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PubMed1995

Second primary cancer after treatment for cervical cancer. An international cancer registries study.

BACKGROUND: The pattern of second cancers after treatment for cervical cancer provides important information on the risk of radiation-induced malignancies. Large numbers of women survive many years and can be studied for late effects. METHODS: Incident second cancers in 86,193 patients with cervical cancer reported to 13 population-based cancer registries in 5 countries were evaluated to estimate the risk of second cancer among very long term survivors. RESULTS: Overall, 7543 second cancers were observed versus 6015 cancers expected based on population rates (observed/expected = 1.2). Lung cancer accounted for nearly half of the excess cancers. Among the 49,828 women treated with radiation, 3750 survived 30 or more years and a two-fold risk of cancers of heavily irradiated organs was seen. Most of the excess cancers were of the rectum, vagina, vulva, ovary, and bladder. Patterns of risk over time since treatment were consistent with a radiation etiology. Significant increases of nonchronic lymphocytic leukemia and cancers of the bone and kidney were also linked to radiotherapy. Women treated surgically were also at significant risk of second cancers, in all likelihood related to cigarette smoking and risk factors similar to those of cervical cancer. CONCLUSIONS: Curative therapy for cervical cancer results in large numbers of long term survivors who develop second cancers very late in life. Radiation is an important cause of this increase and there is no evidence that risk returns to normal levels.

Europe↗
PubMed1989

Human papillomavirus 16 DNA in cervical cancers and in lymph nodes of cervical cancer patients: a diagnostic marker for early metastases?

Human papillomavirus (HPV) 16 is most prevalent in cervical cancers and also persists in metastases. We examined HPV16-DNA-positive primary cancers and several lymph nodes from each of 14 patients to evaluate the use of HPV16 DNA as a diagnostic marker for the detection of early node involvement. The HPV16 DNA was exclusively integrated in 39% of the primary cancers, predominantly episomal in 36%, and integrated and extrachromosomal to a similar extent in 25%. Thirteen of 16 involved lymph nodes contained HPV16 sequences. Integrated viral DNA showed the same pattern in primary tumors and in metastases. The level of extrachromosomal HPV16 DNA, however, appeared to be considerably reduced in some nodes. HPV16 DNA was also detected in 18 out of 59 histologically negative lymph nodes. This result recommends nucleic acid hybridization as a sensitive method for the detection of HPV-DNA-positive cancer cells. The prognostic significance of viral sequences in histologically negative nodes remains to be established.

Biomarkers, Tumor↗
PubMed2026

CTGF/CCN2 Promotes Invasive Growth in Cervical Cancer Spheroids and Is Associated With Metastatic Cervical Cancer Tissue.

BACKGROUND/AIM: Metastatic spread defines the lethality of cervical cancer (CC). Connective tissue growth factor (CTGF/CCN2) regulates cell- extracellular matrix interactions but its role in CC is not well-defined. This study investigates the role of CTGF in driving CC invasive growth and its prevalence in patient tissues. MATERIALS AND METHODS: CC spheroids (C33A, HT3) were treated with recombinant human CTGF (rhCTGF) or a function-blocking antibody (IgG CTGF). Invasive growth was assessed via 3D spheroid assay using a Celigo imaging cytometer. Cancer stem cell (CD133, CD44) and epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin) were analyzed by immunofluorescence. CTGF expression was evaluated using a tissue microarray containing 69 cases in triplicate from pre-invasive, invasive (FIGO I-III), and metastatic cervical lesions, quantified via immunofluorescence scoring. RESULTS: Functional blockade of CTGF significantly reduced 3D spheroid invasive growth in C33A and HT3 cells (p<0.0001). Immunofluorescence revealed that CTGF modulation altered spatial distribution of key proteins: rhCTGF induced surface clustering of CD133 and peripheral N-cadherin enrichment, while CTGF blockade was associated with apparent nuclear/perinuclear enrichment of CD133 and E-cadherin and reduced N-cadherin signal. In patient tissue cores, metastatic samples exhibited the highest CTGF fluorescence intensity. High CTGF expression [immunoreactivity score (IRS) &#x2265; 6] was most prevalent in FIGO stage I (35.5%) compared to stage III (10.0%). Kaplan-Meier analysis revealed that high CTGF mRNA expression was associated with significantly reduced recurrence-free survival (log-rank p=0.0032). CONCLUSION: In 3D models of CC, CTGF appears to regulate an invasive phenotype, presumably by controlling aberrant localization of stemness and EMT markers. Its apparently elevated expression in early-stage cervical carcinomas and metastases, combined with its prognostic value for recurrence-free survival, suggests that CTGF may be involved in triggering the potential for metastasis and could therefore serve as an early prognostic biomarker.

