Cervical Cancer
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Cervical Cancer

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.

In the UK about 2,800 women are diagnosed with cervical cancer each year. (Source: Cancer Research UK)

This page shows only UK resources. For a more extensive list of resources from around the world see CancerIndex: Cervical Cancer Information for Patients and the Public
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Latest Research Publications

Information Patients and the Public (12 links)

Information for Health Professionals / Researchers (5 links)

Latest Research Publications

Showing publications with corresponding authors from the UK (Source: PubMed).

Vaidakis D, Moustaki I, Zervas I, et al.
Knowledge of Greek adolescents on human papilloma virus (HPV) and vaccination: A national epidemiologic study.
Medicine (Baltimore). 2017; 96(1):e5287 [PubMed] Free Access to Full Article Related Publications
The aim of the present study was to identify the sexual behavior, attitudes, beliefs, and knowledge on sexually transmitted infections (STIs) focused on human papilloma virus (HPV) in the Greek adolescent population. The participants were 4547 adolescents, a representative sample for Greek territory with a mean age of 17 years. After written permission from Greek ministry of education each student completed a questionnaire with 36 questions. The fields covered were demographic characteristics, sexual life data, and basic knowledge on HPV. In the present study, 43% and 75% of the participants knew about HPV or cervical cancer, while more than 6 out of 10 did not know the association between the 2. More than 60% of the participants could not answer correctly neither about HPV infection and cervical cancer frequency in sexually active women, nor about protection methods against HPV and cervical cancer. This study shows that the low vaccination coverage of the Greek population may be due to lack of information and awareness of the adolescents and their parents. It is our duty to increase our efforts in order to better educate the population and vaccinate the population as early as possible in their reproductive years.

Dumas L, Ring A, Butler J, et al.
Improving outcomes for older women with gynaecological malignancies.
Cancer Treat Rev. 2016; 50:99-108 [PubMed] Related Publications
The incidence of most gynaecological malignancies rises significantly with increasing age. With an ageing population, the proportion of women over the age of 65 with cancer is expected to rise substantially over the next decade. Unfortunately, survival outcomes are much poorer in older patients and evidence suggests that older women with gynaecological cancers are less likely to receive current standard of care treatment options. Despite this, older women are under-represented in practice changing clinical studies. The evidence for efficacy and tolerability is therefore extrapolated from a younger; often more fit population and applied to in every day clinical practice to older patients with co-morbidities. There has been significant progress in the development of geriatric assessment in oncology to predict treatment outcomes and tolerability however there is still no clear evidence that undertaking a geriatric assessment improves patient outcomes. Clinical trials focusing on treating older patients are urgently required. In this review, we discuss the evidence for treatment of gynaecological cancers as well as methods of assessing older patients for therapy. Potential biomarkers of ageing are also summarised.

Geisler S, Speiser S, Speiser L, et al.
Short-Term Efficacy of Trichloroacetic Acid in the Treatment of Cervical Intraepithelial Neoplasia.
Obstet Gynecol. 2016; 127(2):353-9 [PubMed] Related Publications
OBJECTIVE: To establish the short-term efficacy and tolerability of a single topical 85% trichloroacetic acid treatment for cervical intraepithelial neoplasia (CIN) 1-3.
METHODS: A retrospective case series including all patients with CIN treated with trichloroacetic acid as first-line therapy was performed. Treatment response was evaluated by colposcopy, cervical biopsy, cytology, and type-specific human papillomavirus (HPV) testing 8 weeks after a single trichloroacetic acid treatment. Regression was defined as improvement from high-grade to low-grade CIN and remission was defined as improvement from any grade of CIN to no CIN. For quantification of treatment-related pain, 107 (44.1%) patients rated their subjective perception on a visual analog scale.
RESULTS: A total of 241 women were included in the study with 179 high-grade (CIN 2-3) and 62 low-grade (CIN 1) squamous intraepithelial lesions. For high-grade squamous intraepithelial lesions, the histologic regression rate was 87.7% (95% confidence interval [CI] 82.0-92.1) and the remission rate was 80.3% (95% CI 73.3-85.5). For low-grade squamous intraepithelial lesions, the remission rate was 82.3% (95% CI 70.5-90.8). Human papillomavirus types 16 and 18 were found in 53.7% and 7.3% of all women tested, respectively. Clearance rates of HPV type 16 and HPV type 18 were 73.5% (95% CI 62.5-81.3) and 75.0% (95% CI 46.2-95.0), respectively. Median pain score was 3.0 out of 10.0 (25th and 75th percentiles 2.3 and 4.3, respectively). There were no major side effects observed during treatment or follow-up.
CONCLUSION: A high regression and remission rate and a high HPV clearance rate were observed 8 weeks after topical 85% trichloroacetic acid treatment for patients with CIN.

Kotsopoulos IC, Kucukmetin A, Mukhopadhyay A, et al.
Poly(ADP-Ribose) Polymerase in Cervical Cancer Pathogenesis: Mechanism and Potential Role for PARP Inhibitors.
Int J Gynecol Cancer. 2016; 26(4):763-9 [PubMed] Related Publications
Treatment options for disease recurrence of women treated for locally advanced and advanced cervical cancer are very limited-largely palliative chemotherapy. The low efficacy of the currently available drugs raises the need for new targeted agents. Poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors (PARPi) have emerged as a promising class of chemotherapeutic agents in cancers associated with defects in DNA repair. Their therapeutic potential in cervical cancer is currently being evaluated in 3 ongoing clinical trials. Here we review the available information regarding all the aspects of PARP in cervical intraepithelial neoplasia and invasive cervical cancer, from expression and the mechanism of action to the role of the polymorphisms in the pathogenesis of the disease, as well as the potential of the inhibitors. We finally propose a new unifying theory regarding the role of PARPs in the development of cervical carcinomas.

Kirchheiner K, Pötter R, Tanderup K, et al.
Health-Related Quality of Life in Locally Advanced Cervical Cancer Patients After Definitive Chemoradiation Therapy Including Image Guided Adaptive Brachytherapy: An Analysis From the EMBRACE Study.
Int J Radiat Oncol Biol Phys. 2016; 94(5):1088-98 [PubMed] Related Publications
PURPOSE: This study analyzed functioning and symptom scores for longitudinal quality of life (QoL) from patients with locally advanced cervical cancer who underwent definitive chemoradiation therapy with image guided adaptive brachytherapy in the EMBRACE study.
METHODS AND MATERIALS: In total, 744 patients at a median follow-up of 21 months were included. QoL was prospectively assessed using European Organization for Research and Treatment of Cancer Quality of Life core module 30 (EORTC QLQ-C30) and EORTC cervical cancer module 24 (CX24) questionnaires at baseline, then every 3 months during the first year, every 6 months in the second and third years, and finally yearly thereafter in patients with no evidence of disease. Outcomes were evaluated over time and compared to those from an age-matched female reference population.
RESULTS: General QoL and emotional and social functioning were impaired at baseline but improved during the first 6 months after treatment, to reach a level comparable to that of the reference population, whereas cognitive functioning remained impaired. Both social and role functioning showed the lowest scores at baseline but which increased after treatment to reach a plateau at 6 months and then declined slightly at 3 and 4 years. The overall symptom experience was elevated at baseline and decreased to a level within the range of that of the reference population. Similarly, tumor-related symptoms (eg, pain, appetite loss, and constipation), which were present before treatment, decreased substantially at the first follow-up after treatment. Several treatment-related symptoms developed either immediately after and persisted over time (diarrhea, menopausal symptoms, peripheral neuropathy, and sexual functioning problems) or developed gradually after treatment (lymphedema and dyspnea).
CONCLUSIONS: This longitudinal prospective QoL analysis showed that patients' general QoL and functioning were impaired before treatment compared to those of reference data. Several tumor-related symptoms resolved after treatment, and functioning and general QoL returned to that of the level of the reference population, indicating a transient impact of diagnosis and treatment. However, several treatment-related symptoms and problems did develop and persist, either immediately or gradually after treatment.

