P53、Ki-67基因表达与膀胱癌相关性的回顾性研究
摘要
膀胱癌是我国泌尿外科最常见的肿瘤,占全部恶性肿瘤的3.2%,其中尿路上皮癌占95%以上。膀胱癌生物学行为复杂,具有好多发、易复发的特点,随着肿瘤复发,膀胱癌具有低分化和浸润性生长的倾向。其生物学特征及其临床发展过程并未完全明了。抑癌基因p53所编码的核蛋白,通过调节细胞的增殖周期,诱导DNA受损的细胞凋亡而起到抑癌作用。p53基因易发生突变,其变异的蛋白将失去抑癌作用。Ki-67即细胞核相关抗原(nuclear-associated antigen ki-67)是一种与细胞增殖密切相关的核抗原,在增殖细胞中表达,而在静止细胞中则不表达,Ki-67的异常表达反映了肿瘤细胞的增殖活性。Ki-67是反映癌细胞增殖能力的较好指标。本文查阅2005年3月~2007年12月份膀胱癌患者住院病历,术前未经过化疗、免疫、放射治疗,术后行免疫组化检测p53、Ki-67表达情况,共计149例,患者病历资料完整。统计结果显示p53及Ki-67的表达与膀胱癌的病理分级、临床分期呈正相关, P53、Ki-63共同表达阳性组复发率较单一阳性或阴性组复发率高(P<0.01),说明p53和Ki-67联合表达是判断肿瘤复发更可靠的指标。由此推论通过检测p53、Ki-67在膀胱癌中的表达情况,分析其与膀胱癌的发生、发展的关系,可以判断膀胱癌的恶性程度、预后估计及指导临床术后辅助治疗方案的制定。
Objective: To explore the relationship between the expression of p53 and Ki-67 and patterns, grades and stages of the bladder carcinoma, and evaluate correlation of p53, Ki-67 expression and the bladder carcinoma. Through the expression of P53 and Ki-67, we could judge the prognosis of bladder carcinoma and guide the clinical treatment correctly.
Methods: We collected clinical information of 149 patients with bladder carcinoma treated from March 2005 to December 2007 in the urology department of first Hospital in Jilin University. The collected information included: sexuality, age, preoperative status, clinical stage, operative method, postoperative irrigation method, pathologic grade, p53 expression (>20% was positive), Ki-67 expression (>20% was positive). We followed up patients through out-patient clinic and telephone, and the follow-up period was from three months to two years after operation.
Results:
1. We collected 149 cases. 114 were male and 35 were female. The ages were from 28 to 90, and the mid-age was 66 years old. Pathologic grade: I was 4, and II was 115, and III was 30 cases. Clinical stage: Ta-T1 (superficial pattern) was 84 and T2-T4 (invasive pattern) was 65 cases.
2. P53 and Ki-67 gene expressions were not correlated with age, sexuality, the number and the size of tumors (P>0.05).
3. Positive expressions in I-II grade tumors were 58.8% (P53) and 64.7% (Ki-67) respectively. The positive expressions in III grade tumor were 80.0% (p53) and 90.0% (Ki-67). The differences of the gene expression in two groups had statistical significance (P<0.05). Along with the advance of pathologic grades, the gene expression rates also increased.
4. The expression rates in Ta-T1 (superficial type) tumors were 56.0% (p53) and 63.1% (Ki-67). The expression rates in T2-T4 (invasive type) tumors were 72.3% (p53) and 78.3% (Ki-67). The expressions of p53 and Ki-67 in invasive type bladder carcinoma were both higher than the superficial type and the differences had statistical significance (P<0.05).
5. The expression rate in the high-grade and advanced-stage group (66.7%; 58.5%) was higher than low-grade and early-stage group (42.0%; 38.1%). The difference had statistical significance (P<0.05).
6. Follow-up: We followed up 128 cases of 149 cases. The follow-up rate was 86%. The case with bladder remained were 120, recurrence were in 31 cases, the recurrence rate was 25.8% (31/120). The recurrence rate of p53 and Ki-67 co-expression positive were 37.5% (21/56). The recurrence rate of the single positive expression and negative expression were 15.6% (10/64). The difference between the two groups were statistical significant (X2=7.46, P<0.01).
