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PubMed2005

Is there a benefit of pretreatment laparoscopic transperitoneal surgical staging in patients with advanced cervical cancer?

OBJECTIVE: At present, cervical cancer remains the only gynecologic tumor, which is staged by clinical examination according to FIGO. This is associated with a high percentage of over- and understaging of tumor extent. With the operative, especially laparoscopic staging, exact information about intraabdominal tumor spread, lymph node metastases, and involvement of adjacent organs is possible. However, the advantage of operative staging is still discussed controversially. The aim of this study is to describe the laparoscopic transperitoneal staging procedure in patients with cervical cancer and their oncologic outcome after primary chemoradiation. METHODS: From November 1994 to October 2003, 456 consecutive patients with histologically confirmed primary cervical cancer were admitted to the Department of Gynecology of the Friedrich-Schiller-University Jena, Germany. Out of these, 84 patients with locally advanced tumor (tumor size>or=4 cm) and/or lymph node involvement and/or tumor infiltration to bladder or rectum were selected by a standardized laparoscopic staging procedure for primary chemoradiation. Data of surgery, chemoradiation, and follow-up were analyzed retrospectively for these patients. RESULTS: The mean age of the patients was 54 years (26-80), and the mean body-mass-index was 24.8 (17.9-42.2). Preoperative clinical evaluation showed a stage distribution according to FIGO with stage IB1 in 15.5%, IB2 in 15.5%, IIA in 8.3%, IIB in 23.8%, IIIA in 8.3%, IIIB in 21.4%, IVA in 6%, and IVB in 1.2%. In 15 out of 84 (17.8%) patients, intraabdominal tumor spread was diagnosed by laparascopy. In 24 out of 84 (28.5%) patients, invasion of bladder and/or rectum was proven histologically after biopsy. In 60 out of 84 (71%) patients, lymph node metastases were confirmed histologically. In 2 out of 13 patients with FIGO-stage Ib1, skip metastases in infrarenal paraaortic lymph nodes were seen. Removal of more than 5 pelvic and/or more than 5 positive paraaortic lymph nodes was associated with significant improvement of overall survival. According to the histological findings following laparoscopic staging in 36 out of 84 (43%) patients, a higher tumor stage was diagnosed. If tumor involvement of lymph nodes is also included, an upstaging in 73/84 (87%) of patients has to be noted down. Downstaging was not necessary in any patient following laparoscopic evaluation. CONCLUSION: Only operative staging gives exact information about tumor extension in patients with locally advanced and/or nodal positive cervical cancer and allows individual treatment planning. This can be done successfully by a transperitoneal laparoscopic approach without serious adverse effects delaying chemoradiation. Debulking of tumor-involved lymph nodes significantly improves overall survival and should be performed prior to primary chemoradiation. Laparoscopic staging should be the basis for all treatment studies in order to group patients according to true tumor extent.

Adult↗
PubMed2005

The prevalence of HPV-18 and variants of E6 gene isolated from cervical cancer patients in Taiwan.

BACKGROUND: Cervical cancer is the second most common cancer in women worldwide. It has been considered that human papillomavirus (HPV) is associated with cervical cancer. Currently, more than 80 different serotypes of HPV have been characterized and they are divided into low- and high-risk groups. The most common types that lead to cervical cancer are HPV-16 and -18. The viral oncogenes E6 and E7 are associated with the development of cervical cancer. In previous study, the variants of HPV-16 E6 gene have been reported. It suggests that variants may influence the morbidity of carcinogenesis, but the variant study on HPV-18 remains unknown. OBJECTIVES: To identify the variants of integrated HPV-18 E6 gene in the prevalent infection of HPV-18 of cervical cancer patients. STUDY DESIGN: 25 cervical cancer patients were clinically identified and the biopsies were obtained. The infectious HPV types were identified by PCR and Southern blotting analysis. The DNA fragments of the integrated HPV-18 E6 were amplified by PCR and cloned. The nucleotide sequences were obtained by sequencing. RESULTS: The prevalence of HPV infection in our 25 cases was HPV-18 (100%) and 7 out of these 25 cases (28%) were co-infected with HPV-16. The most dominant mutation among 25 tested patients was a silence mutation C183G of the E6 coding region. CONCLUSIONS: The prevalent HPV infectious serotype is HPV-18, which differs from the worldwide prevalent type. The identified HPV-18 E6 variants had a unique silence mutation located on C183G in E6 coding region.

