Cervical Cancer
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Cervical cancer is a common type of malignancy accounting for about 6% of all cancers found in women. It is a disease in which cancerous cells develop in the uterine cervix (this is the connecting passage between the uterus and vagina). The human papillomaviruses (HPV) are the principal cause of most cervical cancers. The peak incidence of cervical cancer occurs between the ages of 40 to 55. It is rare before the age of 35, however the incidence of cervical cancer in younger women rose dramatically during the two decades after 1960. Regular Pap smear tests may detect abnormal changes in the cervical tissues, before cancer develops. Symptoms of cervical cancer may include vaginal bleeding after intercourse or bleeding between periods. However, in the early stages of the disease there are often no obvious signs or symptoms, so regular smear tests are important.

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Information for Patients and the Public
Information for Health Professionals / Researchers
Latest Research Publications
Human Papillomavirus (HPV), Vaccination, and Cervical Cancer
Cervical Cancer Screening (including the PAP smear test)
Gynacological Cancers

Information Patients and the Public (22 links)

Information for Health Professionals / Researchers (12 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Abid N, Mnif H, Mellouli M, et al.
Uterine tumour resembling ovarian sex cord tumours presenting as multiple endometrial and cervical uterine polyps: a case report.
Pathologica. 2014; 106(2):73-6 [PubMed] Related Publications
BACKGROUND: Uterine tumours resembling ovarian sex-cord tumours (UTROSCT) are very rare, benign uterine tumours, composed solely of sex cord elements. These tumours have a polyphenotypic immunophentype that favours a derivation from uterine mesenchymal stem cells.
CASE REPORT: A 43-year-old female presented with recurrent vaginal bleeding. On hysteroscopy, she had multiple endometrial and cervical polyps that were removed endoscopically. Histologically, the specimen contained epithelioid cells arranged in tubules, trabeculae and anastomosing cords, without significant cellular atypia or mitotic activity. Immunohistochemical studies were performed. The tumour was found to be diffusely positive for vimentin, calretinin and desmin, focally positive for cytokeratin, CD99 and inhibin and negative for chromogranin and CD10. A subsequent total hysterectomy was performed and revealed neoplastic infiltration of the myometrium.
CONCLUSION: A polyphenotypic immunophenotype is a characteristic feature of UTROSCT, and may be helpful in diagnosis and in exclusion of other lesions. Familiarity with this tumour by gynaecologists and pathologists is essential to avoid misdiagnosis:correct diagnosis of this neoplasm is important in patient management.

Related: Endometrial (Uterus) Cancer Endometrial Cancer Ovarian Cancer

Brown DS, Poulos C, Johnson FR, et al.
Adolescent girls' preferences for HPV vaccines: a discrete choice experiment.
Adv Health Econ Health Serv Res. 2014; 24:93-121 [PubMed] Related Publications
PURPOSE: To measure adolescent girls' preferences over features of human papillomavirus (HPV) vaccines in order to provide quantitative estimates of the perceived benefits of vaccination and potential vaccine uptake.
DESIGN/METHODOLOGY/APPROACH: A discrete choice experiment (DCE) survey was developed to measure adolescent girls' preferences over features of HPV vaccines. The survey was fielded to a U.S. sample of 307 girls aged 13-17 years who had not yet received an HPV vaccine in June 2008.
FINDINGS: In a latent class logit model, two distinct groups were identified--one with strong preferences against vaccination which largely did not differentiate between vaccine features, and another that was receptive to vaccination and had well-defined preferences over vaccine features. Based on the mean estimates over the entire sample, we estimate that girls' valuation of bivalent and quadrivalent HPV vaccines ranged between $400 and $460 in 2008, measured as willingness-to-pay (WTP). The additional value of genital warts protection was $145, although cervical cancer efficacy was the most preferred feature. We estimate maximum uptake of 54-65%, close to the 53% reported for one dose in 2011 surveillance data, but higher than the 35% for three doses in surveillance data.
RESEARCH LIMITATIONS/IMPLICATIONS: We conclude that adolescent girls do form clear opinions and some place significant value on HPV vaccination, making research on their preferences vital to understanding the determinants of HPV vaccine demand.
ORIGINALITY/VALUE: DCE studies may be used to design more effective vaccine-promotion programs and for reassessing public health recommendations and guidelines as new vaccines are made available.

Related: USA

Fitzpatrick P, O'Neill S, Mooney T, et al.
Age related influence on screening coverage and satisfaction. with CervicalCheck.
Ir Med J. 2014 Jul-Aug; 107(7):216-7 [PubMed] Related Publications
The aim of this study was to evaluate levels of satisfaction of women attending the CervicalCheck programme and reasons for the age differential in screening uptake. A questionnaire was sent to 5,000 randomly selected attenders with a normal smear test (3,500 aged 25-44, 1,500 aged 45-60). Almost all in both age groups said they would return to CervicalCheck if invited (98.5%; 98.5%) and recommend the service to family/friend (99.6%; 99.5%). The single independent predictor of 'would recommend to family/friend' was willingness to return to CervicalCheck (OR = 31 (5.2-183.7)). Predictors of 'would return if invited' were knowledge of when due to return (OR = 2.5 (1.3-5.0)) and having contacted or having received a letter of invitation from CervicalCheck (OR = 3.1 (1.6-6.1)). Independent predictors of 'knowledge of when due to return' were older age group (OR = 0.5 (0.4-0.7)) and willingness to return to CervicalCheck (OR = 3.2 (1.2-6.3)). The GP is particularly important in informing older women and encouraging attendance.

