HPV16-specific cytotoxic T lymphocyte responses are detected in all HPV16-positive cervical cancer patients

OBJECTIVES: The specific CTL response against human papillomavirus (HPV) antigens in women with cervical cancer has been poorly studied. Immunological monitoring of this response is central for understanding the principles that underlie successful immunotherapeutic strategies. The aim of the study was to investigate the HPV16 E6/E7-specific CTL immune response in a group of untreated HPV16-positive cervical cancer patients. METHODS: Peripheral blood mononuclear cells from 21 untreated cervical cancer patients and 4 healthy controls were isolated prior to any therapy. Autologous monocyte-derived dendritic cells (MDDCs) were transiently transfected with HPV16 E6 or E7 expression vectors and used for one round of in vitro restimulation and as target cells in chromium release assays with restimulated peripheral blood lymphocytes. RESULTS: Transfected monocyte-derived dendritic cells were differentiated to exhibit a fully mature phenotype. HPV16 E6 and E7 transgenes were expressed and translated as measured by RT-PCR and intracellular flow cytometry, respectively. All HPV16-associated cervical cancer patients showed evidence of specific CTLs. Lytic activity for HPV16 E6 (11/12) and/or E7 (8/9) was above 30% at the 100:1 effector to target ratio. None of the HPV16-negative cervical cancer patients or healthy controls were above 15% of lysis. CONCLUSIONS: These data suggest that HPV-specific cytolytic immune responses can be detected in all untreated cervical cancer patients. Our approach, using dendritic cells for restimulation and as target cells, may enhance immunomonitoring of cervical cancer patients.     

Induction of tumor-specific cytotoxicity in tumor infiltrating lymphocytes by HPV16 and HPV18 E7-pulsed autologous dendritic cells in patients with cancer of the uterine cervix

OBJECTIVE: To evaluate the potential of autologous dendritic cells (DC) pulsed with HPV16 and HPV18 E7 oncoprotein in restoring tumor-specific cytotoxicity in populations of tumor infiltrating lymphocytes (TIL) for adoptive immunotherapy of cervical cancer patients. METHODS: Full-length E7-pulsed DC-stimulated CD8(+) T cells derived from peripheral blood (PBL) and from tumor tissues (TIL) were tested and compared for their ability to induce a HLA class-I-restricted cytotoxic T lymphocyte (CTL) response against autologous tumor cells. In addition, in order to correlate cytotoxic activity by CTL with a particular lymphoid subset, analysis of surface antigens and intracellular CD3 zeta chain and two-color flow cytometric analysis of intracellular cytokine expression (IFN-gamma vs IL-4) at the single cell level were performed. RESULTS: DC stimulation induced powerful cytotoxicity against autologous tumor target cells by TIL-derived CD8(+) T cells from all three cervical cancer patients, while autologous Epstein-Barr virus-transformed lymphoblastoid cell lines were not lysed. Killing of autologous tumor cells was higher by CD8(+) T cells from TIL compared to PBL (P > 0.01) and was more strongly inhibited by anti-HLA class I MAb (P > 0.05). Phenotypically, all CTL populations were CD3(+)/CD8(+), with higher levels of CD56 expression by TIL-derived CTL. Finally, although a marked Type 1 cytokine bias (i.e., IFN-gamma(high)/IL-4(low)) was observable in both PBL- and TIL-derived DC-stimulated CD8(+) T cell populations, TIL-derived CD8(+) T cells showed a higher percentage of IFN-gamma-positive cells compared to PBL. CONCLUSIONS: Full-length E7-pulsed DC can consistently restore strong CD8(+) CTL responses against autologous HPV16- and HPV18-infected cervical cancer cells. DC-stimulated TIL may represent a superior source of tumor-specific CTL compared to PBL for adoptive T cell immunotherapy of patients harboring metastatic or recurrent cervical cancer refractory to standard treatment modalities.     

