乳腺癌骨髓微转移检测及肿瘤特异性CTLs细胞的免疫治疗
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摘要
目的:乳腺癌是女性最常见的恶性肿瘤,发病率逐年增高。影响预后的关键因素是远处转移,也是治疗失败的根本原因。虽然采取了以手术为主的综合治疗措施,但远期生存率没有明显提高。多项研究表明,乳腺癌骨髓微转移是临床远处转移灶的先兆,可作为独立因素判断预后,在指导治疗、评价疗效及术后复发、转移的监测上有重要意义。提高乳腺癌患者的生存率、延长生存期,应对骨髓微转移采取治疗。本实验通过对乳腺癌患者骨髓微转移的检测及应用肿瘤特异性CTLs细胞对微转移阳性患者进行治疗,探讨微转移发生规律以及免疫细胞过继治疗对微转移的治疗作用,为乳腺癌的预后判断及制定综合治疗方案提供帮助。
方法:选取我院2007年3月至12月期间收治的可手术乳腺癌病例82例,并经病理学证实。研究对象均为女性,年龄27～80岁,中位年龄44.8岁。术前均未行放、化疗及内分泌治疗。按照国际抗癌联盟(UICC,乳腺癌,2002)肿瘤TNM临床分期标准:Ⅰ期8例、Ⅱ期51例、Ⅲ期23例。另设阴性对照10例。术前1-3天抽取骨髓,应用流式细胞术,联合检测骨髓有核细胞中CK18、CK19的阳性细胞表达率。将23例术前骨髓微转移阳性患者分为二组,治疗组17例,术后应用特异性CTL细胞免疫过继治疗。免疫治疗结束后再接受其余综合治疗。对照组6例,术后不接受特异性CTL细胞免疫过继治疗。其余治疗方式及应用时间与第一组相同。免疫治疗组术中取腋下淋巴结及外周血,术后体外诱导培养特异性CTL细胞,于术后10-14天回输,观察特异性CTL细胞对乳腺癌骨髓微转移的疗效。
结果
1. 82例乳腺癌患者骨髓标本中,23例经FCM检测到CK18~+、CK19~+/CD45~-细胞,骨髓微转移的阳性检出率为28.05%。
2.乳腺癌患者的骨髓微转移阳性率随着原发肿瘤的增大而增高,肿瘤直径≤2cm组、2~5cm组及>5cm组的骨髓微转移阳性率分别为7.69%(1/13)、14.58(7/48)%、71.43%(15/21),三组间有统计学差异, P=0.0007。
3.乳腺癌骨髓微转移阳性率随着临床病理分期增高而增加。临床Ⅰ期组骨髓微转移阳性率12.50%(1/8),Ⅱ期组17.65%(9/51),Ⅲ期56.52%(13/23),三组间有统计学差异,P=0.004。
4.乳腺癌骨髓微转移阳性率随着组织学分级增加而增高。组织学分化Ⅲ级组骨髓微转移阳性率为68.42%(13/19),明显高于Ⅱ级组17.65%(9/51)及Ⅰ级组8.33%(1/12),三组间比较,有统计学差异,P=0.003。
5.乳腺癌患者的骨髓微转移阳性率与患者的年龄、月经状况无关,P>0.05。
6.乳腺癌患者的骨髓微转移阳性率随肿瘤组织ER、PR蛋白表达的增强而降低,ER、PR阳性组骨髓微转移阳性率分别为13.33%(4/30)、10.34%(3/29),明显低于ER、PR阴性组36.54%(19/54)、37.74%(20/53),P<0.05。乳腺癌患者的骨髓微转移与肿瘤组织C-erbB-2的表达无关(P>0.05)。
7.将23例骨髓微转移阳性患者分为二组,治疗组17例均顺利应用特异性肿瘤CTLs细胞过继免疫治疗,其中只有2例患者出现轻度发热、乏力或嗜睡,其他患者未有不适症状。对照组6例未接受治疗。治疗组、对照组于术后20天左右再次抽取骨髓,做微转移检测,并与术前对照,判断疗效。治疗组17例患者中有14例,在治疗后的微转移检测中呈阴性,过继免疫治疗后转阴率为82.4%。对照组6例中,只有1例术后微转移检测为阴性,术后转阴率只有16.7%。差别有统计学意义(P =0.00028)。
结论
1.应用流式细胞术联合CK18、CK19检测乳腺癌骨髓微转移的阳性率为28.05%。
2.本组研究显示,乳腺癌骨髓微转移的阳性率随着临床分期的增加而增高,临床分期与原发肿瘤体积、腋下淋巴结转移等因素直接相关,提示随着肿瘤的侵袭转移能力的增高,肿瘤细胞发生远处播散的机会增加。当处于临床Ⅲ期时,远处转移的机率明显增高。
3.乳腺癌骨髓微转移阳性率随组织学分级增加而升高,说明分化程度低的肿瘤细胞具有更强的增殖、侵袭、转移能力,对这部分病人应加强化疗等综合性治疗,密切关注全身转移情况。
4.乳腺癌骨髓微转移阳性率随ER、PR蛋白表达增强而降低,说明分化愈差的肿瘤细胞,ER、PR丢失愈多,可能具有更强的增殖、侵袭、转移能力。
5.本研究未发现乳腺癌骨髓微转移与患者的年龄、月经状况、病理类型及肿瘤组织中C-erbB-2的表达有关。
6.实验数据还中发现,有近12.50%的临床Ⅰ期患者,骨髓微转移阳性。提示乳腺癌属全身系统性疾病,疾病早期即可发生播散和微转移。必须对骨髓微转移采取相应治疗。
7.本实验数据显示,23例骨髓微转移阳性患者中,治疗组转阴率为82.4%。对照组转阴率为16.7%。差异具有统计学意义(P=0.00028)。特异性CTL细胞免疫过继治疗对乳腺癌骨髓微转移的清除有效。副反应小,易于接受。