Humans↗
PubMed1979

Antibody-dependent cell-mediated cytotoxicity of sera from cancer patients against cultured cervical cancer cell lines.

Cytotoxicity of sera from cervical cancer patients mediated by peripheral blood lymphocytes against cervical cancer cell lines was studied. Percentages of reduction of target QG-K by sera from healthy controls and cervical cancer patients were 4.7% and 32.0%, respectively. Sera from patients with pulmonary tuberculosis also exhibited antibody-dependent cell-mediated cytotoxicity (ADCC) against the cells. Especially, high degree of activity was observed in the sera from patients with stage IV and the activity decreased to the control level in recurrent cases. The titer of the sera varied against different target cell lines, and the activity was found even at 1:10(4) dilution of the sera. These activities remained after absorption of the serum with other tumor cells. Complement-dependent cytotoxic activity of the sera was not observed. The meaning of the cytotoxic activity of the sera from cervical cancer patients was discussed.

Antibodies, Neoplasm↗
PubMed2003

Innovations in the treatment of invasive cervical cancer.

Invasive cervical cancer is characterized by basement membrane-invading lesions capable of metastasizing through the lymphatic and vascular systems. Treatment methods were reviewed by panelists at the Second International Conference on Cervical Cancer (Houston, TX, April 11-14, 2002), and new opportunities for translational research were discussed. Reviews encompassed hysterectomy with or without lymph node dissection or cervical conization in cases with microinvasion and radical trachelectomy with or without lymph node dissection as fertility-sparing surgery. Chemoradiation is used to treat advanced cervical malignancies, and the risks and benefits of radiotherapy are significant. Pelvic exenteration is used to treat certain types of recurrences. Use of the Miami pouch for continent urinary diversion was highlighted. Gynecologic oncologists expect novel in vivo imaging techniques currently being developed to help guide therapy choices within the next decade. The most significant research priorities are large group-randomized trials involving fertility-sparing procedures and the management of microinvasive carcinoma (MICA); better identification of candidates for chemoradiation; and the development of innovative approaches to exenteration. Improving diagnostic technologies, refining the criteria by which therapies are chosen, and preserving fertility remain challenges in selecting the most appropriate treatment for invasive cervical cancer. Research advances in both diagnosis and treatment are expected to improve therapy and outcomes.

Combined Modality Therapy↗
PubMed1979

Tumor-associated antigens in cervical cancer tissues and in sera from patients with cervical cancer or with head and neck cancer.

Hyperimmune New Zealand White rabbit sera prepared against partially purified tumor-associated antigens (TAA) of invasive cervical cancer tissues (CaCx's) were used to demonstrate TAA in CaCx's and circulating TAA (C-TAA) in sera from patients with cervical cancer or with head and neck cancer. Anti-CaCx serum adsorbed with pooled normal cervical tissue (NCx) antigen preparations and with lyophilized pooled normal human plasma gave precipitin in gel reactions with CaCx but not with NCx, which indicated the presence of TAA in CaCx. The adsorbed antisera reacted with sera from patients with cervical and head and neck cancers, which indicated the presence of C-TAA in such sera. False-positive reactions with control sera from normal humans or from patients with benign gynecologic diseases were much less frequently observed. Statistical analysis of data obtained by the testing of 96 coded serum samples from the National Cancer Institute-Mayo Clinic Serum Bank (Rochester, Minn.) revealed that the results were significant and that specificity was high but sensitivity of the assay was relatively low.

Adult↗
PubMed1986

Steroid receptors in uterine cervical cancers.

