinoma. Jpn J Clin Oncol. 2004, 34(9): 525-531
18.金桂龙,丁之玮,贾菊萍.胃癌术后复发转移的超声检查.中国肿瘤临床与康复,2005,12(6):532-534
19.黄涛,任权,玛迎春,等.胃大部切除术后残胃病变的内镜分析.中国内镜杂志,2004,10(1):90-91
20. Shim CS. Role of endoscopic ultrasonography for gastric lesions.Endoscopy, 1998, 30(suppl 1):A55-9
21. Ukrisana P, Wangwinyuvirat M. Evaluation of the sensitivity of the double-contrast upper gastrointestinal series in the diagnosis of gastric.cancer. J Med Assoc Thai, 2004, 87(1):80-86
22.李继明,中超,卢兆桐,等.螺旋CT对胃恶性肿瘤的诊断价值.实用医药杂志,2004,21(7):589-590
23.谢德宁,商秀林.胃癌浸润转移的螺旋CT诊断.中国误诊学杂志,2006,6(6):1063-1064
24. Maccioni F. Current status of gastrointestinal MRI. Abdom Imaging, 2002, 27 (4):358-360
25. Yoo CH, Noh SH, Shin DW, et al. Recurrence following curative resection for gastric carcinoma. Br. J. Surg, 2000, 87(2):236-242
26.王舒宝.复发胃癌及晚期胃癌的外科治疗.中国实用外科杂志2000,20(10):587-588
27. Topuz E, Basaran M, Saip P, et al. Adjuvant intraperitoneal chemotherapy with cisplatinum, mitoxantrone, 5-fluorouracil, and calcium folinate in patients with gastric cancer: a phase Ⅱ study.Am J Clin Oncol. 2002, 25(6):619-624
28.徐光炜.胃癌治疗的现状及问题.外科理论与实践2003,8(1):3-6
29. Lin L, Ye Z, Xue E. Intraoperative ultrasonographic detection of liver metastasis from tumors of the digestive tract. Zhonghua Zhongliu zazhi, 2001, 23 (3): 234-236
30. Kawasaki H, Shibata S, Suzuki H, et al. Hepatic resection for synchronous liver metastases of gastric cancer. Gan To Kagaku Ryoho, 2001, 28 (11): 1740-1742
31. Nagahama T, Maruyama M, Toukairin Y, et al. Hepatic arterial injection therapy (HAI) for metastatic liver tumor from gastric cancer. Gan To Kagaku Ryoho, 2000, 27 (12): 1920-1923
32. Tokairin Y, Maruyama M, Bala H, et al. Pharmacokinetics of "subselective" arterial infusion chemotherap. Gan To Ka gaku Ryoho, 2001, 28 (11): 1795-1798
33.高永辉,周旋,杨冬.胃癌卵巢转移55例分析.中国误诊学杂志,2006,6(5):951
34.金懋林.胃癌内科化学治疗的新进展.医学临床研究,2003,20(10):735-738
35. Webb A, Cunningham D, Scarffe JH, et al. Randomized trial comparing epirubicin, cisplatin and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol, 1997, 15 (1):261-267
36. Bugat R. Irinotecan in the treatment of gastric cancer.Ann Oncol, 2003, 14 (Suppl 2):ⅱ37-ⅱ40
37. Jin ML, Chen Q, Chen FQ, et al.Oxaliplatin in combination with LV5-FU2 in Chinese patients with advanced gastric cancer. Proc Am Soc Clin Oncol, 2002,31:558
38. Tebbntt N, Norman A, Cunningham D, et al.Randomised, multicenter phase Ⅲ study comparing with capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oeosphago-gastric cancer, interim analysis.Proc Am Soc Clin Oncol, 2002, 21:523.
39.李玉升.晚期胃癌的化疗与用药.中华医学杂志2004,84(24):2139-2141
40.刘鹏,邓清华.胃癌放射治疗的进展.国外医学肿瘤学分册,2005,32(7):552-554
41. Kim JP, Yu HJ, Lee JH. Results of immunochemo-surgery for gastric carcinoma. Hepatogastroenterology, 2001, 48(41): 1227-1230
42. Nakahara S, Tsunoda T, Baba T, et al. Dendritic cells stimulated with a bacterial product, OK-432, efficiently induce cytotoxic T lymphocytes specific to tumor rejection peptide.Cancer Res,2003,63(14):4112-4118
43. Kono K, Takahashi A,Ichihara F, et al. Prognostic significance of adoptive immunotherapy with tumor-associated lymphocytes in patients with advanced gastric cancer: a randomized trial.Clin Cancer Res,2002,8(6): 1767-1771
44. Kono K, Takahashi A, Sugai H, et al. Dendritic cells pulsed with HER-2/neu-derived peptides can induce specific T-cell responses in patients with gastric cancer.Clin Cancer Res, 2002, 8(11):3394-400
45.刘毅,周洁.中西医结合治疗晚期胃癌30例.山东中医杂志,2002,21(3):164-165
46.王晓.辨证治晚期胃癌40例.江西中医药,1999,30(4):28-29
47.陈郭君.中医辨证分型治疗.湖北中医杂志,2000,22(3):19.
