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
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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).

Tewari KS, Sill MW, Long HJ, et al.
Improved survival with bevacizumab in advanced cervical cancer.
N Engl J Med. 2014; 370(8):734-43 [PubMed] Related Publications
BACKGROUND: Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer.
METHODS: Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important.
RESULTS: Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan-paclitaxel was not superior to cisplatin-paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P=0.004 in a one-sided test) and higher response rates (48% vs. 36%, P=0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%).
CONCLUSIONS: The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival. (Funded by the National Cancer Institute; GOG 240 ClinicalTrials.gov number, NCT00803062.).

Related: Angiogenesis Inhibitors Cisplatin Paclitaxel Topotecan Bevacizumab (Avastin)

Kellas-Sleczka S, Białas B, Szlag M, et al.
High-dose-rate interstitial brachytherapy for mucinous adenocarcinoma endocervical-type--a case study.
Ginekol Pol. 2013; 84(12):1059-63 [PubMed] Related Publications
BACKGROUND: Adenocarcinoma in cervical cancer has poorer response rate to treatment and requires longer time to achieve complete remission than squamous cell carcinoma [1]. Lower response to chemotherapy and radiotherapy is observed [2,3,4,5] and the optimal management remains undefined [1,4,6,7]. Case: We report a case of a 58-year-old woman with bulky mucinous adenocarcinoma endocervical-type G1, treated previously with radiochemotherapy with no visible response. After subsequent interstitial HDR brachytherapy (iHDR-BT) complete local remission was achieved.
CONCLUSION: Interstitial HDR brachytherapy in bulky mucinous adenocarcinoma endocervical-type may be the best treatment choice that allows to receive a complete local response.

Related: Brachytherapy

Pernelle G, Mehrtash A, Barber L, et al.
Validation of catheter segmentation for MR-guided gynecologic cancer brachytherapy.
Med Image Comput Comput Assist Interv. 2013; 16(Pt 3):380-7 [PubMed] Related Publications
Segmentation of interstitial catheters from MRI needs to be addressed in order for MRI-based brachytherapy treatment planning to become part of the clinical practice of gynecologic cancer radiotherapy. This paper presents a validation study of a novel image-processing method for catheter segmentation. The method extends the distal catheter tip, interactively provided by the physician, to its proximal end, using knowledge of catheter geometry and appearance in MRI sequences. The validation study consisted of comparison of the algorithm results to expert manual segmentations, first on images of a phantom, and then on patient MRI images obtained during MRI-guided insertion of brachytherapy catheters for the treatment of gynecologic cancer. In the phantom experiment, the maximum disagreement between automatic and manual segmentation of the same MRI image, as computed using the Hausdorf distance, was 1.5 mm, which is of the same order as the MR image spatial resolution, while the disagreement between automatic segmentation of MR images and "ground truth", manual segmentation of CT images, was 3.5 mm. The segmentation method was applied to an IRB-approved retrospective database of 10 interstitial brachytherapy patients which included a total of 101 catheters. Compared with manual expert segmentations, the automatic method correctly segmented 93 out of 101 catheters, at an average rate of 0.3 seconds per catheter using a 3 GHz Intel Core i7 computer with 16 GB RAM and running Mac OS X 10.7. These results suggest that the proposed catheter segmentation is both technically and clinically feasible.

Related: Brachytherapy

Gao Q, Liu W, Cai J, et al.
EphB2 promotes cervical cancer progression by inducing epithelial-mesenchymal transition.
Hum Pathol. 2014; 45(2):372-81 [PubMed] Related Publications
EphB2, a receptor tyrosine kinase for ephrin ligands, is overexpressed in various cancers and plays an important role in tumor progression. However, the expression and functions of EphB2 in cervical cancer remain unknown. In this study, we performed immunohistochemistry in clinical cervical specimens and found that EphB2 was overexpressed in the cervical cancer specimens, and its expression correlated with cancer progression. The percentage of EphB2-positive cells increased gradually from 28% in the normal cervix to 40% in high-grade squamous intraepithelial lesions, and ultimately to 69.8% in squamous cell carcinomas (P < .05). We overexpressed EphB2 in HeLa cells and silenced EphB2 in cervical cancer (C33A) cells, which expressed low and high levels of EphB2, respectively. Exogenous EphB2 promoted cell migration, invasion, and an epithelial-mesenchymal transition (EMT) signature, which is a complex process that occurs during organogenesis and cancer metastasis, whereas EphB2 silencing had the opposite effect (P < .05). Furthermore, HeLa cells with exogenous EphB2 exhibited a stem cell-like state that promoted tumorsphere formation in vitro and exhibited tumorigenesis potential in vivo (P < .05), whereas EphB2 silencing in C33A cells inhibited these stem cell properties (P < .05). In addition, we investigated the intracellular signaling pathways in cervical cancer and found that R-Ras expression correlated positively with EphB2 in clinical samples, and its activity was regulated by EphB2 in cervical cancer. These findings demonstrate that EphB2 plays an important role in cervical cancer progression by orchestrating an EMT program through R-Ras activation.

