宫颈上皮内瘤变的当前治疗与术后随诊模式的研究及P16～（INK4a）与HPVDNA杂交捕获II检测在该病诊断和随诊中的价值
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摘要
CIN的当前治疗与术后随诊模式的研究及P16~(INK4a)与HPVDNA杂交捕获Ⅱ检测在CIN诊断和随诊中的价值
研究背景
由于细胞学筛查技术的迅速发展，使得宫颈癌前病变的早期诊断成为可能。同时治疗方法也逐渐标准化：CO_2激光以及LEEP目前已成为治疗CIN的主要方法，特别是对年轻、要求保留生育功能的妇女。但在行局部破坏性治疗或LLETZ治疗后均有一定数目的复发，因此，加强治疗后的随诊及了解与复发有关的危险因素对于预防复发与治疗同样是非常重要的。对于激光治疗不同级别CIN的预后及细胞学联合阴道镜随诊的模式是否优于单独细胞学，目前国内尚无研究。已有文献报道，LLETZ术后影响CIN复发的因素是复杂、多因素的，各家报道结果也不完全一致。对于LLETZ切除CIN标本边缘的详细分析以及标本大小、数目等相关因素尚未见报道。采用新的，更为敏感的方法用于术后随诊是当今研究的热点，如何提高目前现有随诊筛查方法的准确性，及时发现具有复发高危因素的人群具有重要意义。
宫颈腺癌发生率目前占所有宫颈发生率的19％-25％，使用目前的筛查方法对宫颈腺癌的癌前病变的诊断率较低，是宫颈腺癌发生率呈上升趋势的一个主要原因之一。流行病调查结果发现，ACIS在生育年龄的妇女中发生率较高。因此，美国ASCCP以及澳大利亚的宫颈病变临床治疗规范中提出对生育年龄、要求保留生育能力的ACIS或宫颈腺癌IA(1)的患者可实施保守性手术治疗，而对于已生育或不再要求生育的妇女可实施单纯全子宫切除术。对于切缘阳性的妇女可进一步锥切，否则行全子宫切除术。在我国ACIS的发生率也有升高的趋势，但实施保留生育能力手术的妇女为数不多，因此，对于实施保留生育功能手术的ACIS患者的诊断、手术方法及术后随诊模式及预后的研究，对如何管理年轻ACIS患者的具有重要的指导意义。
Study on current protocols for CIN treatment and post-operative follow up and the value of p16~(INK4a) and HPV hybrid capture II used in diagnosis for CIN and post-treatment follow-up
BACKGROUND
With the rapidly development of cytology screen technology, it makes it possible for early diagnosis cervical precancer before it change into cancer. Meanwhile, the main treatment modalities for the management of histological proven CIN, such as CO_2 laser vaporization and conization have been the most effective methods for CIN, especially for young women who want to keep their fertility. But recurrence of CIN after local treatment indicates the necessary and importance for understand the risk factors related to recurrence for surveillance patients. It was reported that the factors effect the relapse of CIN were complicated and multi-factors.
The procotols for post-operative follow up is the focus on this field at present .How to improve the accuracy of the screening methods for follow up and find the group people with high risk factors for recurrence and reduce the frequencies of low risk group of patients are very important.
The incidence of adenocarcinoma now account for as many as 19% of all cervical cancers. One of the reason is that cervical screening is less effective at preventing cervical adenocarcinoma than squamous carcinoma. Adenocarcinoma or ACIS is also significantly related to HR-HPV infection. Epidemiological investigation showed that the incidence of ACIS among reproductive women was high. Therefore, ASCCP and Australia National Cervical Intraepithelial Neoplasma Diagnosis and Treatment guidelines suggest that conservative operation can be performed on young women with ACIS or adenocarcinoma LA (1) desiring to keep their reproductive capactivity, hysterectomy is recommended for young women who already have completed child bearing. If the margins of the initial cone biopsy are involved by ACIS, then a further
研究背景
由于细胞学筛查技术的迅速发展，使得宫颈癌前病变的早期诊断成为可能。同时治疗方法也逐渐标准化：CO_2激光以及LEEP目前已成为治疗CIN的主要方法，特别是对年轻、要求保留生育功能的妇女。但在行局部破坏性治疗或LLETZ治疗后均有一定数目的复发，因此，加强治疗后的随诊及了解与复发有关的危险因素对于预防复发与治疗同样是非常重要的。对于激光治疗不同级别CIN的预后及细胞学联合阴道镜随诊的模式是否优于单独细胞学，目前国内尚无研究。已有文献报道，LLETZ术后影响CIN复发的因素是复杂、多因素的，各家报道结果也不完全一致。对于LLETZ切除CIN标本边缘的详细分析以及标本大小、数目等相关因素尚未见报道。采用新的，更为敏感的方法用于术后随诊是当今研究的热点，如何提高目前现有随诊筛查方法的准确性，及时发现具有复发高危因素的人群具有重要意义。
宫颈腺癌发生率目前占所有宫颈发生率的19％-25％，使用目前的筛查方法对宫颈腺癌的癌前病变的诊断率较低，是宫颈腺癌发生率呈上升趋势的一个主要原因之一。流行病调查结果发现，ACIS在生育年龄的妇女中发生率较高。因此，美国ASCCP以及澳大利亚的宫颈病变临床治疗规范中提出对生育年龄、要求保留生育能力的ACIS或宫颈腺癌IA(1)的患者可实施保守性手术治疗，而对于已生育或不再要求生育的妇女可实施单纯全子宫切除术。对于切缘阳性的妇女可进一步锥切，否则行全子宫切除术。在我国ACIS的发生率也有升高的趋势，但实施保留生育能力手术的妇女为数不多，因此，对于实施保留生育功能手术的ACIS患者的诊断、手术方法及术后随诊模式及预后的研究，对如何管理年轻ACIS患者的具有重要的指导意义。
Study on current protocols for CIN treatment and post-operative follow up and the value of p16~(INK4a) and HPV hybrid capture II used in diagnosis for CIN and post-treatment follow-up
BACKGROUND
With the rapidly development of cytology screen technology, it makes it possible for early diagnosis cervical precancer before it change into cancer. Meanwhile, the main treatment modalities for the management of histological proven CIN, such as CO_2 laser vaporization and conization have been the most effective methods for CIN, especially for young women who want to keep their fertility. But recurrence of CIN after local treatment indicates the necessary and importance for understand the risk factors related to recurrence for surveillance patients. It was reported that the factors effect the relapse of CIN were complicated and multi-factors.
