高危人乳头瘤病毒检测在宫颈上皮内瘤变中的应用研究
|
摘要
目的:本研究探讨高危人乳头瘤病毒(HR-HPV)在宫颈上皮内瘤变(CIN)筛查中的意义及HR-HPV检测在GIN诊断、治疗及随访中的临床价值。
方法:本研究对2007年1月1日至2009年2月28日在山东大学齐鲁医院及济南市第四人民医院妇科阴道镜门诊就诊并在阴道镜下行活检有组织学诊断结果的患者为研究对象。在本次研究中采用第二代杂交捕获实验法检测高危人乳头瘤病毒情况,探讨高危人乳头瘤病毒感染与宫颈上皮内瘤变及年龄、职业等其它因素的关系。数据用EXCEL及SPSS 13.0软件进行统计分析。
结果:
1.20-29岁人群虽然HR-HPV感染率较高,但是高度宫颈上皮内瘤变发病率较低。HR-HPV感染率随年龄增长逐渐下降,各年龄组HR-HPV感染率有显著差异,P＜0.01。
30-49岁HR-HPV感染者是GIN发病高峰。＜30岁人群高度宫颈上皮内瘤变较低,发病率随着宫颈病变程度加重而降低。
高度宫颈上皮内瘤变在＜30岁组和≥30岁组的检出率分别为34.69%和61.88%,经统计学检验两组的检出率有显著差异,P＜0.01。
2.GIN患者及HR-HPV感染者中大多数为自由职业者。经统计学检验其职业分布有显著差异,P＜0.01。
3.有临床症状就诊患者占到58.70%;无临床症状,妇科检查或细胞学检查异常而就诊患者41.30%。
4.本组患者HR-HPV检出率总检出率为75.00%,其中HPV在正常组织及慢性炎症(NILM)中为50.24%,在CIN中89.60%(CIN1 80.49%,CIN2 88.89%,CIN399.19%),宫颈病变程度越重,HR-HPV的检出率越高,HR-HPV在CIN各级别的检出率有显著差异,P＜0.01。组间比较:NILM与CIN1两组HR-HPV检出率有显著差异,P＜0.01;CIN1与CIN2两组无显著差异,P＞0.05;CIN2与CIN3两组有显著差异,P＜0.01。
5.本研究组中宫颈细胞学检查联合HR-HPV病毒检测CIN1~+病变的敏感度为95.11%,特异度为52.88%,阳性预测值为85.63%,阴性预测值为78.57%,均高于单独细胞学检查和单独HR-HPV病毒检测。HR-HPV检测在CIN3~+病变的敏感度为99.28%,特异度为33.17%,阳性预测值为33.33%,阴性预测值为99.27%。这说明HR-HPV检测可有效筛查CIN3~+病变。
随着细胞学改变程度的增加,HPV感染率增大。不同细胞学类型HR-HPV阳性率有显著差异,P＜0.01。
细胞学为ASC-US的病例中CIN1~+的检出率为51.06%;HPV阳性组细胞学为ASC-US的病例中CIN1~+的检出率明显升高为74.07%;而HPV阴性组细胞学为ASC-US的病例中CIN1~+的检出率则降低为20.00%。三组CIN1~+检出率比较有显著差异,P＜0.01。而HR-HPV阴性组细胞学为ASC-US组对高度宫颈上皮内瘤变(CIN2~+)的检出率更低为6.15%(4/65),这说明HR-HPV检测可有效的分流ASC-US。
20-29岁、30-39岁、40-49岁及50岁以上各年龄组HR-HPV DNA负荷量经统计学检验无显著差异,P＞0.05。
细胞学异常者(≥ASC-US)的HPV DNA负荷量明显高于细胞学正常者(WNL),细胞学异常者与正常组HPV DNA负荷量有显著差异(P＜0.05)。
NILM组HPV DNA负荷量较低,与CIN1组无显著差异,P＞0.05:与其它各组有显著差异,P≤0.5。CIN1与CIN2,3组有显著差异,P≤0.5。CIN2,3组之间无显著差异,P＞0.05。HPV病毒负荷量与宫颈病变程度无明显相关性。
6.未经手术治疗的CIN1患者随访6个月自愈率8.33%(6/72),1年后自愈率达31.94%(23/72)。HR-HPV阴性的CIN2患者随访观察1年中无自愈者,但无病变加重趋势。
CIN1,2,3各组在宫颈保守手术术前HR-HPV阳性率分别为60.24%,56.96%,53.00%与术后6个月的HR-HPV阳性率0%,5.06%,22.00%有显著差异,P＜0.05;术后6个月与术后1年HR-HPV阳性率0%,0%,1.00%有显著差异,P＜0.05。
结论:
1.HR-HPV检测筛查宫颈癌前病变对于30岁以上的妇女更有意义。
2.HR-HPV的检测对细胞学诊断为ASC-US者有分流作用。
3.HR-HPV检测对筛查CIN3~+有重要意义。
4.HPV DNA病毒负荷量对宫颈癌前病变可能有预测意义,但与宫颈病变程度无关。
5.HR-HPV检测是CIN有效的病情检测手段。
Objective:
To study the significance of the high-risk HPV test to improve the positive of cervical intraepithelial neoplasia(CIN),and the clinical value in cervical intraepithelial neoplasia'diagnosis treament and follow-up.