Related: EPHB2 Signal Transduction

Barron S, Li Z, Austin RM, Zhao C
Low-grade squamous intraepithelial lesion/cannot exclude high-grade squamous intraepithelial lesion (LSIL-H) is a unique category of cytologic abnormality associated with distinctive HPV and histopathologic CIN 2+ detection rates.
Am J Clin Pathol. 2014; 141(2):239-46 [PubMed] Related Publications
OBJECTIVES: To examine data correlating high-risk human papillomavirus (hrHPV) results in patients with both low-grade squamous intraepithelial lesion (LSIL) and atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion (ASC-H) cytology findings (LSIL-H) with follow-up histopathology.
METHODS: A total of 494 LSIL-H ThinPrep (Hologic, Marlborough, MA) cases with hrHPV testing were identified. Histopathologic follow-up was available in 347 patients.
RESULTS: Among 347 patients with follow-up histopathology after LSIL-H cytology and hrHPV testing, 90.5% tested hrHPV positive. Cervical intraepithelial neoplasia (CIN) 2/3 was diagnosed in 29.4% and CIN 1 in 53.6%. CIN 2/3 was diagnosed in significantly more patients with hrHPV-positive LSIL-H than following hrHPV-negative LSIL-H results. Compared with published institutional data, LSIL-H had significantly lower hrHPV and histopathologic CIN 2/3+ rates (90.5% and 29.4%, with no cervical cancers) than high-grade squamous intraepithelial lesion (HSIL) (95.7% and 70.5%, with 2.4% cervical cancers) but higher rates than LSIL (80.2% and 12.9%) or atypical squamous cells/cannot exclude HSIL (ASC-H) (54.3% and 17.2%). Whereas CIN 2/3 detection rates were similar in HPV-positive LSIL-H and HPV-positive ASC-H, CIN 2/3 findings were more likely with HPV-negative LSIL-H than with HPV-negative ASC-H.
CONCLUSIONS: LSIL-H is a unique category of cytologic abnormality associated with distinctive hrHPV and CIN 2/3+ diagnostic rates.

Elfström KM, Smelov V, Johansson AL, et al.
Long term duration of protective effect for HPV negative women: follow-up of primary HPV screening randomised controlled trial.
BMJ. 2014; 348:g130 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: To assess whether the increased sensitivity of screening for human papillomavirus (HPV) may represent overdiagnosis and to compare the long term duration of protective effect against cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in HPV based and cytology based screening.
DESIGN: 13 year follow-up of the Swedescreen randomised controlled trial of primary HPV screening.
SETTING: Organised cervical screening programme in Sweden.
PARTICIPANTS: 12,527 women aged 32-38 attending organised screening were enrolled and randomised to HPV and cytology double testing (intervention arm, n=6257) or to cytology only, with samples frozen for future HPV testing (control arm, n=6270).
MAIN OUTCOME MEASURES: Cumulative incidence of CIN2+ and CIN3+ (Kaplan Meier curves). Longitudinal test characteristics were calculated for cytology only, HPV testing only, and cytology and HPV testing combined, adjusting for censoring.
RESULTS: The increased detection of CIN2+ in the intervention arm decreased over time. After six years, the cumulative incidence of CIN3+ was similar in both trial arms, and after 11 years the cumulative incidence of CIN2+ became similar in both arms. The longitudinal sensitivity of cytology for CIN2+ in the control arm at three years was similar to the sensitivity of HPV testing in the intervention arm at five years of follow-up: 85.94% (95% confidence interval 76.85% to 91.84%) v 86.40% (79.21% to 91.37%). The sensitivity of HPV screening for CIN3+after five years was 89.34% (80.10% to 94.58%) and for cytology after three years was 92.02% (80.59% to 96.97%).
CONCLUSIONS: Over long term follow-up, the cumulative incidence of CIN2+ was the same for HPV screening and for cytology, implying that the increased sensitivity of HPV screening for CIN2+ reflects earlier detection rather than overdiagnosis. The low long term risks of CIN3+ among women who tested negative in HPV screening, support screening intervals of five years for such women.
TRIAL REGISTRATION: Clinicaltrials.gov NCT00479375.