The procotols for post-operative follow up is the focus on this field at present .How to improve the accuracy of the screening methods for follow up and find the group people with high risk factors for recurrence and reduce the frequencies of low risk group of patients are very important.
The incidence of adenocarcinoma now account for as many as 19% of all cervical cancers. One of the reason is that cervical screening is less effective at preventing cervical adenocarcinoma than squamous carcinoma. Adenocarcinoma or ACIS is also significantly related to HR-HPV infection. Epidemiological investigation showed that the incidence of ACIS among reproductive women was high. Therefore, ASCCP and Australia National Cervical Intraepithelial Neoplasma Diagnosis and Treatment guidelines suggest that conservative operation can be performed on young women with ACIS or adenocarcinoma LA (1) desiring to keep their reproductive capactivity, hysterectomy is recommended for young women who already have completed child bearing. If the margins of the initial cone biopsy are involved by ACIS, then a further
引文
1. Segnan N. Cervical cancer screening. Human benefits and human costs in the evaluation of screening programmes. Eur J Cancer 1994.30A, 873-875.
2. Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer 1993; 54: 594-606.
3. Anderson MC. Invasive carcinoma of the cervix followed local destructive treatment for cervical intraepithelial neoplasia. Br J Obstet Gynecol 1993; 100: 657-663.
4. Soutter WP, Barros Lopes A, Fletcher A, Monaghan JM, Duncan ID, Paraskevaidis E, Kitchener HC. Invasive cervical cancer after conservative therapy for cervical intraepithelial neoplasia. Lancet 1997; 349: 978-980.
5. Wright VC, Davies E, Riopelle MA. Laser sugry for cervical intraepithelial neoplasmia. Principle and results. Am J Obstet Gyneocl 1983; 145: 181.
6. Berget A, Andereasson B, Bock JE. Laser and cryo surgery for cervical intraepithelial neoplasma. Acta Obstet Gynecol Scand. 1991; 70: 231-235.
7. Jordan JL. The treatment of cervical intraepithelial neoplasia by laser vaporization. Br J Obstet Gynecol 1985; 92: 394-398.
8. Woodman CBJ, Collins S, Winter H, Bailer A, Ellis J, et al. Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study. Lancet 2001; 357: 1831-6.
9. Fallani MG, Penna C, Fambrini M, Marchionni M. Laser CO2 vaporization for high-grade cervical intraepithelial neoplasia: a long term follow-up series. Gynecologic Oncology. 2003; 91: 130-133.
10. Flannelly G, Bolger B, Fawzi A, De Barros Lopes, Monaghan JN. Follow up after LLETZ: Could schedules be modified according to risk of recurrence? Br J Obstet Gynae. 2001; 108: 1025-1030.
11. Paraskevaids E, Jandial L, Mann EM, Fisher PM, Kitchener HC. Patterns of treatment failure following laser for cervical intraepithelial neoplasia: implications for follow-up protocol. Obstet Gynecol. 1991; 78(1): 80-83.
12. Frega A, Stentella P, De Ioris A, Piazze J J, Fambrini M, Marchionni M, Cosmi EV. Young women, cervical intraepithelial neoplasia and human papillomavirus: riskfactors for persistence and recurrence. Cancer Lett. 2003; 196(2): 127-34.
13. Sadler L, Saftlas A, Wang W, Exeter M, Whittaker J, McCowan L. Treatment for cervical intraepithelial neoplasia and risk of preterm delivery. JAMA.2004; 291(17): 2100-6.
14. Schiffman MH, Brinton LA. The epidemiology of cervical carcinogenesis. Cancer 1995; 76(10 suppl): 1888-1901.
15. Zielinski GD, Bais AG, Helmerhorst TJ, Verheijen RHM, de Shipper FA, Snijders PJF, Voorhorst FJ, van Kemenade. HPV testing and monitoring of women after treatment of CIN 3: Review of the literature and Meta-analysis. Obstet and Gynecol Survey 2002; 59: 543-553.
1. Prendiville W, Cullimore J, Norman S. Large Loop Excsion of the Transformation Zone(LLETZ). A new method of management for women with cervical intraepithelial neoplasia. Br J Obstet Gynecol 1989; 96: 1054-1060.
2. Kitcener HC, Cruickshank M, Farmery E. The 1993British Society for Colposcopy and Cervial Pathology/ National Co-ordinating Network United Kingdom Colposcopy Survey. Br J Obstet Gynecol 1995; 102: 549-552.
3. Gaideil F, Barry Walsh C, Prendiville W, Clinch J, Turner MJ. Persistence intraepithelial neoplasia after excision for cervical intraepithelial neoplasia grade III. Obstet Gynecol 1997; 89(3): 419-422.
4. Wolf JK, Levenback C, Malpica A, Morris M, Burke T, Mitchell MF. Adenocarcinoma in situ of the cervix significance of cone biopsy margins. Obstet Gynecol 1996; 88(1): 82-86.
5. Paraskevaidis E, Lolis E, Koliopoulos G, Alamanos Y, Fotiou S, Kitchener HC. Cervical intraepithelial neoplasia outcomes following loop excision with clear margin. Obstet Gynecol 2000; 95: 828-
6. Paraskevaidis E, Kalantaridou SN, Paschopoulos M, Zikopoulos K, Diakomanolos E, Dalkalitsis N, MAkrydimas G, Pappa L, Malamou-Mitsi V, Agnantis NJ. Factors affecting outcome after incomplete excision of cervical intraepithelial neoplasia. Eur J Gynecol Oncol. 2003; 24(6): 541-543.
7. Skinner EN, Gehrig PA, Van Le L. High-grade squamous intraepithelial lesions: abbreviating posttreatment. Obstet Gynecol 2004; 103: 488-92.
8. (?) A, Arnesen T, Ames M, Straume B. Resection margins in conization as prognostic marker for relapse in high-grade dysplasia of the uterine cervix in northern Norway: a retrospective long-term follow-up material. Gynecologic Oncology 2004; 93: 479-483.
9. Dietrich CS 3rd, Yancey MK, Miyazawa K, Wlilliams DL, Farley J. Risk factors for early cytologic abnormalities after loop electrocautery excision procedure. Obstet Gynecol 2002; 99: 188-192.
10. Gonzalez DI, Zahn CM, Retzloff MG, Moore WF, Kost ER, Snyder RR. Recurrenceof dysplasia after loop electrosurgical excision procedures with long term follow-up. Am J Obstet Gynceol 2001; 184: 315-321.