Related: Cancer Screening and Early Detection

Kuhs KA, Porras C, Schiller JT, et al.
Effect of different human papillomavirus serological and DNA criteria on vaccine efficacy estimates.
Am J Epidemiol. 2014; 180(6):599-607 [PubMed] Article available free on PMC after 15/09/2015 Related Publications
Two trials of clinically approved human papillomavirus (HPV) vaccines, Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE I/II) and the Papilloma Trial Against Cancer in Young Adults (PATRICIA), reported a 22% difference in vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 2 or worse in HPV-naïve subcohorts; however, serological testing methods and the HPV DNA criteria used to define HPV-unexposed women differed between the studies. We applied previously described methods to simulate these HPV-naïve subcohorts within the Costa Rica HPV16/18 Vaccine Trial and assessed how these criteria affect the estimation of VE. We applied 2 enzyme-linked immunosorbent assay (ELISA) thresholds for HPV16 and HPV18 seropositivity (8 and 7 ELISA units/mL, respectively, for PATRICIA; 54 and 65 ELISA units/mL, respectively, for FUTURE I/II (to approximate the competitive Luminex immunoassay)) and 2 criteria for HPV DNA positivity (12 oncogenic HPV types, plus HPV66 and 68/73 for PATRICIA; or plus HPV6 and 11 for FUTURE I/II). VE was computed in the 2 naïve subcohorts. Using the FUTURE I/II and PATRICIA criteria, VE estimates against cervical intraepithelial neoplasia grade 2 or worse, regardless of HPV type, were 69.0% (95% confidence interval: 40.3%, 84.9%) and 80.8% (95% confidence interval: 52.6%, 93.5%), respectively (P = 0.1). Although the application of FUTURE I/II criteria to our cohort resulted in the inclusion of more sexually experienced women, methodological differences did not fully explain the VE differences.

Li P, Zhou L, Liu X, et al.
Mitotic DNA damages induced by carbon-ion radiation incur additional chromosomal breaks in polyploidy.
Toxicol Lett. 2014; 230(1):36-47 [PubMed] Related Publications
Compared with low linear energy transfer (LET) radiation, carbon-ion radiation has been proved to induce high frequency of more complex DNA damages, including DNA double strands (DSBs) and non-DSB clustered DNA lesions. Chemotherapeutic drug doxorubicin has been reported to elicit additional H2AX phosphorylation in polyploidy. Here, we investigated whether mitotic DNA damage induced by high-LET carbon-ion radiation could play the same role. We demonstrate that impairment of post-mitotic G1 and S arrest and abrogation of post-mitotic G2-M checkpoint failed to prevent mis-replication of damaged DNA and mis-separation of chromosomes. Meanwhile, mitotic slippage only nocodazole-related, cytokinesis failure and cell fusion collectively contributed to the formation of binucleated cells. Chk1 and Cdh1 activation was inhibited when polyploidy emerged in force, both of which are critical components for mitotic exit and cytokinesis. Carbon-ion radiation irrelevant of nocodazole incurred additional DNA breaks in polyploidy, manifesting as structural and numerical karyotype changes. The proliferation of cells given pre-synchronization and radiation was completely inhibited and cells were intensely apoptotic. Since increased chromosomal damage resulted in extensive H2AX phosphorylation during polyploidy, we propose that the additional γ-H2AX during polyploidy incurred by carbon-ion radiation provides a final opportunity for these dangerous and chromosomally unstable cells to be eliminated.

Related: Apoptosis

Stukan M, Dudziak M
Successful treatment of a large symptomatic lymphocyst with percutaneus drainage and repeated iodopovidone sclerotherapy.
Eur J Gynaecol Oncol. 2014; 35(4):456-7 [PubMed] Related Publications
The objective of the case report was to present an easy and safe method for treatment of a large, persistent lymphocyst, through a procedure performed in an ambulatory setting. The patient diagnosed with large (1,800 mi), symptomatic (pains, renal insufficiency) lymphocyst after lymphadenectomy for cervical cancer, was successfully treated with percutaneous drainage (using vascular drains) and five sessions of sclerotherapy with 10% iodopovidone, performed in ambulatory settings. The method was minimally invasive, safe, and effective in management of symptomatic lymphocyst.

Lataifeh I, Obeidat N, Al-Mehaisen L, et al.
A survey of Jordanian obstetricians and gynecologists' knowledge and attitudes toward human papillomavirus infection and vaccination.
Eur J Gynaecol Oncol. 2014; 35(4):429-32 [PubMed] Related Publications
OBJECTIVE: To assess the knowledge and attitudes of Jordanian obstetricians and gynecologists toward human papillomavirus (HPV) infection and its vaccine.
MATERIALS AND METHODS: A self-administered, anonymous questionnaire was distributed to 400 participants attending scientific meetings. The survey focused on three areas: knowledge of HPV infection, vaccine, and attitude toward vaccination of female adolescents.
RESULTS: Survey response rate was of 72.3%. The vast majority knew most of the statements related to knowledge of HPV infection, 66% thought that conventional screening Pap test have a sensitivity of > 75%, and only 44% of them knew that there are 13 to 17 HPV types that cause cervical cancer. The majority of the respondents (79%) knew that the vaccine would lead to long lasting immunity and 45% of the respondents thought that the vaccination would eliminate the need for regular Pap test. The majority (78%) indicated that the vaccine should be given to girls before the beginning of sexually active life. Overall, 67.5% of respondents intend to prescribe HPV vaccines and 79.6% of the respondents intend to recommend the vaccine if it is publicly funded.
CONCLUSION: Most of the gynecologists in Jordan have the intention to recommend HPV vaccine, the deficit in their knowledge of HPV infection and vaccine must be corrected to assure acceptability of the vaccine.

Related: Cancer Screening and Early Detection

Koleli IK, Ozdogan E, Sariibrahim B, et al.
Prognostic factors affecting lymph node involvement in cervical cancer.
Eur J Gynaecol Oncol. 2014; 35(4):425-8 [PubMed] Related Publications
AIM: Clinical and histopathological factors that affect lymph node involvement in cervical cancer and the prognostic importance of these factors were evaluated in this study.
MATERIALS AND METHODS: A total of 179 patients were diagnosed with cervical cancer between January 2001 and June 2010 and were included in this study. The patients' charts were evaluated retrospectively and information was collected by reaching 89 patients and asking questions.
RESULTS: When the prognostic factors that affect pelvic lymph node involvement were evaluated, increased tumor size and increased invasion depth, presence of lymphovascular area involvement, and an advanced stage were observed to statistically significantly increase pelvic lymph node involvement. No relationship was found between tumor histology and grade; parametrial, endometrial, vaginal involvement, and pelvic lymph node involvement.
CONCLUSION: Knowledge of prognostic factors in cervical cancer plays an important role in determining the morbidity and mortality and the treatment strategies.