In cervical cancers, the estrogen receptor (ER) and progestin receptor (PR) were characterized in the cytosol protein. Receptor levels were determined in cytosol, nuclear KCl extract, and nuclear KCl unextractable fraction in various cervical cancer tissues. The androgen receptor (AR) was also similarly characterized. In the cytosol, the estrogen (E2)-ER complex and the promegesterone (R5020)-PR complex were sedimented at approximately the 5S and 8S or the 4S and 8S regions, respectively, by 5-20% linear sucrose gradient centrifugation. A steroid specificity study showed the presence of an estrogen-specific and a progestin-specific binder. The dissociation constant of the specific binder for estrogen (ER), progestin (PR), or androgen (AR) was approximately 10(-10) to 10(-9)M in cytosol, nuclear KCl, and nuclear KCl unextractable fraction in detected cases. Levels were determined by Scatchard analyses, using the dextran-coated charcoal (DCC) adsorption method for the former two and the washing method for the latter one. ER, PR, or AR was detected in some cases of determined cervical cancers (27 cases of squamous cell carcinoma, and 7 cases of adenocarcinoma); regardless of the histological types, ER was detected in almost all cases. PR was not detected in the given cases of cervical adenocarcinoma. It is suggested that estrogen stimulation of PR synthesis in cervical adenocarcinoma may be damaged.

Adenocarcinoma↗
PubMed2006

Randomized controlled trial of human papillomavirus testing versus Pap cytology in the primary screening for cervical cancer precursors: design, methods and preliminary accrual results of the Canadian cervical cancer screening trial (CCCaST).

Since infection with oncogenic human papillomavirus (HPV) has been considered a necessary cause of cervical cancer, tests for oncogenic HPV types have been proposed as adjuncts or replacements to Pap cytology. We designed the Canadian Cervical Cancer Screening Trial (CCCaST) to compare the relative efficacy of HPV DNA testing and Pap cytology in primary screening for cervical cancer and its high-grade precursors. CCCaST randomized women aged 30-69 years in Montreal (Quebec) and in St. John's (Newfoundland) to 1 of 2 screening groups: focus on Pap (conventional) or focus on HPV testing (Hybrid Capture 2). Women in both arms received both tests, but were randomized as to their order, the first test being the index test. Women with an abnormal Pap test or a positive HPV test underwent colposcopy and biopsy, as did a random sample of women with a negative index test. CCCaST enrolled 9,667 women between October 2002 and October 2004. At enrolment, 2.8% had an abnormal Pap test, 6.1% had a positive HPV test and 1.1% were abnormal in both tests. ASC-US was the most frequent cytological abnormality, representing 64% of abnormal Pap results. The frequency of abnormal Pap and HPV results decreased with increasing age and the proportion of HPV-positive results increased with the severity of Pap abnormality. Efficacy analysis will determine if the extra referrals with HPV DNA testing will translate into a relevant increase in high-grade cervical cancer precursor detection. Because of its design, CCCaST will provide sound evidence for formulating cervical cancer screening strategies.

Adult↗
PubMed2003

[Concurrent weekly nedaplatin-based radiotherapy for high risk, recurrent and advanced cervical cancer].

Advanced cervical cancer has been predominantly treated with a combination of external beam and brachytherapy in Japan. Recent studies suggest concurrent use of cisplatin and radiation treatment has superior disease control to radiation only treatment. We have conducted a phase I pilot study of concurrent use of weekly nedaplatin (30 mg/m2) and sequential external beam and brachytherapy in advanced stage or recurrent uterine cervical cancer patients (n = 6). All patients completed the treatment without serious complications. Five patients had complete responses and one a partial response. The average AUC of nedaplatin after one administration was 5.0 micrograms/ml.hr. The therapeutic index was 2. We concluded that concurrent use of weekly nedaplatin and radiation is well tolerated by Japanese women, and may well be an excellent therapeutic modality for selected cases of advanced or recurrent cervical cancer.

Aged↗
PubMed2000

Early cervical cancer.