Bhatia R, Kavanagh K, Cubie HA, et al.
Use of HPV testing for cervical screening in vaccinated women--Insights from the SHEVa (Scottish HPV Prevalence in Vaccinated Women) study.
Int J Cancer. 2016; 138(12):2922-31 [PubMed] Related Publications
The management of cervical disease is changing worldwide as a result of HPV vaccination and the increasing use of HPV testing for cervical screening. However, the impact of vaccination on the performance of HPV based screening strategies is unknown. The SHEVa (Scottish HPV Prevalence in Vaccinated women) projects are designed to gain insight into the impact of vaccination on the performance of clinically validated HPV assays. Samples collated from women attending for first cervical smear who had been vaccinated as part of a national "catch-up" programme were tested with three clinically validated HPV assays (2 DNA and 1 RNA). Overall HR-HPV and type specific positivity was assessed in total population and according to underlying cytology and compared to a demographically equivalent group of unvaccinated women. HPV prevalence was significantly lower in vaccinated women and was influenced by assay-type, reducing by 23-25% for the DNA based assays and 32% for the RNA assay (p = 0.0008). All assays showed over 75% reduction of HPV16 and/or 18 (p < 0.0001) whereas the prevalence of non 16/18 HR-HPV was not significantly different in vaccinated vs unvaccinated women. In women with low grade abnormalities, the proportion associated with non 16/18 HR-HPV was significantly higher in vaccinated women (p < 0.0001). Clinically validated HPV assays are affected differentially when applied to vaccinated women, dependent on assay chemistry. The increased proportion of non HPV16/18 infections may have implications for clinical performance, consequently, longitudinal studies linking HPV status to disease outcomes in vaccinated women are warranted.

Roura E, Travier N, Waterboer T, et al.
The Influence of Hormonal Factors on the Risk of Developing Cervical Cancer and Pre-Cancer: Results from the EPIC Cohort.
PLoS One. 2016; 11(1):e0147029 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In addition to HPV, high parity and hormonal contraceptives have been associated with cervical cancer (CC). However, most of the evidence comes from retrospective case-control studies. The aim of this study is to prospectively evaluate associations between hormonal factors and risk of developing cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC).
METHODS AND FINDINGS: We followed a cohort of 308,036 women recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. At enrollment, participants completed a questionnaire and provided serum. After a 9-year median follow-up, 261 ICC and 804 CIN3/CIS cases were reported. In a nested case-control study, the sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11,16,18,31,33,35,45,52,58, and antibodies against Chlamydia trachomatis and Human herpesvirus 2. Multivariate analyses were performed to estimate hazard ratios (HR), odds ratios (OR) and corresponding 95% confidence intervals (CI). The cohort analysis showed that number of full-term pregnancies was positively associated with CIN3/CIS risk (p-trend = 0.03). Duration of oral contraceptives use was associated with a significantly increased risk of both CIN3/CIS and ICC (HR = 1.6 and HR = 1.8 respectively for ≥ 15 years versus never use). Ever use of menopausal hormone therapy was associated with a reduced risk of ICC (HR = 0.5, 95%CI: 0.4-0.8). A non-significant reduced risk of ICC with ever use of intrauterine devices (IUD) was found in the nested case-control analysis (OR = 0.6). Analyses restricted to all cases and HPV seropositive controls yielded similar results, revealing a significant inverse association with IUD for combined CIN3/CIS and ICC (OR = 0.7).
CONCLUSIONS: Even though HPV is the necessary cause of CC, our results suggest that several hormonal factors are risk factors for cervical carcinogenesis. Adherence to current cervical cancer screening guidelines should minimize the increased risk of CC associated with these hormonal risk factors.

Carozzi FM, Del Mistro A, Cuschieri K, et al.
HPV testing for primary cervical screening: Laboratory issues and evolving requirements for robust quality assurance.
J Clin Virol. 2016; 76 Suppl 1:S22-8 [PubMed] Related Publications
This review aims to highlight the importance of Quality Assurance for Laboratories performing HPV test for Cervical Cancer Screening. An HPV test, to be used as primary screening test, must be validated according to international criteria, based on comparison of its clinical accuracy to HC2 or GP5+/6+ PCR-EIA tests. The number of validated platforms is increasing and appropriate Quality Assurance Programs (QAPs) which can interrogate longitudinal robustness and quality are paramount. This document describes the following topics: (1) the characteristics of an HPV laboratory and the personnel training needs, to ensure an elevated quality of the entire process and the optimal use of the resources; (2) the Quality Assurance, as both internal (IQA) and external quality assessment (EQA) systems, to be implemented and performed, and the description of the existing EQAs, including limitations; (3) general considerations for an optimal EQA program for hrHPV primary screening Due to the importance of Quality Assurance for this field, international efforts are necessary to improve QA International Collaboration.

Sagae S, Monk BJ, Pujade-Lauraine E, et al.
Advances and Concepts in Cervical Cancer Trials: A Road Map for the Future.
Int J Gynecol Cancer. 2016; 26(1):199-207 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Cervical cancer is responsible for more than a quarter of a million deaths globally each year, mostly in developing countries, making therapeutic advances in all health care settings a top priority. The Gynecologic Cancer InterGroup (GCIG) is a worldwide collaboration of leading national research groups that develops and promotes multinational trials in gynecologic cancer. In recognition of the pressing need for action, the GCIG convened an international meeting with expert representation from the GCIG groups and selected large sites in low- and middle-income countries.
METHODS: The focus was to develop a consensus on several concepts for future clinical trials, which would be developed and promoted by the GCIG and launched with major international participation. The first half of the meeting was devoted to a resume of the current state of the knowledge and identifying the gaps in need of new evidence, validating control arms for present and future clinical trials and identifying national and international barriers for studies of cervix cancers. The second half of the meeting was concerned with achieving consensus on a path forward.
RESULTS AND CONCLUSIONS: There were 5 principal outcomes as follows: first, a proposal to expand fertility-preserving options with neoadjuvant chemotherapy; second, validation of the assessment of sentinel lymph nodes using minimally invasive surgery with an emphasis on identification and management of low-volume metastasis, such as isolated tumor cells and micrometastasis; third, evaluation of hypofractionation for palliative and curative radiation under the umbrella of the GCIG Cervix Cancer Research Network; fourth, adding to the advances in antiangiogenesis therapy in the setting of metastatic disease; and fifth, developing a maintenance study among women at high risk of relapse. The latter 2 systemic interventions could study PI3K (phosphatidylinositol-3-kinase) inhibitors, immunotherapy, anti-human papillomavirus approaches, or novel antiangiogenic agents/combinations.