Evaluation of antibody response to human papillomavirus early proteins in women in whom cervical cancer developed 1 to 20 years later

OBJECTIVE: Infection with oncogenic human papillomaviruses (HPVs) is the most important cause of cervical cancer worldwide. After infection there is a long latency period of at least 10 to 15 years during which cervical cancer develops in a small proportion of originally infected women. Up to 50% of these women have at diagnosis antibodies to the HPV oncoproteins E6 and E7, which are rarely found among healthy women. Our purpose was to evaluate whether antibodies to HPV16 and HPV18 E6 and E7 proteins are useful for early diagnosis of cervical cancer by measuring the antibody response in women in whom cervical cancer later developed. STUDY DESIGN: A joint serum bank of 550,000 Swedish, Norwegian, and Finnish women was followed up for 0.5 to 20 years, after which 178 invasive cervical carcinoma (ICC) cases, 150 of whom had squamous cell carcinoma (SCC), and 527 controls were identified. Antibodies to HPV16 and HPV18 E6 and E7 proteins were determined by tag enzyme-linked immunoassays. RESULTS: HPV16/18 E6 and E7 antibodies were detected infrequently (7.0%) in women in whom SCC later developed and yielded a moderately increased estimate of associated relative risk (odds ratio 2.7, 95% CI 1.1-6.4). Sensitivity of the combined antibody tests for the detection of occult SCC varied between 6% and 14% but was not related to time lag between serum sampling and cancer diagnosis. CONCLUSION: HPV16/18 E6 and E7 antibody responses are not sensitive markers of occult cervical cancer.     

A DNA vaccine constructed with human papillomavirus type 16 (HPV16) E7 and E6 genes induced specific immune responses

OBJECTIVE: Cervical cancer is found highly associated with human papillomaviruses type 16 (HPV16). HPV16 E6 and E7 oncogenes are important transforming genes which have become the main focus of anti-cervical cancer therapy. In this study, a recombinant DNA vaccine candidate, termed HPV16-DNA-E6E7, constructed with HPV16 E7 and E6 genes was generated and used to against HPV16-induced tumors. METHODS: We inserted an E7 DNA fragment into E6 gene to produce a recombinant gene (E6E7-DNA). The E6E7-DNA gene was inserted into a mammalian expression vector, pcDNA 3.1+, to construct the DNA vaccine candidate. Animals (C57BL/6 mice) were immunized with the vaccine candidate with various concentrations (50 microg, 100 microg or 200 microg, respectively), and cytotoxicity measurement and tumor protection assay were carried out to examine the immunological effects of the vaccine candidate. RESULTS: Immunization of with HPV16-E6E7-DNA induced HPV16-specific immune response and also conveyed protection against TC-1 induced tumor in vivo. A survival rate (90%) after 45 days of tumor challenge was observed. The animals injected with a higher dosage of the vaccine (200 microg) exhibited prolonged survival duration of more than 55 days. No transforming activity of the vaccine candidate was detected, as determined by focus formation and degradation of endogenous p53. CONCLUSION: Our results demonstrated that the HPV16-E6E7-DNA compound might become a candidate for HPV16 precautionary and immunotherapy.     

Immune responses to human papillomavirus in genital tract of women with cervical cancer

OBJECTIVES: To address a question whether immune responses to HPV infection play a role in control of cervical cancer, we analyzed systemic and mucosal immune responses to HPV in women who underwent radical hysterectomy for cervical cancer (HCC) or loop conization due to cervical dysplasia (LOOP), or had hysterectomy for other reasons (HNN). METHODS: HPV-specific antibodies in sera and vaginal washes were determined by ELISA using recombinant HPV 16 E7 oncoprotein. Cytokines in vaginal washes were assayed by Linco cytokine multiplex method using Luminex technology. Differential gene expression profiling in cervical tumor was determined by microarray analysis and Real-time RT-PCR. RESULTS: While levels of HPV-16 E7-specific IgG in vaginal wash were significantly higher in women undergoing HCC and HNN, the levels of the HPV-16 E7-specific IgA in vaginal wash of women with cervical cancer and cervical dysplasia were lower as compared to patients in HNN. Proinflammatory cytokines, such as IL-6 and IL-8, were dominant in vaginal washes of all subjects studied. However, no pattern of Th1-type and Th2-type cytokine induction was observed as demonstrated by protein analysis as well as differential gene expression profiling in cervical tumor. CONCLUSIONS: These results suggest a selective down-regulation of local HPV-specific IgA responses in women with cervical cancer.     

