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PubMed2004

Toward vaccines against cervical cancer.

Cervical cancer and pre-cancerous lesions of the genital tract are a major threat to the health of women worldwide. Introduction of screening tests to detect cervical cancer precursor lesions has reduced cervical cancer rates in the developed world, but not in developing countries. Approximately 80% of the 470,000 cervical cancer cases diagnosed worldwide each year occur in developing countries. Despite advances in treatment of cervical cancer, about half of the women with the disease will die. Over the last 20 years, several lines of scientific investigation have identified oncogenic human papillomaviruses as etiological agents for cervical cancer, and have led to the development of prophylactic vaccines against this disease.

Animals↗
PubMed1998

Antibodies against early proteins of human papillomaviruses as diagnostic markers for invasive cervical cancer.

Cervical cancer is the most prevalent tumor in developing countries and the second most frequent cancer among females worldwide. Specific human papillomaviruses (HPVs) and, most notably, HPV types 16 and 18 are recognized as being causally associated with this malignancy. Antibodies against early HPV proteins E6 and E7 have been found more often in patients with tumors than in controls. Existing peptide enzyme-linked immunosorbent assays (ELISAs) for the detection of anti-E6 and anti-E7 antibodies in human sera have low levels of sensitivity and specificity and thus are not suitable for use as diagnostic tools. Based on highly purified recombinant native proteins, we developed four sandwich ELISAs for the detection of antibodies against HPV type 16 and 18 E6 and E7 proteins. We demonstrate their sensitivities and high degrees of specificity for cervical cancer. Among a total of 501 serum specimens from unselected patients with invasive cervical cancer, 52.9% reacted positively in at least one of the four assays. In contrast, among 244 serum specimens from control subjects without cervical cancer, only 2 reactive serum specimens (0.8%) were found. For 19 of 19 antibody-positive patients, the HPV type indicated by seroreactivity was identical to the HPV DNA type found in the tumor, which also indicates a high degree of specificity for antibody detection with respect to HPV type. In a direct comparison of 72 serum specimens from patients with cervical cancer, 56% of the specimens reacted in at least one of the four protein ELISAs, whereas 40% reacted in at least one of seven peptide ELISAs covering the four antigens. These assays could be of value for the detection of invasive cervical cancer in settings in which cytology-based early tumor screening is not available, for the clinical management of patients diagnosed with cervical cancer, and for the immunological monitoring of E6 and E7 vaccination trials.

Adult↗
PubMed2004

Identifying the combination of genetic factors that determine susceptibility to cervical cancer.

Cervical cancer is common among women all over the world. Although infection with high-risk types of human papillomavirus (HPV) has been identified as the primary cause of cervical cancer, only some of those infected go on to develop cervical cancer. Obviously, the progression from HPV infection to cancer involves other environmental and host factors. Recent population-based twin and family studies have demonstrated the importance of the hereditary component of cervical cancer, associated with genetic susceptibility. Consequently, single-nucleotide polymorphism (SNP) markers and microsatellites should be considered genetic factors for determining what combinations of genetic factors are involved in precancerous changes to cervical cancer. This study employs a Bayesian network and four different decision tree algorithms, and compares the performance of these learning algorithms. The results of this study raise the possibility of investigations that could identify combinations of genetic factors, such as SNPs and microsatellites, that influence the risk associated with common complex multifactorial diseases, such as cervical cancer.

Algorithms↗
PubMedDate not supplied

The epidemiology of cervical cancer.

Cervical cancer is one of the most common neoplastic diseases affecting women, with a combined worldwide incidence of almost half a million new cases annually, second only to breast cancer. Basic and epidemiologic research conducted during the past 15-20 years have provided overwhelming evidence for an etiologic role for infection with certain types of sexually-transmitted human papillomavirus (HPV) as the primary cause of cervical cancer. The relative risks of cervical cancer following HPV infection as ascertained in case-control and cohort studies are among the highest in cancer epidemiology. The available evidence indicates that the HPV-cervical cancer association satisfies all relevant causal criteria for public health action. Other cervical cancer risk factors, such as smoking, parity, use of oral contraceptives, diet, other infections, and host susceptibility traits must be understood in the context of mediation of acquisition of HPV infection or in influencing events of the natural history of cervical neoplasia that occur following the establishment of a persistent HPV infection. Virtually all cervical carcinoma specimens contain HPV DNA, which suggests that HPV infection is a necessary cause of cervical neoplasia. This is the first instance in which a necessary cause has been demonstrated in cancer epidemiology--a realization that has obvious implications for primary and secondary prevention of this neoplastic disease.