Conclusion:
1. The expression of p53 protein had a close relationship with clinical stages and pathologic grades of the bladder carcinoma. The overexpression of p53 in the bladder carcinoma suggests high malignancy and poor prognosis.
2. The expression of Ki-67 protein increased with the advancement of clinical stages and pathologic grades. It can be one of the tumor markers that could evaluate the biological behavior of bladder carcinoma.
3. The recurrence rate in the group of p53 and Ki-67 positive co-expression were higher than the group of single positive and negative. That suggests p53 and Ki-67 positive co-expression has a correlation with bladder carcinoma recurrence.
4. Through detecting the expression of p53 and Ki-67 in bladder carcinoma, we could determine the malignant potent and prognosis of the cancer, and it also can help us to make the adjunctive therapy after operation.
Objective: To explore the relationship between the expression of p53 and Ki-67 and patterns, grades and stages of the bladder carcinoma, and evaluate correlation of p53, Ki-67 expression and the bladder carcinoma. Through the expression of P53 and Ki-67, we could judge the prognosis of bladder carcinoma and guide the clinical treatment correctly.
Methods: We collected clinical information of 149 patients with bladder carcinoma treated from March 2005 to December 2007 in the urology department of first Hospital in Jilin University. The collected information included: sexuality, age, preoperative status, clinical stage, operative method, postoperative irrigation method, pathologic grade, p53 expression (>20% was positive), Ki-67 expression (>20% was positive). We followed up patients through out-patient clinic and telephone, and the follow-up period was from three months to two years after operation.
Results:
1. We collected 149 cases. 114 were male and 35 were female. The ages were from 28 to 90, and the mid-age was 66 years old. Pathologic grade: I was 4, and II was 115, and III was 30 cases. Clinical stage: Ta-T1 (superficial pattern) was 84 and T2-T4 (invasive pattern) was 65 cases.
2. P53 and Ki-67 gene expressions were not correlated with age, sexuality, the number and the size of tumors (P>0.05).
3. Positive expressions in I-II grade tumors were 58.8% (P53) and 64.7% (Ki-67) respectively. The positive expressions in III grade tumor were 80.0% (p53) and 90.0% (Ki-67). The differences of the gene expression in two groups had statistical significance (P<0.05). Along with the advance of pathologic grades, the gene expression rates also increased.
4. The expression rates in Ta-T1 (superficial type) tumors were 56.0% (p53) and 63.1% (Ki-67). The expression rates in T2-T4 (invasive type) tumors were 72.3% (p53) and 78.3% (Ki-67). The expressions of p53 and Ki-67 in invasive type bladder carcinoma were both higher than the superficial type and the differences had statistical significance (P<0.05).
5. The expression rate in the high-grade and advanced-stage group (66.7%; 58.5%) was higher than low-grade and early-stage group (42.0%; 38.1%). The difference had statistical significance (P<0.05).
6. Follow-up: We followed up 128 cases of 149 cases. The follow-up rate was 86%. The case with bladder remained were 120, recurrence were in 31 cases, the recurrence rate was 25.8% (31/120). The recurrence rate of p53 and Ki-67 co-expression positive were 37.5% (21/56). The recurrence rate of the single positive expression and negative expression were 15.6% (10/64). The difference between the two groups were statistical significant (X2=7.46, P<0.01).
Conclusion:
1. The expression of p53 protein had a close relationship with clinical stages and pathologic grades of the bladder carcinoma. The overexpression of p53 in the bladder carcinoma suggests high malignancy and poor prognosis.
2. The expression of Ki-67 protein increased with the advancement of clinical stages and pathologic grades. It can be one of the tumor markers that could evaluate the biological behavior of bladder carcinoma.
3. The recurrence rate in the group of p53 and Ki-67 positive co-expression were higher than the group of single positive and negative. That suggests p53 and Ki-67 positive co-expression has a correlation with bladder carcinoma recurrence.
4. Through detecting the expression of p53 and Ki-67 in bladder carcinoma, we could determine the malignant potent and prognosis of the cancer, and it also can help us to make the adjunctive therapy after operation.