11. EAGC Course Book on Colposcopy
12. Shafi MI, Finn CB, Luesley DM, Jordan JA, Dunn J. Lesion size and histology of atypical cervical transformation zone. Br J Obstet Gynecol 1991; 98: 490-492.
13. Kierkegaard O, Byrjalsen C, Hansen KC. Association between the colposcopic findings and histology in cervical lesions: the significance of the size of the lesion. Gynecol Oncol. 1994; 57: 66-70.
14. Tidbury P, Singer A, Jenkins D CIN 3: the role of lesion size in invasion. Br J Obstet Gynaecol 1992; 99: 583-585.
15. Bar-Am A, Daniel Y, Ron IG, Niv J, Kupferminc MJ, Bornstein J, Lessing JB. Combined colposcopy, loop conization, and laser vaporization reduces recurrent abnormal cytology and residual disease in cervical dysplasia. Gynecol Oncol. 2000 Jul;78 (1):47-51.
16. Orba A, Arnesen T, Ames M, Straume B. Resection margins in coniztion as prognostic markefor relapse in high-grade dysplasia of the unterine cervix in northern Norway: a retrospective long-term follow-up material. Gynecol Oncol. 2004 May; 93(2): 479-83.
1. Schorge JO, Knowles LM, Lea JS. Adenocarcinoma of the cervix.Curr Treat Options Oncol. 2004 Apr; 5(2): 119-27.
2. H Mitehell. Outcome after a cytological prediction of glandular intraepithelial abnormality. A report to the High Grade Working Party for the Review of the NHMRC. Data provided by the Pap Test Registration of Australia. Nov 2002.
3. Shipman SD, Bristow RE. Adenocarcinoma in situ and early invasive adenocarcinoma of the uterine cervix. Curr Opin Oncol. 2001 Sep; 13(5): 394-8.
4. Wright VC.Cervical squamous and glandular intraepithelial neoplasia: identification and current management approaches. Salud Publica Mex. 2003;45 Suppl 3:S417-29.
5. Bryson P, Stulberg R, Shepherd L, McLelland K, Jeffrey J. Is electrosurgical loop excision with negative margins sufficient treatment for cervical ACIS? Gynecol Oncol. 2004 May; 93(2): 465-8.
6. Poynor EA, Barakat RR, Hoskins WJ.Management and follow-up of patients with adenocarcinoma in situ of the uterine cervix. Gynecol Oncol. 1995 May; 57(2): 158-64.
7. Lea JS, Shin CH, Sheets EE, Coleman RL, Gehrig PA, Duska LR, Miller DS, Schorge JO.Endocervical curettage at conization to predict residual cervical adenocarcinoma in situ.Gynecol Oncol. 2002 Oct; 87(1): 129-32.
8. Schorge JO, Lea JS, Ashfaq R.Postconization surveillance of cervical adenocarcinoma in situ. A prospective trial. J Reprod Med. 2003 Oct; 48(10): 751-5.
9. Soutter WP, Haidopoulos D, Gornall RJ, et al. Is conservative treatment of adenocarcinoma in situ safe? Br J Obstet Gynecol 2001; 108: 1184-1189.
1. Soloman D, Schiffman M, Tarone B. Comparision of three management strategies for patients with atypical squamous cells of undetermined significance (ASCUS): baseline results from a randomized trial. J Natl Cancer Inst 2001; 93: 293-299.
2. Fait G, Kupferminc MJ, Daniel Y, Geva E, Ron IG, Lessing JB, Bar-Aid, A. Contribution of human papillomavirus testing by hybrid capture in the triage of women with repeated abnormal Pap smears before colposcopy referral. Gynecol Oncology 2000; 79: 177-180.
3. Lorincz AT: Hybrid Capture method for detection of HPV DNA in clinical specimens: A tool for clinical management of equivocal Pap smears and for population screening. J Obstet Gynecol Res. 1996; 22: 629-636.
4. Lorincz AT. Screening for cervical cancer: new alternatives and research. Salud Publica Mex. 2003; 45 Suppl 3: S376-87.
5. Rowe LR, Aldeen W, Bents JS. Prevalence and typing of HPV DNA by hybrid capture II in women with ASCUS, ASC-H, LSIL, and AGC on ThinPrep (R) Pap test. Diag Cytopathol. 2004; 30(6): 426-32.
6. Dalstein V, Riethmuller D, Pretet JL, Le Bail Carcal K, Sautiere JL, Carbillet JP, Kantelip B, Schaal JP, Mougin C. Persistence and load of high-risk HPV are predictors for development of high-grade cervical lesions: a longitudinal French cohor study. Int J Cancer. 2003; 106(3): 396-403.
7. Zielinski GD, Bais AG, Helmerborst TJ, Verheijen RH, de Schipper Snijders PJ, Voorhorst FJ, van Kemenade FJ, Rozendaal L. HPV testing and monitoring of women after treatment of CIN 3: Review of the literature and Meta-analysis. Obstet Gynecol Surv. 2004; 59: 543-53.
8. Cox JT, Lorincz AT, Schiffman MH, Sherman ME, Cullen A, Kurman RJ. Human papillomavirus testing by hybrid capture appears to be useful in triaging women with a cytologic diagnosis of atypical squamous cells of undetermined significance. Am J Obstet Gynecol 1995; 172:946-954.
9. Wheeler CM, Greer CE, Becker TM, Hunt WC, Anderson SM, Manos MM. Short-term fluctuations in the detection of cervical human popillomavirus DNA. Obstet Gynecol 1996; 88: 261-8.
10. Hildesheim A, Schiffman MH, Gravitt PE, Glass AG, Greer CE, Zhang T. Persistence of type-specific human Papillomavirus infectin among cytologically normal women. J Infec Dis 1994; 169: 235-40.
11. Sun XW, Kuhn L, Ellerbrock TV, Chiasson MA, Bush TJ, Wright TC. Human Papillomavirus infection in women infected with the human innunodeficiency virus. N Engl Med 1997; 337: 1343-9.
1. Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med 1997, 102,3-8.
2. Pretet JL, Dalstein V, Monnier-Benoit S, Delpeut S, Mougin C. High risk HPV load estimated by Hybrid Capture Ⅱ correlates with HPV16 load measured by real-time PCR in cervical smears of HPV16-infected women. J Clin Virol.