Adult↗
PubMed2003

Genetic alterations in cervical cancer.

In the pathogenesis of cervical cancer the role of human papillomavirus (HPV) infection is well established. However, other than HPV infection the genetics of cervical cancer remains poorly understood. In the pathogenesis of cervical cancel three major factors are involved, two of which are related to the presence of HPV and the third is the recurrent genetic alterations not linked to HPV infection. Several chromosomal regions with recurrent loss of heterozygosity (LOH) in cervical cancer have been identified. However; the putative tumor suppressor genes located in these chromosomal locations are yet to be identified. Recurrent amplifications have been mapped to the short arm of chromosome 3 in invasive cancer. Microsatellite instability and mutator phenotype do not play a major role in cervical carcinogenesis. As in other cancers, cervical cancer too requires the accumulation of genetic alterations for carcinogenesis to occur. Identification of these alterations could help to provide a better understanding of the disease and thus improve treatment.

Chromosomes, Human↗
PubMed1999

Vaginal changes and sexuality in women with a history of cervical cancer.

BACKGROUND: In women with cervical cancer, treatment causes changes in vaginal anatomy and function. The effect of these changes on sexual function and the extent, if any, to which they distress women are not known. METHODS: In 1996 and 1997, we attempted to contact 332 women with a history of early-stage cervical cancer (age range, 26 to 80 years) who had been treated in 1991 and 1992 at the seven departments of gynecological oncology in Sweden and 489 women without a history of cancer (controls) to ask them to answer an anonymous questionnaire about vaginal changes and sexual function. RESULTS: We received completed questionnaires from 256 of the women with a history of cervical cancer and 350 of the controls. A total of 167 of 247 women with a history of cancer (68 percent) and 236 of 330 controls (72 percent) reported that they had regular vaginal intercourse. Twenty-six percent of the women who had cancer and 11 percent of the controls reported insufficient vaginal lubrication for sexual intercourse, 26 percent of the women who had cancer and 3 percent of the controls reported a short vagina, and 23 percent of the women who had cancer and 4 percent of the controls reported an insufficiently elastic vagina. Twenty-six percent of the women who had cancer reported moderate or much distress due to vaginal changes, as compared with 8 percent of the women in the control group. Dyspareunia was also more common among the women who had cervical cancer. The frequency of orgasms and orgasmic pleasure was similar in the two groups. Among the women who had cervical cancer, the type of treatment received had little if any effect on the prevalence of specific vaginal changes. CONCLUSIONS: Women who have been treated for cervical cancer have persistent vaginal changes that compromise sexual activity and result in considerable distress.

Adult↗
PubMedDate not supplied

Chemoradiation: A new approach for the treatment of cervical cancer.

Despite advances in screening, cervical cancer remains a major health problem worldwide. In an effort to improve loco-regional control, both neoadjuvant and chemoradiation have been trialed. Recently, five randomized clinical trials performed by the Gynecologic Oncology Group, the Radiation Therapy Oncology Group and the Southwest Oncology Group have demonstrated a significant advantage both in progression-free and overall survival when cisplatin-based chemotherapy was administered during radiation for advanced stages of cervical cancer. Based on the results of these trials, the US National Cancer Institute released a Clinical Announcement supporting the concurrent use of cisplatin-based chemotherapy with radiation therapy for high-risk early stage and locally advanced stage cervical cancer. Subsequently, an additional prospective randomized trial performed by the National Cancer Institute of Canada was not able to show benefit with the use of chemoradiation compared with radiation alone for patients with locally advanced stage cervical cancer. This article will analyze these six clinical trials in order to determine the role of chemoradiation in the management of patients with cervical cancer. Furthermore, as anemia is one of the most powerful prognostic factors in patients with cervical cancer, we propose to evaluate the relationship between a decreased level of hemoglobin and treatment outcome.