Jakubowicz J, Blecharz P, Skotnicki P, et al.
Toxicity of concurrent chemoradiotherapy for locally advanced cervical cancer.
Eur J Gynaecol Oncol. 2014; 35(4):393-9 [PubMed] Related Publications
AIM OF THE STUDY: The analysis of acute and late toxicity of concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer (LACC) based on review of 120 patients treated in Centre of Oncology in Krakow between 2001 and 2007.
MATERIALS AND METHODS: Medium age of the patients was 52 years (43-66). Overall, 12 patients (10.0%) were in Stage IB2, 54 (45.0%) in Stage II, 43 (35.8%) in Stage III, and 11 (9.2%) in Stage IVA. Squamous cell carcinoma was present in 114 (95.0%) patients. Well-differentiated (grade 1) tumour was found in 39 (32.5%) patients, moderately differentiated (grade 2) in 41 (34.2%), and poorly differentiated (grade 3) in 40 (33.3%). Karnofsky performance status score was 70 in 72 (60.0%) patients, and 80-90 in 48 (40%). External radiation therapy was delivered with high-energy six to 15 MV photon beams using four-field brick technique. The total dose of 50 Gy was given in 25 fractions within five weeks using standard fractionation. Concurrently with external radiotherapy, six cycles of chemotherapy were administered to all the patients as an intravenous infusion of once-weekly cisplatin 40 mg/m2. On completion of external beam radiotherapy, low-dose rate brachytherapy with tandem and two colpostats was performed to deliver the dose of 40 Gy to point A in two 20 Gy insertions at weekly intervals.
RESULTS: Of the 120 patients in the investigated group, 78 (65%) were disease-free for five years. Symptoms of acute treatment-related toxicity grade 3 or 4 (WHO) occurred in 21.6% of patients including leucopoenia in 7.5%. anaemia in 5.0%, nausea and vomiting in 3.3%, diarrhea in 5.0%, and urinary tract infection in 0.8%. Full planned treatment (teleradiotherapy + chemotherapy + brachytherapy) completed 78.3% of the group; full planned radiotherapy without full chemotherapy completed 20% of the patients. Late treatment complications of grade 3 or 4 were observed in two (1.6%) patients (narrowing of large intestine requiring surgery and recto-vaginal fistula).
CONCLUSIONS: In patients with LACC treated with CCRT, the most frequent acute toxic effects include: haematological disorders (leucopoenia, anaemia), gastrointestinal disorders (nausea and vomiting, diarrhea), vulvo-vaginal disorders, and urinary tract infection. The most frequent late toxic effects included: rectal bleeding, bowel complications requiring surgery, stenosis or recto-vaginal fistula, and haematuria.

Related: Brachytherapy Cisplatin

Mazarico E, Gómez-Roig MD, Miñano J, et al.
Relationship of human papilloma virus multiple genotype infection with patient's age and type of cervical lesion.
Eur J Gynaecol Oncol. 2014; 35(4):378-81 [PubMed] Related Publications
PURPOSE OF INVESTIGATION: To document the prevalence of infection by multiple genotypes of the human papilloma virus (HPV) in patients with cervical pathology in a study population, and to determine the relationship between multiple genotype infection, age of the patient, and the type of cervical pathology.
MATERIALS AND METHODS: Prospective, cross-sectional descriptive study. A total of 1,007 patients were recruited among women seen at the cervical pathology clinic of Sant Joan de Déu University Hospital in Barcelona (Spain) between January 2003 and March 2011. Statistical analyses were done with SPSS v.19 software. Differences between groups were considered statistically significant atp < 0.05.
RESULTS: There was 28.3% of the women (286 cases) that were infected by multiple HPV genotypes. The mean number of genotypes identified was 2.52 (range 2 to 8). Mean age of the patients with multiple genotype infection was 32.31 years, and mean age of the patients with single genotype infection was 37.27 years (p < 0.001). The prevalence of infection by multiple HPV genotypes was 28% in patients with cervical intraepithelial neoplasia grade 1 (CIN 1) and 33% in patients with grade CIN 2-3 lesions, and both prevalence rates were significantly higher than in patients with carcinoma (20%) (p = 0.03).
CONCLUSIONS: In the present study population the authors found no evidence of higher prevalence of multiple HPV genotype infection in women with carcinoma. Age of women with multiple infection was lower than those with single infection.

Boutas I, Sofoudis C, Kalampokas E, et al.
Fertility preservation in women with early stage cervical cancer. Review of the literature.
Eur J Gynaecol Oncol. 2014; 35(4):373-7 [PubMed] Related Publications
Within the last decades, the percentage of diagnosed cervical cancer in women of reproductive age has increased. The possibility of diagnosing small cervical tumors (< or = twocm) in childbearing age, can be explained due to the fact that many women, are aware of the benefits of Pap smear or colposcopy examination. Many demand a more conservative policy to handle such lesions in order to have an uneventful pregnancy in the near future.

Related: Cancer Screening and Early Detection

Montes L, Andrade CM, Michelin MA, Murta EF
The importance of alpha/beta (alpha/13) interferon receptors and signaling pathways for the treatment of cervical intraepithelial neoplasias.
Eur J Gynaecol Oncol. 2014; 35(4):368-72 [PubMed] Related Publications
INTRODUCTION: Immunotherapies have been effective in treating various forms of cancer, including cervical intraepithelial neoplasias (CINs) predominantly caused by human papilloma virus (HPV).
DEVELOPMENT: To establish persistent infections in stratified epithelia, HPV induces proliferative lesions. Viral gene products are able to change gene expression and cellular proteins. Interferons (IFNs) are inducible glycoproteins that have immunomodulatory, antiviral, antiproliferative, and antiangiogenic effects. In particular, interferon-alpha (IFN-alpha) has been shown to inhibit the development and progression of cervical cancer. In this review, actions of interferons alpha/beta (alpha/beta), including their receptors and signaling pathways, are described, as well as their clinical importance in the immune response against cervical lesions.
CONCLUSION: The interaction of IFN-alpha/beta with its receptor results in a series of phosphorylation events. These mechanisms can be ineffective in IFN response, then it can also compromise the therapeutic effects of immunotherapy.