Atjimakul T, Boonyapipat S, Chichareon S, Phukaoloun M
Cytomorphologic and clinical factors of having high-grade cervical intraepithelial neoplasia/invasive carcinoma in women with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) smears.
J Med Assoc Thai. 2013; 96(11):1389-94 [PubMed] Related Publications
OBJECTIVE: To determine the predictors for high-grade cervical intraepithelial neoplasia (CIN)/invasive carcinoma in women with atypical squamous cells, cannot exclude the high-grade squamous intraepithelial lesion (ASC-H) smears.
MATERIAL AND METHOD: All women with ASC-H, who underwent colposcopy and had histolopathologic diagnosis between January 2004 and December 2011, were recruited. Clinical and cytomorphologic features were correlated with final histological diagnosis. Univariate and multivariate analysis were used to determine predicting factors for high-grade CIN/ invasive cancer
RESULTS: Among 136,638 smears performed, 193 (0.14%) smears were reported as ASC-H and 121 smears were available for review. The underlying pathology were negative/reactive (N/R) 57 (47.1%), CIN 1 23 (19.0%), CIN 2-3 39 (32.0%), and invasive cancer 2 (1.6%). On univariate analysis, predicting factors of having high-grade CIN included a high N/C ratio, greater nuclear hyperchromasia, nuclear membrane irregularities, and the coarse chromatin. The multivariate analysis showed that a high nuclear-to-cytoplasmic (N/C) ratio (OR = 8.6, 95% CI = 1.1-70.1) and greater nuclear hyperchromasia (OR = 5.8, 95% CI = 1.6-20.8) were the independent predictors for high-grade CIN or invasive carcinoma.
CONCLUSION: The presence of a high N/C ratio and greater nuclear hyperchromasia could be used to predict high-grade CIN or invasive carcinoma in ASC-H smears.

Strander B, Hällgren J, Sparén P
Effect of ageing on cervical or vaginal cancer in Swedish women previously treated for cervical intraepithelial neoplasia grade 3: population based cohort study of long term incidence and mortality.
BMJ. 2014; 348:f7361 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To determine factors influencing long term risks for acquiring or dying from invasive cervical or vaginal cancer in women previously treated for cervical intraepithelial neoplasia grade 3 (CIN3).
DESIGN: Population based cohort study conducted in 1958-2008, followed up until 2009 in the Swedish Cancer Registry and Swedish Cause of Death Register, linked to the Swedish Population Register. Standardised incidence and mortality ratios were calculated for the risk of acquiring or dying from vaginal or cervical cancer, with the general female population in Sweden as reference. Relative risks in multivariable regression models were also calculated, adjusting for follow-up duration, treatment period, and age at CIN3 treatment or attained age.
SETTING: Entire female population of Sweden.
PARTICIPANTS: 150,883 women in Sweden diagnosed and treated with CIN3 and followed up for invasive cervical or vaginal cancer, and related mortality. The cohort comprised 3,148,222 woman years.
MAIN OUTCOME MEASURES: Standardised incidence and mortality ratios, stratified by period for treatment. Relative standardised incidence ratios and standardised mortality ratios for age at acquiring or dying from cervical or vaginal cancer (attained age), adjusted for preset variables.
RESULTS: Women previously diagnosed with CIN3 had an increased risk of dying from invasive cervical or vaginal cancer, compared with the general female population (standardised mortality ratio 2.35, 95% confidence interval 2.11 to 2.61). After age 60 years, these women had an accelerated increased risk of acquiring invasive cancer; a similar steep increase in mortality risk was seen after age 70. Regression analyses indicated that the increase in risk over time is highly attributable to ageing.
CONCLUSIONS: Women previously treated for CIN3 are at increased risk of developing and dying from cervical or vaginal cancer, compared with the general female population. The risk accelerates above age 60 years, suggesting a need for lifelong surveillance of these women.