引文
1. 郭应禄主编. 泌尿. 男性生殖系肿瘤. 北京人民卫生出版社, 2000,25-43.
2. Lann DL. Proplylaxis for recurrent transitional cell carcinoma. Uroloy, 1991,37(Suppl 5):21.
3. Gerdes J, S chwab U, LemkeH, et al. Int J Cancer, 1983,31:13-15.
4. Fujimoto K, Yamada Y, Okajima E, et al. Frequent association of P53 gene mutation in invasive bladder cancer [J]. Cancer Res, 1992,52:1393-1398.
5. Levine AJ, Momand J, Finlay CA. The p53 tumor suppressor gene [J]. Nature, l99l,351:453-457.
6. 吴明明, 马洪顺, 虞颂庭, 等. 癌基因P53及其蛋白产物表达与膀胱癌发生及病理关系[J]. 中华泌尿外科杂志, 1994,15: 412-414.
7. Wu TT, Lee YH, Huang JK. p53 mutation and bcl-2 expression in transitional cell carcinoma of the urinary bladder [J]. Zhonghua Yi Xue Za Zhi (Taipei). 2001,64(1):9-14.
8. Vet JAM, Witjes JA, Marras SAE, et al. Predictive value of p53 mutations analyzed in bladder washings for progression of high risk superficial bladder cancer. Clin Cancer Res, 1996,2: 1055-1061.
9. Sarkis AS, Dalbagin G, Gordon C, et al. Nuclear over expression of P53 protein in transitional cell bladder carcinoma: a marker fordisease progression. J Natl Cancer Inst, 1993,85:53-59.
10. Wang X, Jones TD, Maclennan GT, et al. P53 expression in small cell carcinoma of the urinary bladder: biological and prognostic implications [J]. Anticancer Res. 2005,25(3B):2001-2004.
11. 王春喜, 王立波, 候宇川, 等. P53 蛋白表达与膀胱移行细胞癌临床病理及预后关系的研究. 白求恩医科大学学报, 2001,27(6): 614-616.
12. Gonter P, Casetta G, Zitella A, et al. Evaluation of p53 protein overexpression, Ki-67 proliferative activity and mitotic index as markers of tumour recurrence in superficial transitional cell carcinoma of the bladder [J]. Eur Urol, 2000,38(3):287-296.
13. Kilicli-Camur N, Kilicaslan I, Gulluoglu MG, et al. Impact of p53 and Ki-67 in predicting recurrence and progression of superficial l (pTa and pT1) urothelial cell carcinomas of urinary bladder [J]. PatholInt, 2002,52(7):463-469.
14. Cheng HL, Trink B, Tzai TS, et al. Overexpression of c-met as a prognostic indicator for transitional cell carcinoma of the urinary bladder: a comparison with p53 nuclear accumulation [J]. J Clin Oncol, 2002,20(6):1544-1550.
15. Wade M, Seigne JD. Surgical management of bladder cancer in 2003 [J]. Expert Rev Anticancer Ther, 2003,3(6):781-792.
16. Bernardini S, Billerey C, Martin M, et al. The predictive value of muscularis mucosse invasion and p53 overexpression on progression of stage T1 bladder carcinoma [J]. J Urol, 2001,165(1):42-46.
17. Saint F, Salomon L, Quintela R, et al. Do prognostic parameters of remission versus relapse after Bacillus Calmette-Guerin (BCG) immunotherapy exist ? analysis of a quarter century of literature [J]. Eur Urol, 2003, 43(4): 351-360.
18. Fontana D, Bellina M, Galietti F, et al. Intravesical bacillus calmette guerin (BCG) as inducer of tumor-suppressing proteins p53 and p21 Waf1-Cip1 during treatment of superficial bladder cancer [J]. J Urol, 1999,162(1):225-230.
19. Smith ND, Rubenstein JN, Eggener SE, et al. The p53 tumor suppress gene and nuclear protein: basic science review and relevance in the management of bladder cancer [J]. J Urol, 2003, 169(4):1219-1228.