Related: Signal Transduction

Hyle EP, Naidoo K, Su AE, et al.
HIV, tuberculosis, and noncommunicable diseases: what is known about the costs, effects, and cost-effectiveness of integrated care?
J Acquir Immune Defic Syndr. 2014; 67 Suppl 1:S87-95 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Unprecedented investments in health systems in low- and middle-income countries (LMICs) have resulted in more than 8 million individuals on antiretroviral therapy. Such individuals experience dramatically increased survival but are increasingly at risk of developing common noncommunicable diseases (NCDs). Integrating clinical care for HIV, other infectious diseases, and NCDs could make health services more effective and provide greater value. Cost-effectiveness analysis is a method to evaluate the clinical benefits and costs associated with different health care interventions and offers guidance for prioritization of investments and scale-up, especially as resources are increasingly constrained. We first examine tuberculosis and HIV as 1 example of integrated care already successfully implemented in several LMICs; we then review the published literature regarding cervical cancer and depression as 2 examples of NCDs for which integrating care with HIV services could offer excellent value. Direct evidence of the benefits of integrated services generally remains scarce; however, data suggest that improved effectiveness and reduced costs may be attained by integrating additional services with existing HIV clinical care. Further investigation into clinical outcomes and costs of care for NCDs among people living with HIV in LMICs will help to prioritize specific health care services by contributing to an understanding of the affordability and implementation of an integrated approach.

Campos NG, Burger EA, Sy S, et al.
An updated natural history model of cervical cancer: derivation of model parameters.
Am J Epidemiol. 2014; 180(5):545-55 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Mathematical models of cervical cancer have been widely used to evaluate the comparative effectiveness and cost-effectiveness of preventive strategies. Major advances in the understanding of cervical carcinogenesis motivate the creation of a new disease paradigm in such models. To keep pace with the most recent evidence, we updated a previously developed microsimulation model of human papillomavirus (HPV) infection and cervical cancer to reflect 1) a shift towards health states based on HPV rather than poorly reproducible histological diagnoses and 2) HPV clearance and progression to precancer as a function of infection duration and genotype, as derived from the control arm of the Costa Rica Vaccine Trial (2004-2010). The model was calibrated leveraging empirical data from the New Mexico Surveillance, Epidemiology, and End Results Registry (1980-1999) and a state-of-the-art cervical cancer screening registry in New Mexico (2007-2009). The calibrated model had good correspondence with data on genotype- and age-specific HPV prevalence, genotype frequency in precancer and cancer, and age-specific cancer incidence. We present this model in response to a call for new natural history models of cervical cancer intended for decision analysis and economic evaluation at a time when global cervical cancer prevention policy continues to evolve and evidence of the long-term health effects of cervical interventions remains critical.

Li XR, Chu HJ, Lv T, et al.
miR-342-3p suppresses proliferation, migration and invasion by targeting FOXM1 in human cervical cancer.
FEBS Lett. 2014; 588(17):3298-307 [PubMed] Related Publications
FOXM1 is a well-established oncogenic factor that has been reported to be involved in multiple biological processes including cell proliferation, growth, angiogenesis, migration and invasion. It can also be regulated by miRNAs. In this study, we reported that FOXM1 is directly targeted by miR-342-3p, which is down-regulated along with its host gene, EVL, in human cervical cancer tissues compared to the adjacent normal tissues. Functional studies suggested that the overexpression of miR-342-3p inhibits cell proliferation, migration and invasion in cervical cell lines. FOXM1 is upregulated and negatively correlates with miR-342-3p in cervical cancer tissues, and the overexpression of FOXM1 rescues the phenotype changes induced by the overexpression of miR-342-3p.

Related: FOXM1

Bonde J, Rebolj M, Ejegod DM, et al.
HPV prevalence and genotype distribution in a population-based split-sample study of well-screened women using CLART HPV2 human papillomavirus genotype microarray system.
BMC Infect Dis. 2014; 14:413 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Human papillomavirus (HPV) genotyping assays are becoming increasingly attractive for use in mass screening, as they offer a possibility to integrate HPV screening with HPV vaccine monitoring, thereby generating a synergy between the two main modes of cervical cancer prevention. The Genomica CLART HPV2 assay is a semi-automated PCR-based microarray assay detecting 35 high-risk and low-risk HPV genotypes. However, few reports have described this assay in cervical screening. An aim of the present study, Horizon, was to assess the prevalence of high-risk HPV infections in Copenhagen, Denmark, an area with a high background risk of cervical cancer where women aged 23-65 years are targeted for organized screening.
METHODS: Material from 5,068 SurePath samples of women participating in routine screening and clinical follow-up of cervical abnormalities was tested using liquid based cytology, CLART HPV2 and Hybrid Capture 2 (HC2).
RESULTS: At least one of the 35 defined genotypes was detected by CLART in 1,896 (37%) samples. The most frequent high-risk genotypes were HPV 16 (7%), HPV 52 (5%), and HPV 31 (4%). The most frequent low-risk genotypes were HPV 53 (5%), HPV 61 (4%), and HPV 66 (3%). Among 4,793 women targeted by the screening program (23-65 years), 1,166 (24%) tested positive for one or more of the 13 high-risk genotypes. This proportion decreased from 40% at age 23-29 years to 10% at age 60-65 years. On HC2, 1,035 (20%) samples were positive for any high-risk and thus CLART showed a higher analytical sensitivity for 13 high-risk HPV genotypes than HC2, and this was found in all age-groups and in women normal cytology.
CONCLUSIONS: CLART performed well with a positive reproducibility for high-risk genotypes of 86%, and a negative reproducibility of 97%. This report furthermore updates the genotype distribution in Denmark prior to the inclusion of the HPV-vaccinated cohorts into the screening program, and as such represents a valuable baseline for future vaccine impact assessment.