48.董安荣,赵建霞,卢金玉.晚期胃癌辨治探析.辽宁中医杂志,2000,27(10):443-444
49.许玲,孙人志,施俊.中医证型分类的文献研究.世界华人消化杂志,2004,12(6):1457-1459
50.郑爱华,郭娜,李国良.殛癌隳瘤散治疗胃癌48例临床观察.辽宁中医学院学报,2001,3(2):119-120
51.周荣耀,吴丽英,倪爱娣,等.抗炎Ⅰ号静脉注射液治疗24例中晚期胃癌的临床观察.上海中医药杂志,2000,34(8:15-16
52.杨永健,刘昕,潘兴斌,等.铁筷子对胃癌及白血病K562细胞体外生长的抑制效应.中医药学报,2001,29(6):50-51
53.周丹,王凤梅.消癌平片抗肿瘤作用研究.吉林中医药,2002,22(1):57
54.陈云逸.胃癌的中医药治疗进展.中医药导报,2005,11(12):71-73
55.郑坚,顾缨,周浩,等.健脾中药对进展期胃癌生存期及转移复发状况的作用.辽宁中医杂志,2003,30(8):683-684
56.杨金坤,郑坚,沈克平,等.中药胃肠安防治进展期胃癌术后转移的临床研究.中国中西医结合杂志,2003,23(8):580-582
57.许尤琪,薛惠宁,诸晓秋,等.健脾活血解毒中药抗胃癌术后转移的临床观察.中西医结合学报,2003,1(3):192-194
58.王志学,焦中华.消瘤平移合剂抗肿瘤术后转移的临床及实验研究.山东中医药大学学报,1999,23(4):213-216
59.赵健雄,沈世林,曲勇,等.扶正抑瘤颗粒对食管癌胃癌术后患者免疫功能及血液流变学影响的临床观察.中华实用中西医杂志,2003,16(4):517-518
60.卜平,周荣卿,陈齐鸣.扶正化瘀化对胃癌患者术后转移的抑制作用及T淋巴细胞亚群的影响.中医杂志,2001,42(4):226-227
61.卜平,周荣卿.扶正化瘀方对胃癌转移及血液流变学的影响.中国中西医结合脾胃杂志,2000,8(4):193-195
62.杨继泉,张斌斌.中医药治疗中晚期胃癌102例临床疗效分析.中医杂志,2000,41(8):483-484
63.林丽珠.生存质量在中医肿瘤学综合疗效评价中的作用.中国肿瘤,2001,10(2):80-82
64.曾益新.肿瘤学.北京:人民卫生出版社,1999,425
2.孙燕,周际昌主编.临床肿瘤内科手册(第4版).北京:人民卫生出版社,2003,328-336
3.罗荣城,韩焕兴主编.肿瘤综合治疗新进展.北京:人民军医出版社,2003,4-9
4.陈峻青.胃癌根治术后复发形式和方法的选择.中国实用外科杂志,1995,15(12):709-710
5. Yoo CH, Noh SH, Shin DW, et al. Recurrence following curative resection for gastric carcinoma. Br J Snrg, 2002, 87(2): 236-242
6. Oki E, Maehara Y, Tokunaga E, et al. Detection of disseminated cancer cells in bone marrow of gastric cancer using real time quantitative reverse transcriptase polymerase chain reaction. Cancer Lett, 2002, 188(1-2): 191-198
7. Matsumoto M, Natsugoe S, Ishigami S, et al. Lymph node micrometastasis and lymphatic mapping determined by reverse transciptase-polymerase chain reaction in pN0 gastric carcinoma. Surgery, 2002, 131 (6):630-635.
8. Kudoh, A., Daikoku, T., Sugaya, Y, et al. Quantitative detection of micrometastases in the lymph nodes of gastric cancer patients with real-time RT-PCR:a comparative study with immunohistochemistry.Int J Cancer,2003, 105(1): 136-143
9. Okada Y, Fujiwara Y, Yamamoto H, et al.Genetic detection of lymph node micrometastases in patients with gastric carcinoma by multiple-marker reverse transcriptase-polymerase chain reaction assay. Cancer,2001,92(8):2056-2064
10. Sumikura S, Ishigami S, Natsugoe S, et al. Disseminated cancer cells in the blood and expression of sialylated antigen in gastric cancer. Cancer Lett 2003, 200(1):77-83
11. Majima T, Ichikura T, Takayama E, et al. Detecting circulating cancer cells using reverse transcriptase-polymerase chain reaction for cytokeratin mRNA in peripheral blood from patients with gastric cancer. Jpn J Clin Oncol, 2000, 30(11):499-503
12. Ikeguchi M, Ohro S, Maeda Y, et al. Detection of cancer cells in the peripheral blood of gastric cancer patients. Int J Mol Med, 2003, 11 (2):217-221.