20. Esrig D, Elmajian D, Groshen S, et al. Accumulation of nuclear p53 and tumor progression in bladder cancer [J]. N Engl J Med, 1994,331(19):1259-1264.
21. Pagliaro L C, Keyhani A, Williams D, et al. Repeated intravesical instilllations of an adenoviral vector in patients with locally advanced bladder cancer: a phase I study of p53 gene therapy [J]. J Clin Oncol, 2003,21(12):2247-2253.
22. Rotterud R, Berner A, Holm R, et al. Cell cycle inhibitors and outcome after radiotherapy in bladder cancer patients [J]. Acta Oncol, 2002,41(5):463-470.
23. Ramos SD, Navarra FS, Villamon FR, et al. Comparative study ofp53, Bcl-2, and C-erbB-2 expression in low-grade papillary bladder tumors [J]. Arch Esp Urol, 2003,56(3):277-285.
24. Okamura K, Miyake K, Koshikawa T, et al. Growth fractions of transitional cell carcinomas of the bladder defined by the monoclonal antibody Ki-67. J Urol, 1990 Oct; 144(4): 875-878.
25. 林秀芳, 杨发端, 黄 旭, 等. Ki-67 抗原表达与膀胱癌生物学行为的关系. 临床与实验病理学杂志, 2000 feb; 16(1):54.
26. Bozlu M, Orhan D, Baltacl S, et al. The prognostic value of proliferating cell nuclear antigen, Ki-67 and nuclear organizer region in transitional cell carcinoma of the bladder [J]. Int Urol Nephrol, 2002,33(1):59.
27. Krause FS, Fell G, Biehler KH. Immunohistochemical examina- tions (Ki67, p53, nm23) and DNA cytophotometry in bladder cancer [J]. Anticancer Res, 2000, 20(6D): 5023.
28. 桂律, 许祖德, 罗金芳, 等. 膀胱尿路上皮癌 MMP-2 表达及其与 FAK, p53, bcl-2, Ki-67 的关系. 临床与实验病理学杂志, 2003Feb;19(1):63-66.
29. 王平, 董德平, 陈莉, 等. Survivin, Ki67 在膀胱癌中的表达及其临床意义. 中华实验外科杂志, 2006,23(6):765.
30. Tsuji M, Kojima K, Murakami Y, et al. Prognostic value of Ki-67 antigen and p53 protein in urinary bladder cancer: immunohis- tochemical analysis of radical cystectomy specimens. Br J Urol; 1997,79: 367-372.
31. Zlotta AR, Schulman CC. Biological markers in superficial bladder tumors and their prognostic significance. Urol Clin North Am, 2000 Feb; 27(1): 179-89.
32. Valero Puerto JA, Redondo Martinez E. Jiemenez Gon zalez C, et a1. Inverted transitional cell papilloma: the expression of the ki-67 nuclear antigen as a prognostic factor. Arch Esp Urol, 1995,48: 887-895.
1. 吴阶平主编 . 泌尿外科学 . 济南 : 山东科学技术出版社 , 2005;965.
2. Lann DL. Proplylaxis for recurrent transitional cell carcinoma. Uroloy, 1991,37(Suppl5):21.
3. Levine AJ, Momand J, Finlay CA. The p53 tumor suppressor gene [J]. Nature, l99l(351):453-57.
4. Gerdes J, Schwab U, Lemke H. et a1. Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Caner, 1983.31:13-15.
5. Di Giuseppc JA, Redston MS, Yeo CJ, et al. p53-independent expression of the cyclin-dependent kinase in hibitor P21 in pancreatic carcinoma. Am J Pathol, 1995;47:884-888.
6. Al-Sukhun S and Hussain M: Current understanding of the biology of advanced bladder cancer [J]. Cancer, 2003,97(suppl 8):2064-2075.
7. 吴明明, 马洪顺, 虞颂庭, 等. 癌基因P53及其蛋白产物表达与膀胱癌发生及病理关系 [J]. 中华泌尿外科杂志. 1994,15: 412-414.
8. Wu TT, Lee YH, Huang JK. p53 mutation and bcl-2 expression in transitional cell carcinoma of the urinary bladder [J]. Zhonghua Yi Xue Za Zhi (Taipei). 2001,64(1):9-14.