Committee opinion no. 607: Gynecologic concerns in children and adolescents with cancer.
Obstet Gynecol. 2014; 124(2 Pt 1):403-8 [PubMed] Related Publications
Advancements in radiation therapy, chemotherapy, surgery, and multimodal treatment have dramatically improved childhood cancer survival. However, cancer and its treatment may have immediate or delayed adverse effects on reproductive health. Gynecologists should be prepared to manage gynecologic concerns in young cancer patients and survivors before, during, and after their treatment. Gynecologists may be consulted regarding pubertal concerns; heavy menstrual bleeding and anemia; sexuality; contraception; ovarian function, including fertility preservation; and breast and cervical cancer screening. The science of fertility preservation is a rapidly evolving field; therefore, a referral to a reproductive endocrinologist is recommended to explore the full range of available options.

Related: Breast Cancer Cancer Screening and Early Detection Cancer Prevention and Risk Reduction Children's Cancer Web: Home Page

Lynge E, Rygaard C, Baillet MV, et al.
Cervical cancer screening at crossroads.
APMIS. 2014; 122(8):667-73 [PubMed] Related Publications
Cervical screening has been one of the most successful public health prevention programmes. For 50 years, cytology formed the basis for screening, and detected cervical intraepithelial lesions (CIN) were treated surgically to prevent progression to cancer. In a high-risk country as Denmark, screening decreased the incidence of cervical cancer from 34 to 11 per 100,000, age-standardized rate (World Standard Population). Screening is, however, also expensive; Denmark (population: 5.6 million) undertakes close to half a million tests per year, and has 6-8 CIN-treated women for each prevented cancer case. The discovery of human papillomavirus (HPV) as the cause of cervical cancer dramatically changed perspectives for disease control. Screening with HPV testing was launched around 1990, and preventive HPV vaccination was licensed in 2006. Long-term randomized controlled trials (RCT) demonstrated that HPV testing provides better protection against cervical cancer than cytology, but it requires extra repeated testing. HPV vaccination RCTs, furthermore, have proved that HPV vaccination protects against vaccine-type high-grade CIN in women vaccinated prior to sexual activity, but less so in women vaccinated later. The challenge now is therefore to find an algorithm for screening of a heterogeneous population including non-vaccinated women; women vaccinated prior to start of sexual activity; and women vaccinated later.

Related: Cancer Screening and Early Detection

Tian XP, Qian D, He LR, et al.
The telomere/telomerase binding factor PinX1 regulates paclitaxel sensitivity depending on spindle assembly checkpoint in human cervical squamous cell carcinomas.
Cancer Lett. 2014; 353(1):104-14 [PubMed] Related Publications
Paclitaxel is a main ingredient in the combination chemotherapy treatment of advanced human cervical squamous cell carcinomas. We investigated the roles and underlying molecular mechanisms of PinX1 in cervical squamous cell carcinomas (CSCC) cells response to paclitaxel and its clinical significances. The expression dynamics of PinX1 was first examined by immunohistochemistry in 122 advanced CSCC patients treated with cisplatin/paclitaxel chemotherapy. The expression of PinX1 was significantly associated with the effects of cisplatin/paclitaxel chemotherapy in advanced CSCCs (P<0.05). High expression of PinX1 correlated with CSCC's response to cisplatin/paclitaxel chemotherapy, and was an independent predictor of shortened survival (P<0.05). A series of in vivo and in vitro assays were performed to elucidate the function of PinX1 on CSCC cells chemosensitivity to paclitaxel and underlying mechanisms. In CSCC cells, the levels of PinX1 were only associated with the cytotoxicity and sensitivity of paclitaxel, in which knockdown of PinX1 dramatically enhanced paclitaxel cytotoxicity, whereas the reestablishment of PinX1 levels substantially reduced the paclitaxel-induced killing effect. In addition, we identified that the ability of PinX1 to stabilize the tension between sister kinetochores and maintain the spindle assembly checkpoint was the main reason CSCC cells undergo apoptosis when treated with paclitaxel, and further studies demonstrated that shortened distance between sisters kinetochores by nocodazole confers upon PinX1-replenished cells a sensitivity to the death inducing paclitaxel effects. Furthermore, our study of CSCC cells xenografts in nude mice confirmed the role of PinX1 in paclitaxel sensitivity in vivo. Our data reveal that PinX1 could be used as a novel predictor for CSCC patient response to paclitaxel, and the role of PinX1-mediated paclitaxel sensitivity might represent a new direction for the development of a new generation of microtubule drugs.

Related: Apoptosis Cisplatin Paclitaxel

Zhen S, Hua L, Takahashi Y, et al.
In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by CRISPR/Cas9.
Biochem Biophys Res Commun. 2014; 450(4):1422-6 [PubMed] Related Publications
Deregulated expression of high-risk human papillomavirus oncogenes (E6 and E7) is a pivotal event for pathogenesis and progression in cervical cancer. Both viral oncogenes are therefore regarded as ideal therapeutic targets. In the hope of developing a gene-specific therapy for HPV-related cancer, we established CRISPR/Cas9 targeting promoter of HPV 16 E6/E7 and targeting E6, E7 transcript, transduced the CRISPR/Cas9 into cervical HPV-16-positive cell line SiHa. The results showed that CRISPR/Cas9 targeting promoter, as well as targeting E6 and E7 resulted in accumulation of p53 and p21 protein, and consequently remarkably reduced the abilities of proliferation of cervical cancer cells in vitro. Then we inoculated subcutaneously cells into nude mice to establish the transplanted tumor animal models, and found dramatically inhibited tumorigenesis and growth of mice incubated by cells with CRISPR/Cas9 targeting (promoter+E6+E7)-transcript. Our results may provide evidence for application of CRISPR/Cas9 targeting HR-HPV key oncogenes, as a new treatment strategy, in cervical and other HPV-associated cancer therapy.