Objective: Breast cancer is the most common malignant tumor among women, the incidence is becoming higher in recent years. There is no significant improvement of long-term survival rate though comprehensive measures including surgery are taken. The major reason is associated with metastasis to remote organs. It is showed that, by clinical statistics, bone marrow micrometastasis of breast cancer is the signal of distant metastasis. The detection of micrometastasis may be one of targets to predict the prognosis of breast cancer. It not only help us supervise metastasis dynamically, observe the treatment effect, but also has been an independent factor of predicting the prognosis of breast cancer. Therefore, improving the prognosis of breast cancer needs the treatment of bone marrow micrometastasis. In this research, we have detected bone marrow micrometastasis of breast cancer patients, then used tumor specific CTLs as the treatment method of bone marrow micrometastasis, and discussed the regulations of bone marrow micrometastasis. By this study, we want to find a suitable way to predict the prognosis and increase the long-term survival rate of breast cancer patients.
Methods: 82 breast cancer cases in our hospital were taken between March and December in 2007. All of them were female, aged from 27 to 82, with a mean of 44.8, and have been proved by patheology. 10 were used as normal person negative control. According to the UICC breast cancer TNM, Detected the cell positive rate of CK18 and CK19 in bone marrow by FCM. Bone marrow puncture was done in 1-3Ddays before operation. In the 82 cases, 23 were detected to be CK18 and CK19 positive expression ones. 23 were divided into two groups: 17 had been treated with CTLs immunotherapy after operation, other therapies would be done in sequence. Therapies of the other 6 were same except the use of CTLs. Each patient with immunotherapy had been collected lymph nodes and peripheral blood. CTLs were cultivated from these two tissues, and injected into the same patient 10-14 days after operation. Then observed the effect of CTLs.
Results
1.From bone marrow specimen of 82 breast cancer patients, CK18.+、CK19~+/CD45~- cells were detected in 23 cases by FCM, breast cancer bone marrow micrometastasis positive detection rate was 28.05%.
2. Bone marrow micrometastasis positive rate in breast cancer patients was increased by protopathic tumor size. The micrometastasis positive rate was 7.69%(1/13)、14.58(7/48)%、71.43%(15/21) respective for the≤2cm、2~5cm and>5cm (in diameter). There are statistical significance among three groups, P=0.0007.