Beral V
Reprint of "Cancer of the cervix: A sexually transmitted infection?".
Cancer Epidemiol. 2015; 39(6):1148-51 [PubMed] Related Publications
When mortality patterns for cancer of the uterine cervix were compared with trends in incidence of sexually transmitted diseases in both England and Wales and in Scotland, there were striking associations between the temporal, social class, occupational, and geographic distributions of these diseases. The data suggest that exposure to sexually transmitted infection is an important determinant of cervical cancer. Although they are still young, women born after 1940 are already experiencing increased cervical-cancer mortality. If cervical-cancer prevention and therapy remain unchanged, this generation's high risk of death from cervical cancer will probably continue to operate throughout their lives.

Dareng EO, Jedy-Agba E, Bamisaye P, et al.
Influence of Spirituality and Modesty on Acceptance of Self-Sampling for Cervical Cancer Screening.
PLoS One. 2015; 10(11):e0141679 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Whereas systematic screening programs have reduced the incidence of cervical cancer in developed countries, the incidence remains high in developing countries. Among several barriers to uptake of cervical cancer screening, the roles of religious and cultural factors such as modesty have been poorly studied. Knowledge about these factors is important because of the potential to overcome them using strategies such as self-collection of cervico-vaginal samples. In this study we evaluate the influence of spirituality and modesty on the acceptance of self-sampling for cervical cancer screening.
METHODOLOGY: We enrolled 600 participants in Nigeria between August and October 2014 and collected information on spirituality and modesty using two scales. We used principal component analysis to extract scores for spirituality and modesty and logistic regression models to evaluate the association between spirituality, modesty and preference for self-sampling. All analyses were performed using STATA 12 (Stata Corporation, College Station, Texas, USA).
RESULTS: Some 581 (97%) women had complete data for analysis. Most (69%) were married, 50% were Christian and 44% were from the south western part of Nigeria. Overall, 19% (110/581) of the women preferred self-sampling to being sampled by a health care provider. Adjusting for age and socioeconomic status, spirituality, religious affiliation and geographic location were significantly associated with preference for self-sampling, while modesty was not significantly associated. The multivariable OR (95% CI, p-value) for association with self-sampling were 0.88 (0.78-0.99, 0.03) for spirituality, 1.69 (1.09-2.64, 0.02) for religious affiliation and 0.96 (0.86-1.08, 0.51) for modesty.
CONCLUSION: Our results show the importance of taking cultural and religious beliefs and practices into consideration in planning health interventions like cervical cancer screening. To succeed, public health interventions and the education to promote it must be related to the target population and its preferences.

Gage JC, Hunt WC, Schiffman M, et al.
Risk Stratification Using Human Papillomavirus Testing among Women with Equivocally Abnormal Cytology: Results from a State-Wide Surveillance Program.
Cancer Epidemiol Biomarkers Prev. 2016; 25(1):36-42 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Clinical guidelines for cervical cancer screening have incorporated comparative risks of cervical intraepithelial neoplasia grade 3 or cancer (CIN3(+)) for various screening outcomes to determine management. Few cohorts are large enough to distinguish CIN3(+) risks among women with minor abnormalities versus negative cytology because of low incidence. The New Mexico Human Papillomavirus (HPV) Pap Registry offers a unique opportunity to evaluate cervical cancer screening in a diverse population across a broad-spectrum of health service delivery.
METHODS: Kaplan-Meier and logistic-Weibull survival models were used to estimate cumulative risks of CIN3(+) among women ages 21 to 64 who were screened in New Mexico between 2007 and 2011 with negative, equivocal or mildly abnormal cytology, that is, atypical squamous cells of undetermined significance (ASC-US; with or without HPV triage), or low-grade squamous intraepithelial lesions (LSIL).
RESULTS: We identified 452,045 women meeting the selection criteria. The 3-year CIN3(+) risks for women with negative, ASC-US, and LSIL cytology were 0.30%, 2.6%, and 5.2%, respectively. HPV triage of ASC-US stratified 3-year CIN3(+) risks were 0.72% for HPV-negative and 7.7% for HPV-positive. Risks tended to decline after age 30 for all screening results.
CONCLUSIONS: In this state-wide population-based cohort, cytology and HPV triage of ASC-US stratified women's CIN3(+) risk into similar patterns observed previously, suggesting the validity of screening guidelines for diverse populations in the United States. Absolute risk estimates should be compared across other large populations.
IMPACT: Strategies for HPV triage of ASC-US derived from clinical trials are upheld in large clinical practice settings and across diverse screening populations in the United States.

Khan S, Woolhead G
Perspectives on cervical cancer screening among educated Muslim women in Dubai (the UAE): a qualitative study.
BMC Womens Health. 2015; 15:90 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cervical cancer (CC) is the seventh leading cause of death among women in the United Arab Emirates (UAE), with most deaths attributed to late detection of this cancer. The UAE lacks a national CC screening programme. Thus, cervical screening is only performed opportunistically during women's visits to health facilities. CC screening rates in the UAE are as low as 16.9 %, and little is known about the perspectives of the nation's educated Muslim women regarding screening. Consequently, the aim of this study is to explore Muslim women's perspectives towards cervical screening in Dubai to promote strategies for increasing its uptake, thereby leading to a decrease in morbidity and mortality associated with CC.
METHODS: Interpretivist and social constructivist epistemological approaches were applied for this qualitative study. Data were obtained through 13 in-depth interviews. Purposive and snowballing methods were used to recruit six South Asian women and seven Emirati women living in Dubai. Thematic content analysis was concurrently applied with comparative analysis to the data.
RESULTS: Four themes regarding women's perceptions of CC emerged from the data. First, CC was considered a 'silent disease' that could be detected with early screening. However, it was also associated with extramarital sexual relations, which negatively influenced screening uptake. Second, women's fear, pain and embarrassment, along with cultural influences, deterred them from undergoing screening. Third, a growing mistrust of allopathic medicine and impersonal healthcare promoted a negative view of screening. Last, women became aware of screening mainly when they were pregnant or receiving fertility treatment.
CONCLUSIONS: The study highlighted a number of important factors relating to cultural, religious and sexual behaviour that shaped educated Muslim women's perspectives on CC screening. Evidently, the current opportunistic approach to screening is flawed. A national awareness programme on CC screening should be developed, tailored to the sociocultural norms of the Muslim community, to promote knowledge regarding the causes of CC and the importance of screening.