Prime-boost vaccination strategy in women with high-grade, noncervical anogenital intraepithelial neoplasia: clinical results from a multicenter phase II trial

The objective of this study was to determine the clinical effectiveness of a prime-boost human papillomavirus (HPV) vaccine regimen. A nonrandomized phase II prime-boost vaccine trial was conducted. Women with biopsy-proven anogenital intraepithelial neoplasia (AGIN) 3 were vaccinated with three doses of a recombinant fusion protein comprising HPV 16, E6/E7/L2 (TA-CIN) followed by one dose of a recombinant vaccinia virus encoding HPV 16 and 18 E6/E7 (TA-HPV). Clinical responses were evaluated by serial photographs, symptomatology, and biopsies before and after vaccination. Twenty-nine women were vaccinated; 27 with vulval intraepithelial neoplasia 3 and 2 with vaginal intraepithelial neoplasia grade 3. Clinical responses were seen in five women (17%), with one complete and five partial responses. Fifteen women (62%) had symptomatic improvement. No serious adverse effects were recorded. This is the first trial of a prime-boost vaccination regimen using heterologous HPV vaccines (TA-CIN followed by TA-HPV) in the management of AGIN. Since the prime-boost approach in this cohort offered no significant advantages over single TA-HPV vaccination, there are no further studies planned using this protocol. Future studies are warranted to define responders to immunotherapy.     

Quantification of human papillomavirus DNA in the plasma of patients with cervical cancer

Plasma human papillomavirus (HPV)-DNA level was measured to evaluate the clinical usefulness of circulating DNA for cervical cancer management. DNA extracted from pretreatment plasma of 50 cervical cancer patients and from serial longitudinal plasma of 21 patients was quantified for HPV16/HPV18 by means of quantitative polymerase chain reaction. Another 15 patients with low-grade lesion (LG), 18 patients with high-grade lesion (HG), and 96 normal individuals were studied as controls. Plasma HPV16-DNA was detectable in 50% of cancer patients. The incidence and median level were statistically higher than those in LG patients and normal, but similar to HG patients. Plasma HPV18-DNA was only detected in 6% of cancer patients and 1% of normal. Same type of HPV present in plasma was also detected in its primary tumor; and the level of plasma HPV16-DNA was dependent on the viral load in primary tumor. Plasma HPV-DNA was not detected in 16 of 21 patients after treatment, and those patients had complete response to therapy. HPV-DNA persisted or reappeared in five patients after treatment (one had persistent disease and another had recurrence). Plasma HPV-DNA might be a valuable marker for monitoring therapeutic response and disease progression in cervical cancer.     

人乳头瘤病毒16/18型与宫颈癌

人乳头瘤病毒（HPV）16/18型和宫颈癌的关系密切,在宫颈癌发生发展中起重要作用。HPV16最易导致宫颈鳞癌,HPV18最易导致宫颈腺癌。HPV16/18致癌机制主要是通过病毒基因组中致癌蛋白E6,E7与抑癌基因p53和pRb结合,E6抑制p53的活性,E7灭活Rb基因的活性,致肿瘤发生。常用的HPV检测方法有原位杂交法（ISH）、第二代杂交捕获试验（HCⅡ）、聚合酶链反应（PCR）等。针对HPV16/18的预防和治疗性疫苗成为研究热点。综述HPV16/18型和宫颈癌关系研究进展。     

Cervical cancer screening: which HPV test should be used—L1 or E6/E7?