Related: Vaginal Cancer

Ojesina AI, Lichtenstein L, Freeman SS, et al.
Landscape of genomic alterations in cervical carcinomas.
Nature. 2014; 506(7488):371-5 [PubMed] Related Publications
Cervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide. The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established. Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as several copy-number alterations in the pathogenesis of cervical carcinomas. Here we report whole-exome sequencing analysis of 115 cervical carcinoma-normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumour-normal pairs. Previously unknown somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%) and ERBB2 (6%). We also observe somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines (Tp*C sites) than adenocarcinomas. Gene expression levels at HPV integration sites were statistically significantly higher in tumours with HPV integration compared with expression of the same genes in tumours without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest new strategies to combat this disease.

Related: HLA-B TP53 FBXW7 gene

Shen S, Zhang Y, Zhang R, Gong X
Sarsasapogenin induces apoptosis via the reactive oxygen species-mediated mitochondrial pathway and ER stress pathway in HeLa cells.
Biochem Biophys Res Commun. 2013; 441(2):519-24 [PubMed] Related Publications
Sarsasapogenin is a sapogenin from the Chinese medical herb Anemarrhena asphodeloides Bunge. In the present study, we revealed that sarsasapogenin exhibited antitumor activity by inducing apoptosis in vitro as determined by Hoechst staining analysis and double staining of Annexin V-FITC/PI. In addition, cell cycle arrest in G2/M phase was observed in sarsasapogenin-treated HeLa cells. Moreover, the results revealed that perturbations in the mitochondrial membrane were associated with the deregulation of the Bax/Bcl-2 ratio which led to the upregulation of cytochrome c, followed by activation of caspases. Meanwhile, treatment of sarsasapogenin also activated Unfolded Protein Response (UPR) signaling pathways and these changes were accompanied by increased expression of CHOP. Salubrinal (Sal), a selective inhibitor of endoplasmic reticulum (ER) stress, partially abrogated the sarsasapogenin-related cell death. Furthermore, sarsasapogenin provoked the generation of reactive oxygen species, while the antioxidant N-acetyl cysteine (NAC) effectively blocked the activation of ER stress and apoptosis, suggesting that sarsasapogenin-induced reactive oxygen species is an early event that triggers ER stress mitochondrial apoptotic pathways. Taken together, the results demonstrate that sarsasapogenin exerts its antitumor activity through both reactive oxygen species (ROS)-mediate mitochondrial dysfunction and ER stress cell death.

Related: Mitochondrial Mutations in Cancer

Singh C, Manivel JC, Truskinovsky AM, et al.
Variability of pathologists' utilization of p16 and ki-67 immunostaining in the diagnosis of cervical biopsies in routine pathology practice and its impact on the frequencies of cervical intraepithelial neoplasia diagnoses and cytohistologic correlations.
Arch Pathol Lab Med. 2014; 138(1):76-87 [PubMed] Related Publications
CONTEXT: The use of p16 in cervical biopsies improves the accuracy of cervical intraepithelial neoplasia (CIN) diagnosis and grading and decreases its interpathologist variability.
OBJECTIVE: To determine the impact of the frequency of use of p16 immunostains in cervical biopsies on pathologists' diagnoses of CIN grade 1 and grade 2 or above (CIN1 and CIN2+) and on cytohistologic correlations.
DESIGN: We identified all cervical biopsy specimens with cytologic correlations subjected or not to p16 staining from January 1, 2005, to September 30, 2010; calculated each pathologist's percentage of p16 use; and correlated it with their major cytohistologic discrepancy rates, CIN2+ diagnoses, and CIN1/CIN2+ ratios.
RESULTS: During the study period, each of the 23 pathologists interpreted 59 to 1811 (mean, 518) of 11 850 cervical biopsy specimens, used p16 for 0% to 21.31% (mean, 10.14%) of these, had CIN2+ detection rates of 9.5% to 24.1% (mean, 18.9%), and CIN1/CIN2+ ratios of 0.7 to 4.5 (mean, 1.5). Compared to the 12 "low users" of p16, who used p16 fewer times than the institution's mean for p16 use, the 11 "high users" of p16 diagnosed more biopsies (8391 versus 3459), had a lower rate of major cytohistologic discrepancies (12.62% versus 14.92%, P < .001), a higher rate of CIN2+ diagnoses (19.9% versus 16.4%, P < .001), a lower range of CIN2+ rates (15.0%-23.1% versus 9.5%-24.1%), and lower CIN1/CIN2+ ratios (1.2 versus 2.3).
CONCLUSIONS: We found a high intrainstitutional variability of p16 use in cervical biopsies, CIN2+ rates, and CIN1/CIN2+ ratios. Use of p16 for greater than 10% of cervical biopsies was associated with improved cytohistologic correlation rates and with lower variability in the frequencies of histologic diagnoses.