Jordan SJ, Wilson LF, Nagle CM, et al.
Cancers in Australia in 2010 attributable to and prevented by the use of combined oral contraceptives.
Aust N Z J Public Health. 2015; 39(5):441-5 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: To estimate the proportion and number of cancers occurring in Australia in 2010 attributable to combined oral contraceptive pill (OCP) use.
METHODS: We estimated the population attributable fraction (PAF) for cancers causally associated with combined OCP use (breast, cervix), and the proportion of endometrial and ovarian cancers prevented (prevented fraction [PF]). We used standard formulae incorporating prevalence of combined OCP use in the Australian population, relative risks of cancer associated with this exposure and cancer incidence.
RESULTS: An estimated 105 breast and 52 cervical cancers (0.7% and 6.4% of each cancer, respectively) in Australia in 2010 were attributable to current use of combined OCP. Past combined OCP use was estimated to have prevented 1,032 endometrial and 308 ovarian cancers in 2010, reducing the number of cancers that would otherwise have occurred by 31% and 19%, respectively.
CONCLUSIONS: A small proportion of breast and cervical cancers is attributable to combined OCP use; OCP use is likely to have prevented larger numbers of endometrial and ovarian cancers.
IMPLICATIONS: Women seeking contraceptive advice should be told of potential adverse effects, but should also be told that - along with reproductive health benefits - combined OCP use can reduce long-term risks of ovarian and endometrial cancers.

Zhang R, Shen C, Zhao L, et al.
Dysregulation of host cellular genes targeted by human papillomavirus (HPV) integration contributes to HPV-related cervical carcinogenesis.
Int J Cancer. 2016; 138(5):1163-74 [PubMed] Free Access to Full Article Related Publications
Integration of human papillomavirus (HPV) viral DNA into the human genome has been postulated as an important etiological event during cervical carcinogenesis. Several recent reports suggested a possible role for such integration-targeted cellular genes (ITGs) in cervical carcinogenesis. Therefore, a comprehensive analysis of HPV integration events was undertaken using data collected from 14 publications, with 499 integration loci on human chromosomes included. It revealed that HPV DNA preferred to integrate into intragenic regions and gene-dense regions of human chromosomes. Intriguingly, the host cellular genes nearby the integration sites were found to be more transcriptionally active compared with control. Furthermore, analysis of the integration sites in the human genome revealed that there were several integration hotspots although all chromosomes were represented. The ITGs identified were found to be enriched in tumor-related terms and pathways using gene ontology and KEGG analysis. In line with this, three of six ITGs tested were found aberrantly expressed in cervical cancer tissues. Among them, it was demonstrated for the first time that MPPED2 could induce HeLa cell and SiHa cell G1/S transition block and cell proliferation retardation. Moreover, "knocking out" the integrated HPV fragment in HeLa cell line decreased expression of MYC located ∼500 kb downstream of the integration site, which provided the first experimental evidence supporting the hypothesis that integrated HPV fragment influence MYC expression via long distance chromatin interaction. Overall, the results of this comprehensive analysis implicated that dysregulation of ITGs caused by viral integration as possibly having an etiological involvement in cervical carcinogenesis.

Crosbie EJ, Bailey A, Sargent A, et al.
The PapilloCheck Assay for Detection of High-Grade Cervical Intraepithelial Neoplasia.
J Clin Microbiol. 2015; 53(11):3553-9 [PubMed] Free Access to Full Article Related Publications
Human papillomavirus (HPV) testing is used in primary cervical screening, as an adjunct to cervical cytology for the management of low grade abnormal cytology, and in a test of cure. PapilloCheck (Greiner Bio-One) is a PCR-based DNA microarray system that can individually identify 24 HPV types, including the 13 high-risk (HR) types identified by Hybrid Capture 2 (HC2). Here, we compare PapilloCheck with HC2 for the detection of high-grade cervical intraepithelial neoplasia (CIN2+) in a total of 8,610 cervical cytology samples from the ARTISTIC population-based cervical screening study. We performed a retrospective analysis of 3,518 cytology samples from round 1 ARTISTIC enriched for underlying CIN2+ (n = 723) and a prospective analysis of 5,092 samples from round 3 ARTISTIC. Discrepant results were tested using the Roche reverse line blot (RLB) or Linear Array (LA) assay. The relative sensitivity and specificity of HR PapilloCheck compared with that of HC2 for the detection of CIN2+ in women aged over 30 years were 0.94 (95% confidence interval [CI], 0.91, 0.97) and 1.05 (95% CI, 1.04, 1.05), respectively. HC2 missed 44/672 (7%) CIN2+ lesions, while HR PapilloCheck missed 74/672 (11%) CIN2+ lesions. Thirty-six percent of HC2-positive normal cytology samples were HR HPV negative by both PapilloCheck and RLB/LA, indicating that the use of HR PapilloCheck rather than HC2 in population-based primary screening would reduce the number of additional tests required (e.g., reflex cytology) in women where underlying CIN2+ is extremely unlikely. HR PapilloCheck could be a suitable HPV detection assay for use in the cervical screening setting.

Wuntakal R, Papadopoulos AJ, Montalto SA, et al.
Location of Sentinel Lymph Node in Cervical Carcinoma and Factors Associated With Unilateral Detection.
Int J Gynecol Cancer. 2015; 25(9):1663-8 [PubMed] Related Publications
OBJECTIVE: The aims of this study were to assess locality of the sentinel lymph node (SLN) in cervical carcinoma and examine factors affecting bilateral SLN detection.
METHODS: This was a retrospective review of SLN data (anatomical location, count and laterality) in patients with early-stage cervical cancer (International Federation of Gynecology and Obstetrics stage IA1 with lymphovascular space invasion to stage IIA) using intraoperative gamma probe and blue dye. The preoperative single-photon emission computed tomography with computed tomography was used to detect laterality, number of the SLNs, and rare locations. Patients were treated between January 2005 to January 2015 at the West Kent Gynaecological Oncology Centre, Maidstone Hospital, Maidstone, United Kingdom.
RESULTS: A total of 132 women were investigated. The most common SLN location was the external iliac (38.6%) followed by obturator (25.3%) and internal iliac (23.6%) regions. A small percentage was identified in presacral (1.4%) and para-aortic regions (0.7%). Older age (P = 0.01) and an elevated body mass index (P = 0.03) were associated with decreased SLN count by preoperative single-photon emission computed tomography with computed tomography, and only age affected SLN count by gamma probe (P = 0.01). Initial surgery, large loop excision of the transformation zone, or cone biopsy of the cervix had no effect on SLN count. There was no difference observed in bilateral detection with respect to surgical approach (open: n = 48/laparoscopic: n = 84). However, older age was independently associated with a decrease in bilateral SLN detection (P = 0.003). In these patients who underwent unilateral full pelvic lymphadenectomy, all the nonsentinel nodes were negative.
CONCLUSIONS: The majority of SLNs were located in the external iliac, obturator, and internal iliac regions. Both older age and an elevated body mass index were associated with a reduced SLN count. Unilateral detection of SLN was independently associated with older age, which may be due to sclerosis in the lymphatic vessels or reduced perfusion in the pelvis in these women. If no SLN is detected on one side, the consensus is to perform a full pelvic lymphadenectomy on that side of the pelvis.