9. Vet JAM, Witjes JA, Marras SAE, et al. Predictive value of p53mutations analyzed in bladder washings for progression of high risk superficial bladder cancer. Clin Cancer Res, 1996,2: 1055-1061.
10. Sarkis AS, Dalbagin G, Gordon C, et al. Nuclear over expression of P53 protein in transitional cell bladder carcinoma: a marker for disease progression. J Natl Cancer Inst, 1993;85:53-59.
11. 王春喜, 王立波, 候宇川, 等. P53 蛋白表达与膀胱移行细胞癌临 床 病 理 及 预 后 关 系 的 研 究 . 白 求 恩 医 科 大 学 学 报 , 2001;27(6):614-616.
12. 周兴, 梅骅, 刘春晓. 膀胱癌 p53 蛋白核蓄积的临床意义. 现代泌尿外科杂志. 2000;5(3):132-135.
13. Wang X, Jones TD, Maclennan GT, et al. P53 expression in small cell carcinoma of the urinary bladder: biological and prognostic implications [J]. Anticancer Res. 2005,25(3B):2001-2004.
14. Bates SA, Phillips P, Clarke, et al. p14ARF links the tumor supperssors RB and p53. Nature, 1998,395(6698):124-125.
15. Piston E, Faynel J. p53 immunodetection of liquid-based processed urinary samples helps to identify bladder tumors with a higher risk of progression [J]. Br J Cancer, 2005,93(2):242-247.
16. Wong FW. Immunohistochemical antibody Ki-67. Gynecol Obster, 1994,37:123.
17. Popov Z, Gil-Diez-De-Medina S, Ravery V, et a1. Prognostic value of EGF receptor and tumor cell proliferation in bladder cancer: therapeutic implications. Urol Oncol, 2004,22(2):93.
18. Stavropoulos NE, Filiadis I, Ioaehim E, et a1. Prognostic significance of p53, bcl-2 and Ki-67 in high risk superficial bladder cancer. Anticancer Res, 2002,22(6B):3759.
19. Bozlu M, Orhan D, Baltacl S, et al. The prognostic value of proliferating cell nuclear antigen, Ki-67 and nuclear organizer region in transitional cell carcinoma of the bladder [J]. Int Urol Nephrol, 2002,33(1):59.
20. Nakopoulo L, Vourlakou C, Zervas A, et al. The prevalence of bcl-2, p53 and Ki-67 immunofeaetivity in transitional cell bladder carcinoma and their clinicopathologic correlates [J]. Hum Pathol, 1998,29(2): 146.
21. Pfistcr C, Laeombe K, Vezina MC, et al. Prognostic value of the proliferative index determined by Ki-67 immunostaining in superficial bladder tumors [J]. Hum Pathol. 1999,30(11):1350.
22. Krause FS, Fell G, Biehler KH. Immunohistochemical examina- tions (Ki67, p53, nm23) and DNA cytophotometry in bladder cancer [J]. Anticancer Res, 2000,20(6D):5023.
23. 桂律, 许祖德, 罗金芳, 等. 膀胱尿路上皮癌 MMP-2 表达及其与 FAK, p53, bcl-2, Ki-67 的关系. 临床与实验病理学杂志. 2003Feb;19(1):63-66.
24. 王平, 董德平, 陈莉, 等. Survivin, Ki67 在膀胱癌中的表达及其临床意义. 中华实验外科杂志. 2006,23(6):765.
25. Valero Puerto JA, Redondo Martinez E. Jiemenez Gon zalez C, et a1. Inverted transitional cell papilloma:the expression of the ki-67nuclear antigen as a prognostic factor. Arch Esp Urol, 1995,48: 887-895.
26. 张磊, 洪宝发, 徐阿祥, 等. 浅表性膀胱癌组织学形态及Ki-67、p53 表达与肿瘤复发的关系. 解放军医学杂志, 2005, 30(9):804-806.
27. Fradet Y. Molecular and immunologic approaches in the manage- ment of bladder cancer. Urologic Clinics of North America, 1992, 18:515.