3. Digene Corporation. Digene HPV test hybrid capture Ⅱ test. In vitro test. A signal amplified hybridization microplate assay for the chemiluminescent detection of human papillomavirus, 1998.
4. STATA. Statistics data analysis. Stata Coroperation, 1984-2001. 2004 Oct; 31(2):140-7.
5. Dulce MHH, Laura OB, Miriam GJ, et al. Association between high-risk human papillomavirus DNA load and precursor lesions of cervical cancer in Mexican women. Gynecologic Oncology 2003; 90: 310-317.
6. Zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 2000, 92:690-698.
7．谢天恩，胡志红 主编 普通病毒学 科技出版社 北京 2002年，第一版，155—156．
8. Sellors JW, Mahony JR, Kaczorowaki J, et al. Prevalence and predictors of human papillamavirus infection in women in Ontario, Canada. CMAJ 2000; 163(5):503-508.1. Duensing S, Munger K. Centrosome abnormalities, genomic instability and carcinogenic progression. Biochim Biophys Acta 2001; 1471: 81-88.
2. zur Hausen H. Immortalization of human cells and their malignant conversion by high risk human papillomavirus genotypes. Semin Cancer Biol 1999, 9: 405-411.
3. zur Hausen H. Intracellular surveillance pf persisting viral infections. Human genital cancer results from deficient cellular control of papillomavirus gene expression. Lancet 1986, 2: 489-491.
4. Von Knebel Doeberitz M. New markers for cervical dysplasia to visualize the genomic chaos created by aberrant oncogenic papillomavirus infections. Eur J Can. 2002, 38:2229-2242.
5. Stoler MH, Schiffman M. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study. JAMA 2001, 285: 1500-1505.
6. Solomom D, Schiffman M, Tarone R, et al. Comparision of three management strategies for patients with atypical squaous cells of undetermined significance baseline results from a randomized trial. J Natl Cancer Inst 2001, 93:293-299.
7. Nevins JR. TheRb/E2Fpathway and cancer. Hum Mol Genet 2001,10:699-703.
8. Bibbo M, Klump WJ, De Cecco J, et al. Procedure for immunocytochemial detection of P~(161NK4A) antigen in thinlayer, liquid-based specimens. Acta Cytol 2002, 46:25-55.
9. Klaes R, Friedrich T, Spitkovsky D, et al. Overexpression of pl6INK4A as specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int Viral 2000;
10. Luft F, Klaes R, Nees M, et al. Detection of integrated papillomavirus sequences by ligation-mediated PCR(DIPS-PCR)and molecular characterization in cervical cancer cells. Int J Cancer 2001, 92:9-17.
1. Alvarez RD, Helm CW, Edwards RP, et al. Prospective randomized trial of LLETZ versus laser ablation in patients with cervical intraepithelial neoplasia. Gynecol Oncol 1994; 54: 175-179.
2. Bigrigg A, Haffenden DK, Sheehan AL, Coding BW, Read MD. Efficacy and safety of large-loop excision of the treansformation zone. Lancet 1994; 343: 32-34.
3. Nuovo J, Melnikow J, Willan AR, et al. Treatment outcomes for squamous intraepithelial lesions. Int J Gynaecol Obstet 2000; 68: 25-33.
4. Remmink AJ, Walboomers JM, Helmerhorst TJ, et al. The presence of persistent high-risk HPV, genotypes in dyspalsic cervical lesions is associated with progressive disease: natural history up to 36 months. Int J Cancer 1995; 61: 306-311.
5. Schiffman MH, Brinton LA. The epidemiology of cervical carcinogenesis. Cancer 1995;1995;76(10 Suppl): 1888-1901.
6. Sano T, Oyama T, Kashiwabara K, et al. Expression status pf p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions. Am J Pathol 1998, 153: 1741-1748.
7. Guijon F, Pataskevas M, McNicol P. Human papillomavirus infection and the size and grade of cervical intraepithelial neoplastic lesions associated with failure of therapy. Int J Gynecol Obstet, 1993, 42: 137-142.
8. Nagai N, Mukai K, Oshita T, Shiroyama Y, Ohama K. Human papillomavirus DNA status after loop excision for cervical intraepithelial neolpasia grade III-A prospective study. Int J Mol Med 2004; 13: 589-93.
9. Ferenczy A, Mitao M, Nagai N, Silverstein SJ: Latent papillomavirus and recurring genital warts. New Engl J Med 1985; 313: 784.
10. Orbo A, Arnesen T, Ames M, Straume B. Resection margins in conization as prognostic marker for relapse in high-grade dysplasia of the uterine cervix in Norway retrospective long-term follow-up material.DNA copy number during the progression of cervical intraepithelial neoplasia. J Gen Virol 2000, 81: 1825-1832.
14. Zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 2000, 92:690-698.
15. zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogensis. J Natl Cancer Inst 2000, 92: 690-698.
16. zur Hausen H. Intracellular surveillance pf persisting viral infections. Human genital cancer results from deficient cellular control of papillomavirus gene expression. Lancet 1986, 2: 489-491.
17. Von Knebel Doeberitz M. New markers for cervical dysplasia to visualize the genomic chaos created by aberrant oncogenic papillomavirus infections. Eur J Can. 2002, 38:2229-2242.
18. Stoler MH, Schiffman M. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study. JAMA 2001, 285: 1500-1505.
19. Selvey LA, Dunn LA, Tindle RW, et al. Human papillomavirus(HPV)type 18 E7 protein is a short-lived steroid-inducible phosphoprotein in HPV-transformed cell lines. J Gen Virol 1994; 75: 1647-1653.
20. Solomom D, Schiffman M, Tarone R, et al. Comparision of three management strategies for patients with atypical squaous cells of undetermined significance baseline results from a randomized trial. J Natl Cancer Inst 2001, 93: 293-299.
21. Expressiom status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions. Am J Pathol 1998; 153: 1741-1748.
22. Mantovani F, Banks L. The human papillomavirus E6protein and its contribution to malignant progression. Oncogene 2001, 20: 7874-7887.
23. Storey A, Massimi P, Dawson K, et al. Conditional immortalization of primary cells by human papillomavirus type 18 E6 and EJ-ras defines an E6 activity in G0/G1 phase which can be substituted for mutations in p53. Oncogene 1995,11:653-661.
24. Durst M, Seagon S, Wanschura S, et al.Malignant progression of an HPV16-immortalized human keratinocyte cell line(HPKIA) in vitro. Cancer Genet Cytogenet 1995; 85: 105-112.