Gaudet M, Hamm J, Aquino-Parsons C
Incidence of ano-genital and head and neck malignancies in women with a previous diagnosis of cervical intraepithelial neoplasia.
Gynecol Oncol. 2014; 134(3):523-6 [PubMed] Related Publications
OBJECTIVE: The objective of this study was to determine if women with a history of Cervical Intraepithelial Neoplasia grades 2 and 3 (CIN2 and CIN3) are at increased long-term risk for developing non-cervix HPV-related malignancies.
MATERIAL AND METHODS: Women diagnosed with CIN2 or CIN3 between 1980 and 2005 were identified from the British Columbia (BC) Cancer Agency Cervical Cancer Screening Program's database. These patients' records were then cross-referenced with the BC Cancer Registry for diagnosis of vulvar, vaginal, anal or head and neck (HN) cancers during the period subsequent to their diagnosis of CIN. Standardized incidence ratios (SIR) were generated according to expected rates of each cancer.
RESULTS: 54,320 women with a diagnosis of CIN2 or CIN3 were identified between 1985 and 2005. The crude incidence rate for non-cervix HPV-related cancers was 35.4 per 100,000 person-years (8.6 for vagina, 17.6 for vulva, 3.7 for anal canal and 5.5 for HN). The SIR was 1.9 (95% CI 1.3-2.7) for all non-cervix cancers, 6.7 (95% CI: 3.0-12.8) for vagina, 2.9 (95% CI: 1.7-4.6) for vulva, 1.8 (95% CI: 0.4-4.7) for anal canal, and 0.6 (95% CI: 0.2-1.4) for HN. There were statistically significant increases in anal cancers for years 5-9 and in HN cancers for years 0.5-5.
CONCLUSION: BC women with a history of CIN2 or CIN3 are at relatively high risk of developing non-cervical HPV-related malignancies. The findings of this study suggest that interventions such as vaccination against high-risk HPV or long-term screening for these other cancers should be evaluated.

Related: Anal Cancer Head and Neck Cancers Head and Neck Cancers - Molecular Biology Vaginal Cancer Vulva Cancer

Gage JC, Schiffman M, Katki HA, et al.
Reassurance against future risk of precancer and cancer conferred by a negative human papillomavirus test.
J Natl Cancer Inst. 2014; 106(8) [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Primary human papillomavirus (HPV) testing (without concurrent Pap tests) every 3 years is under consideration in the United States as an alternative to the two recommended cervical cancer screening strategies: primary Pap testing every 3 years, or concurrent Pap and HPV testing ("cotesting") every 5 years. Using logistic regression and Weibull survival models, we estimated and compared risks of cancer and cervical intraepithelial neoplasia grade 3 or worse (CIN3+) for the three strategies among 1011092 women aged 30 to 64 years testing HPV-negative and/or Pap-negative in routine screening at Kaiser Permanente Northern California since 2003. All statistical tests were two sided. Three-year risks following an HPV-negative result were lower than 3-year risks following a Pap-negative result (CIN3+ = 0.069% vs 0.19%, P < .0001; Cancer = 0.011% vs 0.020%, P < .0001) and 5-year risks following an HPV-negative/Pap-negative cotest (CIN3+ = 0.069% vs 0.11%, P < .0001; Cancer = 0.011% vs 0.014%, P = .21). These findings suggest that primary HPV testing merits consideration as another alternative for cervical screening.

Related: Cancer Screening and Early Detection

Boers A, Bosgraaf RP, van Leeuwen RW, et al.
DNA methylation analysis in self-sampled brush material as a triage test in hrHPV-positive women.
Br J Cancer. 2014; 111(6):1095-101 [PubMed] Related Publications
BACKGROUND: Primary high-risk human papillomavirus (hrHPV) testing in cervical cancer screening shows relatively low specificity, which makes triage testing necessary. In this study, DNA methylation analysis was compared with cytology for triage testing in hrHPV-positive women. Moreover, feasibility of DNA methylation analysis directly on brush-based self-sampled specimens was assessed.
METHODS: Non-responding women from population-based screening were invited to self-collect a cervico-vaginal specimen for hrHPV testing; hrHPV-positive women were referred to a physician for triage liquid-based cytology. DNA methylation analysis was performed on 128 hrHPV-positive physician-collected triage samples and 50 matched brush self-samples with QMSP for C13ORF18, EPB41L3, JAM3 and TERT.
RESULTS: In physician-taken triage material, DNA methylation analysis of JAM3 showed the highest combined specificity (88%) and sensitivity (82%) for detection of CIN3+, whereas cytology showed a specificity of 48% and a sensitivity of 91%. Out of 39 women with abnormal cytology and normal histology (false-positive by cytology), 87% were negative for JAM3 and 90% for C13ORF18 methylation. Agreement between DNA methylation analysis performed directly on the matched self-sampled material and physician-taken samples was 88% for JAM3 (κ=0.75, P<0.001) and 90% for C13ORF18 (κ=0.77; P<0.001).
CONCLUSIONS: DNA methylation analysis as a triage test in hrHPV-positive women is an attractive alternative to cytology. Furthermore, DNA methylation is feasible directly on brush-based self-samplers and showed good correlation with matched physician-taken samples. Direct molecular triage on self-collected specimens could optimise the screening program, especially for non-responders, as this would eliminate the need for an additional physician-taken scraping for triage testing.