Agodi A, Barchitta M, Quattrocchi A, et al.
DAPK1 Promoter Methylation and Cervical Cancer Risk: A Systematic Review and a Meta-Analysis.
PLoS One. 2015; 10(8):e0135078 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The Death-Associated Protein Kinase 1 (DAPK1) gene has been frequently investigated in cervical cancer (CC). The aim of the present study was to carry out a systematic review and a meta-analysis in order to evaluate DAPK1 promoter methylation as an epigenetic marker for CC risk.
METHODS: A systematic literature search was carried out. The Cochrane software package Review Manager 5.2 was used. The fixed-effects or random-effects models, according to heterogeneity across studies, were used to calculate odds ratios (ORs) and 95% Confidence Intervals (CIs). Furthermore, subgroup analyses were conducted by histological type, assays used to evaluate DAPK1 promoter methylation, and control sample source.
RESULTS: A total of 20 papers, published between 2001 and 2014, on 1929 samples, were included in the meta-analysis. DAPK1 promoter methylation was associated with an increased CC risk based on the random effects model (OR: 21.20; 95%CI = 11.14-40.35). Omitting the most heterogeneous study, the between study heterogeneity decreased and the association increased (OR: 24.13; 95% CI = 15.83-36.78). The association was also confirmed in all the subgroups analyses.
CONCLUSIONS: A significant strong association between DAPK1 promoter methylation and CC was shown and confirmed independently by histological tumor type, method used to evaluate methylation and source of control samples. Methylation markers may have value in early detection of CC precursor lesions, provide added reassurances of safety for women who are candidates for less frequent screens, and predict outcomes of women infected with human papilloma virus.

Bradbury M, Founta C, Taylor W, et al.
Pathological Risk Factors and Outcomes in Women With Stage IB2 Cervical Cancer Treated With Primary Radical Surgery Versus Chemoradiotherapy.
Int J Gynecol Cancer. 2015; 25(8):1476-83 [PubMed] Related Publications
OBJECTIVE: Both radical hysterectomy with pelvic lymphadenectomy and primary chemoradiotherapy have been shown to be effective in the management of women with stage IB2 cervical cancer. This study aims to review the outcomes related to each treatment modality and the effects of pathological risk factors on overall survival (OS) and disease-free survival.
METHODS: We performed a retrospective study of 92 women with stage IB2 cervical cancer who were treated at the Northern Gynecological Oncology Center (Gateshead, United Kingdom) across a 22-year period between January 1991 and July 2013. Women were divided into those undergoing primary surgery and those undergoing primary radiotherapy/chemoradiotherapy. The main outcome measures were OS and progression-free survival (PFS). Pathological risk factors of survival were assessed using multivariate analysis.
RESULTS: Sixty-seven women (72.8%) underwent primary surgery, and 25 women (27.2%) had primary radiotherapy/chemoradiotherapy. Thirty-one of 67 women (46.3%) required adjuvant radiotherapy/chemoradiotherapy after surgery because of positive lymph nodes in 77.4% of cases. The median follow-up was 57.5 months (range, 3-137 months). Thirty-two women (34.8%) had disease recurrence: 6 women (16.7%) in the group undergoing surgery alone, 15 women (48.4%) in the group requiring adjuvant treatment after surgery, and 11 women (44%) in the group having primary radiotherapy/chemoradiotherapy. Overall survival and PFS were higher for women undergoing surgery alone (91.7% and 83.3%) compared with women requiring adjuvant treatment after surgery (54.8% and 51.4%) and those having primary radiotherapy/chemoradiotherapy (60% and 56%) (P = 0.0004 and P = 0.005, respectively). Lymph node metastasis was a significant pathological risk factor of OS and PFS in multivariate analysis.
CONCLUSIONS: Most women require adjuvant treatment after surgery because of positive lymph nodes. Because survival outcomes for women requiring dual treatment are similar to those for women undergoing primary chemoradiotherapy, nodal assessment before definitive treatment should guide the management of these women and identify a low-risk group that can be treated with surgery alone.

Awunor O, Berger D, Kirisits C
A multicenter study to quantify systematic variations and associated uncertainties in source positioning with commonly used HDR afterloaders and ring applicators for the treatment of cervical carcinomas.
Med Phys. 2015; 42(8):4472-83 [PubMed] Related Publications
PURPOSE: The reconstruction of radiation source position in the treatment planning system is a key part of the applicator reconstruction process in high dose rate (HDR) brachytherapy treatment of cervical carcinomas. The steep dose gradients, of as much as 12%/mm, associated with typical cervix treatments emphasize the importance of accurate and precise determination of source positions. However, a variety of methodologies with a range in associated measurement uncertainties, of up to ±2.5 mm, are currently employed by various centers to do this. In addition, a recent pilot study by Awunor et al. ["Direct reconstruction and associated uncertainties of (192)Ir source dwell positions in ring applicators using gafchromic film in the treatment planning of HDR brachytherapy cervix patients," Phys. Med. Biol. 58, 3207-3225 (2013)] reported source positional differences of up to 2.6 mm between ring sets of the same type and geometry. This suggests a need for a comprehensive study to assess and quantify systematic source position variations between commonly used ring applicators and HDR afterloaders across multiple centers.
METHODS: Eighty-six rings from 20 European brachytherapy centers were audited in the form of a postal audit with each center collecting the data independently. The data were collected by setting up the rings using a bespoke jig and irradiating gafchromic films at predetermined dwell positions using four afterloader types, MicroSelectron, Flexitron, GammaMed, and MultiSource, from three manufacturers, Nucletron, Varian, and Eckert & Ziegler BEBIG. Five different ring types in six sizes (Ø25-Ø35 mm) and two angles (45° and 60°) were used. Coordinates of irradiated positions relative to the ring center were determined and collated, and source position differences quantified by ring type, size, and angle.
RESULTS: The mean expanded measurement uncertainty (k = 2) along the direction of source travel was ±1.4 mm. The standard deviation associated with the source position reproducibility was within ±1.0 mm for all afterloaders. Maximum source positional variations of 2.1 and 3.9, 1.8 and 5.4, and 2.3 and 3.4 mm were observed at standard treatment positions for the Ø26, Ø30, and Ø32 mm sized 45° and 60° rings, respectively. Mean positional differences between a majority of the rings were within ±1.0 mm. Mean positional differences between a majority of the intracenter ring sets were within the expanded measurement uncertainty. When comparing the 45°-60° source paths, mean differences of 1.6, 0.9, and 0.9 mm were observed across the Ø26, Ø30 (MicroSelectron), and Ø32 mm (GammaMed) rings, respectively. When comparing to manufacturer source path models, maximum offsets of 1.9 and 2.1, 2.6 and 2.3, and 0.8 and 1.6 mm were observed for the Ø26, Ø30 (MicroSelectron), and Ø30 mm (Flexitron) sized 45° and 60° rings, respectively. When comparing the audit to ring commissioning data of participating centers, mean differences of up to 2.4 mm were observed.
CONCLUSIONS: A majority of the audited rings showed a good degree of manufacturer consistency; however, substantial positional variation observed between some rings emphasizes the importance of commissioning each ring before clinical use. Differences observed between audit and commissioning data also indicate some variation in source treatment positions across centers.