3. Breast cancer bone marrow micrometastasis positive rate was increased by the clinical TNM staging increased. Bone marrow micrometastasis positive rate was 12.50% (1/8), 17.65% (9/51), and 56.52% (13/23) respectively for StageⅠ,ⅡandⅢ. There are statistical significance among three groups, P=0.004.
4 Breast cancer bone marrow micrometastasis positive rate was increased with histological grade increasing. Positive rate of the Grade III group was 68.42% (13/19), higher than the Grade II group 17.65% (9/51) and Grade I group 8.33% (1/12), There are statistical significance among three groups, P =0.003.
5. There was not relationship between breast cancer bone marrow micrometastasis positive rate and their ages and menstruation, P>0.05.
6. Bone marrow micrometastasis positive rate in breast cancer patients was decreased with ER and PR expressions in tumor tissues intensified. Bone marrow micrometastasis positive rate in ER and PR positive groups was 13.33%(4/30)、10.34%(3/29) respectively, lower than ER and PR negative group 36.54%(19/54)、37.74%(20/53), P<0.05. There was not relationship between bone marrow micrometastasis positive rate and C-erbB-2 expression in the tumor tissues(P>0.05)
7. 23 breast cancer bone marrow micrometastasis positive patients had been divided into 2 groups: there were 17 patients in foscarnet group, and all had immunotherapy of tumor specific CTLs successfully. Only 2 patients had slight fever, anoresia or sleepiness, other patients had no discomfort feelings. Other 6 patients without CTLs treatment as control group. Each of the 23 cases had bone marrow micrometastasis detection 20 days later of operation. Then compared the micrometastasis positive detection rate with the one before operation, and predicted the effect. Among 17 patients of foscarnet group, there were 14 cases who could not be detected bone marrow micrometastasis, the immunotherapy clearance rate (negative rate) was 82.4%. Among 6 patients of control group, there were only 1 case who could not be detected bone marrow micrometastasis, the clearance rate (negative rate) was 16.7%. There are statistical significance between two groups (P =0.00028).
Conclusion
1. Breast cancer micrometastasis cell positive rate of CK18 and CK19 in bone marrow detecteted by FCM .is 28.05%.
2 In this research, breast cancer bone marrow micrometastasis positive rate is increased by the clinical TNM staging increased. The clinical TNM staging in breast cancer relates to the size of the primary tumor and the axillary lymph nodes metastasis. The more invading ability the tumor has, the more chance to metastasis will be. Breast cancer patients of grade III group have more chances for bone marrow micrometastasis.
3. Breast cancer bone marrow micrometastasis positive rate increases as histological grading going up, which indicates that low-differentiated cancer cells have stronger ability to reproduce, invade and transfer. It is necessary to use complex therapies to these patients and observe the distant metastasis.
4. Breast cancer bone marrow micrometastasis positive rate relates to ER and PR protein expressions in tumor tissues. Breast cancer bone marrow micrometastasis positive rate decreases with ER and PR protain expressions intensified,which indicates that the lower tumor cells differentiate, the lower ER and PR express, and they are more capable to infiltrate and metastasis.
5. No relationship is found between breast cancer bone marrow micrometastasis positive detection rate of the 82 cases and their ages, menstruation, pathological typing or the C-erbB-2 expression in the tumor tissues.
6. The data has also shown that there is 12.50% (1/8) bone marrow micrometastasis in clinicalⅠ, which indicates that breast cancer is ageneral disease. Its metastasis and spread may occur in early phase of the disease. It is obvious that treatment to bone marrow metastasis must be done.
7. Among the 23 breast cancer bone marrow micrometastasis positive patients, the immunotherapy clearance rate (negative rate) is 82.4%, the clearance rate (negative rate) of control group is 16.7%. There are statistical significance between two groups, P=0.00028. Tumor specific CTLs immunotherapy has the ability to clean the bone marrow micrometastasis of breast cancer. The side-effect is slight, and patients are easy to accept the therapy.