Cervical cancer can and should be a historical disease. The reality, however, is that every year more than half a million women are diagnosed with cervical cancer and a quarter of a million die of this disease. The causal factor for cervical cancer is a persistent HPV infection and therefore a vaccine was developed: prophylactic HPV vaccination will reduce cervical cancer by 70%. Screening based on cytology will miss more than 40% of the abnormalities. The introduction of vaccination should lead to the reintroduction of cervical cancer screening based on HPV detection. Primary HPV screening followed by cytology will detect almost all abnormalities. Not all HPV tests, however, are the same! Clinicians are generally not aware that there is a huge difference among HPV tests. If a low grade lesion progresses to a high grade or invasive cancer, their HPV is likely to integrate. During integration L1 expression can be lost, but E6/E7 expression will always remain present. If the viral HPV is completely integrated then a L1 test looking for only L1 expression will miss this (pre)cancer, while the E6/E7 test will not miss it. HPV tests used in cervical cancer screening should be based on the early (E) and the late (L) genes in order not to miss the abnormality.     

信号诱导增殖相关蛋白1和16、18型人乳头瘤病毒E6蛋白在宫颈癌中的表达及临床意义

目的:探讨信号诱导增殖相关蛋白1(SIPA1)和16、18型人乳头瘤病毒E6蛋白(HPV16/18E6)在宫颈癌中的表达及其与临床病理之间的关系。方法:Western blot检测宫颈癌C33A、HT3、SiHa、HeLa和CaSki细胞株中HPV16/18E6和SIPA1蛋白表达;免疫组织化学Envi-sion法检测正常宫颈组织(40例)和宫颈癌组织(174例)石蜡标本中HPV16/18E6和SIPA1蛋白;分析SIPA1和HPV16/18E6相互之间及其与宫颈癌盆腔淋巴结转移之间的关系。结果:宫颈癌细胞系中SIPA1与HPV16/18E6表达呈负相关。SIPA1在正常宫颈组织和宫颈癌组织中阳性率分别为87.5%和58.6%,差异有高度统计学意义(χ2=11.78,P=0.001);SIPA1蛋白在有和无盆腔淋巴结转移时阳性率分别为19.0%和71.2%,差异有高度统计学意义(χ2=21.45,P=0.000),且SIPA1阴性者发生淋巴结转移风险高于阳性者(OR=5.011,95%CI2.311～10.866,P<0.01)。HPV16/18E6在正常宫颈组织和宫颈癌组织中的阳性率分别为30.0%和79....     

Cervical cancer prevention: the impact of HPV vaccination

Cervical cancer remains a critical public health problem that is second only to breast cancer in overall disease burden for women throughout the world. In spite of the success of cervical cancer screening, Pap cytology screening is yet to be effectively implemented or has failed to reduce cervical cancer rates to an appreciable extent. Screening appears to benefit only a small fraction of women although a much larger percentage endures the inconvenience of the Pap test in order to avoid cervical cancer. The establishment of Human Papillomavirus (HPV) infection as the necessary cause of cervical precancers and cancers provides a tremendous opportunity for cervical cancer prevention through vaccination. HPV 16 and 18 which cause 70% of cervical cancers worldwide. Thus a prophylactic vaccine to prevent HPV related precancerous lesions and cancers would save lives, reduce the need for costly medical procedures and provide both women and communities throughout the world with substantial benefits. Based on the induction of neutralizing antibodies by non infectious Virus Like Particles (VLP) of L1 capside protein, prophylactic HPV vaccines have consistently induced high titter of neutralizing antibodies with minimal side effects and induce more than 90% protection from persistent HPV 16-18 infection and HPV 16 and 18 associated high-grade Cervical Intraepithelial Neoplasia (CIN) in proof of concept efficacy trials. HPV 16-18 vaccination will prevent HPV16-18 incident infection, and subsequently decrease in 90% the frequency of abnormal Pap attributable to these types and in about 50% overall abnormal Pap. HPV vaccination will reduce the number of women who require colposcopy, biopsy and cervical treatment for precancerous cervical lesions. The level of protection from death due to cervical cancer could exceed 95%. Three large phases prophylactic HPV VLP trials are now in progress and will form the basis for licensing of candidate vaccines in 2006. HPV vaccination targeting young female adolescents, aged 11 to 16 years, with a catch-up of those aged 17-25 years, would be a strategy to be addressed. Cervical cancer screening strategies, that will be cost-effective for the proper surveillance of women protected by HPV vaccination, are under analysis.     