28. Fradet Y. Markers of prognosis in superficial bladder cancer. Semin Urol, 1992,1:28.
2. Lann DL. Proplylaxis for recurrent transitional cell carcinoma. Uroloy, 1991,37(Suppl 5):21.
3. Gerdes J, S chwab U, LemkeH, et al. Int J Cancer, 1983,31:13-15.
4. Fujimoto K, Yamada Y, Okajima E, et al. Frequent association of P53 gene mutation in invasive bladder cancer [J]. Cancer Res, 1992,52:1393-1398.
5. Levine AJ, Momand J, Finlay CA. The p53 tumor suppressor gene [J]. Nature, l99l,351:453-457.
6. 吴明明, 马洪顺, 虞颂庭, 等. 癌基因P53及其蛋白产物表达与膀胱癌发生及病理关系[J]. 中华泌尿外科杂志, 1994,15: 412-414.
7. Wu TT, Lee YH, Huang JK. p53 mutation and bcl-2 expression in transitional cell carcinoma of the urinary bladder [J]. Zhonghua Yi Xue Za Zhi (Taipei). 2001,64(1):9-14.
8. Vet JAM, Witjes JA, Marras SAE, et al. Predictive value of p53 mutations analyzed in bladder washings for progression of high risk superficial bladder cancer. Clin Cancer Res, 1996,2: 1055-1061.
9. Sarkis AS, Dalbagin G, Gordon C, et al. Nuclear over expression of P53 protein in transitional cell bladder carcinoma: a marker fordisease progression. J Natl Cancer Inst, 1993,85:53-59.
10. Wang X, Jones TD, Maclennan GT, et al. P53 expression in small cell carcinoma of the urinary bladder: biological and prognostic implications [J]. Anticancer Res. 2005,25(3B):2001-2004.
11. 王春喜, 王立波, 候宇川, 等. P53 蛋白表达与膀胱移行细胞癌临床病理及预后关系的研究. 白求恩医科大学学报, 2001,27(6): 614-616.
12. Gonter P, Casetta G, Zitella A, et al. Evaluation of p53 protein overexpression, Ki-67 proliferative activity and mitotic index as markers of tumour recurrence in superficial transitional cell carcinoma of the bladder [J]. Eur Urol, 2000,38(3):287-296.
13. Kilicli-Camur N, Kilicaslan I, Gulluoglu MG, et al. Impact of p53 and Ki-67 in predicting recurrence and progression of superficial l (pTa and pT1) urothelial cell carcinomas of urinary bladder [J]. PatholInt, 2002,52(7):463-469.
14. Cheng HL, Trink B, Tzai TS, et al. Overexpression of c-met as a prognostic indicator for transitional cell carcinoma of the urinary bladder: a comparison with p53 nuclear accumulation [J]. J Clin Oncol, 2002,20(6):1544-1550.
15. Wade M, Seigne JD. Surgical management of bladder cancer in 2003 [J]. Expert Rev Anticancer Ther, 2003,3(6):781-792.
16. Bernardini S, Billerey C, Martin M, et al. The predictive value of muscularis mucosse invasion and p53 overexpression on progression of stage T1 bladder carcinoma [J]. J Urol, 2001,165(1):42-46.
17. Saint F, Salomon L, Quintela R, et al. Do prognostic parameters of remission versus relapse after Bacillus Calmette-Guerin (BCG) immunotherapy exist ? analysis of a quarter century of literature [J]. Eur Urol, 2003, 43(4): 351-360.
18. Fontana D, Bellina M, Galietti F, et al. Intravesical bacillus calmette guerin (BCG) as inducer of tumor-suppressing proteins p53 and p21 Waf1-Cip1 during treatment of superficial bladder cancer [J]. J Urol, 1999,162(1):225-230.
19. Smith ND, Rubenstein JN, Eggener SE, et al. The p53 tumor suppress gene and nuclear protein: basic science review and relevance in the management of bladder cancer [J]. J Urol, 2003, 169(4):1219-1228.
20. Esrig D, Elmajian D, Groshen S, et al. Accumulation of nuclear p53 and tumor progression in bladder cancer [J]. N Engl J Med, 1994,331(19):1259-1264.