Methods:
The clients came from outpatient of QuLu Hospital,Shandong University and The Forth People Hospital,Jinan from January 1,2007 to February 28,2009,their cervical diseases confirmed by pathology with colposcopy,HPV DNA was analyzed by Hybrid capture Assay(HC-Ⅱ).To detect the relationship between HPV infection and cerveical intraepithelial neoplasia and age,occupation,and other factors.All the data was managed and analysed by Excel and SPSS 13.0 software.
Results:
1.Although the infection rate of HR-HPV was higher in 20-29 year-old women, but lower incidence of severe cervical lesion.The infection rate of HR-HPV was declined with increasing age,and the difference was significant(P＜0.01).
The peak incidence of CIN was 30-49 year-old women.Although,there are higher HR-HPV infection in＜30-year-old women,lower incidence of severe cervical lesion.
The detection rate of severe cervical intraepithelial neoplasia in＜30 and≥30 year-old women were 34.69%and 61.88%respectively,and the difference was significant(P＜0.01).
2.More than half of CIN and HR-HPV infected people were freelance.It was significant difference in different career(P＜0.01).
3.Visting to clinics with clinical symptom make up to 58.70%;Visting to clinics without clinical symptom but with abnormal result of gynecologic examination and liquid-based cytologic test make up to 41.30%.
4.In this study,HR-HPV positive rate is 75.00%,which in normal tissue and chronic cervicitis(NILM) is 50.24%,in CIN is 89.60%(CIN1 80.49%,CIN2 88.89%,CIN3 99.19%),in cervical cancer is 100%.The HPV positive rate was increasing with the degree of cervical lesions increased,and the difference was significant(P＜0.01).It was significantly different between NILM and CIN1(P＜0.01);no significantly different between CIN1 and CIN2(P＞0.05);significantly different between CIN2 and CIN3,(P＜0.01).
5.In the study,the sensitivity of screening CIN1~+ by adopting the high-risk HPV test combining liquid-based cytologic test is 95.11%,the specificity is 52.88%,the positive predictive value is 85.63%,and the negative predictive value is 78.57%, which were superior to individual liquid-based cytologic test or high-risk HPV test. The sensitivity of screening CIN3~+ by adopting the high-risk HPV test is 96.48%,the specificity is 33.50%.the positive predictive value is 33.33%,and the negative predictive value is 99.27%.It showed that the high-risk HPV test could screen high grade intraepithelial neoplasia effectively.
With cytological level increased,the HR-HPV positive rate was increasing.It was significantly different between HPV positive rates of different cytology types,P＜0.01.
For ASC-US tycology cases,the CIN1~+ detection rate was 51.06%,while the rate increased to 78.57%in HR-HPV positive group,decreased to 20.00%in HR-HPV negative group,and the difference was significant(P＜0.01).And the CIN2~+ detection rate was only 6.15%(4/65) in HR-HPV negative group.The high-risk HPV test could divert cytologic diagnosis of ASC-US through increasing the detection rate of intraepithelial neoplasia.
The difference of HPV DNA virus loads was no significant difference between 20-29 years,30-39 years,40-49 years and 50-59 years groups(P＞0.05).
The HPV DNA loads of the women whose liquid-based cytologic test were abnormal(≥ASC-US) is high than the women whose liquid-based cytologic test were normal and it was significantly different between the two groups(P＜0.01).
The HPV DNA loads was no significantly different between NILM and CIN1(P＞0.05);significant difference between NILM and CIN2,3(P≤0.5).It was significant difference between CIN1 and CIN2,3(P＞0.05);no significant difference between CIN2 and CIN3(P＞0.05).
6.CIN1 patients untreated were followed up,the natural cure of 6 months and 1 year were 8.33%(6/72) and 31.94%(23/72),respectively.There was no self-cure in HR-HPV negative CIN 2 patients with followed-up 1 year,while their lesions were not increased.
HR-HPV position rate in CIN1,2,3 before cervical conservative surgery were 60.24%,56.96%,53.00%,respectively;it were 0%,5.06%,22.00%after 6 months; 0%,0%,1.00%after 1 year.There was significantly different between CIN preoperative conservative surgery and after for 6 months,P＜0.05;Significantly different between after for 6 months and 1 year,P＜0.05.
Conclusions:
1.It's more meaningful to apply HR-HPV test checked precancerous lesions of cervical cancer for women over the age of 30.
2.The high-risk HPV test is diverted cytologic diagnosis of ASC-US.
3.The high-risk HPV test is of great significance for the high degree of cervical intraepithelial neoplasia.
4.The HPV DNA virus loads may be presage the high risk of cervical lesion,but was not relate with the degree of cervical lesion.
5.The HPV DNA test is a valuable tool in monitoring cervical intraepithelial neoplasia.