Female↗
PubMed2004

The role of chemotherapy in locally advanced, metastatic and recurrent cervical cancer.

Cervical cancer is among the major health problems world-wide although advances in screening programs. Surgery and radiotherapy are the treatment modalities of choice for early and locally advanced cervical cancer. However, the role of chemotherapy in this setting has been better investigated in the latest years. To improve loco-regional control in locally advanced disease, authors have tested both neo-adjuvant chemotherapy and concurrent chemoradiotherapy. From 1999 NCI clinical announcement, concurrent cisplatin-based chemoradiation is considered the treatment of choice for cervical cancer patients requiring radiation therapy. Neo-adjuvant chemotherapy is reaching encouraging results in IB bulky-IIA cervical cancer, but further investigation are ongoing in locally advanced cervical setting. The optimal treatment for patients with metastatic or recurrent cervical cancer is still undefined and chemotherapy is used with palliation intent. Cisplatin remains the most active cytotoxic agents, although combinations of cisplatin with paclitaxel, topotecan, vinorelbine, have shown encouraging results in phase II and in early phase III studies. This paper reviews the role of chemotherapy in the management of patients with locally advanced, metastatic and recurrent cervical cancer. Studies discussed in this paper were selected trough a search in the med-line database performed in October 2003.

Antineoplastic Agents↗
PubMed2004

Advances in the development of therapeutic nucleic acids against cervical cancer.

Cervical cancer is the second most common neoplastic disease affecting women worldwide. Basic, clinical and epidemiological analyses indicate that expression of high-risk human papillomaviruses (HPVs) E6/E7 genes is the primary cause of cervical cancer and represent ideal targets for the application of therapeutic nucleic acids (TNAs). Antisense oligodeoxyribonucleotides (AS-ODNs) and ribozymes (RZs) are the most effective TNAs able to inhibit in vivo tumour growth by eliminating HPV-16 and HPV-18 E6/E7 transcripts. Expression of multiple RZs directed against alternative target sites by triplex expression systems may result in the abrogation of highly variable HPVs. More recently, RNA interference (RNAi) gene knockdown phenomenon, induced by small interfering RNA (siRNA), has demonstrated its potential value as an effective TNA for cervical cancer. siRNA and aptamers as TNAs will have a place in the armament for cervical cancer. TNAs against cervical cancer is in a dynamic state, and clinical trials will define the TNAs in preventive and therapeutic roles to control tumour growth, debulk tumour mass, prevent metastasis and facilitate immune interaction.

Female↗
PubMed2003

New drugs in the treatment of recurrent or metastatic cervical cancer.

Cervical cancer is the second major cause of death in women. In locally-advanced or refractory cervical cancer, cisplatin-based chemotherapy still represents the best chance of cure, although chemotherapy in these patients usually results in excessive toxicity and short duration of response. Newly developed chemotherapy agents, widely used in other cancers, have been employed as single agents and in combination with cisplatin in the treatment of locally advanced or recurrent cervical cancer. Several phase II-studies have been performed in order to assess the effectiveness of gemcitabine, paclitaxel, vinorelbine and camptothecines in cervical cancer. When used as single agents, these compounds have an overall response rate (ORR) of 8-25%. Cisplatin-combined regimens may offer improved efficacy, with a ORR between 41 and 60%. Toxicity remains the more limiting factor in the treatment of irradiated or pretreated patients. New targets must be identified for innovative therapeutic approaches that could improve the response rate and survival of cervical cancer patients.

Female↗
PubMedDate not supplied

Epidemiology of genital papillomaviruses and cervical cancer.

Cervical cancer is an extremely common disease. Its natural history has been well described, and individual risk factors have been defined. It is clear from the epidemiologic evidence that cervical cancer has a multifactorial etiology involving infection with sexually transmitted agents such as genital papillomaviruses and cofactors such as pregnancy, smoking, use of hormonal contraceptives, and diet. The evidence implicating papillomavirus as an etiologic agent of cervical cancer has come from a variety of observational laboratory studies. Genital papillomaviruses induce dysplastic lesions. Most invasive cervical cancers contain papillomavirus DNA, as do cell lines derived from cervical cancers. Viral DNA, appears to be integrated into cellular DNA, and integration involves highly conserved, transcriptionally active regions of the viral DNA.