21. Pagliaro L C, Keyhani A, Williams D, et al. Repeated intravesical instilllations of an adenoviral vector in patients with locally advanced bladder cancer: a phase I study of p53 gene therapy [J]. J Clin Oncol, 2003,21(12):2247-2253.
22. Rotterud R, Berner A, Holm R, et al. Cell cycle inhibitors and outcome after radiotherapy in bladder cancer patients [J]. Acta Oncol, 2002,41(5):463-470.
23. Ramos SD, Navarra FS, Villamon FR, et al. Comparative study ofp53, Bcl-2, and C-erbB-2 expression in low-grade papillary bladder tumors [J]. Arch Esp Urol, 2003,56(3):277-285.
24. Okamura K, Miyake K, Koshikawa T, et al. Growth fractions of transitional cell carcinomas of the bladder defined by the monoclonal antibody Ki-67. J Urol, 1990 Oct; 144(4): 875-878.
25. 林秀芳, 杨发端, 黄 旭, 等. Ki-67 抗原表达与膀胱癌生物学行为的关系. 临床与实验病理学杂志, 2000 feb; 16(1):54.
26. Bozlu M, Orhan D, Baltacl S, et al. The prognostic value of proliferating cell nuclear antigen, Ki-67 and nuclear organizer region in transitional cell carcinoma of the bladder [J]. Int Urol Nephrol, 2002,33(1):59.
27. Krause FS, Fell G, Biehler KH. Immunohistochemical examina- tions (Ki67, p53, nm23) and DNA cytophotometry in bladder cancer [J]. Anticancer Res, 2000, 20(6D): 5023.
28. 桂律, 许祖德, 罗金芳, 等. 膀胱尿路上皮癌 MMP-2 表达及其与 FAK, p53, bcl-2, Ki-67 的关系. 临床与实验病理学杂志, 2003Feb;19(1):63-66.
29. 王平, 董德平, 陈莉, 等. Survivin, Ki67 在膀胱癌中的表达及其临床意义. 中华实验外科杂志, 2006,23(6):765.
30. Tsuji M, Kojima K, Murakami Y, et al. Prognostic value of Ki-67 antigen and p53 protein in urinary bladder cancer: immunohis- tochemical analysis of radical cystectomy specimens. Br J Urol; 1997,79: 367-372.
31. Zlotta AR, Schulman CC. Biological markers in superficial bladder tumors and their prognostic significance. Urol Clin North Am, 2000 Feb; 27(1): 179-89.
32. Valero Puerto JA, Redondo Martinez E. Jiemenez Gon zalez C, et a1. Inverted transitional cell papilloma: the expression of the ki-67 nuclear antigen as a prognostic factor. Arch Esp Urol, 1995,48: 887-895.
1. 吴阶平主编 . 泌尿外科学 . 济南 : 山东科学技术出版社 , 2005;965.
2. Lann DL. Proplylaxis for recurrent transitional cell carcinoma. Uroloy, 1991,37(Suppl5):21.
3. Levine AJ, Momand J, Finlay CA. The p53 tumor suppressor gene [J]. Nature, l99l(351):453-57.
4. Gerdes J, Schwab U, Lemke H. et a1. Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Caner, 1983.31:13-15.
5. Di Giuseppc JA, Redston MS, Yeo CJ, et al. p53-independent expression of the cyclin-dependent kinase in hibitor P21 in pancreatic carcinoma. Am J Pathol, 1995;47:884-888.
6. Al-Sukhun S and Hussain M: Current understanding of the biology of advanced bladder cancer [J]. Cancer, 2003,97(suppl 8):2064-2075.
7. 吴明明, 马洪顺, 虞颂庭, 等. 癌基因P53及其蛋白产物表达与膀胱癌发生及病理关系 [J]. 中华泌尿外科杂志. 1994,15: 412-414.
8. Wu TT, Lee YH, Huang JK. p53 mutation and bcl-2 expression in transitional cell carcinoma of the urinary bladder [J]. Zhonghua Yi Xue Za Zhi (Taipei). 2001,64(1):9-14.