25. Scheffner M. Ubiquitin, E6-AP, and their role in p53 inactivation. Pharmacol Ther 1998, 78: 129-139.
26. Henhstermann A, Linares LK, Ciechanoveer A, et al. Complete switch from Mdm2 to human papillomavirus E6-mediated degradation of p53 in cervical cancer cells. Proc Natl Acad Sci USA, 2001,98:1218-1223.
27. Tlsty TD, Briot A, Gualberto A, et al. Genomic instability and cancer. Mutat Res 1995; 337:1-7.
28. Frost M, Babak JB, Gianani R, et al. Localization of telomerase hTERT protein and hTR in benign mucosa, dysplasia, and squamous cell carcinoma of the cervix. Am J Clin Pathol 2000, 114:726-734.
29. Jarboe EA, Liaw KL, Thompson LC, et al. Analysis of telomerase as a diagnostic biomarker of cervical dysplasia and carcinoma. Oncogene 2002. 21: 664-673.
30. Cheng S, Schmidt-Grimminger DC, Murant T, et al. Differentiation-dependent up-regulation of the human papillomavirus E7gene reactivates celluler DNA replication in supra-basal differentiated keratinocytes. Genes Dev 1995, 9: 2335-2349.
31. Dyson N. The regulation of E2F by pRB-family protein. Geness Dev 1998,12: 2245-2262.
32. Munger K, Basile JR, Duensing S, et al. Biological activities and molecular targets of the human papillomavirus E7 oncoprotein. Oncogene 2001, 20: 7888-7898.
33. Maeda MY, Simoes M, Walkamatsu A, et al. Relevance of the rates of PCNA, Ki-67 and p53 according to the epithelial compartment in cervical lesions. Pathologica 2001, 93: 189-195.
34. Jian Y, Schmidt-Grimminger DC, Chien WM, et al. Post-transcriptional induction of p21cipl protein by human papillomavirus E7 inhibits unscheduled DNA synthesis reactivated in differentiated keratinocytes. Oncogene 1998; 17: 2027-2038.
35. Freeman A, Morris LS, Mills AD, et al. Minichromosome maintenance proteins as biological markers of dysplasia and malignancy. Clin Cancer Res 1999, 5: 2121-2132.
36. Sano T, Oyama T, Kashiwabara K, et al. Expression status pf p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions. Am J Pathol 1998,153: 1741-1748.
37. Klaes R, Friedrich T, Spitkovsky D, et al. Overexpression of p16INK4A as specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int Viral 2000;
38. Nevins JR. TheRb/E2Fpathway and cancer. Hum Mol Genet 2001, 10: 699-703.
39. Khleif SN, Degregori J, Yee CL, et al. Inhibition of cyclin D-CCDK4/CDK6 activity is associatied with an E2F-mediated induction of cyclin kinase inhibitior activity. Pro Natl Acad Sci USA, 1996; 93: 4350-4354.
40. Keating JT, Ince T, Crum CP, et al. Surrogate biomarkers of HPVinfection in cervical neoplasia screening and diagnosis. Adv Anat Pathol 2001; 8: 83-92.
41. Bibbo M, Klump WJ, De Cecco J, et al. Procedure for immunocytochemial detection of P~(16INK4A) antigen in thinlayer, liquid-based specimens. Acta Cytol 2002, 46: 25-55.
42. Luft F, Klaes R, Nees M, et al. Detection of integrated papillomavirus sequences by ligation-mediated PCR(DIPS-PCR)and molecular characterization in cervical cancer cells. Int J Cancer 2001, 92: 9-17.
43. Wentzensen N, Ridder R, Klaes R, et al. Characterization of viral-cellular fusion transcripts in alarge series of HPV16 and 18 positive anogenital lesions. Oncogene 2002, 21: 419-426.
2. Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer 1993; 54: 594-606.
3. Anderson MC. Invasive carcinoma of the cervix followed local destructive treatment for cervical intraepithelial neoplasia. Br J Obstet Gynecol 1993; 100: 657-663.
4. Soutter WP, Barros Lopes A, Fletcher A, Monaghan JM, Duncan ID, Paraskevaidis E, Kitchener HC. Invasive cervical cancer after conservative therapy for cervical intraepithelial neoplasia. Lancet 1997; 349: 978-980.
5. Wright VC, Davies E, Riopelle MA. Laser sugry for cervical intraepithelial neoplasmia. Principle and results. Am J Obstet Gyneocl 1983; 145: 181.
6. Berget A, Andereasson B, Bock JE. Laser and cryo surgery for cervical intraepithelial neoplasma. Acta Obstet Gynecol Scand. 1991; 70: 231-235.
7. Jordan JL. The treatment of cervical intraepithelial neoplasia by laser vaporization. Br J Obstet Gynecol 1985; 92: 394-398.
8. Woodman CBJ, Collins S, Winter H, Bailer A, Ellis J, et al. Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study. Lancet 2001; 357: 1831-6.
9. Fallani MG, Penna C, Fambrini M, Marchionni M. Laser CO2 vaporization for high-grade cervical intraepithelial neoplasia: a long term follow-up series. Gynecologic Oncology. 2003; 91: 130-133.
10. Flannelly G, Bolger B, Fawzi A, De Barros Lopes, Monaghan JN. Follow up after LLETZ: Could schedules be modified according to risk of recurrence? Br J Obstet Gynae. 2001; 108: 1025-1030.
11. Paraskevaids E, Jandial L, Mann EM, Fisher PM, Kitchener HC. Patterns of treatment failure following laser for cervical intraepithelial neoplasia: implications for follow-up protocol. Obstet Gynecol. 1991; 78(1): 80-83.
12. Frega A, Stentella P, De Ioris A, Piazze J J, Fambrini M, Marchionni M, Cosmi EV. Young women, cervical intraepithelial neoplasia and human papillomavirus: riskfactors for persistence and recurrence. Cancer Lett. 2003; 196(2): 127-34.
13. Sadler L, Saftlas A, Wang W, Exeter M, Whittaker J, McCowan L. Treatment for cervical intraepithelial neoplasia and risk of preterm delivery. JAMA.2004; 291(17): 2100-6.
14. Schiffman MH, Brinton LA. The epidemiology of cervical carcinogenesis. Cancer 1995; 76(10 suppl): 1888-1901.
15. Zielinski GD, Bais AG, Helmerhorst TJ, Verheijen RHM, de Shipper FA, Snijders PJF, Voorhorst FJ, van Kemenade. HPV testing and monitoring of women after treatment of CIN 3: Review of the literature and Meta-analysis. Obstet and Gynecol Survey 2002; 59: 543-553.