Related: Cancer Screening and Early Detection

Spinillo A, Gardella B, Chiesa A, et al.
Diagnostic accuracy of colposcopy in relation to human papillomavirus genotypes and multiple infection.
Gynecol Oncol. 2014; 134(3):527-33 [PubMed] Related Publications
OBJECTIVE: The aim of this study is to evaluate the diagnostic accuracy of colposcopy for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) in relation to the detection of human papillomavirus (HPV) type 16 and multiple HPV infection.
METHODS: A cohort study of 2526 subjects attending a colposcopic service because of cytological abnormalities. HPV genotypes were identified using the INNO-LIPA genotyping system.
RESULTS: The final colposcopic/pathological diagnoses were as follows: 1282 (50.8%) negative, 709 (28.1%) CIN1, 169 (6.7%) CIN2, 318 (12.6%) CIN3 and 48 (1.9%) invasive cervical cancer, respectively. Among women with ASCUS/LSIL, assuming any colposcopic abnormality as a cut-off, there were no significant differences in the sensitivities (83.8%, 95% CI=76-89.6 as compared to 84.1%, 95% CI=73.2-91.1, p=0.9) and ROC curves (0.61, 95% CI=0.58-0.65 as compared to 0.59, 95% CI=0.54-0.64, p=0.5) in the detection of CIN3+ lesions between subjects with single and multiple high-risk infection, and between subjects infected by HPV16 (83.1%, 95% CI=73.7-89.7, ROC=0.59, 95% CI=0.54-063) or other high-risk HPVs (84.7%, 95% CI=75.6-90.8, ROC=0.62, 95% CI=0.58-0.66, p=0.8 and p=0.6 compared to HPV16). After correction for confounders, the odds ratios of CIN3+ associated with any abnormal colposcopic findings were 2.47 (95%CI=1.44-4.23, p=0.001) among HPV16 positive, 3.34 (95% CI=2.16-5.42, p<0.001) among other high-risk HPVs and 1.3 (95% CI=0.72-2.48, p=0.36) among subjects with negative/low-risk HPVs.
CONCLUSION: In routine clinical practice, multiple infection or HPV16 positivity did not affect colposcopic accuracy in the diagnosis of CIN3+ lesions. The sensitivity of colposcopy was poor among subjects who were uninfected or infected by low-risk HPV genotypes.

Cortés-Gutiérrez EI, D'ávila-Rodríguez MI, Cerda-Flores RM
Chromosomal damage as prognosis marker in cervical carcinogenesis.
Tsitol Genet. 2014 May-Jun; 48(3):54-63 [PubMed] Related Publications
Cancer of the uterine cervix is the third most common cancer in women worldwide and the most common cancer among Mexican and Latin American women. Risk factors that have been associated with the development of cervical intraepithelial neoplasia suggest that Human Papillomavirus (HPV) types 16, 18, 31, and 33 entail a high risk of developing a malignancy of this type. The accumulation of genetic alterations allows the growth of neoplastic cells; chromosomal instability is an event that occurs in the precancerous stages. The candidate cancer risk biomarkers include cytogenetic endpoints, such as chromosomal aberrations, sister chromatid exchange, micronuclei, and the outcomes of comet assay and DNA breakage detection-fluorescence in situ hybridization. The patterns identified in these cytogenetic studies indicate that chromosomal instability is a transient and chromosomally unstable intermediate in the development of cervical lesions. In this context, the mechanisms that may underlie the progressive increase in genetic instability in these patients seem to be related directly to HPV infection. The studies discussed in this paper show that chromosomal instability may serve as a biomarker by predicting the progression of cervical intraepithelial neoplasia. Nevertheless, these results should be validated in larger, prospective studies.

Related: FISH

Wang Z, Zeng X, Ma Y, et al.
Antitumor efficiency of D-alpha-tocopheryl polyethylene glycol 1000 succinate-b-poly(epsilon-caprolactone-ran-lactide) nanoparticle-based delivery of docetaxel in mice bearing cervical cancer.
J Biomed Nanotechnol. 2014; 10(8):1509-19 [PubMed] Related Publications
Pharmaceutical nanotechnology holds potential in cancer chemotherapy. In this research, the docetaxel-loaded D-alpha-tocopheryl polyethylene glycol 1000 succinate-b-poly(epsilon-caprolactone-ran-lactide) (TPGS-b-(PCL-ran-PLA)) nanoparticles were prepared by a modified nanoprecipitation method and then the particle size, surface morphology, nanoparticle stability, in vitro drug release and cellular uptake of nanoparticles were characterized. Finally, we evaluated the therapeutic effects of nanoparticle formulation in comparison with Taxotere both in vitro and in vivo. The size of TPGS-b-(PCL-ran-PLA) nanoparticles was about 150 nm and much smaller than PCL nanoparticles (about 185 nm) and the absolute value of zeta potential was higher than PCL nanoparticles (16.49 mV vs. 13.17 mV). FESEM images further confirmed the morphology and size of nanoparticles. The drug-loaded nanoparticles were considered to be stable, showing no change in the particle size and surface charge during three-month storage of its aqueous solution. In vitro drug release of TPGS-b-(PCL-ran-PLA) nanoparticles was much faster than PCL and PCL-TPGS nanoparticles. The cumulative drug release of docetaxel-loaded TPGS-b-(PCL-ran-PLA), PCL-TPGS, and PCL NPs were 38.00%, 34.48% and 29.04%, respectively. TPGS-b-(PCL-ran-PLA) nanoparticles showed an obvious increase of cellular uptake. Due to the advantages of TPGS-b-(PCL-ran-PLA) nanoparticles, it could achieve significantly higher level of cytotoxicity in vitro and better inhibition effect of tumor growth on xenograft BALB/c nude mice tumor model than commercial Taxotere at the same dose (1.49-fold more effective). The TPGS-b-(PCL-ran-PLA) could be used as a novel and potential biodegradable polymeric material for nanoformulation in cervical cancer chemotherapy.