9. Vet JAM, Witjes JA, Marras SAE, et al. Predictive value of p53mutations analyzed in bladder washings for progression of high risk superficial bladder cancer. Clin Cancer Res, 1996,2: 1055-1061.
10. Sarkis AS, Dalbagin G, Gordon C, et al. Nuclear over expression of P53 protein in transitional cell bladder carcinoma: a marker for disease progression. J Natl Cancer Inst, 1993;85:53-59.
11. 王春喜, 王立波, 候宇川, 等. P53 蛋白表达与膀胱移行细胞癌临 床 病 理 及 预 后 关 系 的 研 究 . 白 求 恩 医 科 大 学 学 报 , 2001;27(6):614-616.
12. 周兴, 梅骅, 刘春晓. 膀胱癌 p53 蛋白核蓄积的临床意义. 现代泌尿外科杂志. 2000;5(3):132-135.
13. Wang X, Jones TD, Maclennan GT, et al. P53 expression in small cell carcinoma of the urinary bladder: biological and prognostic implications [J]. Anticancer Res. 2005,25(3B):2001-2004.
14. Bates SA, Phillips P, Clarke, et al. p14ARF links the tumor supperssors RB and p53. Nature, 1998,395(6698):124-125.
15. Piston E, Faynel J. p53 immunodetection of liquid-based processed urinary samples helps to identify bladder tumors with a higher risk of progression [J]. Br J Cancer, 2005,93(2):242-247.
16. Wong FW. Immunohistochemical antibody Ki-67. Gynecol Obster, 1994,37:123.
17. Popov Z, Gil-Diez-De-Medina S, Ravery V, et a1. Prognostic value of EGF receptor and tumor cell proliferation in bladder cancer: therapeutic implications. Urol Oncol, 2004,22(2):93.
18. Stavropoulos NE, Filiadis I, Ioaehim E, et a1. Prognostic significance of p53, bcl-2 and Ki-67 in high risk superficial bladder cancer. Anticancer Res, 2002,22(6B):3759.
19. Bozlu M, Orhan D, Baltacl S, et al. The prognostic value of proliferating cell nuclear antigen, Ki-67 and nuclear organizer region in transitional cell carcinoma of the bladder [J]. Int Urol Nephrol, 2002,33(1):59.
20. Nakopoulo L, Vourlakou C, Zervas A, et al. The prevalence of bcl-2, p53 and Ki-67 immunofeaetivity in transitional cell bladder carcinoma and their clinicopathologic correlates [J]. Hum Pathol, 1998,29(2): 146.
21. Pfistcr C, Laeombe K, Vezina MC, et al. Prognostic value of the proliferative index determined by Ki-67 immunostaining in superficial bladder tumors [J]. Hum Pathol. 1999,30(11):1350.
22. Krause FS, Fell G, Biehler KH. Immunohistochemical examina- tions (Ki67, p53, nm23) and DNA cytophotometry in bladder cancer [J]. Anticancer Res, 2000,20(6D):5023.
23. 桂律, 许祖德, 罗金芳, 等. 膀胱尿路上皮癌 MMP-2 表达及其与 FAK, p53, bcl-2, Ki-67 的关系. 临床与实验病理学杂志. 2003Feb;19(1):63-66.
24. 王平, 董德平, 陈莉, 等. Survivin, Ki67 在膀胱癌中的表达及其临床意义. 中华实验外科杂志. 2006,23(6):765.
25. Valero Puerto JA, Redondo Martinez E. Jiemenez Gon zalez C, et a1. Inverted transitional cell papilloma:the expression of the ki-67nuclear antigen as a prognostic factor. Arch Esp Urol, 1995,48: 887-895.
26. 张磊, 洪宝发, 徐阿祥, 等. 浅表性膀胱癌组织学形态及Ki-67、p53 表达与肿瘤复发的关系. 解放军医学杂志, 2005, 30(9):804-806.
27. Fradet Y. Molecular and immunologic approaches in the manage- ment of bladder cancer. Urologic Clinics of North America, 1992, 18:515.
28. Fradet Y. Markers of prognosis in superficial bladder cancer. Semin Urol, 1992,1:28.