Herweijer E, Feldman AL, Ploner A, et al.
The Participation of HPV-Vaccinated Women in a National Cervical Screening Program: Population-Based Cohort Study.
PLoS One. 2015; 10(7):e0134185 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Concerns have been raised that HPV-vaccination might affect women's cervical screening behavior. We therefore investigated the association between opportunistic HPV-vaccination and attendance after invitation to cervical screening.
METHODS: A cohort of all women resident in Sweden, born 1977-1987 (N=629,703), and invited to cervical screening, was followed October 2006 - December 2012. Invitations to screening were identified via the National Quality Register for Cervical Cancer Prevention, as was the primary outcome of a registered smear. Vaccination status was obtained from two nationwide health data registers. Hazard ratios (HR) were estimated using Cox regression adjusted for age, education level and income (HRadj). Women were individually followed for up to 6 years, of which the first and second screening rounds were analyzed separately.
RESULTS: Screening attendance after three years of follow-up was 86% in vaccinated women (N=4,897) and 75% in unvaccinated women (N=625,804). The crude HR of screening attendance in vaccinated vs. unvaccinated women was 1.31 (95% CI 1.27-1.35) in the first screening round. Adjustment for education and income reduced but did not erase this difference (HRadj=1.09, 95% CI 1.05-1.13). In the second screening round, attendance was likewise higher in HPV-vaccinated women (crude HR=1.26, 95% CI 1.21-1.32; HRadj=1.15, 95% CI 1.10-1.20).
CONCLUSIONS: HPV-vaccination is so far associated with equal or higher attendance to cervical screening in Sweden in a cohort of opportunistically vaccinated young women. Most but not all of the difference in attendance was explained by socioeconomic differences between vaccinated and unvaccinated women. HPV vaccine effectiveness studies should consider screening attendance of HPV-vaccinated women when assessing incidence of screen-detected cervical lesions.

Watson-Jones D, Mugo N, Lees S, et al.
Access and Attitudes to HPV Vaccination amongst Hard-To-Reach Populations in Kenya.
PLoS One. 2015; 10(6):e0123701 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Sub-Saharan Africa bears the greatest burden of cervical cancer. Human papillomavirus (HPV) vaccination programmes to prevent the disease will need to reach vulnerable girls who may not be able access health and screening services in the future. We conducted formative research on facilitators and barriers to HPV vaccination and potential acceptability of a future HPV vaccination programme amongst girls living in hard-to-reach populations in Kenya.
METHODS: Stakeholder interviews with Ministry of Health staff explored barriers to and support for the uptake of HPV vaccination. A situation assessment was conducted to assess community services in Maasai nomadic pastoralist communities in Kajiado County and in Korogocho informal settlement in Nairobi city, followed by focus group discussions (n=14) and semi-structured interviews (n=28) with health workers, parents, youth, and community and religious leaders. These covered marriage, knowledge of cervical cancer and HPV, factors that might inhibit or support HPV vaccine uptake and intention to accept HPV vaccine if a programme was in place.
RESULTS: Reported challenges to an HPV vaccination programme included school absenteeism and drop-out, early age of sex and marriage, lack of parental support, population mobility and distance from services. Despite little prior knowledge of cervical cancer and HPV, communities were interested in receiving HPV vaccination. Adequate social mobilisation and school-based vaccination, supplemented by out-reach activities, were considered important facilitating factors to achieve high coverage. There was some support for a campaign approach to vaccine delivery.
CONCLUSIONS: Given the high level of support for a vaccine against cervical cancer and the experience of reaching pastoralist and slum-dwellers for other immunizations, implementing an HPV vaccine programme should be feasible in such hard-to-reach communities. This may require additional delivery strategies in addition to the standard school-based delivery, with vaccine offered at multiple venues, potentially through a campaign approach.

Holl K, Nowakowski AM, Powell N, et al.
Human papillomavirus prevalence and type-distribution in cervical glandular neoplasias: Results from a European multinational epidemiological study.
Int J Cancer. 2015; 137(12):2858-68 [PubMed] Free Access to Full Article Related Publications
Cervical glandular neoplasias (CGN) present a challenge for cervical cancer prevention due to their complex histopathology and difficulties in detecting preinvasive stages with current screening practices. Reports of human papillomavirus (HPV) prevalence and type-distribution in CGN vary, providing uncertain evidence to support prophylactic vaccination and HPV screening. This study [108288/108290] assessed HPV prevalence and type-distribution in women diagnosed with cervical adenocarcinoma in situ (AIS, N = 49), adenosquamous carcinoma (ASC, N = 104), and various adenocarcinoma subtypes (ADC, N = 461) from 17 European countries, using centralised pathology review and sensitive HPV testing. The highest HPV-positivity rates were observed in AIS (93.9%), ASC (85.6%), and usual-type ADC (90.4%), with much lower rates in rarer ADC subtypes (clear-cell: 27.6%; serous: 30.4%; endometrioid: 12.9%; gastric-type: 0%). The most common HPV types were restricted to HPV16/18/45, accounting for 98.3% of all HPV-positive ADC. There were variations in HPV prevalence and ADC type-distribution by country. Age at diagnosis differed by ADC subtype, with usual-type diagnosed in younger women (median: 43 years) compared to rarer subtypes (medians between 57 and 66 years). Moreover, HPV-positive ADC cases were younger than HPV-negative ADC. The six years difference in median age for women with AIS compared to those with usual-type ADC suggests that cytological screening for AIS may be suboptimal. Since the great majority of CGN are HPV16/18/45-positive, the incorporation of prophylactic vaccination and HPV testing in cervical cancer screening are important prevention strategies. Our results suggest that special attention should be given to certain rarer ADC subtypes as most appear to be unrelated to HPV.