方法:本研究对2007年1月1日至2009年2月28日在山东大学齐鲁医院及济南市第四人民医院妇科阴道镜门诊就诊并在阴道镜下行活检有组织学诊断结果的患者为研究对象。在本次研究中采用第二代杂交捕获实验法检测高危人乳头瘤病毒情况,探讨高危人乳头瘤病毒感染与宫颈上皮内瘤变及年龄、职业等其它因素的关系。数据用EXCEL及SPSS 13.0软件进行统计分析。
结果:
1.20-29岁人群虽然HR-HPV感染率较高,但是高度宫颈上皮内瘤变发病率较低。HR-HPV感染率随年龄增长逐渐下降,各年龄组HR-HPV感染率有显著差异,P＜0.01。
30-49岁HR-HPV感染者是GIN发病高峰。＜30岁人群高度宫颈上皮内瘤变较低,发病率随着宫颈病变程度加重而降低。
高度宫颈上皮内瘤变在＜30岁组和≥30岁组的检出率分别为34.69%和61.88%,经统计学检验两组的检出率有显著差异,P＜0.01。
2.GIN患者及HR-HPV感染者中大多数为自由职业者。经统计学检验其职业分布有显著差异,P＜0.01。
3.有临床症状就诊患者占到58.70%;无临床症状,妇科检查或细胞学检查异常而就诊患者41.30%。
4.本组患者HR-HPV检出率总检出率为75.00%,其中HPV在正常组织及慢性炎症(NILM)中为50.24%,在CIN中89.60%(CIN1 80.49%,CIN2 88.89%,CIN399.19%),宫颈病变程度越重,HR-HPV的检出率越高,HR-HPV在CIN各级别的检出率有显著差异,P＜0.01。组间比较:NILM与CIN1两组HR-HPV检出率有显著差异,P＜0.01;CIN1与CIN2两组无显著差异,P＞0.05;CIN2与CIN3两组有显著差异,P＜0.01。
5.本研究组中宫颈细胞学检查联合HR-HPV病毒检测CIN1~+病变的敏感度为95.11%,特异度为52.88%,阳性预测值为85.63%,阴性预测值为78.57%,均高于单独细胞学检查和单独HR-HPV病毒检测。HR-HPV检测在CIN3~+病变的敏感度为99.28%,特异度为33.17%,阳性预测值为33.33%,阴性预测值为99.27%。这说明HR-HPV检测可有效筛查CIN3~+病变。
随着细胞学改变程度的增加,HPV感染率增大。不同细胞学类型HR-HPV阳性率有显著差异,P＜0.01。
细胞学为ASC-US的病例中CIN1~+的检出率为51.06%;HPV阳性组细胞学为ASC-US的病例中CIN1~+的检出率明显升高为74.07%;而HPV阴性组细胞学为ASC-US的病例中CIN1~+的检出率则降低为20.00%。三组CIN1~+检出率比较有显著差异,P＜0.01。而HR-HPV阴性组细胞学为ASC-US组对高度宫颈上皮内瘤变(CIN2~+)的检出率更低为6.15%(4/65),这说明HR-HPV检测可有效的分流ASC-US。
20-29岁、30-39岁、40-49岁及50岁以上各年龄组HR-HPV DNA负荷量经统计学检验无显著差异,P＞0.05。
细胞学异常者(≥ASC-US)的HPV DNA负荷量明显高于细胞学正常者(WNL),细胞学异常者与正常组HPV DNA负荷量有显著差异(P＜0.05)。
NILM组HPV DNA负荷量较低,与CIN1组无显著差异,P＞0.05:与其它各组有显著差异,P≤0.5。CIN1与CIN2,3组有显著差异,P≤0.5。CIN2,3组之间无显著差异,P＞0.05。HPV病毒负荷量与宫颈病变程度无明显相关性。
6.未经手术治疗的CIN1患者随访6个月自愈率8.33%(6/72),1年后自愈率达31.94%(23/72)。HR-HPV阴性的CIN2患者随访观察1年中无自愈者,但无病变加重趋势。
CIN1,2,3各组在宫颈保守手术术前HR-HPV阳性率分别为60.24%,56.96%,53.00%与术后6个月的HR-HPV阳性率0%,5.06%,22.00%有显著差异,P＜0.05;术后6个月与术后1年HR-HPV阳性率0%,0%,1.00%有显著差异,P＜0.05。
结论:
1.HR-HPV检测筛查宫颈癌前病变对于30岁以上的妇女更有意义。
2.HR-HPV的检测对细胞学诊断为ASC-US者有分流作用。
3.HR-HPV检测对筛查CIN3~+有重要意义。
4.HPV DNA病毒负荷量对宫颈癌前病变可能有预测意义,但与宫颈病变程度无关。
5.HR-HPV检测是CIN有效的病情检测手段。
Objective:
To study the significance of the high-risk HPV test to improve the positive of cervical intraepithelial neoplasia(CIN),and the clinical value in cervical intraepithelial neoplasia'diagnosis treament and follow-up.
Methods:
The clients came from outpatient of QuLu Hospital,Shandong University and The Forth People Hospital,Jinan from January 1,2007 to February 28,2009,their cervical diseases confirmed by pathology with colposcopy,HPV DNA was analyzed by Hybrid capture Assay(HC-Ⅱ).To detect the relationship between HPV infection and cerveical intraepithelial neoplasia and age,occupation,and other factors.All the data was managed and analysed by Excel and SPSS 13.0 software.
Results:
1.Although the infection rate of HR-HPV was higher in 20-29 year-old women, but lower incidence of severe cervical lesion.The infection rate of HR-HPV was declined with increasing age,and the difference was significant(P＜0.01).
The peak incidence of CIN was 30-49 year-old women.Although,there are higher HR-HPV infection in＜30-year-old women,lower incidence of severe cervical lesion.