Age Factors↗
PubMed2005

Human papillomavirus infection and P53 codon 72 genotypes in a Hispanic population at high-risk for cervical cancer.

Cervical cancer mortality is high in Texas, especially among Hispanic women living in south Texas and adjacent Mexico. Though human papillomavirus (HPV) infection has a causal role in the development of cervical cancer, there are no published data on the prevalence of HPV genotypes in this underscreened region. We studied 398 Hispanic women on both sides of the border along the lower Rio Grande River to determine the prevalence of HPV genotypes and risk factors for cervical cancer. Using a nested PCR system HPV was detected in 62% of cervical specimens, including all the known high-risk HPV genotypes, with HPV16 and HPV18 the most frequent (30.6% and 23.0%, respectively). Multiple infections were common (29.4% of the infected specimens), and where this occurred we were more likely to find high-risk HPV genotypes. We examined host p53 codon 72 genotype frequencies and found that patients with cervical abnormalities and women with HPV16 and HPV18 infections had a lower genotype frequency of the homozygous (AA) previously reported to be associated with cervical cancer, than uninfected women with no abnormalities. In this US/Mexico border population high rates of potentially oncogenic HPV viruses and multiple infections are consistent with observed elevated cervical cancer rates. These data are further evidence that in this underserved population HPV infections are associated with high rates of malignancy, but that host p53 genotypic variations are unlikely to be primary factors in oncogenesis.

Adolescent↗
PubMed2004

[The guidelines for diagnostics and treatment of cervical cancer].

Cervical cancer is one of the most common cancers in women. The purpose of this article is to analyze the main diagnostic and treatment strategies for all stages and recurrences of cervical cancer. The article reviews the epidemiological situation, clinical features, diagnostic procedures for detection of this tumor and for evaluation of the dissemination of the disease, staging criteria, TNM (Tumor, Nodes, Metastases) and FIGO (Federation Internationale de Gynecologie et d'Obstetrique) classification, as well as treatment and prognosis. Surgical treatment (radical type II or III hysterectomy and lymphonodectomy) for early stage I and IIA cervical cancer is the main treatment method. Delivery of adjuvant postoperative radiation therapy or concomitant chemoradiation depends on the prognostic factors (tumor penetration to cervical tissues, lymphovascular invasion, tumor invasion to paracervical tissues, and surgical margins). For treatment of more advanced stages of cervical cancer (IIB, IIIA, IIIB, IVA) concomitant chemoradiation: external beam radiotherapy with chemotherapy and brachytherapy is used. Description of the treatment guidelines for each stage of cervical cancer is given in this article. These guidelines are useful for good treatment practice.

Adult↗
PubMed2003

Imaging in cervical cancer.

Cervical cancer traditionally has been staged clinically. Advances in imaging could improve the staging of cervical cancer by facilitating the detection of lymph node metastases and micrometastases in distant organs. Such progress could lead to improvements in treatment selection and therefore increase overall survival rates. At the Second International Conference on Clinical Cancer (Houston, TX, April 11-14, 2002), a panel composed of gynecologic oncologists, radiation oncologists, and diagnostic radiologists reviewed relevant technologies. Advances in lymphangiography, ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and lymphatic mapping were reviewed, along with the impact of these advances on the diagnosis, treatment, and survival of patients with cervical cancer. Few cancer centers still use lymphangiography, but the sensitivity of this method ranges from 28% to 83%, with specificity ranging from 47% to 100%. The roles of transabdominal and transvaginal ultrasonography in evaluating cervical cancer are expected to expand when new contrast agents increase the sensitivity of these techniques to parametrial invasion and lymph node metastases; meanwhile, ultrasonography's most significant contributions may involve the identification of uterine and cervical leiomyomas and the evaluation of urinary tract obstruction. Advances in CT have made it a rival technique to MRI, but limitations prevent CT from providing definitive information on certain parameters. MRI, which is valuable because of its superior soft tissue contrast resolution, multiplanar capabilities, and cost-effectiveness, is used to determine the size of the cervix and to detect certain types of invasion, characteristics of lymph nodes, and the presence of disease in the ureter, lung, and liver. PET with 2-[fluorine-18]fluoro-2-deoxy-D-glucose has been found to detect abnormal lymph node regions better than CT does but PET can also be used in conjunction with CT to measure tumor dimensions. PET also has become a method for identifying tumors that are unresponsive to chemoradiation. When used together with immunohistochemical and molecular techniques as well as conventional stains, sentinel lymph node mapping, an important development in the surgical management of solid tumors, is expected to improve gynecologic cancer management. Advances in imaging methods and in contrast agents, along with advances in the combined use of the two, are expected to make imaging technologies more valuable in cervical cancer assessment.