方法:选取我院2007年3月至12月期间收治的可手术乳腺癌病例82例,并经病理学证实。研究对象均为女性,年龄27～80岁,中位年龄44.8岁。术前均未行放、化疗及内分泌治疗。按照国际抗癌联盟(UICC,乳腺癌,2002)肿瘤TNM临床分期标准:Ⅰ期8例、Ⅱ期51例、Ⅲ期23例。另设阴性对照10例。术前1-3天抽取骨髓,应用流式细胞术,联合检测骨髓有核细胞中CK18、CK19的阳性细胞表达率。将23例术前骨髓微转移阳性患者分为二组,治疗组17例,术后应用特异性CTL细胞免疫过继治疗。免疫治疗结束后再接受其余综合治疗。对照组6例,术后不接受特异性CTL细胞免疫过继治疗。其余治疗方式及应用时间与第一组相同。免疫治疗组术中取腋下淋巴结及外周血,术后体外诱导培养特异性CTL细胞,于术后10-14天回输,观察特异性CTL细胞对乳腺癌骨髓微转移的疗效。
结果
1. 82例乳腺癌患者骨髓标本中,23例经FCM检测到CK18~+、CK19~+/CD45~-细胞,骨髓微转移的阳性检出率为28.05%。
2.乳腺癌患者的骨髓微转移阳性率随着原发肿瘤的增大而增高,肿瘤直径≤2cm组、2~5cm组及>5cm组的骨髓微转移阳性率分别为7.69%(1/13)、14.58(7/48)%、71.43%(15/21),三组间有统计学差异, P=0.0007。
3.乳腺癌骨髓微转移阳性率随着临床病理分期增高而增加。临床Ⅰ期组骨髓微转移阳性率12.50%(1/8),Ⅱ期组17.65%(9/51),Ⅲ期56.52%(13/23),三组间有统计学差异,P=0.004。
4.乳腺癌骨髓微转移阳性率随着组织学分级增加而增高。组织学分化Ⅲ级组骨髓微转移阳性率为68.42%(13/19),明显高于Ⅱ级组17.65%(9/51)及Ⅰ级组8.33%(1/12),三组间比较,有统计学差异,P=0.003。
5.乳腺癌患者的骨髓微转移阳性率与患者的年龄、月经状况无关,P>0.05。
6.乳腺癌患者的骨髓微转移阳性率随肿瘤组织ER、PR蛋白表达的增强而降低,ER、PR阳性组骨髓微转移阳性率分别为13.33%(4/30)、10.34%(3/29),明显低于ER、PR阴性组36.54%(19/54)、37.74%(20/53),P<0.05。乳腺癌患者的骨髓微转移与肿瘤组织C-erbB-2的表达无关(P>0.05)。
7.将23例骨髓微转移阳性患者分为二组,治疗组17例均顺利应用特异性肿瘤CTLs细胞过继免疫治疗,其中只有2例患者出现轻度发热、乏力或嗜睡,其他患者未有不适症状。对照组6例未接受治疗。治疗组、对照组于术后20天左右再次抽取骨髓,做微转移检测,并与术前对照,判断疗效。治疗组17例患者中有14例,在治疗后的微转移检测中呈阴性,过继免疫治疗后转阴率为82.4%。对照组6例中,只有1例术后微转移检测为阴性,术后转阴率只有16.7%。差别有统计学意义(P =0.00028)。
结论
1.应用流式细胞术联合CK18、CK19检测乳腺癌骨髓微转移的阳性率为28.05%。
2.本组研究显示,乳腺癌骨髓微转移的阳性率随着临床分期的增加而增高,临床分期与原发肿瘤体积、腋下淋巴结转移等因素直接相关,提示随着肿瘤的侵袭转移能力的增高,肿瘤细胞发生远处播散的机会增加。当处于临床Ⅲ期时,远处转移的机率明显增高。
3.乳腺癌骨髓微转移阳性率随组织学分级增加而升高,说明分化程度低的肿瘤细胞具有更强的增殖、侵袭、转移能力,对这部分病人应加强化疗等综合性治疗,密切关注全身转移情况。
4.乳腺癌骨髓微转移阳性率随ER、PR蛋白表达增强而降低,说明分化愈差的肿瘤细胞,ER、PR丢失愈多,可能具有更强的增殖、侵袭、转移能力。
5.本研究未发现乳腺癌骨髓微转移与患者的年龄、月经状况、病理类型及肿瘤组织中C-erbB-2的表达有关。
6.实验数据还中发现,有近12.50%的临床Ⅰ期患者,骨髓微转移阳性。提示乳腺癌属全身系统性疾病,疾病早期即可发生播散和微转移。必须对骨髓微转移采取相应治疗。
7.本实验数据显示,23例骨髓微转移阳性患者中,治疗组转阴率为82.4%。对照组转阴率为16.7%。差异具有统计学意义(P=0.00028)。特异性CTL细胞免疫过继治疗对乳腺癌骨髓微转移的清除有效。副反应小,易于接受。
Objective: Breast cancer is the most common malignant tumor among women, the incidence is becoming higher in recent years. There is no significant improvement of long-term survival rate though comprehensive measures including surgery are taken. The major reason is associated with metastasis to remote organs. It is showed that, by clinical statistics, bone marrow micrometastasis of breast cancer is the signal of distant metastasis. The detection of micrometastasis may be one of targets to predict the prognosis of breast cancer. It not only help us supervise metastasis dynamically, observe the treatment effect, but also has been an independent factor of predicting the prognosis of breast cancer. Therefore, improving the prognosis of breast cancer needs the treatment of bone marrow micrometastasis. In this research, we have detected bone marrow micrometastasis of breast cancer patients, then used tumor specific CTLs as the treatment method of bone marrow micrometastasis, and discussed the regulations of bone marrow micrometastasis. By this study, we want to find a suitable way to predict the prognosis and increase the long-term survival rate of breast cancer patients.