Antineoplastic Agents↗
PubMed2005

Rapid enrichment of human papillomavirus (HPV)-specific polyclonal T cell populations for adoptive immunotherapy of cervical cancer.

The majority of cervical cancers are caused by human papillomavirus type 16 (HPV16). Cervical cancer is associated with an ineffective host immune response against the HPV16 oncoproteins, characterized by the lack of the strong E6-specific T-helper type 1 (Th1) immunity that is generally present in healthy individuals, the presence of improperly polarized HPV16E6- and E7-specific CD4(+) T cells and increased numbers of regulatory T cells. Therefore, immunotherapeutic intervention is likely to require a modality that deletes the regulatory T cell component and enhances the HPV16-specific Type 1 T cell response. HLA-matched allogeneic stem cell transplantation may offer such a modality, because it involves the eradication of host immune cells and enables the transfer of donor derived tumor-specific T cells to the patient. As a first step in the development of such a treatment, we evaluated the success rate of a protocol for enrichment of HPV16E6-specific CD4(+) T cells from healthy donor PBMC on the basis of their IFNgamma secretion. After a short in vitro stimulation with overlapping 30 amino acid long HPV16E6 peptides, we enriched the IFNgamma secreting cells by magnetic cell sorting. The obtained polyclonal CD4(+) T cell populations recognized distinct epitopes within HPV16E6, as well as E6 protein, processed and presented by autologous professional antigen presenting cells. The described protocol proved successful in PBMC from more than half of the healthy adult blood donors. These HPV16E6-specific CD4(+) T cells may turn out to be an essential component of future adoptive T cell therapy for advanced cervical cancer, by orchestrating CTL dependent and independent tumoricidal mechanisms.

CD4-Positive T-Lymphocytes↗
PubMed1988

Objective results of the operative treatment of cervical cancer.

Surgical staging of cervical cancer samples the retroperitoneal lymph nodes and, at some centres, the parametria. While better than subjective clinical staging, its value is limited because the results of a sampling procedure differ widely from those of a systematic lymphadenectomy. Additionally, considering the pathology of parametrial involvement, it seems unlikely that biopsy can find the majority of parametrial cancer deposits. The most precise data on the spread of cervical cancer are produced by radical hysterectomy and systematic lymhadenectomy. The tumour size has proven to be the most important prognostic criterion and therefore the best suited for patient classification. Tumour size can be measured by a number of methods. Between 1971 and 1987, 583 of 867 patients with Stage Ib to IIb cervical cancer underwent surgical treatment. Lymphadenectomy was systematic and hysterectomy included the resection of the entire parametria at the pelvic wall. In a total of 359 serial giant sections were of sufficient quality for evaluation; most were Stage IIb cases. The frequency of positive pelvic lymph nodes was 30.3% among 132 Stage Ib cases and 44.7% among Stage IIb cases. Most tumours occupied over 40% of the cervical volume. Five-year survival by clinical stage failed to show a statistically significant difference between Stages Ib and IIb. Objective classification by tumour size showed the patients with the smallest tumours to have a five-year survival rate of 92.1%. The patients with the largest still-operable tumours occupying 80% to 100% or more of the cervix still had a five-year survival rate of 65%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1997

Occupation and cervical cancer: an opportunity for prevention.

Cervical cancer remains an important health problem for women. Few published studies have examined cervical cancer with respect to a woman's occupation. This study examines the association of cervical cancer mortality and occupation in a large national database. The purpose of the study is to recommend which occupations may most require health promotion activities. Mortality data from the National Occupational Mortality Surveillance System were used to calculate the proportion of deaths from cervical cancer according to occupation. This study is based on standardized death certificate data for almost 2 million deaths among women in 27 states, covering the period 1985-1990. Our results are consistent with those in previous studies, with service and apparel manufacturing workers showing elevated risk. Data presented show a difference in cervical cancer mortality by occupational group. Identification of these occupations suggests which women could be targeted for preventive services. Women in occupations with low socioeconomic status are less likely to have access to health promotion programs. Resources should be directed to these women.