1. Prendiville W, Cullimore J, Norman S. Large Loop Excsion of the Transformation Zone(LLETZ). A new method of management for women with cervical intraepithelial neoplasia. Br J Obstet Gynecol 1989; 96: 1054-1060.
2. Kitcener HC, Cruickshank M, Farmery E. The 1993British Society for Colposcopy and Cervial Pathology/ National Co-ordinating Network United Kingdom Colposcopy Survey. Br J Obstet Gynecol 1995; 102: 549-552.
3. Gaideil F, Barry Walsh C, Prendiville W, Clinch J, Turner MJ. Persistence intraepithelial neoplasia after excision for cervical intraepithelial neoplasia grade III. Obstet Gynecol 1997; 89(3): 419-422.
4. Wolf JK, Levenback C, Malpica A, Morris M, Burke T, Mitchell MF. Adenocarcinoma in situ of the cervix significance of cone biopsy margins. Obstet Gynecol 1996; 88(1): 82-86.
5. Paraskevaidis E, Lolis E, Koliopoulos G, Alamanos Y, Fotiou S, Kitchener HC. Cervical intraepithelial neoplasia outcomes following loop excision with clear margin. Obstet Gynecol 2000; 95: 828-
6. Paraskevaidis E, Kalantaridou SN, Paschopoulos M, Zikopoulos K, Diakomanolos E, Dalkalitsis N, MAkrydimas G, Pappa L, Malamou-Mitsi V, Agnantis NJ. Factors affecting outcome after incomplete excision of cervical intraepithelial neoplasia. Eur J Gynecol Oncol. 2003; 24(6): 541-543.
7. Skinner EN, Gehrig PA, Van Le L. High-grade squamous intraepithelial lesions: abbreviating posttreatment. Obstet Gynecol 2004; 103: 488-92.
8. (?) A, Arnesen T, Ames M, Straume B. Resection margins in conization as prognostic marker for relapse in high-grade dysplasia of the uterine cervix in northern Norway: a retrospective long-term follow-up material. Gynecologic Oncology 2004; 93: 479-483.
9. Dietrich CS 3rd, Yancey MK, Miyazawa K, Wlilliams DL, Farley J. Risk factors for early cytologic abnormalities after loop electrocautery excision procedure. Obstet Gynecol 2002; 99: 188-192.
10. Gonzalez DI, Zahn CM, Retzloff MG, Moore WF, Kost ER, Snyder RR. Recurrenceof dysplasia after loop electrosurgical excision procedures with long term follow-up. Am J Obstet Gynceol 2001; 184: 315-321.
11. EAGC Course Book on Colposcopy
12. Shafi MI, Finn CB, Luesley DM, Jordan JA, Dunn J. Lesion size and histology of atypical cervical transformation zone. Br J Obstet Gynecol 1991; 98: 490-492.
13. Kierkegaard O, Byrjalsen C, Hansen KC. Association between the colposcopic findings and histology in cervical lesions: the significance of the size of the lesion. Gynecol Oncol. 1994; 57: 66-70.
14. Tidbury P, Singer A, Jenkins D CIN 3: the role of lesion size in invasion. Br J Obstet Gynaecol 1992; 99: 583-585.
15. Bar-Am A, Daniel Y, Ron IG, Niv J, Kupferminc MJ, Bornstein J, Lessing JB. Combined colposcopy, loop conization, and laser vaporization reduces recurrent abnormal cytology and residual disease in cervical dysplasia. Gynecol Oncol. 2000 Jul;78 (1):47-51.
16. Orba A, Arnesen T, Ames M, Straume B. Resection margins in coniztion as prognostic markefor relapse in high-grade dysplasia of the unterine cervix in northern Norway: a retrospective long-term follow-up material. Gynecol Oncol. 2004 May; 93(2): 479-83.
1. Schorge JO, Knowles LM, Lea JS. Adenocarcinoma of the cervix.Curr Treat Options Oncol. 2004 Apr; 5(2): 119-27.
2. H Mitehell. Outcome after a cytological prediction of glandular intraepithelial abnormality. A report to the High Grade Working Party for the Review of the NHMRC. Data provided by the Pap Test Registration of Australia. Nov 2002.
3. Shipman SD, Bristow RE. Adenocarcinoma in situ and early invasive adenocarcinoma of the uterine cervix. Curr Opin Oncol. 2001 Sep; 13(5): 394-8.
4. Wright VC.Cervical squamous and glandular intraepithelial neoplasia: identification and current management approaches. Salud Publica Mex. 2003;45 Suppl 3:S417-29.
5. Bryson P, Stulberg R, Shepherd L, McLelland K, Jeffrey J. Is electrosurgical loop excision with negative margins sufficient treatment for cervical ACIS? Gynecol Oncol. 2004 May; 93(2): 465-8.
6. Poynor EA, Barakat RR, Hoskins WJ.Management and follow-up of patients with adenocarcinoma in situ of the uterine cervix. Gynecol Oncol. 1995 May; 57(2): 158-64.
7. Lea JS, Shin CH, Sheets EE, Coleman RL, Gehrig PA, Duska LR, Miller DS, Schorge JO.Endocervical curettage at conization to predict residual cervical adenocarcinoma in situ.Gynecol Oncol. 2002 Oct; 87(1): 129-32.
8. Schorge JO, Lea JS, Ashfaq R.Postconization surveillance of cervical adenocarcinoma in situ. A prospective trial. J Reprod Med. 2003 Oct; 48(10): 751-5.
9. Soutter WP, Haidopoulos D, Gornall RJ, et al. Is conservative treatment of adenocarcinoma in situ safe? Br J Obstet Gynecol 2001; 108: 1184-1189.
1. Soloman D, Schiffman M, Tarone B. Comparision of three management strategies for patients with atypical squamous cells of undetermined significance (ASCUS): baseline results from a randomized trial. J Natl Cancer Inst 2001; 93: 293-299.
2. Fait G, Kupferminc MJ, Daniel Y, Geva E, Ron IG, Lessing JB, Bar-Aid, A. Contribution of human papillomavirus testing by hybrid capture in the triage of women with repeated abnormal Pap smears before colposcopy referral. Gynecol Oncology 2000; 79: 177-180.