Related: MKI67

Berardi R, Nacciarriti D, Tamburrano T, et al.
Compliance with breast and cervical cancer screening programs in women: results from a population-based study.
Tumori. 2013 Sep-Oct; 99(5):565-71 [PubMed] Related Publications
AIMS AND BACKGROUND: Women's adherence to mammography and PAP test screening guidelines is a fundamental topic regarding women's health. The aim of the study was to evaluate the knowledge and compliance to breast and cervical cancer screening programs in women living in three Italian towns, where a public screening program, consisting of free mammography every two years and free PAP test every three years, is ongoing.
METHODS: An anonymous survey was mailed to a random sample of women. Eight 120-min focus discussions with groups of women exploring perceptions, knowledge and practices were carried out after analysis of the returned surveys.
RESULTS: Replies were received from 1345 women (response rate, 27%). Almost every woman knew of the screening program, but women's practice of mammography was age-dependent: up to 72% of the women performed it before the age of 50. Conversely, the age of the first PAP test was rather late: up to 70% of the women performed it at over 30 years of age. Women with a lower educational level reported being screened less than those with a higher level. During the group discussions, women's perceptions, knowledge and beliefs regarding cancer and screening, together with aspects of the health care system, appeared to strongly influence the preventive practices. Many women deplored being infrequently instructed by health professionals.
CONCLUSIONS: Despite the limitations of the study due to the low response rate, we believe that health professionals should invest on encouraging factors and reduce the deterring factors to optimize screening practices.

Related: Breast Cancer Breast Cancer Screening Cancer Screening and Early Detection

Chih H, Lee AH, Colville L, et al.
Sitting time, physical activity and cervical intraepithelial neoplasia in Australian women: a preliminary investigation.
Health Promot J Austr. 2013; 24(3):219-23 [PubMed] Related Publications
ISSUE ADDRESSED: Physical activity affects the immune system, which in turn may modify the risk of cervical intraepithelial neoplasia (CIN). The effect of sitting on CIN is unknown. This study investigated the relationship between sitting time, physical activity and the risk of CIN.
METHODS: Community-dwelling adult women within metropolitan Perth, Western Australia, who had had a Papanicolaou (Pap) smear test at any of five clinics and medical centres, were approached by their general practitioners. In total, 348 women were recruited and interviewed for information on sitting time, physical activity level and lifetime physical activity exposure using the International Physical Activity Questionnaire (IPAQ)--short form. Associations of exposure variables with CIN risk were assessed by unconditional logistic regression analyses.
RESULTS: The prevalence of abnormal Pap smear status indicating CIN was found to be 15.8%. Women with prolonged sitting duration (≥42 h per week) had significantly increased risk of CIN (adjusted OR 3.49, 95% CI 1.12-10.88) than women who sat less than 24.5h per week. Although the effect of total physical activity level was non-significant (P=0.408), being always involved in physical activity during the entire life appeared to be inversely associated with the CIN risk (P=0.036).
CONCLUSIONS: Prolonged sitting time was significantly associated with increased risk of abnormal Pap smear status indicating CIN. SO WHAT?: This preliminary investigation highlights a new prospect for health-promotion intervention to reduce the risk of CIN. Health practitioners should encourage women to reduce their sitting time and maintain physically active throughout their life course.

Quddus MR, Manna P, Sung CJ, et al.
Prevalence, distribution, and viral burden of all 15 high-risk human papillomavirus types in adenosquamous carcinoma of the uterine cervix: a multiplex real-time polymerase chain reaction-based study.
Hum Pathol. 2014; 45(2):303-9 [PubMed] Related Publications
Human papillomavirus (HPV) 16 and 18 are the types most commonly found in cervical adenosquamous carcinoma. Multiple HPV types have been found in cervical adenocarcinoma but not in the adenosquamous variant. Type-specific detection of high-risk (HR) HPV allows the detection of co-infection by multiple HPV types and assessment of viral load per cell. Our aim was to identify and quantify all HR HPV types in cervical adenosquamous carcinoma and to correlate viral loads with prognosis-related histologic features. All 15 HR HPV types were tested for by multiplex real-time polymerase chain reaction, and standard curves were created for each type. Viral loads were determined retrospectively. Prognosis-related histologic features were correlated with specific HPV types and the viral loads. A total of 80% of the tumors examined expressed HPV. Types 16/18 were detected in 86% of these cases, whereas the remaining 14% of the positive cases were infected by other types. A single type of virus was detected in 67% of cases, 2 in 29%, and 3 in 4%. Poor prognostic features were seen in 84.6% of the tumors infected with HPV 16, 46% of those infected with HPV 18, and 100% of those infected with other types. As expected, HPV 16, HPV 18, or both were the most frequent viral types; HPV 73 was the next most frequent type. Multiple HPV types were detected in 33% of the tumors. Non-HPV 16/18 cases had low viral loads, but all of these had poor prognosis-related histologic features. Two of the three recurrent cases had multiple viral types.