Related: Docetaxel

Negri G, Herz M, Deola S, et al.
Abnormal cervical cytology after allogeneic bone marrow transplantation.
Am J Clin Pathol. 2014; 142(2):222-6 [PubMed] Related Publications
OBJECTIVES: Allogeneic bone marrow transplantation (BMT) is a procedure mostly used for high-risk hematologic malignances. In women, follow-up protocols after BMT include gynecologic checkups with Papanicolaou (Pap) smears.
METHODS: We evaluated 117 Pap smears in 54 women who underwent allogeneic BMT and correlated the smear morphology with the BMT-related medical treatment.
RESULTS: Abnormal Pap smears after BMT were found in 13 (24.1%) women. Four (7.4%) women had at least one smear with atypical squamous cells of unknown significance, six (11.1%) had a low-grade squamous intraepithelial lesion, and three (5.6%) had atypical squamous cells/high-grade lesion cannot be excluded (ASC-H). The three patients with ASC-H showed high-grade atypia mimicking cancer but had a negative follow-up. Nine women, including the three with ASC-H, had undergone a conditioning therapy for BMT that included busulfan. No association between other drugs and therapy-related atypia was found.
CONCLUSIONS: Pap smears after BMT show a high incidence of dysplastic lesions. Moreover, conditioning including busulfan is often associated with therapy-related cytologic atypia, which may lead to unnecessary colposcopies and biopsies. Knowledge of the patient's history and a careful evaluation of the smears are mandatory in these cases.

Lim K, Stewart J, Kelly V, et al.
Dosimetrically triggered adaptive intensity modulated radiation therapy for cervical cancer.
Int J Radiat Oncol Biol Phys. 2014; 90(1):147-54 [PubMed] Related Publications
PURPOSE: The widespread use of intensity modulated radiation therapy (IMRT) for cervical cancer has been limited by internal target and normal tissue motion. Such motion increases the risk of underdosing the target, especially as planning margins are reduced in an effort to reduce toxicity. This study explored 2 adaptive strategies to mitigate this risk and proposes a new, automated method that minimizes replanning workload.
METHODS AND MATERIALS: Thirty patients with cervical cancer participated in a prospective clinical study and underwent pretreatment and weekly magnetic resonance (MR) scans over a 5-week course of daily external beam radiation therapy. Target volumes and organs at risk (OARs) were contoured on each of the scans. Deformable image registration was used to model the accumulated dose (the real dose delivered to the target and OARs) for 2 adaptive replanning scenarios that assumed a very small PTV margin of only 3 mm to account for setup and internal interfractional motion: (1) a preprogrammed, anatomy-driven midtreatment replan (A-IMRT); and (2) a dosimetry-triggered replan driven by target dose accumulation over time (D-IMRT).
RESULTS: Across all 30 patients, clinically relevant target dose thresholds failed for 8 patients (27%) if 3-mm margins were used without replanning. A-IMRT failed in only 3 patients and also yielded an additional small reduction in OAR doses at the cost of 30 replans. D-IMRT assured adequate target coverage in all patients, with only 23 replans in 16 patients.
CONCLUSIONS: A novel, dosimetry-triggered adaptive IMRT strategy for patients with cervical cancer can minimize the risk of target underdosing in the setting of very small margins and substantial interfractional motion while minimizing programmatic workload and cost.

Nagel CI, Thomas SK, Richardson DL, et al.
Adnexal masses requiring surgical intervention in women with advanced cervical cancer.
Gynecol Oncol. 2014; 134(3):552-5 [PubMed] Related Publications
OBJECTIVE: Surgical evaluation of adnexal masses in patients with cervical cancer can be considered in order to optimize treatment outcomes and rule out a second pathologic process. Our objective was to review treatment patterns and outcomes in women with advanced cervical cancer (ACC) and an adnexal mass.
METHODS: A retrospective review was performed with IRB approval of patients treated for advanced cervical cancer at our institution between 1990 and 2011. Patients were identified using institutional databases and tumor registries. Descriptive statistics were performed using Microsoft Excel 2011 and Instat was used to perform Fisher's exact test and student T-tests.
RESULTS: Two hundred twenty eight patients with stage IIB-IVB cervical cancer were identified, 50 (22%) of whom had an adnexal mass on initial imaging studies (31 stage IIB, 15 stage IIIB, 3 stage IVA, 3 stage IVB). The mean follow up time of patients with adnexal masses was 22 months (range 3-128 months). Thirteen of 50 (26%) patients underwent surgical evaluation of the adnexal mass. Six were found to have cervical cancer metastatic to the adnexae, while seven had benign adnexal lesions. Thirty-seven of 50 (74%) patients were conservatively managed. All 37 women had cystic masses <8 cm or complex masses <5 cm in size. Thirty-four of the 37 (92%) patients had resolution of their adnexal mass and 3 were deemed stable on follow up imaging. Twenty three percent of surgically managed patients and 57% of conservatively managed patients had disease recurrence (p=0.05). There were no recurrences in the adnexa.
CONCLUSION: Twelve percent of women with ACC and an adnexal mass have ovarian metastases. Patients with cystic masses less than 8 cm and complex masses less than 5 cm in size can be expectantly managed.

Goerling U, Jaeger C, Walz A, et al.
The efficacy of short-term psycho-oncological interventions for women with gynaecological cancer: a randomized study.
Oncology. 2014; 87(2):114-24 [PubMed] Related Publications
OBJECTIVES: We aimed to examine the efficacy of two psycho-oncological interventions in anxiety, depression, and self-perceived as well as physiological stress in inpatients with gynaecological cancer.
METHODS: Forty-five women were included in the trial. Thirty-five were categorized as being at high risk of anxiety and depression, and were randomized to either a single psycho-oncological therapy session or a single-session relaxation intervention.
RESULTS: A significant decrease in anxiety [mean (t0) = 12, mean (t1) = 7.47, p = 0.001] and depression [mean (t0) = 9.71, mean (t1) = 6.35, p < 0.001] was observed in the psycho-oncological intervention group. In the relaxation group, anxiety also significantly decreased [mean (t0) = 11.67, mean (t1) = 8.22, p = 0.003], whereas depression did not. A comparative analysis of both interventions showed a trend in favour of psycho-oncological therapy for the treatment of depression (F = 3.3, p = 0.078). However, self-reported stress (p = 0.031) and different objective stress parameters only significantly decreased in the relaxation group.
CONCLUSIONS: Psycho-oncological interventions should represent an essential part of interdisciplinary care for gynaecological cancer patients. Both types of intervention may reduce anxiety. However, the single psycho-oncological therapy session might be slightly more effective in treating depression, whereas the single-session relaxation intervention seems to have a stronger effect on physiological stress parameters.

Related: Ovarian Cancer

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