3. Lorincz AT: Hybrid Capture method for detection of HPV DNA in clinical specimens: A tool for clinical management of equivocal Pap smears and for population screening. J Obstet Gynecol Res. 1996; 22: 629-636.
4. Lorincz AT. Screening for cervical cancer: new alternatives and research. Salud Publica Mex. 2003; 45 Suppl 3: S376-87.
5. Rowe LR, Aldeen W, Bents JS. Prevalence and typing of HPV DNA by hybrid capture II in women with ASCUS, ASC-H, LSIL, and AGC on ThinPrep (R) Pap test. Diag Cytopathol. 2004; 30(6): 426-32.
6. Dalstein V, Riethmuller D, Pretet JL, Le Bail Carcal K, Sautiere JL, Carbillet JP, Kantelip B, Schaal JP, Mougin C. Persistence and load of high-risk HPV are predictors for development of high-grade cervical lesions: a longitudinal French cohor study. Int J Cancer. 2003; 106(3): 396-403.
7. Zielinski GD, Bais AG, Helmerborst TJ, Verheijen RH, de Schipper Snijders PJ, Voorhorst FJ, van Kemenade FJ, Rozendaal L. HPV testing and monitoring of women after treatment of CIN 3: Review of the literature and Meta-analysis. Obstet Gynecol Surv. 2004; 59: 543-53.
8. Cox JT, Lorincz AT, Schiffman MH, Sherman ME, Cullen A, Kurman RJ. Human papillomavirus testing by hybrid capture appears to be useful in triaging women with a cytologic diagnosis of atypical squamous cells of undetermined significance. Am J Obstet Gynecol 1995; 172:946-954.
9. Wheeler CM, Greer CE, Becker TM, Hunt WC, Anderson SM, Manos MM. Short-term fluctuations in the detection of cervical human popillomavirus DNA. Obstet Gynecol 1996; 88: 261-8.
10. Hildesheim A, Schiffman MH, Gravitt PE, Glass AG, Greer CE, Zhang T. Persistence of type-specific human Papillomavirus infectin among cytologically normal women. J Infec Dis 1994; 169: 235-40.
11. Sun XW, Kuhn L, Ellerbrock TV, Chiasson MA, Bush TJ, Wright TC. Human Papillomavirus infection in women infected with the human innunodeficiency virus. N Engl Med 1997; 337: 1343-9.
1. Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med 1997, 102,3-8.
2. Pretet JL, Dalstein V, Monnier-Benoit S, Delpeut S, Mougin C. High risk HPV load estimated by Hybrid Capture Ⅱ correlates with HPV16 load measured by real-time PCR in cervical smears of HPV16-infected women. J Clin Virol.
3. Digene Corporation. Digene HPV test hybrid capture Ⅱ test. In vitro test. A signal amplified hybridization microplate assay for the chemiluminescent detection of human papillomavirus, 1998.
4. STATA. Statistics data analysis. Stata Coroperation, 1984-2001. 2004 Oct; 31(2):140-7.
5. Dulce MHH, Laura OB, Miriam GJ, et al. Association between high-risk human papillomavirus DNA load and precursor lesions of cervical cancer in Mexican women. Gynecologic Oncology 2003; 90: 310-317.
6. Zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 2000, 92:690-698.
7．谢天恩，胡志红 主编 普通病毒学 科技出版社 北京 2002年，第一版，155—156．
8. Sellors JW, Mahony JR, Kaczorowaki J, et al. Prevalence and predictors of human papillamavirus infection in women in Ontario, Canada. CMAJ 2000; 163(5):503-508.1. Duensing S, Munger K. Centrosome abnormalities, genomic instability and carcinogenic progression. Biochim Biophys Acta 2001; 1471: 81-88.
2. zur Hausen H. Immortalization of human cells and their malignant conversion by high risk human papillomavirus genotypes. Semin Cancer Biol 1999, 9: 405-411.
3. zur Hausen H. Intracellular surveillance pf persisting viral infections. Human genital cancer results from deficient cellular control of papillomavirus gene expression. Lancet 1986, 2: 489-491.
4. Von Knebel Doeberitz M. New markers for cervical dysplasia to visualize the genomic chaos created by aberrant oncogenic papillomavirus infections. Eur J Can. 2002, 38:2229-2242.
5. Stoler MH, Schiffman M. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study. JAMA 2001, 285: 1500-1505.
6. Solomom D, Schiffman M, Tarone R, et al. Comparision of three management strategies for patients with atypical squaous cells of undetermined significance baseline results from a randomized trial. J Natl Cancer Inst 2001, 93:293-299.
7. Nevins JR. TheRb/E2Fpathway and cancer. Hum Mol Genet 2001,10:699-703.
8. Bibbo M, Klump WJ, De Cecco J, et al. Procedure for immunocytochemial detection of P~(161NK4A) antigen in thinlayer, liquid-based specimens. Acta Cytol 2002, 46:25-55.
9. Klaes R, Friedrich T, Spitkovsky D, et al. Overexpression of pl6INK4A as specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int Viral 2000;
10. Luft F, Klaes R, Nees M, et al. Detection of integrated papillomavirus sequences by ligation-mediated PCR(DIPS-PCR)and molecular characterization in cervical cancer cells. Int J Cancer 2001, 92:9-17.
1. Alvarez RD, Helm CW, Edwards RP, et al. Prospective randomized trial of LLETZ versus laser ablation in patients with cervical intraepithelial neoplasia. Gynecol Oncol 1994; 54: 175-179.
2. Bigrigg A, Haffenden DK, Sheehan AL, Coding BW, Read MD. Efficacy and safety of large-loop excision of the treansformation zone. Lancet 1994; 343: 32-34.
3. Nuovo J, Melnikow J, Willan AR, et al. Treatment outcomes for squamous intraepithelial lesions. Int J Gynaecol Obstet 2000; 68: 25-33.
4. Remmink AJ, Walboomers JM, Helmerhorst TJ, et al. The presence of persistent high-risk HPV, genotypes in dyspalsic cervical lesions is associated with progressive disease: natural history up to 36 months. Int J Cancer 1995; 61: 306-311.
5. Schiffman MH, Brinton LA. The epidemiology of cervical carcinogenesis. Cancer 1995;1995;76(10 Suppl): 1888-1901.
6. Sano T, Oyama T, Kashiwabara K, et al. Expression status pf p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions. Am J Pathol 1998, 153: 1741-1748.