13. Noh YH, Kim JA, Lim GR, et al.Detection of circulating tumor cells in patients with gastrointestinal tract cancer using RT-PCR and its clinical implications. Exp Mol Med, 2001, 33(1):8-14
14. Wang Z, Zhang X, Xu H, et al.Detection of peritoneal micrometastasis by reverse transcriptase-polymerase chain reaction for heparanase mRNA and cytology in peritoneal wash samples.J Surg Oncol,2005, 90(2):59-65
15. Vogel P, Ruschoff J, Kummel S, et al. Prognostic value of microscopic peritoneal dissemination: comparison between colon and gastric cancer. Dis Colon Rectum, 2000, 43(1):92-100
16. Ueno H, Yoshida K, Hirai T, et al. Quantitative detection of carcinoembryonic antigen messenger RNA in the peritoneal cavity of gastric cancer patients by real-time quantitative reverse transcription polymerase chain reaction. Anticancer Res, 2003, 23(2C): 1701-1708
17. Kodera Y, Nakanishi H, Ito S, et al. Detection of Disseminated Cancer Cells in Linitis Plastica-type Gastric Carcinoma. Jpn J Clin Oncol. 2004, 34(9): 525-531
18.金桂龙,丁之玮,贾菊萍.胃癌术后复发转移的超声检查.中国肿瘤临床与康复,2005,12(6):532-534
19.黄涛,任权,玛迎春,等.胃大部切除术后残胃病变的内镜分析.中国内镜杂志,2004,10(1):90-91
20. Shim CS. Role of endoscopic ultrasonography for gastric lesions.Endoscopy, 1998, 30(suppl 1):A55-9
21. Ukrisana P, Wangwinyuvirat M. Evaluation of the sensitivity of the double-contrast upper gastrointestinal series in the diagnosis of gastric.cancer. J Med Assoc Thai, 2004, 87(1):80-86
22.李继明,中超,卢兆桐,等.螺旋CT对胃恶性肿瘤的诊断价值.实用医药杂志,2004,21(7):589-590
23.谢德宁,商秀林.胃癌浸润转移的螺旋CT诊断.中国误诊学杂志,2006,6(6):1063-1064
24. Maccioni F. Current status of gastrointestinal MRI. Abdom Imaging, 2002, 27 (4):358-360
25. Yoo CH, Noh SH, Shin DW, et al. Recurrence following curative resection for gastric carcinoma. Br. J. Surg, 2000, 87(2):236-242
26.王舒宝.复发胃癌及晚期胃癌的外科治疗.中国实用外科杂志2000,20(10):587-588
27. Topuz E, Basaran M, Saip P, et al. Adjuvant intraperitoneal chemotherapy with cisplatinum, mitoxantrone, 5-fluorouracil, and calcium folinate in patients with gastric cancer: a phase Ⅱ study.Am J Clin Oncol. 2002, 25(6):619-624
28.徐光炜.胃癌治疗的现状及问题.外科理论与实践2003,8(1):3-6
29. Lin L, Ye Z, Xue E. Intraoperative ultrasonographic detection of liver metastasis from tumors of the digestive tract. Zhonghua Zhongliu zazhi, 2001, 23 (3): 234-236
30. Kawasaki H, Shibata S, Suzuki H, et al. Hepatic resection for synchronous liver metastases of gastric cancer. Gan To Kagaku Ryoho, 2001, 28 (11): 1740-1742
31. Nagahama T, Maruyama M, Toukairin Y, et al. Hepatic arterial injection therapy (HAI) for metastatic liver tumor from gastric cancer. Gan To Kagaku Ryoho, 2000, 27 (12): 1920-1923
32. Tokairin Y, Maruyama M, Bala H, et al. Pharmacokinetics of "subselective" arterial infusion chemotherap. Gan To Ka gaku Ryoho, 2001, 28 (11): 1795-1798
33.高永辉,周旋,杨冬.胃癌卵巢转移55例分析.中国误诊学杂志,2006,6(5):951
34.金懋林.胃癌内科化学治疗的新进展.医学临床研究,2003,20(10):735-738
35. Webb A, Cunningham D, Scarffe JH, et al. Randomized trial comparing epirubicin, cisplatin and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol, 1997, 15 (1):261-267
36. Bugat R. Irinotecan in the treatment of gastric cancer.Ann Oncol, 2003, 14 (Suppl 2):ⅱ37-ⅱ40
37. Jin ML, Chen Q, Chen FQ, et al.Oxaliplatin in combination with LV5-FU2 in Chinese patients with advanced gastric cancer. Proc Am Soc Clin Oncol, 2002,31:558
38. Tebbntt N, Norman A, Cunningham D, et al.Randomised, multicenter phase Ⅲ study comparing with capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oeosphago-gastric cancer, interim analysis.Proc Am Soc Clin Oncol, 2002, 21:523.