Early cervical cancer includes a broad range of disease, from clinically undetectable microinvasive cancer to large, bulky tumors that replace the entire cervix. Further subgrouping of this category is therefore necessary to define the optimal treatment approach for individual cases. The International Federation of Gynecology and Obstetrics (FIGO) staging system stratifies stage I tumors into two broad categories, stage IA (microinvasive) and stage IB (gross tumor). Management of women with stage IA disease is controversial. In the United States, patients with stromal invasion of less than 3 mm and no lymphvascular involvement are usually treated conservatively with simple hysterectomy. In selected patients who desire fertility, cone biopsy with negative surgical margins is also considered. Patients with invasion of more than 3 mm or lymphvascular space involvement are at risk for pelvic lymph node metastasis and are most often treated with radical hysterectomy and pelvic lymphadenectomy. Stage IB1 cervical cancer is managed by either radical surgery or radiotherapy with equivalent recurrence and survival rates. In patients with tumors less than 4 cm in diameter, the decision between radical surgery and radiotherapy is guided by patients' overall health and treatment preferences. For younger women, radical surgery is preferred because ovarian function can be preserved and vaginal stenosis secondary to radiation can be avoided. Radiation therapy is preferred for women who may not tolerate radical surgery. We always prefer primary radiation therapy for patients with tumors larger than 4 cm in diameter. Recent data convincingly demonstrate that the addition of cisplatin-based chemotherapy significantly improves overall survival rates in cervical cancer patients who undergo radiation therapy.

Antineoplastic Agents↗
PubMed2003

Risk of cervical cancer associated with extending the interval between cervical-cancer screenings.

BACKGROUND: Although contemporary guidelines suggest that the intervals between Papanicolaou tests can be extended to three years among low-risk women with previous negative tests, the excess risk of cervical cancer associated with less frequent than annual screening is uncertain. METHODS: We determined the prevalence of biopsy-proven cervical neoplasia among 938,576 women younger than 65 years of age, stratified according to the number of previous consecutive negative Papanicolaou tests. Using a Markov model that estimates the rate at which dysplasia will progress to cancer, we estimated the risk of cancer within three years after one or more negative Papanicolaou tests, as well as the number of additional Papanicolaou tests and colposcopic examinations that would be required to avert one case of cancer given a particular interval between screenings. RESULTS: Among 31,728 women 30 to 64 years of age who had had three or more consecutive negative tests, the prevalence of biopsy-proven cervical intraepithelial neoplasia of grade 2 was 0.028 percent and the prevalence of grade 3 neoplasia was 0.019 percent; none of the women had invasive cervical cancer. According to our model, the estimated risk of cancer with annual Papanicolaou tests for three years was 2 in 100,000 among women 30 to 44 years of age, 1 in 100,000 among women 45 to 59 years of age, and 1 in 100,000 among women 60 to 64 years of age; these risks would be 5 in 100,000, 2 in 100,000, and 1 in 100,000, respectively, if screening were performed once three years after the last negative test. To avert one additional case of cancer by screening 100,000 women annually for three years rather than once three years after the last negative test, an average of 69,665 additional Papanicolaou tests and 3861 colposcopic examinations would be needed in women 30 to 44 years of age and an average of 209,324 additional Papanicolaou tests and 11,502 colposcopic examinations in women 45 to 59 years of age. CONCLUSIONS: As compared with annual screening for three years, screening performed once three years after the last negative test in women 30 to 64 years of age who have had three or more consecutive negative Papanicolaou tests is associated with an average excess risk of cervical cancer of approximately 3 in 100,000.

Adolescent↗
PubMed1998

Knowledge and attitude of general outpatient attendants in Nigeria to cervical cancer.

OBJECTIVES: This study sets out to determine: a. How much women in low socio-economic settings know about cancer and cervical cancer. b. Their source of information. c. Their general attitude to cervical cancer. DESIGN: A cross sectional study. SETTING: General outpatient (GOP) department of a tertiary hospital in Ibadan, Nigeria. SUBJECTS: 254 randomly selected women aged 20 to 65 years attending or visiting the GOP department in a University Teaching Hospital were studied. MAIN OUTCOME MEASURES: Knowledge about cancer and cervical cancer as well as source of information. RESULTS: The response rate was 100%. Of the respondents, 90% had heard of cancer at one time or the other while only 15% had heard of cervical cancer. The media (38%) and peers (36%) were the major sources of information on cancer. Fifty five percent, 53% and 61% had no knowledge while 40% and 23% had poor to moderate overall knowledge of cervical cancer. CONCLUSION: Knowledge about cervical cancer is poor in these women, unlike findings in developed countries. There is need to educate our women on the early warning signs of cervical cancer as failure to recognise the early symptoms and signs contribute to the late presentation common in Nigeria.