Adult↗
PubMed2001

Indole-3-carbinol and diindolylmethane induce apoptosis of human cervical cancer cells and in murine HPV16-transgenic preneoplastic cervical epithelium.

Dietary indole-3-carbinol (I3C) has clinical benefits for both cervical cancer and laryngeal papillomatosis, and causes apoptosis of breast cancer cells in vitro. We asked whether I3C and its major acid-catalyzed condensation product diindolylmethane (DIM), which is produced in the stomach after consumption of cruciferous vegetables, could induce apoptosis of cervical cancer cell lines. We also asked whether this effect could be observed in vivo. In vitro, both I3C and DIM caused accumulation of DNA strand breaks in three cervical cancer cell lines. Induction of apoptosis was confirmed by nuclear morphology, nucleosome leakage, altered cytoplasmic membrane permeability and caspase 3 activation. Neither I3C nor DIM caused apoptotic changes in normal human keratinocytes. In C33A cervical cancer cells, DIM was more potent than I3C [dose at which the number of viable cells was 50% of that in untreated cultures (LD(50)) = 50-60 micromol/L for DIM and 200 micromol/L for I3C in a mitochondrial function assay] and faster acting. Furthermore, I3C reduced Bcl-2 protein in a time- and dose-dependent manner. In HPV16-transgenic mice, which develop cervical cancer after chronic estradiol exposure, apoptotic cells were detected in cervical epithelium by TdT-mediated dUTP nick-end labeling staining and by immunohistochemical staining of active caspase 3 only in mice exposed to 17beta-estradiol (E2) and fed I3C. Rare apoptotic cells were also observed by hematoxylin and eosin staining in the spinous layer of the cervical epithelium in both control and transgenic mice. Estradiol reduced the percentage of these late-stage apoptotic cells in the cervical epithelium of transgenic, E2-treated mice, but this reduction was prevented by I3C. These data confirm the proapoptotic action of I3C on transformed cells in vitro, extend the observations to cervical cancer cells and to DIM and show for the first time that dietary I3C results in increased apoptosis in target tissues in vivo.

Animals↗
PubMed2006

The allelic distribution of -308 Tumor Necrosis Factor-alpha gene polymorphism in South African women with cervical cancer and control women.

BACKGROUND: Cervical cancer is due to infection with specific high-risk types of human papillomavirus (HPV). Although the incidence of genital HPV infection in various population groups is high, most of these regress without intervention. Investigating genetic host factors and cellular immune responses, particularly cytokines, could help to understand the association between genital HPV infection and carcinogenesis. The tumor necrosis factor alpha (TNF-alpha) cytokine plays an important role in all stages of cervical cancer and has the ability to induce the regression of human tumors. Therefore the aim of the study was to investigate the allelic distribution of -308 TNF-alpha gene polymorphism in South African women with cervical cancer compared to control women. METHODS: Included in our study were women with histologically proven cancer of the cervix (n = 244) and hospital-based controls (n = 228). All patients and controls were from mixed race and black population groups in South Africa. The detection of a bi-allelic -308 (A/G) polymorphism in the promoter region of TNF-alpha was investigated using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) technique. The distributions of the allelic frequencies were stratified in both patients and controls into two South African ethnic population groups. RESULTS: In this study we observed no association between the distribution of -308 TNF-alpha polymorphism and the risk of developing cervical cancer even after combining the data from the two ethnic populations (X2 = 2.26). In addition, using the chi-squared test we found no significant association between the known risk factors for cervical cancer and the allele distribution of -308 TNF-alpha. However, the frequency of the rare high-producing allele -308A of TNF-alpha was significantly lower in the South African population when compared to Caucasians and Chinese population groups. CONCLUSION: We demonstrated no association between -308 TNF-alpha polymorphism and the risk of cervical cancer among two South African ethnic population groups. However, as the distribution of the -308A TNF-alpha was notably different between the control groups of South Africa and other population groups this result suggests that ethnic disparity may influence the levels of TNF-alpha produced.