Methods: 82 breast cancer cases in our hospital were taken between March and December in 2007. All of them were female, aged from 27 to 82, with a mean of 44.8, and have been proved by patheology. 10 were used as normal person negative control. According to the UICC breast cancer TNM, Detected the cell positive rate of CK18 and CK19 in bone marrow by FCM. Bone marrow puncture was done in 1-3Ddays before operation. In the 82 cases, 23 were detected to be CK18 and CK19 positive expression ones. 23 were divided into two groups: 17 had been treated with CTLs immunotherapy after operation, other therapies would be done in sequence. Therapies of the other 6 were same except the use of CTLs. Each patient with immunotherapy had been collected lymph nodes and peripheral blood. CTLs were cultivated from these two tissues, and injected into the same patient 10-14 days after operation. Then observed the effect of CTLs.
Results
1.From bone marrow specimen of 82 breast cancer patients, CK18.+、CK19~+/CD45~- cells were detected in 23 cases by FCM, breast cancer bone marrow micrometastasis positive detection rate was 28.05%.
2. Bone marrow micrometastasis positive rate in breast cancer patients was increased by protopathic tumor size. The micrometastasis positive rate was 7.69%(1/13)、14.58(7/48)%、71.43%(15/21) respective for the≤2cm、2~5cm and>5cm (in diameter). There are statistical significance among three groups, P=0.0007.
3. Breast cancer bone marrow micrometastasis positive rate was increased by the clinical TNM staging increased. Bone marrow micrometastasis positive rate was 12.50% (1/8), 17.65% (9/51), and 56.52% (13/23) respectively for StageⅠ,ⅡandⅢ. There are statistical significance among three groups, P=0.004.
4 Breast cancer bone marrow micrometastasis positive rate was increased with histological grade increasing. Positive rate of the Grade III group was 68.42% (13/19), higher than the Grade II group 17.65% (9/51) and Grade I group 8.33% (1/12), There are statistical significance among three groups, P =0.003.
5. There was not relationship between breast cancer bone marrow micrometastasis positive rate and their ages and menstruation, P>0.05.
6. Bone marrow micrometastasis positive rate in breast cancer patients was decreased with ER and PR expressions in tumor tissues intensified. Bone marrow micrometastasis positive rate in ER and PR positive groups was 13.33%(4/30)、10.34%(3/29) respectively, lower than ER and PR negative group 36.54%(19/54)、37.74%(20/53), P<0.05. There was not relationship between bone marrow micrometastasis positive rate and C-erbB-2 expression in the tumor tissues(P>0.05)
7. 23 breast cancer bone marrow micrometastasis positive patients had been divided into 2 groups: there were 17 patients in foscarnet group, and all had immunotherapy of tumor specific CTLs successfully. Only 2 patients had slight fever, anoresia or sleepiness, other patients had no discomfort feelings. Other 6 patients without CTLs treatment as control group. Each of the 23 cases had bone marrow micrometastasis detection 20 days later of operation. Then compared the micrometastasis positive detection rate with the one before operation, and predicted the effect. Among 17 patients of foscarnet group, there were 14 cases who could not be detected bone marrow micrometastasis, the immunotherapy clearance rate (negative rate) was 82.4%. Among 6 patients of control group, there were only 1 case who could not be detected bone marrow micrometastasis, the clearance rate (negative rate) was 16.7%. There are statistical significance between two groups (P =0.00028).