7. Guijon F, Pataskevas M, McNicol P. Human papillomavirus infection and the size and grade of cervical intraepithelial neoplastic lesions associated with failure of therapy. Int J Gynecol Obstet, 1993, 42: 137-142.
8. Nagai N, Mukai K, Oshita T, Shiroyama Y, Ohama K. Human papillomavirus DNA status after loop excision for cervical intraepithelial neolpasia grade III-A prospective study. Int J Mol Med 2004; 13: 589-93.
9. Ferenczy A, Mitao M, Nagai N, Silverstein SJ: Latent papillomavirus and recurring genital warts. New Engl J Med 1985; 313: 784.
10. Orbo A, Arnesen T, Ames M, Straume B. Resection margins in conization as prognostic marker for relapse in high-grade dysplasia of the uterine cervix in Norway retrospective long-term follow-up material.DNA copy number during the progression of cervical intraepithelial neoplasia. J Gen Virol 2000, 81: 1825-1832.
14. Zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 2000, 92:690-698.
15. zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogensis. J Natl Cancer Inst 2000, 92: 690-698.
16. zur Hausen H. Intracellular surveillance pf persisting viral infections. Human genital cancer results from deficient cellular control of papillomavirus gene expression. Lancet 1986, 2: 489-491.
17. Von Knebel Doeberitz M. New markers for cervical dysplasia to visualize the genomic chaos created by aberrant oncogenic papillomavirus infections. Eur J Can. 2002, 38:2229-2242.
18. Stoler MH, Schiffman M. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study. JAMA 2001, 285: 1500-1505.
19. Selvey LA, Dunn LA, Tindle RW, et al. Human papillomavirus(HPV)type 18 E7 protein is a short-lived steroid-inducible phosphoprotein in HPV-transformed cell lines. J Gen Virol 1994; 75: 1647-1653.
20. Solomom D, Schiffman M, Tarone R, et al. Comparision of three management strategies for patients with atypical squaous cells of undetermined significance baseline results from a randomized trial. J Natl Cancer Inst 2001, 93: 293-299.
21. Expressiom status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions. Am J Pathol 1998; 153: 1741-1748.
22. Mantovani F, Banks L. The human papillomavirus E6protein and its contribution to malignant progression. Oncogene 2001, 20: 7874-7887.
23. Storey A, Massimi P, Dawson K, et al. Conditional immortalization of primary cells by human papillomavirus type 18 E6 and EJ-ras defines an E6 activity in G0/G1 phase which can be substituted for mutations in p53. Oncogene 1995,11:653-661.
24. Durst M, Seagon S, Wanschura S, et al.Malignant progression of an HPV16-immortalized human keratinocyte cell line(HPKIA) in vitro. Cancer Genet Cytogenet 1995; 85: 105-112.
25. Scheffner M. Ubiquitin, E6-AP, and their role in p53 inactivation. Pharmacol Ther 1998, 78: 129-139.
26. Henhstermann A, Linares LK, Ciechanoveer A, et al. Complete switch from Mdm2 to human papillomavirus E6-mediated degradation of p53 in cervical cancer cells. Proc Natl Acad Sci USA, 2001,98:1218-1223.
27. Tlsty TD, Briot A, Gualberto A, et al. Genomic instability and cancer. Mutat Res 1995; 337:1-7.
28. Frost M, Babak JB, Gianani R, et al. Localization of telomerase hTERT protein and hTR in benign mucosa, dysplasia, and squamous cell carcinoma of the cervix. Am J Clin Pathol 2000, 114:726-734.
29. Jarboe EA, Liaw KL, Thompson LC, et al. Analysis of telomerase as a diagnostic biomarker of cervical dysplasia and carcinoma. Oncogene 2002. 21: 664-673.
30. Cheng S, Schmidt-Grimminger DC, Murant T, et al. Differentiation-dependent up-regulation of the human papillomavirus E7gene reactivates celluler DNA replication in supra-basal differentiated keratinocytes. Genes Dev 1995, 9: 2335-2349.
31. Dyson N. The regulation of E2F by pRB-family protein. Geness Dev 1998,12: 2245-2262.
32. Munger K, Basile JR, Duensing S, et al. Biological activities and molecular targets of the human papillomavirus E7 oncoprotein. Oncogene 2001, 20: 7888-7898.
33. Maeda MY, Simoes M, Walkamatsu A, et al. Relevance of the rates of PCNA, Ki-67 and p53 according to the epithelial compartment in cervical lesions. Pathologica 2001, 93: 189-195.
34. Jian Y, Schmidt-Grimminger DC, Chien WM, et al. Post-transcriptional induction of p21cipl protein by human papillomavirus E7 inhibits unscheduled DNA synthesis reactivated in differentiated keratinocytes. Oncogene 1998; 17: 2027-2038.
35. Freeman A, Morris LS, Mills AD, et al. Minichromosome maintenance proteins as biological markers of dysplasia and malignancy. Clin Cancer Res 1999, 5: 2121-2132.
36. Sano T, Oyama T, Kashiwabara K, et al. Expression status pf p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions. Am J Pathol 1998,153: 1741-1748.
37. Klaes R, Friedrich T, Spitkovsky D, et al. Overexpression of p16INK4A as specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int Viral 2000;
38. Nevins JR. TheRb/E2Fpathway and cancer. Hum Mol Genet 2001, 10: 699-703.
39. Khleif SN, Degregori J, Yee CL, et al. Inhibition of cyclin D-CCDK4/CDK6 activity is associatied with an E2F-mediated induction of cyclin kinase inhibitior activity. Pro Natl Acad Sci USA, 1996; 93: 4350-4354.
40. Keating JT, Ince T, Crum CP, et al. Surrogate biomarkers of HPVinfection in cervical neoplasia screening and diagnosis. Adv Anat Pathol 2001; 8: 83-92.
41. Bibbo M, Klump WJ, De Cecco J, et al. Procedure for immunocytochemial detection of P~(16INK4A) antigen in thinlayer, liquid-based specimens. Acta Cytol 2002, 46: 25-55.
42. Luft F, Klaes R, Nees M, et al. Detection of integrated papillomavirus sequences by ligation-mediated PCR(DIPS-PCR)and molecular characterization in cervical cancer cells. Int J Cancer 2001, 92: 9-17.
43. Wentzensen N, Ridder R, Klaes R, et al. Characterization of viral-cellular fusion transcripts in alarge series of HPV16 and 18 positive anogenital lesions. Oncogene 2002, 21: 419-426.