Novaes HM, de Soárez PC, Silva GA, et al.
Cost-effectiveness analysis of introducing universal human papillomavirus vaccination of girls aged 11 years into the National Immunization Program in Brazil.
Vaccine. 2015; 33 Suppl 1:A135-42 [PubMed] Related Publications
OBJECTIVES: To evaluate the impact and cost-effectiveness of introducing universal human papillomavirus (HPV) vaccination into the National Immunization Program (NIP) in Brazil.
METHODS: The Excel-based CERVIVAC decision support model was used to compare two strategies: (1) status quo (with current screening program) and (2) vaccination of a cohort of 11-year-old girls. National parameters for the epidemiology and costs of cervical cancer were estimated in depth. The estimates were based on data from the health information systems of the public health system, the PNAD 2008 national household survey, and relevant scientific literature on Brazil. Costs are expressed in 2008 United States dollars (US$), and a 5% discount rate is applied to both future costs and future health benefits.
RESULTS: Introducing the HPV vaccine would reduce the burden of disease. The model estimated there would be 229 deaths avoided and 6677 disability-adjusted life years (DALYs) averted in the vaccinated cohort. The incremental cost-effectiveness ratios (ICERs) per DALY averted from the perspectives of the government (US$ 7663), health system (US$ 7412), and society (US$ 7298) would be considered cost-effective, according to the parameters adopted by the World Health Organization. In the sensitivity analysis, the ICERs were most sensitive to variations in discount rate, disease burden, vaccine efficacy, and proportion of cervical cancer caused by types 16 and 18. However, universal HPV vaccination remained a cost-effective strategy in most variations of the key estimates.
CONCLUSIONS: Vaccine introduction could contribute additional benefits in controlling cervical cancer, but it requires large investments by the NIP. Among the essential conditions for attaining the expected favorable results are immunization program sustainability, equity in a population perspective, improvement of the screening program, and development of a surveillance system.

Bergeron C, Ikenberg H, Sideri M, et al.
Prospective evaluation of p16/Ki-67 dual-stained cytology for managing women with abnormal Papanicolaou cytology: PALMS study results.
Cancer Cytopathol. 2015; 123(6):373-81 [PubMed] Related Publications
BACKGROUND: Testing for the presence of the human papillomavirus (HPV) is widely accepted for triaging Papanicolaou cytology results categorized as atypical squamous cells of undetermined significance (ASC-US). In contrast, HPV testing has limited use in triaging cytological low-grade squamous intraepithelial lesions (LSILs) due to prevalence rates of typically >80%. In the current study, the authors assessed the diagnostic performance of p16/Ki-67 dual-stained cytology in triaging ASC-US and LSIL cases within the prospective, multicentric Primary ASC-US LSIL Marker Study (PALMS).
METHODS: A total of 575 ASC-US cases and 529 LSIL cases from a cohort of 27,349 women who were prospectively enrolled into the PALMS study in 5 European countries were tested with p16/Ki-67 dual-stained cytology and Hybrid Capture 2 (HC2) HPV testing. Colposcopy-guided biopsy results of cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) were used as clinical endpoints.
RESULTS: p16/Ki-67 dual-stained cytology demonstrated comparable (ASC-US: 94.4% for dual-stained cytology vs 100% for HC2 testing; P = .317) or lower (LSIL: 85.7% for dual-stained cytology vs 98.4% for HC2 testing; P = .005) sensitivity for CIN2+, but higher levels of specificity compared with HC2 HPV testing in both ASC-US (78.7% vs 60.4%; P<.001) and LSIL (53.3% vs 15.6%; P<.001) cases. Positive predictive values for CIN2+ were substantially higher for dual-stained cytology versus HC2 HPV testing, especially in LSIL, and in ASC-US cases for women aged <30 years.
CONCLUSIONS: The clinical usefulness and efficiency of triaging women with ASC-US or LSIL Papanicolaou cytology results by p16/Ki-67 dual-stained cytology testing has been confirmed in this prospective, pan-European study. The high positive predictive value of dual-stained cytology for the presence of high-grade CIN may help to reduce the number of unnecessary colposcopy referrals.

Tanton C, Soldan K, Beddows S, et al.
High-Risk Human Papillomavirus (HPV) Infection and Cervical Cancer Prevention in Britain: Evidence of Differential Uptake of Interventions from a Probability Survey.
Cancer Epidemiol Biomarkers Prev. 2015; 24(5):842-53 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The third British National Survey of Sexual Attitudes and Lifestyles (Natsal-3) provides an opportunity to explore high-risk human papillomavirus (HR-HPV) and uptake of cervical screening and HPV vaccination in the general population.
METHODS: Natsal-3, a probability sample survey of men and women ages 16 to 74, resident in Britain, interviewed 8,869 women in 2010 to 2012. We explored risk factors for HR-HPV (in urine from 2,569 sexually experienced women ages 16 to 44), nonattendance for cervical screening in the past 5 years, and noncompletion of HPV catch-up vaccination.
RESULTS: HR-HPV was associated with increasing numbers of lifetime partners, younger age, increasing area-level deprivation, and smoking. Screening nonattendance was associated with younger and older age, increasing area-level deprivation (age-adjusted OR 1.91, 95% confidence interval, 1.48-2.47 for living in most vs. least deprived two quintiles), Asian/Asian British ethnicity (1.96, 1.32-2.90), smoking (1.97, 1.57-2.47), and reporting no partner in the past 5 years (2.45, 1.67-3.61 vs. 1 partner) but not with HR-HPV (1.35, 0.79-2.31). Lower uptake of HPV catch-up vaccination was associated with increasing area-level deprivation, non-white ethnicity, smoking, and increasing lifetime partners.
CONCLUSIONS: Socioeconomic markers and smoking were associated with HR-HPV positivity, nonattendance for cervical screening, and noncompletion of catch-up HPV vaccination.
IMPACT: The cervical screening program needs to engage those missing HPV catch-up vaccination to avoid a potential widening of cervical cancer disparities in these cohorts. As some screening nonattenders are at low risk for HR-HPV, tailored approaches may be appropriate to increase screening among higher-risk women.

Apter D, Wheeler CM, Paavonen J, et al.
Efficacy of human papillomavirus 16 and 18 (HPV-16/18) AS04-adjuvanted vaccine against cervical infection and precancer in young women: final event-driven analysis of the randomized, double-blind PATRICIA trial.
Clin Vaccine Immunol. 2015; 22(4):361-73 [PubMed] Free Access to Full Article Related Publications
We report final event-driven analysis data on the immunogenicity and efficacy of the human papillomavirus 16 and 18 ((HPV-16/18) AS04-adjuvanted vaccine in young women aged 15 to 25 years from the PApilloma TRIal against Cancer In young Adults (PATRICIA). The total vaccinated cohort (TVC) included all randomized participants who received at least one vaccine dose (vaccine, n = 9,319; control, n = 9,325) at months 0, 1, and/or 6. The TVC-naive (vaccine, n = 5,822; control, n = 5,819) had no evidence of high-risk HPV infection at baseline, approximating adolescent girls targeted by most HPV vaccination programs. Mean follow-up was approximately 39 months after the first vaccine dose in each cohort. At baseline, 26% of women in the TVC had evidence of past and/or current HPV-16/18 infection. HPV-16 and HPV-18 antibody titers postvaccination tended to be higher among 15- to 17-year-olds than among 18- to 25-year-olds. In the TVC, vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or greater (CIN1+), CIN2+, and CIN3+ associated with HPV-16/18 was 55.5% (96.1% confidence interval [CI], 43.2, 65.3), 52.8% (37.5, 64.7), and 33.6% (-1.1, 56.9). VE against CIN1+, CIN2+, and CIN3+ irrespective of HPV DNA was 21.7% (10.7, 31.4), 30.4% (16.4, 42.1), and 33.4% (9.1, 51.5) and was consistently significant only in 15- to 17-year-old women (27.4% [10.8, 40.9], 41.8% [22.3, 56.7], and 55.8% [19.2, 76.9]). In the TVC-naive, VE against CIN1+, CIN2+, and CIN3+ associated with HPV-16/18 was 96.5% (89.0, 99.4), 98.4% (90.4, 100), and 100% (64.7, 100), and irrespective of HPV DNA it was 50.1% (35.9, 61.4), 70.2% (54.7, 80.9), and 87.0% (54.9, 97.7). VE against 12-month persistent infection with HPV-16/18 was 89.9% (84.0, 94.0), and that against HPV-31/33/45/51 was 49.0% (34.7, 60.3). In conclusion, vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high-grade cervical abnormalities, and catch-up vaccination up to 18 years of age is most likely effective. (This study has been registered at ClinicalTrials.gov under registration no. NCT001226810.).