Cervical cancer vaccines: progress and prospects

Cervical cancer remains a leading cause of cancer-related mortality in women, particularly in developing countries. The causal association between genital human papillomavirus (HPV) infection and cervical cancer has been firmly established and the oncogenic potential of certain HPV types has been clearly demonstrated. In recognition of the causal association of cervical cancer with this sexually transmitted viral infection, substantial interest has arisen to develop effective prophylactic and therapeutic vaccines. Prophylactic strategies currently under investigation focus on the induction of effective humoral and cellular immune responses that are potentially protective against subsequent HPV infection. Papillomavirus-like particles have been synthesized to induce neutralizing antibody responses, and impressive immunoprophylactic effects have been demonstrated in both animals and humans. For the treatment of existing HPV infection, techniques to augment cellular immunity by enhancing viral antigen recognition are under investigation. Vaccines targeting the oncogenic proteins E6 and E7 of HPV-16 and -18 are the focus of current clinical trials for cervical cancer patients. It is hoped that the development of successful HPV-specific vaccines will diminish the costs of existing cervical cancer screening programs and reduce the morbidity and mortality associated with the treatment of cervical neoplasias.     

宫颈癌患者淋巴结HPV16/18感染及血清鳞状细胞癌抗原检测的临床意义

目的:探讨宫颈癌患者淋巴结HPV16/18感染及术前血清鳞状细胞癌抗原(SCCA)水平与临床病理参数的相关性,以及宫颈分泌物及淋巴结中HPV16/18感染和术前血清SCCA水平三者之间的关系。方法:采用实时荧光定量PCR法检测35例宫颈癌患者的宫颈分泌物及淋巴结HPV16/18阳性率,同时用ELISA法检测术前血清SCCA水平。结果:宫颈癌患者宫颈分泌物及淋巴结HPV16/18阳性率分别为80%(28/35)和20%(7/35)。7例组织学阳性淋巴结及28例阴性淋巴结HPV16/18阳性率分别为85.71%(6/7)和3.57%(1/28)。SCCA阳性率为37.14%(13/35)。淋巴结HPV16/18阳性感染与术前SCCA水平相关(r=0.650,P0.01),两者均与淋巴结转移、间质浸润深度及脉管累及有关(P0.05),而和宫颈分泌物HPV16/18阳性感染无关(P0.05)。结论:HPV16/18在组织学阳性淋巴结中感染率高,与宫颈癌患者淋巴结转移密切相关。而阴性淋巴结中的HPV16/18检出提示微转移。术前SCCA水平与淋巴结转移相关。     

Distribution of HPV16 and 18 intratypic variants in normal cytology, intraepithelial lesions, and cervical cancer in a Mexican population