Adult↗
PubMed1998

Missed opportunities for cervical cancer screening of HMO members developing invasive cervical cancer (ICC).

OBJECTIVE: To identify potential missed opportunities and to suggest interventions for cervical cancer screening in members of a prepaid health plan by examining the membership histories and medical records of women who had no Pap smear performed in the 3 years prior to the diagnosis of ICC. METHODS: Medical records of all 642 members of a prepaid health plan developing ICC during the period from 1988 to 1994 were reviewed and details of patient interaction with the health care system were abstracted. Assessment of screening history and history of clinic visits was limited to the period 36 months prior to diagnosis, but excluded the last 6 months prior to diagnosis, so as to avoid including smears or visits which were part of the evaluation that led to the recognition of ICC. RESULTS: Of women developing ICC, 384/642 (60%) had not had a smear in the period from 36 months to 6 months preceding the diagnosis. Of these 384 unscreened women, 241 (63%) had been insured by our HMO for at least 30 of the 36 months prior to diagnosis. Contact with the medical system in one of the primary care outpatient clinics was documented in 180/241 (75%) of these long-standing members during the specified period. Considering only Internal Medicine and Family Practice clinic visits, 169/241 (70%) had been seen at least once and 101/241 (42%) had been seen 3 or more times. CONCLUSION: Most long-standing HMO members developing ICC without benefit of recent Pap smear screening were seen in primary care outpatient clinics in the 3 years preceding their diagnosis.

Female↗
PubMed1992

Cancer screening behaviors among U.S. women: breast cancer, 1987-1989, and cervical cancer, 1988-1989.

Data from the Behavioral Risk Factor Surveillance System (BRFSS) were used to examine trends in breast and cervical cancer screening behaviors among U.S. women in selected states. Data reported are from the 1987, 1988, and 1989 BRFSS for breast cancer screening (mammography) and from the 1988 and 1989 BRFSS for cervical cancer screening (Papanicolaou [Pap] smear). Results are presented as either state-specific or state-aggregate data for the years noted above. State-specific analyses indicated that self-reported mammography utilization increased between 1987 and 1989. Although whites and blacks reported similar mammography utilization rates both for screening and for a current or previous breast problem, disparities were evident among women of different ages and incomes. The proportion of women who reported ever having had a Pap smear and having heard of a Pap smear were extremely high and remained fairly consistent across the 2 survey years. State-aggregate analyses, however, showed that the percentage of women who had had a Pap smear within the previous year was negatively associated with age and positively associated with income. A higher proportion of blacks than whites obtained Pap smears. These results indicate that certain segments of the population are not taking full advantage of available breast and cervical cancer screening technologies. Public health strategies, such as those outlined in the Breast and Cervical Cancer Mortality Prevention Act of 1990 (Public Law 101-354), should enhance screening opportunities for these women.

Adult↗
PubMed1982

Tumour-associated antigens in cervical cancer tissues and in the sera of Nigerian women with cervical cancer.

Soluble antigens and membrane-bound antigens were prepared from a pool of cervical cancer (CaCx) tissues. The soluble antigens were extracted by homogenization in Earle's balanced salt solution containing antibiotics, and the membrane-bound antigens were extracted by 3 M potassium chloride. For isolation of partially purified tumour-associated antigens (TAA), ammonium sulphate precipitation, ion exchange chromatography and gel filtration methods were employed. Hyperimmune rabbit sera prepared against partially purified CaCx tissue antigens, absorbed with pooled normal cervical (NCx) tissue antigen preparation and pooled normal human sera (NHuS), demonstrated three tumour-associated antigens (TAA-1, -2, and -3) in the soluble antigen preparations by the immunoprecipitin-in-gel reactions. Only one TAA (probably identical to TAA-3 of the soluble antigens) was obtained in the KCl extract. Similarly, the antisera detected circulating TAA (C-TAA) in the sera of twenty-seven of thirty-six (75%) patients with cervical cancer, one of eighteen (5.6%) women with benign gynaecological diseases, one of seventy-two (1.4%) pregnant women and none of thirty-six (0%) healthy controls. The test indicated high specificity, and the procedure shows great potential for immunodiagnosis of cervical cancer.

Animals↗
PubMed1986

[Epidemiologic factors in cervical cancer--investigation on 306 pairs of partners. Jiangxi Co-operative Group of Cervical Cancer].