The detection rate of severe cervical intraepithelial neoplasia in＜30 and≥30 year-old women were 34.69%and 61.88%respectively,and the difference was significant(P＜0.01).
2.More than half of CIN and HR-HPV infected people were freelance.It was significant difference in different career(P＜0.01).
3.Visting to clinics with clinical symptom make up to 58.70%;Visting to clinics without clinical symptom but with abnormal result of gynecologic examination and liquid-based cytologic test make up to 41.30%.
4.In this study,HR-HPV positive rate is 75.00%,which in normal tissue and chronic cervicitis(NILM) is 50.24%,in CIN is 89.60%(CIN1 80.49%,CIN2 88.89%,CIN3 99.19%),in cervical cancer is 100%.The HPV positive rate was increasing with the degree of cervical lesions increased,and the difference was significant(P＜0.01).It was significantly different between NILM and CIN1(P＜0.01);no significantly different between CIN1 and CIN2(P＞0.05);significantly different between CIN2 and CIN3,(P＜0.01).
5.In the study,the sensitivity of screening CIN1~+ by adopting the high-risk HPV test combining liquid-based cytologic test is 95.11%,the specificity is 52.88%,the positive predictive value is 85.63%,and the negative predictive value is 78.57%, which were superior to individual liquid-based cytologic test or high-risk HPV test. The sensitivity of screening CIN3~+ by adopting the high-risk HPV test is 96.48%,the specificity is 33.50%.the positive predictive value is 33.33%,and the negative predictive value is 99.27%.It showed that the high-risk HPV test could screen high grade intraepithelial neoplasia effectively.
With cytological level increased,the HR-HPV positive rate was increasing.It was significantly different between HPV positive rates of different cytology types,P＜0.01.
For ASC-US tycology cases,the CIN1~+ detection rate was 51.06%,while the rate increased to 78.57%in HR-HPV positive group,decreased to 20.00%in HR-HPV negative group,and the difference was significant(P＜0.01).And the CIN2~+ detection rate was only 6.15%(4/65) in HR-HPV negative group.The high-risk HPV test could divert cytologic diagnosis of ASC-US through increasing the detection rate of intraepithelial neoplasia.
The difference of HPV DNA virus loads was no significant difference between 20-29 years,30-39 years,40-49 years and 50-59 years groups(P＞0.05).
The HPV DNA loads of the women whose liquid-based cytologic test were abnormal(≥ASC-US) is high than the women whose liquid-based cytologic test were normal and it was significantly different between the two groups(P＜0.01).
The HPV DNA loads was no significantly different between NILM and CIN1(P＞0.05);significant difference between NILM and CIN2,3(P≤0.5).It was significant difference between CIN1 and CIN2,3(P＞0.05);no significant difference between CIN2 and CIN3(P＞0.05).
6.CIN1 patients untreated were followed up,the natural cure of 6 months and 1 year were 8.33%(6/72) and 31.94%(23/72),respectively.There was no self-cure in HR-HPV negative CIN 2 patients with followed-up 1 year,while their lesions were not increased.
HR-HPV position rate in CIN1,2,3 before cervical conservative surgery were 60.24%,56.96%,53.00%,respectively;it were 0%,5.06%,22.00%after 6 months; 0%,0%,1.00%after 1 year.There was significantly different between CIN preoperative conservative surgery and after for 6 months,P＜0.05;Significantly different between after for 6 months and 1 year,P＜0.05.
Conclusions:
1.It's more meaningful to apply HR-HPV test checked precancerous lesions of cervical cancer for women over the age of 30.
2.The high-risk HPV test is diverted cytologic diagnosis of ASC-US.
3.The high-risk HPV test is of great significance for the high degree of cervical intraepithelial neoplasia.
4.The HPV DNA virus loads may be presage the high risk of cervical lesion,but was not relate with the degree of cervical lesion.
5.The HPV DNA test is a valuable tool in monitoring cervical intraepithelial neoplasia.
引文
1.WHO.Cervical cancer control:a guideline to essential practice.2006
2.朗景和,迎接子宫颈癌预防的全球挑战与机遇.中华妇科杂志,2002;37(3):1-2
3.赵方辉,戎寿德,乔友林.宫颈癌及其癌前病变筛查方法现状.中国医学科学院学报,2001;23(6):638-641
4.Gray SH,Walzer TB.New strategies for cervical cancer screening in adolescents.Curr Opin Pediatr.2004 Aug;16(4):344-349.
5.Bekkers RL,Massuger LF,et al.Epidemiological and clinical aspects of human papillomavirus detection in the prevention of cancer.Rev Med Virol,2004,14:95.
6.黄婴,吴令英HPV在宫颈病变中的临床意义 癌症进展杂志,2004,2(5):331-338。
7.Senior K.Cervical cancer research focuses on the HPV E7 gene.Lancet Oncol,2002,3:585.
8.Lorincz A T,Castle P E,Sherman M E,et al.Viral load of human papillomavirus and risk of CIN3 or cervical cance.Lancet,2002,360:228-229.
9.DalsteinV,RiethmulletD,Pretet J L,et al.Persistence and load of high-risk HPV are predictors for development of high-grade cervicallesions:a longitudinal French cohort study,lant J Cancer,2003,162:396.