Kuku S, Proctor I, Loddo M, et al.
Do Cell-Cycle Phase-Specific Markers Predict Disease Grade, Stage, and Outcome in Cervical Carcinoma?
Int J Gynecol Cancer. 2015; 25(6):1066-72 [PubMed] Related Publications
AIMS: Multiparameter analysis of cell cycle markers has shown a strong relationship between cell cycle progression and tumor grade, stage, and clinical outcome in penile, renal, ovarian, and breast cancers. We sought to link expression of cell cycle phase-specific markers in cervical cancer to tumor grade, stage, and clinical outcome to investigate their potential use as prognostic and predictive markers.
METHODS: Pretreatment biopsy material was obtained from 35 patients with cervical cancer (stage IB2-IVA) and 12 normal cervix control cases. Each patient was treated with neoadjuvant chemotherapy followed by chemoradiation. Immunohistochemical staining was performed using a panel of cell cycle phase markers: replication licensing factors: Mcm2 (minichromosome maintenance 2) and geminin, and the standard proliferation marker Ki67 (clone MIB-1).
RESULTS: The expression levels of each cell cycle biomarker were very high in all cases of squamous cell carcinoma of the cervix regardless of grade or stage of disease. In our cohort, all cases displayed an aggressive, so-called actively cycling phenotype. Univariate analysis showed that none of the cell cycle biomarkers predicted grade, stage, or clinical outcome.
CONCLUSIONS: Cell cycle phase-specific markers do not appear to predict disease grade, stage, or outcome in our sample of patients with cervical cancer. This is not surprising, given that the expression of each cell cycle biomarker was very high in all cases.Indeed, all the cases of squamous cell carcinoma of the cervix (n = 28) and all but 1 of the adenocarcinomas (n = 7) in this study displayed an aggressive "actively cycling" phenotype. This predominance of actively cycling tumors is unusual and may reflect the viral etiology underlying the disease. These preliminary findings raise many interesting questions including the prognostic value of disease grade and markers of proliferation in cervical tumors as reliable prognostic indicators. Further work on a larger cohort of patients is warranted.

Cuzick J, Myers O, Hunt WC, et al.
Human papillomavirus testing 2007-2012: co-testing and triage utilization and impact on subsequent clinical management.
Int J Cancer. 2015; 136(12):2854-63 [PubMed] Free Access to Full Article Related Publications
In the United States, high-risk human papillomavirus (HPV) testing is recommended for women with atypical squamous cells of unknown significance (ASC-US) cytology, and co-testing with cytology and HPV is a recommended option for screening women aged ≥ 30 years. No population-based data are available to examine utilization of HPV testing in the United States. Using the New Mexico HPV Pap Registry data resource, we describe population trends (2007-2012) in utilization and positivity rates for HPV testing as a routine co-testing screening procedure and for triage of ASC-US and other cytologic outcomes. For women aged 30-65 years co-testing increased from 5.2% in 2007 to 19.1% in 2012 (p < 0.001). Overall 82% of women with ASC-US cytology who did not receive co-testing also had an HPV test. HPV positivity was age and cytology result dependent but did not show time trends. For women with negative cytology, 64% received an additional screening test within 3 years if no co-test was done or if it was positive, but this was reduced to 47% with a negative co-test. Reflex HPV testing for ASC-US cytology is well established and occurs in most women. Evidence for reflex testing is also observed following other abnormal cytology outcomes. Co-testing in women aged 30-65 years has more than tripled from 2007 to 2012, but was still only used in 19.1% of women aged 30-65 years attending for screening in 2012. Women receiving co-testing had longer repeat screening intervals, but rescreening within 3 years is still very common even with co-testing.

Ngou J, Gilham C, Omar T, et al.
Comparison of analytical and clinical performances of the digene HC2 HPV DNA assay and the INNO-LiPA HPV genotyping assay for detecting high-risk HPV infection and cervical neoplasia among HIV-positive African women.
J Acquir Immune Defic Syndr. 2015; 68(2):162-8 [PubMed] Related Publications
OBJECTIVES: To compare the Hybrid Capture 2 human papillomaviruses (HPV) DNA assay (HC2) and the INNO-LiPA HPV Genotyping Extra assay (INNO-LiPA) for cervical cancer screening in HIV-1-infected African women.
DESIGN: The tests were compared for agreement in detecting high-risk HPV (hr-HPV) and performance to detect squamous intraepithelial lesions (SIL), by cytology, and cervical intraepithelial neoplasia, by histology, in cervical samples from 1224 women in Burkina Faso (N = 604) and South Africa (N = 620).
RESULTS: When considering the 13 hr-HPV types detected by HC2, 634 (51.8%) and 849 (69.4%) samples were positive by HC2 and INNO-LiPA, respectively. Agreement between assays was 73.9% [adjusted kappa coefficient value, 0.44 (95% confidence interval: 0.43 to 0.53)]. Agreement improved with analysis restricted to women with high-grade cervical lesions [adjusted kappa coefficient value, 0.83 (95% confidence interval: 0.74 to 0.91)]. The prevalence of hr-HPV, as determined by HC2 and INNO-LiPA, was 34.5% and 54.5%, respectively, in samples with normal cytology, 48.0% and 68.0%, respectively, in samples with atypical squamous cells of undetermined significance, 51.8% and 75.2%, respectively, in samples with low-grade SIL, and 86.3% and 89.8%, respectively, in samples with high-grade SIL/atypical squamous cells that cannot exclude HSIL. Sensitivity, specificity, positive, and negative predictive values for the diagnosis of histological high-grade lesions (CIN2+) were 88.8%, 55.2%, 24.7% and 96.7%, and 92.5%, 35.1%, 19.1% and 96.6% for HC2 and INNO-LiPA, respectively.
CONCLUSIONS: HC2 has lower analytical sensitivity but higher specificity than INNO-LiPA for diagnosing high-grade lesions; the 2 tests presented a comparable clinical sensitivity. HC2 might be suitable for cervical cancer screening in HIV-1-infected African women, but its use in resource-limited settings merits to be further evaluated in comparison with other prevention strategies.

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