To investigate the epidemiologic factors in Jingan and Tonggu counties, high incidence areas of cervical cancer, the 306 patient-control pairs were studied in 1980. These patients with various stages of cervical cancer were pathologically diagnosed in mass screening. The controls were healthy women of the same tribe and occupation, living in the same village as the patients. The age difference between the patients and the controls were not over 2-3 years. The ratio of the patients to the controls was 1:1. 36 doubtful factors were investigated by direct inquiry with uniform tables. After statistical analysis, it was found that sexual activity, smegma and cervical erosion are the high risk factors in causing cervical cancer. These three factors coexist, the relative risk was 11.2. It suggests that these factors have a comprehensive effect in causing cervical cancer. In view of the above, we suggested a preliminary plan for preventing and blocking of the development of cervical cancer and experiments in Jingan county are being carried out.

China↗
PubMed2000

Efficacy of a liquid-based thin layer method for cervical cancer screening in a population with a low incidence of cervical cancer.

The performance of the ThinPrep(R) Pap Testtrade mark (TP) (Cytyc Corp., Boxborough, MA) for detection of cervical cancer precursors in a population with a low incidence of disease was evaluated. This prospective trial compared results obtained with TP to those obtained with the standard cytologic smear in women from the general community who were being screened for cervical cancer from January 1, 1995-December 31, 1997 by physicians in private practice (n x 130, 381 conventional examinations and 39,864 TP examinations). In the TP series there was a significant increase in the proportion of "satisfactory" examinations (91.9% TP vs. 72.2% conventional) and positive diagnoses (5.5% TP vs 2.4% conventional, odds ratio x 2.21; 95% confidence interval (CI), 2.08-2.34). The likelihood of detecting a high-grade squamous intraepithelial lesion (HSIL) by TP was significantly greater than in controls (odds ratio x 1.86; 95% CI, 1.68-2.06). Detection of low-grade squamous intraepithelial lesions (LSIL), or atypical squamous cells of undetermined significance (ASCUS), was significantly greater in the TP series than in controls (LSIL odds ratio x 3.41; 95% CI, 3.07-3.79; ASCUS odds ratio x 1.68; 95% CI, 1.56-1.82). A histologic lesion was confirmed in 141 (93%) of the biopsies for HSIL (130 HSIL or greater, 10 LSIL, 1 SIL not otherwise specified). In conclusion, both diagnostic sensitivity and sample adequacy were significantly improved using the ThinPrep(R) Pap test under routine conditions in an outpatient population with a low incidence of cervical cancer.

Adult↗
PubMed1992

Invasive cervical cancer following cryotherapy for cervical intraepithelial neoplasia or human papillomavirus infection.

OBJECTIVE: To determine the following: 1) the causes for the failure of cervical cryotherapy to prevent cervical cancer, and 2) whether cervical cryotherapy is associated with the development of cervical adenocarcinoma rather than squamous carcinoma. METHODS: We reviewed the medical charts of 327 women with cervical cancer. One hundred forty-seven for whom pertinent history was missing were contacted by telephone or at clinic visits. History obtained verbally was confirmed by outside medical records. Cervical biopsies (N = 16) and endocervical curettages (ECCs) (N = 15) performed before cryotherapy and biopsies at the diagnosis of cancer (N = 21) were reviewed. RESULTS: Twenty-one women with cervical cancer had a history of cryotherapy for cervical intraepithelial neoplasia (CIN) or human papillomavirus infection (HPV). The interval between cryotherapy and cancer was more than 2 years in 19 and more than 5 years in ten. Several categories of pre-treatment errors were identified. Evaluation before cryotherapy was appropriate in only nine cases. Interpretive errors were noted in three of 16 cervical biopsies and ten of 15 ECCs. After cryotherapy, 12% of women had appropriate follow-up. Of the invasive cancers that developed, 24% in the cryotherapy group and 21% in the non-cryotherapy group were adenocarcinomas. CONCLUSIONS: Careful evaluation before cryotherapy, accurate pathology reports, and consistent long-term follow-up are necessary if cryotherapy is to be used to treat CIN or HPV. We found no evidence that cryotherapy is associated with the development of cervical adenocarcinoma.

Adenocarcinoma↗