10.DC Swan,M Rajeevan,G Tortolero-Luna,et al.Human papillomavirus type 16 E2and E6/E7 variants.Gyecol Oncol,Mar 2005;96(3):695-700.
11.乌兰娜 吴瑞芳 周艳秋.人乳头状病毒基因亚型与宫颈病变的关系[J]中国妇产科临床杂志,6(5):346-350.
12.郎景和 子宫颈病变防治的几个问题 世界医学杂志,2004,8(11):1-3
13.Burd E M.Human Papillomavirus and cervical cancer.Clin Microbiol Rev,2003,16:1-17
14. CK Ong , SY Chan, MS Campo, et al. Evolution of human papillomavirus type 18:an ancient phylogenetic root in Africa and intratype diversity reflect coevolution with human ethnic groups. J. Virol. Nov 1993; 67: 6424-6431.
15. MA De Boer, LA Peters, MF Aziz, et al. Human papillomavirus type 18 variants: histopathology and E 6/E7 polymorphisms in three countries. Int J Cancer, Apr 2005; 114(3):422-425.
16. J Aho, C Hankins, C Tremblay, P Forest, et al. Genomic polymorphism of human papillomavirus type 52 predisposes toward persistent infection in sexually active women. J Infect Dis, Jul 2004; 190(1):46 -52 .
17. Mdel Refugio Gonzalez-Losa, MA Laviada Miery Teran, M Puerto-Solis, et al. Molecular variants of H PV type 16 E6 among Mexican women with LSIL and invasive cancer. J lin Virol, Feb 2004; 29(2): 95-98.
18. I Zehbe, J Mytilineos, I Wikstrom, et al. Association between human papillomavirus 16 E6 variants and human leukocyte antigen class I polymorphism in cervical cancer of Swedish women. Hum Immunol, May 2003;64(5):538-542.
19. S Kang, YT Jeon, JW Kim, et al. Polymorphism in the E6 gene of human papillomavirus type 16 in the cervical tissues of Korean women. Int J Gynecol Cancer, Jan 2005; 15(1):107-112.
20. PA Heinzel, SY Chan, L Ho, et al. Variation of human papillomavirus type 6 (HPV-6) and H PV-11 genomes sampled throughout the world.J.Clin. M icrobiol, Jul 1995; 33:1746 — 1754.
21. Robert Kovelman, Graham K. Bilter, Ann Roman, et al. Human papillomavirus type 6 : classification of clinical isolates and functional analysis of E2 proteins. J .Gen. Virol, Sep 1999;80:2445-2451.
22. Lizano M , Berumen J, Guido M C, et a 1. Association between human papillomavirus type 18 variants and histopathology of cervical cancer. J Natl Cancer Inst. 1997 Aug 20;89(16):1227-1231.
23. Benta JS. Liquid-based cytology for cervical cancer screening. Expert Rev Mol Diagn.2005, 5(6): 857-71
24. Mareel V, Jacobs, et al. Distribution of 37 mucosotropic HPV types in Women with cytologycally normal cervical smear: T he age-related pattenrs for h igh-risk and low-risk Types. Int J Cancer, 2000, 87: 221.
25. Georgette, Damasus, Awatai, et al. Human papillomavirus and cervical screening. Curr Opin Obstet Gynecol, 2003 15: 473
26. Shailnl I , Kulasingam, et al. Evaluation of human papilomavirus sensitivity,sepecificity, and frecuency of referral. JAMA, 2002, 288: 1749
27. Melkert PW, Hopman E , van den Brule AJ, et al. Prevalence of HPV in cytomorphologicaly normal cervical smears, as determined by the polymerase chain reaction, is age-dependent. Int J Cancer. 1993 Apr 1 ;53(6):919-923.
28. Thomas C, Wright Jr, et al. Interim gridance for the use of human papilloavirus DNA test as an adjunct to cervical cytology for screening. Obstet Gynecol, 2004,103: 304.
29.Joel Coste, Cross sectional study of conventional smears, microlayer cytology, and human papilomavirus DNA testing for cervical cancer screening. British Medicine Journal, 2003. 6(4): 215-9
30. Shastri SS, Dinshaw K, Amin G, et al. Concurrent evaluation of visual,cytological and HPV testing as screening methods for the early detection of cervical neoplasia in Mumbai, India. Bull World Health Organ. 2005 5; 83:186-94
31. Ostor AG. Natural history of cervical intraepithelial neoplasia: acritical review. Int J Gynecol Pathol 1993, 12: 186-92.
33. Ruud LM, Bekkers, et al. Epidemiological and clinical aspects of human papillomavirus detection in the prevention of cervical cancer. Rev Med Virol,2004, 14: 95.
33. Sheman ME, Lorincz AT, ScottDR, et al. Baseline cytology, human papiolmavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis [J]. J Natl Cancer Inst, 20003,95(1): 46-52.
34. Soomon D, Schiffman MH, Tarone R. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial[J].J Natl Cancer Inst,2001,93(4):293-299.
35.Solomon D,Schiffman MH,Tarone R.Comparision of three management strategies for patients with atypical squamous cells of undetermined significance:baseline results from a randomized trial[J].J Natl Cancer Inst,2001,93(4):293-299.