Conclusion
1. Breast cancer micrometastasis cell positive rate of CK18 and CK19 in bone marrow detecteted by FCM .is 28.05%.
2 In this research, breast cancer bone marrow micrometastasis positive rate is increased by the clinical TNM staging increased. The clinical TNM staging in breast cancer relates to the size of the primary tumor and the axillary lymph nodes metastasis. The more invading ability the tumor has, the more chance to metastasis will be. Breast cancer patients of grade III group have more chances for bone marrow micrometastasis.
3. Breast cancer bone marrow micrometastasis positive rate increases as histological grading going up, which indicates that low-differentiated cancer cells have stronger ability to reproduce, invade and transfer. It is necessary to use complex therapies to these patients and observe the distant metastasis.
4. Breast cancer bone marrow micrometastasis positive rate relates to ER and PR protein expressions in tumor tissues. Breast cancer bone marrow micrometastasis positive rate decreases with ER and PR protain expressions intensified,which indicates that the lower tumor cells differentiate, the lower ER and PR express, and they are more capable to infiltrate and metastasis.
5. No relationship is found between breast cancer bone marrow micrometastasis positive detection rate of the 82 cases and their ages, menstruation, pathological typing or the C-erbB-2 expression in the tumor tissues.
6. The data has also shown that there is 12.50% (1/8) bone marrow micrometastasis in clinicalⅠ, which indicates that breast cancer is ageneral disease. Its metastasis and spread may occur in early phase of the disease. It is obvious that treatment to bone marrow metastasis must be done.
7. Among the 23 breast cancer bone marrow micrometastasis positive patients, the immunotherapy clearance rate (negative rate) is 82.4%, the clearance rate (negative rate) of control group is 16.7%. There are statistical significance between two groups, P=0.00028. Tumor specific CTLs immunotherapy has the ability to clean the bone marrow micrometastasis of breast cancer. The side-effect is slight, and patients are easy to accept the therapy.
引文
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8 刘运江, 吴风云, 吴祥德. 乳腺癌骨髓微转移检测及其临床意义. 临床外科杂志, 2004, 12(9): 46~49
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10 刘运江, 刘现义. hMAM 检测乳腺癌骨髓微转移及其意义. 中国肿瘤临床, 2006, 33(10): 549~552
11 Stephan B, Florian D1. Evaluation of bone marrow in breast cancer patients: prediction of clinical outcome and respons to therapy. The Breast 2003, 12: 397-404
12 Chambers AF, MacDonald IC, Schmidt EE, et al. Clinical targets for antimetastasis therapy. Adv Cancer Res, 2000, 79: 91~121
13 Sohoenfeld A, Kruger K H, Gomn J, et al. The detection of micrometastases in the peripheral blood and bone marrow of patients with breast cancer using immunohistochemistry andreverse transcriptase polymerase chain reaction for keratin
19[J]. Eur J Cancer, 1997, 33 (6): 854~861
14 Gardner B, Feldman J. Are positive axillary nodes in breast cancer markers for incurable dieases?〔J〕Ann Sug, 1993, 218 (3): 270
15 Funke I, Schraut W. Meta analyses of studies on bone marrow micrometastases: An independent prognostic impact remains to be substantiated [J]. J Clin Oncol, 1998, 16(2) :557 ~566
16 Solakoglu O, Maierhofer C, Lahr G, et al. Heterogeneous proliferativepotential of occult metastatic cells in bone marrow of patients with solidepithelial tumors〔J〕. PNAS, 2002, 99(4): 2246-2251