Diagnostic Imaging↗
PubMed2002

Update on human papillomavirus vaccines for cervical cancer.

Cervical cancer is a leading cause of cancer related mortality in women, particularly in developing countries. As a result of several recent advances in molecular biology, the causal association between 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 a 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 immune responses that are potentially protective against subsequent HPV infection. Using recombinant techniques to express the L1 major capsid protein, papillomavirus-like particles (VLPs) have been synthesized in order 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 improve cellular immunity by enhancing viral antigen recognition are being studied. For this purpose, the oncogenic proteins E6 and E7 of HPV-16 and -18 are the focus of current clinical trials for cervical cancer patients. The development of successful HPV-specific vaccines may offer an attractive and cost-effective alternative to existing screening and treatment programs for cervical cancer.

Animals↗
PubMed1996

The presence of human papillomavirus-16/-18 E6, p53, and Bcl-2 protein in cervicovaginal smears from patients with invasive cervical cancer.

Cervical cancer is the second leading cause of death from cancer in women worldwide, and recent epidemiological studies have strongly implicated the sexually transmitted human papillomavirus (HPV) as a causative agent. The ability of high-risk HPVs to contribute to malignant progression seems to depend on expression of the viral E6 and E7 oncogenes. The E6 oncoprotein forms a complex with the cellular tumor suppressor protein p53, leading to degradation of p53 via ubiquitin-dependent proteolysis. Thus, E6 expression results in the loss of p53 function in cells, including stimulation of apoptosis and inhibition of the expression of the antiapoptotic protein bcl-2. Recently, we found increased bcl-2 expression in cervical carcinoma cell lines containing mutated or E6-inactivated p53 (X. L. Liang, S. Mungal, A. Ayscue, J. D. Meissner, P. Wodnicki, G. Gordon, S. Lockett, and B. Herman. J. Cell. Biochem., 57: 509-520, 1995). Based on these findings, we examined Papanicolaou smears from 94 women with varying degrees of cervical disease for the presence or absence of p53, HPV-16/18 E6, and bcl-2 proteins using immunofluorescence microscopy. Our findings indicate that there is a statistically significant, inverse association between the presence of p53 and invasive cervical disease [odds ratio (OR), 0.3; 95% confidence interval (CI), 0.1-0.7]. Moreover, the odds of being diagnosed with an invasive stage of cervical cancer were 3.7 times higher (95% CI, 1.6-8.8) for women positive for the E6 protein and 17 times higher (95% CI, 5.5-58.3) for women positive for the bcl-2 protein compared with women negative for E6 and bcl-2. Women with invasive cervical cancer were also 4.59 times more likely to test positive for the presence of more than one marker (95% CI, 1.8-11.8). Chi(2) analysis demonstrated a strong association between the presence of E6 and bcl-2 (P < 0.001) as well as between the presence of E6 of bcl-2 and diagnosis (P = 0.015 and < 0.001, respectively). In the multivariate analysis, the presence of bcl-2 (OR, 18.8; 95% CI, 5.5-67.8) and age at diagnosis (> or = 50 years; OR, 7.8; 95% CI, 2.5-24.5) showed significant association with Invasive cervical disease. These findings indicate that: (a) the presence of the bcl-2 protein is strongly associated with the development of invasive cervical disease: (b) the pattern of the presence of high-risk HPV-E6, p53, and bcl-2 proteins may be useful for identifying women at increased risk for the development of invasive cervical cancer; and (c) a defect in apoptosis may partially underlie the development of cervical cancer.

Adult↗
PubMed2004

[Clonality detection of cervical cancer and cervical intraepithelial neoplasia by human androgen receptor gene analysis].