Adult↗
PubMedDate not supplied

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.

Antigens, Viral↗
PubMed2001

Prevention of cervical cancer with vaccines.

Worldwide, cervical cancer is one of the most common cancers in women. This is especially true in developing countries, where Papanicolaou smear screening, an effective preventive measure against cervical cancer, is insufficiently implemented. With growing evidence for human papillomavirus as a central etiologic factor in cervical neoplasia, development of a vaccine against this virus has emerged as an important objective in prevention of cervical cancer. International efforts in vaccine development have culminated in advancement of various vaccine strategies and initiation of human clinical trials. Reports from animal vaccine trials and early phase I human trials indicate markedly enhanced immune response through vaccination. However, the clinical significance of these results requires confirmation from long-term human trials.

Animals↗
PubMed2002

Host genetic polymorphism analysis in cervical cancer.

BACKGROUND: The natural history of cervical cancer comprises a latency period that probably involves long-term immunologic tolerance of human papillomavirus infection. Identifying host determinants of viral persistence may help to better understand the mechanisms of tolerance and may lead to the development of tests that can allow more focused follow-up of high-risk individuals. METHODS: Genotypic frequencies of 12 polymorphic loci in four candidate genes from 127 cervical cancer patients were compared with a control group of 108 female blood donors. Genotypes were determined by PCR amplification and direct sequencing of isolated genomic DNA. RESULTS: The tumor necrosis factor-alpha (TNFalpha) -238 polymorphism was significantly underrepresented in cervical cancer patients [heterozygotes (HETs), odds ratio (OR) = 0.33; 95% confidence interval (CI), 0.11-0.96], as was the TNFalpha -376 polymorphism (P = 0.02; 0% for any variant genotype in cases vs 4.7% in controls). The NRAMP1 3' untranslated region STP+86 polymorphism also appeared to be inversely associated with cervical cancer, but this result did not reach statistical significance (HET, OR = 0.57; 95% CI, 0.32-1.02). The p53 codon 72 arginine allele showed a suggestive negative association with cervical cancer (HET, OR = 0.49; 95% CI, 0.14-1.63; homozygotes, OR = 0.35; 95% CI, 0.11-1.17). The remaining alleles tested showed no association with cervical cancer. CONCLUSIONS: We identified host genetic polymorphisms that may be associated with cervical cancer risk, some of which have been linked to potential functional effects on cellular immune responses or antigen processing. We failed to confirm earlier reports of increased cervical cancer susceptibility in women who harbor the p53 P72R allele. Although our findings support the general hypothesis that host immunogenetic determinants other than class II MHC may be important in the development of cervical cancer, further analysis of the HLA gene cluster comprising the implicated TNFalpha single-nucleotide polymorphisms will be required to determine whether their association is linkage independent.

Cation Transport Proteins↗
PubMedDate not supplied

Cancer in first degree relatives of Latin American women with cervical cancer. A pilot study.