39.李玉升.晚期胃癌的化疗与用药.中华医学杂志2004,84(24):2139-2141
40.刘鹏,邓清华.胃癌放射治疗的进展.国外医学肿瘤学分册,2005,32(7):552-554
41. Kim JP, Yu HJ, Lee JH. Results of immunochemo-surgery for gastric carcinoma. Hepatogastroenterology, 2001, 48(41): 1227-1230
42. Nakahara S, Tsunoda T, Baba T, et al. Dendritic cells stimulated with a bacterial product, OK-432, efficiently induce cytotoxic T lymphocytes specific to tumor rejection peptide.Cancer Res,2003,63(14):4112-4118
43. Kono K, Takahashi A,Ichihara F, et al. Prognostic significance of adoptive immunotherapy with tumor-associated lymphocytes in patients with advanced gastric cancer: a randomized trial.Clin Cancer Res,2002,8(6): 1767-1771
44. Kono K, Takahashi A, Sugai H, et al. Dendritic cells pulsed with HER-2/neu-derived peptides can induce specific T-cell responses in patients with gastric cancer.Clin Cancer Res, 2002, 8(11):3394-400
45.刘毅,周洁.中西医结合治疗晚期胃癌30例.山东中医杂志,2002,21(3):164-165
46.王晓.辨证治晚期胃癌40例.江西中医药,1999,30(4):28-29
47.陈郭君.中医辨证分型治疗.湖北中医杂志,2000,22(3):19.
48.董安荣,赵建霞,卢金玉.晚期胃癌辨治探析.辽宁中医杂志,2000,27(10):443-444
49.许玲,孙人志,施俊.中医证型分类的文献研究.世界华人消化杂志,2004,12(6):1457-1459
50.郑爱华,郭娜,李国良.殛癌隳瘤散治疗胃癌48例临床观察.辽宁中医学院学报,2001,3(2):119-120
51.周荣耀,吴丽英,倪爱娣,等.抗炎Ⅰ号静脉注射液治疗24例中晚期胃癌的临床观察.上海中医药杂志,2000,34(8:15-16
52.杨永健,刘昕,潘兴斌,等.铁筷子对胃癌及白血病K562细胞体外生长的抑制效应.中医药学报,2001,29(6):50-51
53.周丹,王凤梅.消癌平片抗肿瘤作用研究.吉林中医药,2002,22(1):57
54.陈云逸.胃癌的中医药治疗进展.中医药导报,2005,11(12):71-73
55.郑坚,顾缨,周浩,等.健脾中药对进展期胃癌生存期及转移复发状况的作用.辽宁中医杂志,2003,30(8):683-684
56.杨金坤,郑坚,沈克平,等.中药胃肠安防治进展期胃癌术后转移的临床研究.中国中西医结合杂志,2003,23(8):580-582
57.许尤琪,薛惠宁,诸晓秋,等.健脾活血解毒中药抗胃癌术后转移的临床观察.中西医结合学报,2003,1(3):192-194
58.王志学,焦中华.消瘤平移合剂抗肿瘤术后转移的临床及实验研究.山东中医药大学学报,1999,23(4):213-216
59.赵健雄,沈世林,曲勇,等.扶正抑瘤颗粒对食管癌胃癌术后患者免疫功能及血液流变学影响的临床观察.中华实用中西医杂志,2003,16(4):517-518
60.卜平,周荣卿,陈齐鸣.扶正化瘀化对胃癌患者术后转移的抑制作用及T淋巴细胞亚群的影响.中医杂志,2001,42(4):226-227
61.卜平,周荣卿.扶正化瘀方对胃癌转移及血液流变学的影响.中国中西医结合脾胃杂志,2000,8(4):193-195
62.杨继泉,张斌斌.中医药治疗中晚期胃癌102例临床疗效分析.中医杂志,2000,41(8):483-484
63.林丽珠.生存质量在中医肿瘤学综合疗效评价中的作用.中国肿瘤,2001,10(2):80-82
64.曾益新.肿瘤学.北京:人民卫生出版社,1999,425
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