OBJECTIVE: To assess the clonality of cervical cancer and cervical intraepithelial neoplasia (CIN) by the study of X-chromosome inactivation pattern with human androgen receptor gene (HUMARA) analysis. METHODS: Tissue DNA from samples of 26 invasive cervical cancers (9 in stage I, 10 in stage II and 7 in stage III), 31 CINs (12 CINI, 10 CIN II and 9 CIN III) and 33 normal cervixes was extracted, and then digested with methylation sensitive restriction endonuclease Hha I. HUMARA fragment was amplified with PCR method and PCR product was electrophoresed. Clonality was assessed by observing the electrophoresis bands. RESULTS: Heterozygotic rate of HUMARA was 89%. Monoclonal rates of cervical cancer, CIN, and normal cervix were 92%, 38% and 10%, respectively. Differences between cervical cancer and CIN and between cervical cancer and normal cervix were both extremely statistically significant (P < 0.001). Difference between CIN and normal cervix was also statistically significant (P = 0.012). Monoclonal rate of cervical cancer in stage I, II, III was 6/7, 90% and 7/7 respectively, without significant difference between them (P > 0.05). Monoclonal rate of CINI, II, III was 20%, 38% and 63% respectively, showing increasing tendency with grade, but without significant difference between them (P > 0.05). CONCLUSIONS: Invasive cervical cancer is a result of clonal proliferation of cancer cells. Active intervention or close follow up should be given to CIN with monoclonality.

Adult↗
PubMed1998

Clinical models of chemoprevention for cervical cancer.

Cervical carcinoma creates a worldwide, significant population burden that potentially could be reduced by new preventive strategies for cervical cancer such as chemoprevention. Given the vast array of clinical and molecular information available relating to cervical cancer and the precursor lesions along with a growing number of new molecular techniques, a model is needed to guide further investigation. Such a model would facilitate research design, guide hypothesis development and testing, and focus the use of molecular data collection and analysis. This article reviews the clinical and molecular data of cervical cancer and the precursor lesions in order to develop a model for chemoprevention research in cervical cancer.

Chemoprevention↗
PubMed2000

Cervical cancer.

Cervical cancer is the second most common type of cancer in women worldwide, after breast cancer. A preponderance of evidence supports a causal link between human papillomavirus infection and cervical neoplasia. The presence of high-risk human papillomavirus genital subtypes increases the risk of malignant transformation. Widespread use of the Papanicolaou smear has dramatically reduced the incidence of cervical cancer in developed countries. Accurate and early recognition of abnormal cytologic changes prevents progression of the disease from preinvasive to invasive. Research is under way to determine if efforts to reduce the false-negative rate of the Papanicolaou smear should include rescreening programs and fluid-based technology. Once cervical cancer is diagnosed, clinical staging takes place. Early-stage tumors can be managed with cone biopsy or simple hysterectomy. Higher stage tumors can be treated surgically or with radiotherapy. Advanced metastatic disease may respond to radiation therapy and concurrent chemotherapy. Protein markers for detection of recurrence and vaccines for prevention of cervical cancer are under investigation.

Adenocarcinoma↗
PubMed2003

Role of systemic chemotherapy in metastatic cervical cancer.

Cervical cancer is a chemoresponsive tumor. Concurrent chemotherapy with cisplatin and radiotherapy has resulted in improved survival in patients with locally advanced cervical cancer and is now standard of care. There are many active drugs in metastatic cervical cancer with cisplatin being the most active single agent. Although response rates are significantly higher with cisplatin combinations, to date, there is no evidence to suggest this is associated with an improved survival. However, this is still an area that is attracting much research interest. The role of chemotherapy in metastatic cervical cancer will be reviewed together with some of the new areas of research.

Antineoplastic Agents↗
PubMed1999

Human papillomavirus vaccines for cervical cancer.

Cervical cancer is one of the most common causes of cancer-related death in women. As a result of several recent advances in molecular biology, the association between human papillomavirus (HPV) infection and cervical cancer has been firmly established, and the oncogenic potential of certain HPV types has been clearly demonstrated. Several lines of evidence suggest the importance of the host's immune response, especially cellular immune response, in the pathogenesis of HPV-associated cervical lesions. These observations form a compelling rationale for the development of vaccine therapy to combat HPV infection. Both prophylactic and therapeutic HPV vaccine strategies are being developed. Prophylactic strategies currently under investigation focus on the induction of effective humoral immune responses against subsequent HPV infection. In this respect, impressive immunoprophylactic effects have been demonstrated in animals using papillomavirus-like particles (VLPs). VLPs are antigenic and protective, but are devoid of any viral DNA that may be carcinogenic to the host. For treatment of existing HPV infection, techniques to improve cellular immunity by enhancing viral antigen recognition are being studied. For this purpose, the oncogenic proteins E6 and E7 of HPV-16 and -18 are the focus of current clinical trials for cervical cancer patients. The development of successful HPV-specific vaccines may offer an attractive alternative to existing screening and treatment programs for cervical cancer.

Animals↗