OBJECTIVE: Several intratype variants of HPV16 and 18 have been identified. These variants are associated with populations from different geographic regions, and show a differential distribution among the severity of the cervical lesion, most likely due to different pathogenic potential. The objective of this study was to investigate the variant distribution of HPV16 and 18 in a Mexican population and its association with the severity of the cervical lesion and the histological lineage of cervical cancer. METHODS: HPV types 16 and 18 detection was performed in 412 samples of preinvasive and invasive specimens from patients attending a Primary Health-Care Center, an Early Cervical Lesion Clinic, or a Cancer Center. Distribution of HPV variants was correlated with the cytological findings and tumor cell types using contingency tables. Statistical difference was tested with the Fisher's Exact Test or its Fisher-Freeman-Halton extension for RXC tables. Alpha value was set at the P < 0.05. RESULTS: Among the 277 women included in this study without cancer, 63.5% (176 cases) had a normal cytology; from the remaining 101 women, 53.5% were LSIL (54 cases), and 46.5% HSIL (47 cases). From a total of 135 invasive carcinomas, 78.5% were squamous (106 cases); 6.6% adenocarcinoma (9 cases); 9.6% adenosquamous (ADSC) (13 cases); and 5.1% were undifferentiated carcinoma (7 cases). HPV16 E and AA-a were evenly distributed among preinvasive and invasive lesions. However, the isolate AA-c was exclusively found in cervical cancer. HPV18 Var-1(E) was almost exclusively found in invasive lesions, while the HPV18 Var-2(Af) predominated in normal or preinvasive lesions. In invasive cancer, this variant was found only in squamous tumors. CONCLUSIONS: The differential distribution of HPV16 and 18 variants in cervical lesions we found further supports experimental data on the different pathogenic potential of HPV16 and 18 variants for cervical cancer development.     

Correlation of human papillomavirus and adeno-associated virus 2 infection in cytology with Korean women

The purpose of our prospective study was to investigate the prevalence of adeno-associated virus (AAV) and human papillomavirus (HPV) 16 and/or HPV 18 infection in Korean women with normal cervical smears and those with HPV-associated cervical intraepithelial neoplasia (CIN) and cancer in cytobrush samples, and to evaluate the correlation between AAV 2 and HPV 16 and/or HPV 18 infection. AAV 2 was detected in CIN I (9.7%), CIN II (20%), CIN III (22.8%), and cancer (10%). HPV 16 was detected in CIN I (42%), CIN II (55%), CIN III (54.3%), and cancer (70%). HPV 18 was detected in CIN I (51.6%), CIN II (50%), CIN III (62.8%), and cancer (43.3%). HPV 16 or HPV 18 was detected in CIN I (18.3%), CIN II (80%), CIN III (71.4%), and cancer (80%). In normal and HPV-infected group, AAV 2 DNA was detected in 16.3% and 4.4% of samples, respectively. HPV 16 was detected in 10.2% of normal patients and in 44.4% of HPV-infected patients, and HPV 18 was detected in 12.2% of normal patients and in 40% of HPV-infected patients. HPV 16 or HPV 18 was detected in 18.3% of normal patients and in 57.7% of HPV infection. The correlation between AAV 2 and HPV 16 was statistically significant in normal and CIN I/II group only, and AAV 2 and HPV 16 and/or HPV 18 showed no correlation. Therefore, the correlation between AAV and HPV were not statistically significant. These data support the previous reports that AAV might not be associated with cervical tumorigenesis.     

Presence of Oncogenic HPV DNAs in Cervical Carcinoma Tissues and Pelvic Lymph Nodes Associating with Proliferating Cell Nuclear Antigen Expression

The presence of oncogenic HPV DNAs (HPV-16/18) in cervical carcinomas and their normal and metastatic pelvic lymph nodes and the expression patterns of proliferating cell nuclear antigen (PCNA) in cervical carcinomas were retrospectively studied to elucidate the possible roles of them in malignant transformation and progression of the disease. HPV-16/18 DNAs were detected by polymerase chain reaction using HPV E6 type-specific primers in 79 patients with cervical cancer: 31 patients who had pelvic lymph node metastasis (group I) and 48 patients without pelvic lymph node metastasis (group II) who were proven by pathologic examination of surgical specimens. HPV-16 or -18 DNAs were detectable in cervical carcinoma tissues in 60 patients from 79 cervical cancer patients (75.9%; HPV-16 was 67.1% and HPV-18 was 8.9%). HPV DNAs were amplified from metastatic pelvic lymph nodes in 13 patients of group I (42%) and from nonmetastatic lymph nodes in 7 group I patients (22.5%). Recurrence was identified in 9 group I patients (29.0%) in 3 years of follow-up. HPV DNAs were amplified from nonmetastatic lymph nodes in 11 group II patients (22.9%). Two group II patients, who had HPV-16 DNA by PCR in nonmetastatic nodes, were recurrent. PCNA was overexpressed in 66.7% of HPV-16- or -18-positive cervical cancers and 16.7% of HPV-16- or -18-negative cervical cancers. However, the expression levels of PCNA in cervical cancers were not influenced by the presence of oncogenic HPV DNA or pathologic metastasis in the pelvic lymph nodes. In conclusion, HPV DNA could be amplified from some metastatic and nonmetastatic pelvic lymph nodes and the detectability of oncogenic HPV DNA in pelvic lymph nodes may represent the poor outcome in the treatment of disease. The expression of PCNA protein which was associated with presence of oncogenic HPV DNAs in cervical cancers, suggesting activation of S phase of cell cycle, may contribute to the malignant progression by HPV-16 or -18.     