36.Zidlinski GD,Bais AG,Helmerhorst TJ,et al.HPV testing and monitoring of women after treatment of CIN3:review of the literature and Meta-analysis[J].Obstet Gynecol Surv,2004,59(7):543-553.
37.姜波铃,肖长义.人白细胞抗原、人乳头瘤病毒感染于宫颈癌相关性的研究进展[J].中国临床医学,2007,14(3):377-379.
38.Santos AL,Derchain SF,Martins MR,et al.Human papillomavirus viral load in predictinghigh-grade CIN in woman with cervical smears showing only atypicalsquamous cells or low-gade squamous intraepithelial lesion[J].Sao Paulo Med J,2003,121(6):238-243.
39.Szoke K,Sapy T,Krasznai Z,et al.Moderate variation of the oncogenicpotential among high-risk human papillomavirus of the oncogenicpotential among high-risk human papillomavirus types ingynecologic patients with cervical abnormalities[J].J Med Virol,2003,71(4):585-592.
[1]Parkin DM Bray FI,Devesa SS.Cancer burden in the year 20000.The global picture(J).Eur J Cander,2001,37(supp 18):S4.
[2]李连弟,鲁凤珠,张思维,等.中国恶性肿瘤20年变化趋势及近期预测分析(J).中华肿瘤杂志,1997,19(6):3.
[3]Walboomers JM,Jacobs MV,Monas MM,et al.Human pap illomavirus is a necessary cause of invasive cervical cancer worldwide[J].J Pathol,1999,189:12.
[4]Munoz N,Bosch FX,de Sanjose S,et al.Ep idemiologic classification of human pap illoma virus types associated with cercical[J].N Engl J Med,2003,348(6):518.
[5]Madrigal M,Janicek MF,Sevin BU,et al.In vitro antigene therapy targeting HPV-16 E6 and E7 in cervical carcinoma(J).Gynecol Oncol,1997,64(1):18.
[6]DiPaolo JA,Alvarez2 Salas LM.Advances in the development of therapeutic nucleic acids against cervical cancer(J).Expert Op in Biol Ther,2004,4(8):1251
[7]Alvarez-Salas LM,Arpawong TE,DiPaolo JA.Growth inhibition of cervical tumor cells by antisense oligodeoxynucleotides directed to the human pap illomavirus type 16 E6 gene(J).Antisense Nucleic Acid Drug Dev,1999,9(5):441.
[8]LI L,DA J,STUCKI M,et al.Antiproliferative activity and toxicity of 2-methoxyestradiol in cervical cancer xenograft mice[J].Gynecol Cancer,2005,15(2):301-307.
[9]Hasan S,Stucki M,Hassa PO.Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactivator p300[J].Mol Cell,2001,7(6):1 221-1 231.
[10]Fujii T,Saito M,Iwasaki E,et al.Intratumo injection of small interfering RNA-targeting human papillomavirus 18 E6 and E7 successfully inhibits the growth of cervical cancer[J].Int J Oncol,2006,29(3):541-548.
[11]Butz k,Ristriani T,Hengstermannn A,et al siRNA targeting of the viral E6oncogene efficiently kills human papillomavirus-positive cancer cells[J].Oncogene,2003,22(38):5938.
[12]Ambrosini G,Adida C,Altieri DC.A norel anti—abobtosis gene,surviving,expressed in cancer and lymphoma[J].Net Meal,1997,3(8):917.
[13]徐咏莲,刘少阳,江大琼.宫颈癌中Survivin、Ki67、cyclinB1的表达及临床意义[J].现代妇产科进展,2004,13(3):184.
[14]Zaffaroni N,Pennati M,Folini M.Validation of telomerase and survivin as anticancer therapeutic targets using ribozymes and small-in-terfering RNAs[J].Methods MolBiol,2007,36(1):239-263.
[15]Lopez R,Garrido E,Pina P,et al.HOXB homeobox gene expression in cervical carcinomal[J].Int Gynecol Cancer,2006,16(1):329-335.
[16]Panares RL,Garcia AA.Bevacizumab in the management of solid tumors[J].Expert Rev Anticancer Ther,2007,7(4):433-445.
[17]Ranieri G,Patruno R,Ruggieri E,et al.Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer:from the biology to the clinic[J].Curr Med Chem,2006,13(16):1845-1857.
[18]Fujimoto J,Toyoki H,Sato E,et al.Expression of cyclooxygenase-2 related to angiogenesis in uterine cervical cancers[J].J Biomed Sci,2006,13(6):825-832.
[19]新药介绍.多靶点抗肿瘤药物—瓦他拉尼.药学进展[J],2008,32,(8):378.
[20]许小兵,血管紧张素转化酶抑制剂抗肿瘤作用的研究进展[J].2008,21,(3):325-329.
2.朗景和,迎接子宫颈癌预防的全球挑战与机遇.中华妇科杂志,2002;37(3):1-2
3.赵方辉,戎寿德,乔友林.宫颈癌及其癌前病变筛查方法现状.中国医学科学院学报,2001;23(6):638-641
4.Gray SH,Walzer TB.New strategies for cervical cancer screening in adolescents.Curr Opin Pediatr.2004 Aug;16(4):344-349.
5.Bekkers RL,Massuger LF,et al.Epidemiological and clinical aspects of human papillomavirus detection in the prevention of cancer.Rev Med Virol,2004,14:95.