17 Sharp JA, Sung V, Slavin J, et al. Tumor cells are the source of osteopontin and bone sialoprotein expression in human breast cancer. Lab Invest,1999,79(7):869~877
18 Braun S, Kentenich C, Janni W, et al. Lack of Effect of Adjuvant Chemotherapy on the Elimination of Single Dormant Tumor Cells in Bone Marrow of High Risk Breast Cancer Patients [J]. J Clin Oncol, 2000, 18 (1) : 80 - 88
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20 Klaus Pantel, Magnus VON, Knebel D. Detection and clinical relevance of micrometastiatic cancer [J]. Cells Current Opinion in Onco1ogy, 2000, 12 :95 - 101
21 Klein C A, Blankenstein TJ, Schmidt Kittler O, et al. Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer [J]. Lancet, 2002, 360 (9334) :683 - 689
22 Slade MJ, Smith BM, Sinnett HD, et al. Quantitative polymerase chain reaction for the detection of micrometastases in patients with breast cancer J Clin Oncol, 1999: 17:870-879
23 龚非力. 医学免疫学[M]. 北京:科学出版社, 2000
24 Frances S, Kenny, Rina H, et al. Overexpression of cyclin D1 messen -ger RNA predicts for poor prognosis in estrogen receptor positive breast cance〔rJ〕. Clinical Cancer Research, 1999, 5: 2069
25 Schmidt Wolf IG, Negrin RS, Kiem HP, et al. Use of a SCID mouse human lymphoma model to evaluate cytokine induced killer cells with potent antitumor cell activity [J]. J Exp Med, 1991, 174(1): 139-149
26 Micheletti F, Bazzaro M, Canella A, et al. The lifespan of major histo compatibility complex class-Ι/ peptide complexes determinesthe efficiency of cytotoxic Tlymphocyte responses [J]. Immunology, 1999, 96 (3): 411 - 415
27 Idmann TA, Dubois S, Tagaya Y, et al. Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes implications for immuno -therapy [J]. Immunity, 2001,14: 105 - 110
28 Mohamadzadeh M, Ronald L. Dendritic cells: In the forefront ofimmunopathogensis and vaccine development-A review. J Immune Based Ther Vaccine, 2004, 2(1): 1-14
29 Heiser A, Coleman D, Dannull J. et al. Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL reponses against metastatic prostate tumors. J Clin Invest, 2002, 109(3): 409-417 10 Jefford M, Maraskovsky E, Cebon J, et al. The use of dendritic cells in cancer therapy. Lancet, 2001, 2(6): 343-353
30 Micheletti F, Bazzaro M, Canella A, et al. The lifespan of majohistocompatibility complex class-Ι/ peptide complexes determinesthe efficiency of cytotoxic Tlymphocyte responses [J]. Immunology, 1999, 96 (3): 411 - 415
31 Illing RO, Kennedy JE, Wu F. The safety and feasibility of extracorpo real high intensity focused ultrasound (HIFU) for the treatment of liver and kidney tumors in a Western population [J]. Br J Cancer, 2005, 17: 890
32 Toes RE, van der Voort EIH, Schoenberger SP, et al. Enhancement of tumor out growth through CTL tolerization after peptide vaccination is avoided by peptide presentation on dendriticcells [J]. J Immunol, 1998, 160(9): 4449- 4456
33 Leaschow D, Waluoas TL, Blucslod SA. CD28/ B7 system of T cell costimulstion. Ann Rev Immunol, 1996, 14: 233-258
34 Flood PM, Horvat B, Loukides JA. et al. Production of interleukin-2 and interleukin-4 by immune CD4ˉCD8+andtheir role in the generate on of antigen-specific cytotoxic T cells. Eur J Immunol. 1991, 21 (8): 186
35 Murphy GP, Tjoa BA, Simmons SJ, et al. Phase I prostate cancer vaccine trial: report of a study involving 37 patients with disease recurrence following primary treatment. Prostate. 1999, 39: 54-59
36 刘运江,张建立,单保恩. 乳腺癌患者腋窝淋巴结来源的DC体外诱导肿瘤特异性CTL的实验研究. 细胞与分子免疫学杂志, 2007, 23(1): 60 - 63
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