Clinical significance of serum human papillomavirus DNA in cervical carcinoma

OBJECTIVE: To study the association between serum human papillomavirus (HPV) deoxyribonucleic acid (DNA) and clinicopathologic prognostic factors and the clinical usefulness of serum HPV DNA in early-stage cervical cancer. METHODS: Deoxyribonucleic acids extracted from cervical tissues and sera of patients with stage IB or IIA cervical cancer and 40 controls including patients with cervical carcinoma in situ or benign disease were examined for HPV DNA with L1 consensus and types 16- and 18-specific E7 primers. Multivariable logistic regression was used to determine significant correlates of positive serum HPV DNA, and the receiver operating characteristic curve was applied in risk-factor assessment. RESULTS: Human papillomavirus DNA was not detected in sera from patients with carcinoma in situ or benign disease. Among the 112 patients with cervical cancer, we detected 27 positive samples (24.1%) in serum. Positive HPV DNA in serum was significantly associated with lymphovascular invasion and deep stromal invasion with or without parametrial extension (P <.001 for both conditions), pelvic lymph nodal metastasis (P =.001), large tumor size, and elevated levels of serum squamous cell carcinoma antigen (P <.001 for both conditions). When serum HPV DNA was used to predict high-risk patients who require adjuvant therapy, a sensitivity of 45.2%, a specificity of 88.6%, a positive predictive value of 70.4%, and a negative predictive value of 72.9% were obtained. CONCLUSION: The presence of serum HPV DNA in patients with early-stage cervical cancer was correlated with poor prognosis factors that warrant adjuvant therapy.     

HPV16/18E6蛋白和PKR/p-PKR在宫颈病变的表达及意义

目的:探讨宫颈病变组织HPV16/18感染对蛋白激酶R(PKR)激活的影响及两者在宫颈癌形成、演进过程中的作用和对宫颈癌患者预后的影响。方法:用免疫组化SP法检测HPV16/18型E6蛋白(E6)、PKR、磷酸化型PKR(p-PKR)在63例宫颈癌、114例宫颈上皮内瘤样病变(CINⅠ~Ⅲ)、15例正常宫颈组织的表达。结果:E6蛋白与PKR在各组的阳性表达率与宫颈病变级别呈正相关(P<0.05,P<0.05),E6蛋白与PKR在各组的阳性表达率呈正相关(P<0.05);宫颈癌组PKR阳性表达率明显高于p-PKR(P<0.01);E6、PKR阳性表达率与肿瘤大小有关(P<0.05,P<0.05);宫颈癌患者病情进展与临床分期显著相关(P<0.01),病情进展与E6、p-PKR阳性表达率相关(P<0.05,P<0.05)。结论:HPV16/18感染可阻碍PKR激活,突破机体防御HPV16/18感染的机制,在宫颈癌的发生及演进过程中可能起了重要作用,对宫颈癌患者预后不利;p-PKR能抑制宫颈癌患者病情进展,可能改善其预后。