6.黄婴,吴令英HPV在宫颈病变中的临床意义 癌症进展杂志,2004,2(5):331-338。
7.Senior K.Cervical cancer research focuses on the HPV E7 gene.Lancet Oncol,2002,3:585.
8.Lorincz A T,Castle P E,Sherman M E,et al.Viral load of human papillomavirus and risk of CIN3 or cervical cance.Lancet,2002,360:228-229.
9.DalsteinV,RiethmulletD,Pretet J L,et al.Persistence and load of high-risk HPV are predictors for development of high-grade cervicallesions:a longitudinal French cohort study,lant J Cancer,2003,162:396.
10.DC Swan,M Rajeevan,G Tortolero-Luna,et al.Human papillomavirus type 16 E2and E6/E7 variants.Gyecol Oncol,Mar 2005;96(3):695-700.
11.乌兰娜 吴瑞芳 周艳秋.人乳头状病毒基因亚型与宫颈病变的关系[J]中国妇产科临床杂志,6(5):346-350.
12.郎景和 子宫颈病变防治的几个问题 世界医学杂志,2004,8(11):1-3
13.Burd E M.Human Papillomavirus and cervical cancer.Clin Microbiol Rev,2003,16:1-17
14. CK Ong , SY Chan, MS Campo, et al. Evolution of human papillomavirus type 18:an ancient phylogenetic root in Africa and intratype diversity reflect coevolution with human ethnic groups. J. Virol. Nov 1993; 67: 6424-6431.
15. MA De Boer, LA Peters, MF Aziz, et al. Human papillomavirus type 18 variants: histopathology and E 6/E7 polymorphisms in three countries. Int J Cancer, Apr 2005; 114(3):422-425.
16. J Aho, C Hankins, C Tremblay, P Forest, et al. Genomic polymorphism of human papillomavirus type 52 predisposes toward persistent infection in sexually active women. J Infect Dis, Jul 2004; 190(1):46 -52 .
17. Mdel Refugio Gonzalez-Losa, MA Laviada Miery Teran, M Puerto-Solis, et al. Molecular variants of H PV type 16 E6 among Mexican women with LSIL and invasive cancer. J lin Virol, Feb 2004; 29(2): 95-98.
18. I Zehbe, J Mytilineos, I Wikstrom, et al. Association between human papillomavirus 16 E6 variants and human leukocyte antigen class I polymorphism in cervical cancer of Swedish women. Hum Immunol, May 2003;64(5):538-542.
19. S Kang, YT Jeon, JW Kim, et al. Polymorphism in the E6 gene of human papillomavirus type 16 in the cervical tissues of Korean women. Int J Gynecol Cancer, Jan 2005; 15(1):107-112.
20. PA Heinzel, SY Chan, L Ho, et al. Variation of human papillomavirus type 6 (HPV-6) and H PV-11 genomes sampled throughout the world.J.Clin. M icrobiol, Jul 1995; 33:1746 — 1754.
21. Robert Kovelman, Graham K. Bilter, Ann Roman, et al. Human papillomavirus type 6 : classification of clinical isolates and functional analysis of E2 proteins. J .Gen. Virol, Sep 1999;80:2445-2451.
22. Lizano M , Berumen J, Guido M C, et a 1. Association between human papillomavirus type 18 variants and histopathology of cervical cancer. J Natl Cancer Inst. 1997 Aug 20;89(16):1227-1231.
23. Benta JS. Liquid-based cytology for cervical cancer screening. Expert Rev Mol Diagn.2005, 5(6): 857-71
24. Mareel V, Jacobs, et al. Distribution of 37 mucosotropic HPV types in Women with cytologycally normal cervical smear: T he age-related pattenrs for h igh-risk and low-risk Types. Int J Cancer, 2000, 87: 221.
25. Georgette, Damasus, Awatai, et al. Human papillomavirus and cervical screening. Curr Opin Obstet Gynecol, 2003 15: 473
26. Shailnl I , Kulasingam, et al. Evaluation of human papilomavirus sensitivity,sepecificity, and frecuency of referral. JAMA, 2002, 288: 1749
27. Melkert PW, Hopman E , van den Brule AJ, et al. Prevalence of HPV in cytomorphologicaly normal cervical smears, as determined by the polymerase chain reaction, is age-dependent. Int J Cancer. 1993 Apr 1 ;53(6):919-923.
28. Thomas C, Wright Jr, et al. Interim gridance for the use of human papilloavirus DNA test as an adjunct to cervical cytology for screening. Obstet Gynecol, 2004,103: 304.
29.Joel Coste, Cross sectional study of conventional smears, microlayer cytology, and human papilomavirus DNA testing for cervical cancer screening. British Medicine Journal, 2003. 6(4): 215-9
30. Shastri SS, Dinshaw K, Amin G, et al. Concurrent evaluation of visual,cytological and HPV testing as screening methods for the early detection of cervical neoplasia in Mumbai, India. Bull World Health Organ. 2005 5; 83:186-94
31. Ostor AG. Natural history of cervical intraepithelial neoplasia: acritical review. Int J Gynecol Pathol 1993, 12: 186-92.
33. Ruud LM, Bekkers, et al. Epidemiological and clinical aspects of human papillomavirus detection in the prevention of cervical cancer. Rev Med Virol,2004, 14: 95.