BACKGROUND: Cervical cancer is the most frequent cancer of women in Latin America, being strongly associated with infection by certain human papillomavirus (HPV) types. Familial cancer clustering can be due to interactions between infectious agents and host genes. MATERIALS AND METHODS: A cancer-related family history of first degree relatives was elicited in 335 women with invasive cervical cancer (probands) and in 335 women without cancer (controls) in Honduras, Peru and Uruguay, and the frequency of reported familial cancers among the relatives was compared between proband and control relatives. RESULTS: The mean age at the time of interview was 49.8 years for the probands and 50.1 years for the controls (NS). 3852 proband relatives had 114 primary cancers of the following major localisations: 22 uterus, 16 lung, 12 stomach and 64 others. 3333 control relatives had 101 primary cancers of the following major localizations: 18 uterus, 13 stomach, 12 breast, 11 intestinal, 10 lung and 37 others. The frequency of all cancer diagnosis among proband relatives was similar to the frequency among control relatives (odds ratio= 1.01; 95% confidence interval: 0.69-1.47). Nine haemolymphatic malignancies were reported among proband relatives versus 2 in control relatives (odds ratio=3.46; 95% confidence interval: 0.74-16.29). CONCLUSION: All cancer combined did not appear to be more frequent in first degree relatives of women with cervical cancer diagnosis, but haemolymphatic malignancies, a minor part of the cancer burden, may be overrepresented in relatives of women with cervical cancer, pointing to a pathogenic role of familial e.g. hereditary, immunosuppression.

Case-Control Studies↗
PubMed2005

HLA-DQB1 and cervical cancer in Venezuelan women.

BACKGROUND: Cervical cancer represents a major health problem in Venezuela as well as in other Latin American countries. High-risk human papillomavirus (HR-HPV) infection is known as the major risk factor of cervical cancer. However, whether or not a HR-HPV-infected woman progresses to cervical cancer may depend on the immune system effectors induced by viral antigens presented by her specific human leukocyte antigens (HLA) alleles. The role of the HLA system in presenting peptides to antigen-specific T-cells may be critical for genetic susceptibility and genetic resistance to cervical carcinoma. OBJECTIVE: We aimed to investigate the relationship between HLA-DQB1, HPV infection, and cervical cancer in Venezuelan women. METHODS: Blood samples and cervical swabs were obtained from 36 patients and 79 healthy controls; additional cervical biopsies were obtained from all the patients. HPV DNA was detected by PCR and HLA-DQB1 genotyping was performed using a PCR-SSP protocol. RESULTS.: A positive association with cervical cancer was observed for HLA-DQB1*0201-0202 and *0402 alleles, however after Bonferroni correction only HLA-DQB1*0402 remained statistically significant (P value = 0.004, RR = 5.067). CONCLUSION: This is the first report of HLA-DQB1 alleles associated with cervical carcinoma in Venezuelan women. Larger studies are needed to assess whether these HLA-DQB1*0201-0202 and *0402 alleles have a direct effect on disease susceptibility.

Adult↗
PubMed1997

Preventing avoidable death: the case of cervical cancer in Hong Kong.

Cervical cancer remains an important cause of avoidable morbidity and mortality in Hong Kong. This paper briefly reviews the epidemiology of cervical cancer and explores the evidence on the effectiveness of screening. The essential components of a successful cervical cancer screening programme, based on international experience, are discussed. The present situation in Hong Kong is then examined and the options outlined for the way ahead.

Journal Article↗
PubMed2000

Association between high-risk HPV types, HLA DRB1* and DQB1* alleles and cervical cancer in British women.

Cervical scrapes from 116 British women referred with cervical cancer were tested for the presence of high oncogenic risk human papillomavirus (HPV) genotypes (HPV(hr)). Ninety-four per cent of the scrapes had one or more of these virus types and 66% were HPV16-positive. HPV18 was more frequent in adenocarcinoma. No evidence was found for an increased cancer risk associated with the HPV16 E6 350G variant. The HLA DRB1* and DQB1* alleles in these women and in 155 women with normal cytology and negative for HPV(hr) DNA were compared. DQB1*0301 alone (2P = 0.02) and in combination with DRB1*0401 (2P = 0.02) was found to be associated with cervical cancer. This was more marked in cancers positive for HPV types other than HPV16. In contrast, DRB1*1501 alone and in combination with DQB1*0602 was not significantly elevated in cancers overall, but did show some excess in HPV16-positive cancers (2P = 0.05), associated with HPV16-positive cervical cancers. Taking all cancers together, a marginally significant protective effect was found for DQB1*0501 (2P = 0.03) but no protective effect could be seen for DRB1*1301.

Adenocarcinoma↗