33. Sheman ME, Lorincz AT, ScottDR, et al. Baseline cytology, human papiolmavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis [J]. J Natl Cancer Inst, 20003,95(1): 46-52.
34. Soomon D, Schiffman MH, Tarone R. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial[J].J Natl Cancer Inst,2001,93(4):293-299.
35.Solomon D,Schiffman MH,Tarone R.Comparision of three management strategies for patients with atypical squamous cells of undetermined significance:baseline results from a randomized trial[J].J Natl Cancer Inst,2001,93(4):293-299.
36.Zidlinski GD,Bais AG,Helmerhorst TJ,et al.HPV testing and monitoring of women after treatment of CIN3:review of the literature and Meta-analysis[J].Obstet Gynecol Surv,2004,59(7):543-553.
37.姜波铃,肖长义.人白细胞抗原、人乳头瘤病毒感染于宫颈癌相关性的研究进展[J].中国临床医学,2007,14(3):377-379.
38.Santos AL,Derchain SF,Martins MR,et al.Human papillomavirus viral load in predictinghigh-grade CIN in woman with cervical smears showing only atypicalsquamous cells or low-gade squamous intraepithelial lesion[J].Sao Paulo Med J,2003,121(6):238-243.
39.Szoke K,Sapy T,Krasznai Z,et al.Moderate variation of the oncogenicpotential among high-risk human papillomavirus of the oncogenicpotential among high-risk human papillomavirus types ingynecologic patients with cervical abnormalities[J].J Med Virol,2003,71(4):585-592.
[1]Parkin DM Bray FI,Devesa SS.Cancer burden in the year 20000.The global picture(J).Eur J Cander,2001,37(supp 18):S4.
[2]李连弟,鲁凤珠,张思维,等.中国恶性肿瘤20年变化趋势及近期预测分析(J).中华肿瘤杂志,1997,19(6):3.
[3]Walboomers JM,Jacobs MV,Monas MM,et al.Human pap illomavirus is a necessary cause of invasive cervical cancer worldwide[J].J Pathol,1999,189:12.
[4]Munoz N,Bosch FX,de Sanjose S,et al.Ep idemiologic classification of human pap illoma virus types associated with cercical[J].N Engl J Med,2003,348(6):518.
[5]Madrigal M,Janicek MF,Sevin BU,et al.In vitro antigene therapy targeting HPV-16 E6 and E7 in cervical carcinoma(J).Gynecol Oncol,1997,64(1):18.
[6]DiPaolo JA,Alvarez2 Salas LM.Advances in the development of therapeutic nucleic acids against cervical cancer(J).Expert Op in Biol Ther,2004,4(8):1251
[7]Alvarez-Salas LM,Arpawong TE,DiPaolo JA.Growth inhibition of cervical tumor cells by antisense oligodeoxynucleotides directed to the human pap illomavirus type 16 E6 gene(J).Antisense Nucleic Acid Drug Dev,1999,9(5):441.
[8]LI L,DA J,STUCKI M,et al.Antiproliferative activity and toxicity of 2-methoxyestradiol in cervical cancer xenograft mice[J].Gynecol Cancer,2005,15(2):301-307.
[9]Hasan S,Stucki M,Hassa PO.Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactivator p300[J].Mol Cell,2001,7(6):1 221-1 231.
[10]Fujii T,Saito M,Iwasaki E,et al.Intratumo injection of small interfering RNA-targeting human papillomavirus 18 E6 and E7 successfully inhibits the growth of cervical cancer[J].Int J Oncol,2006,29(3):541-548.
[11]Butz k,Ristriani T,Hengstermannn A,et al siRNA targeting of the viral E6oncogene efficiently kills human papillomavirus-positive cancer cells[J].Oncogene,2003,22(38):5938.
[12]Ambrosini G,Adida C,Altieri DC.A norel anti—abobtosis gene,surviving,expressed in cancer and lymphoma[J].Net Meal,1997,3(8):917.
[13]徐咏莲,刘少阳,江大琼.宫颈癌中Survivin、Ki67、cyclinB1的表达及临床意义[J].现代妇产科进展,2004,13(3):184.
[14]Zaffaroni N,Pennati M,Folini M.Validation of telomerase and survivin as anticancer therapeutic targets using ribozymes and small-in-terfering RNAs[J].Methods MolBiol,2007,36(1):239-263.
[15]Lopez R,Garrido E,Pina P,et al.HOXB homeobox gene expression in cervical carcinomal[J].Int Gynecol Cancer,2006,16(1):329-335.
[16]Panares RL,Garcia AA.Bevacizumab in the management of solid tumors[J].Expert Rev Anticancer Ther,2007,7(4):433-445.
[17]Ranieri G,Patruno R,Ruggieri E,et al.Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer:from the biology to the clinic[J].Curr Med Chem,2006,13(16):1845-1857.
[18]Fujimoto J,Toyoki H,Sato E,et al.Expression of cyclooxygenase-2 related to angiogenesis in uterine cervical cancers[J].J Biomed Sci,2006,13(6):825-832.
[19]新药介绍.多靶点抗肿瘤药物—瓦他拉尼.药学进展[J],2008,32,(8):378.
[20]许小兵,血管紧张素转化酶抑制剂抗肿瘤作用的研究进展[J].2008,21,(3):325-329.