Schefter T, Winter K, Kwon JS, et al.
RTOG 0417: efficacy of bevacizumab in combination with definitive radiation therapy and cisplatin chemotherapy in untreated patients with locally advanced cervical carcinoma.
Int J Radiat Oncol Biol Phys. 2014; 88(1):101-5 [PubMed] Related Publications
PURPOSE: Radiation Therapy Oncology Group 0417 was a phase II study that explored the safety and efficacy of the addition of bevacizumab to chemoradiation therapy. The safety results have been previously reported. Herein we report the secondary efficacy endpoints of overall survival (OS), locoregional failure (LRF), para-aortic nodal failure (PAF), distant failure (DF), and disease-free survival (DFS).
METHODS AND MATERIALS: Eligible patients with bulky Stage IB-IIIB disease were treated with once-weekly cisplatin (40 mg/m2) chemotherapy and standard pelvic radiation therapy and brachytherapy. Bevacizumab was administered at 10 mg/kg intravenously every 2 weeks for 3 cycles during chemoradiation. For OS, failure was defined as death of any cause and was measured from study entry to date of death. LRF was defined as any failure in the pelvis. PAF was defined as any para-aortic nodal failure. DF was analyzed both including and excluding PAF. DFS was measured from study entry to date of first LRF. DF was measured with or without PAF or death. OS and DFS were estimated by the Kaplan-Meier method, and LRF and DF rates were estimated by the cumulative incidence method.
RESULTS: 49 eligible patients from 28 institutions were enrolled between 2006 and 2009. The median follow-up time was 3.8 years (range, 0.8-6.0 years). The surviving patients had a median follow-up time of 3.9 years (range, 2.1-6.0 years). Most patients had tumors of International Federation of Gynecology and Obstetrics Stage IIB (63%), and 80% were squamous. The 3-year OS, DFS, and LRF were 81.3% (95% confidence interval [CI], 67.2%-89.8%), 68.7% (95% CI, 53.5%-79.8%), and 23.2% (95% CI, 11%-35.4%), respectively. The PAF, DF without PAF, and DF with PAF at 3 years were 8.4% (95% CI, 0.4%-16.3%), 14.7% (95% CI, 4.5%-24.9%), and 23.1% (95% CI 11.0%-35.2%), respectively.
CONCLUSION: In this study, bevacizumab in combination with standard pelvic chemoradiation therapy for locally advanced cervical cancer showed efficacy results that are promising and may warrant further investigation.

Related: Angiogenesis Inhibitors Cisplatin VEGFA Bevacizumab (Avastin)

Chen AA, Heideman DA, Boon D, et al.
Human papillomavirus 33 worldwide genetic variation and associated risk of cervical cancer.
Virology. 2014; 448:356-62 [PubMed] Related Publications
Human papillomavirus (HPV) 33, a member of the HPV16-related alpha-9 species group, is found in approximately 5% of cervical cancers worldwide. The current study aimed to characterize the genetic diversity of HPV33 and to explore the association of HPV33 variants with the risk for cervical cancer. Taking advantage of the International Agency for Research on Cancer biobank, we sequenced the entire E6 and E7 open reading frames of 213 HPV33-positive cervical samples from 30 countries. We identified 28 HPV33 variants that formed 5 phylogenetic groups: the previously identified A1, A2, and B (sub)lineages and the novel A3 and C (sub)lineages. The A1 sublineage was strongly over-represented in cervical cases compared to controls in both Africa and Europe. In conclusion, we provide a classification system for HPV33 variants based on the sequence of E6 and E7 and suggest that the association of HPV33 with cervical cancer may differ by variant (sub)lineage.

Kalantari M, Osann K, Calleja-Macias IE, et al.
Methylation of human papillomavirus 16, 18, 31, and 45 L2 and L1 genes and the cellular DAPK gene: Considerations for use as biomarkers of the progression of cervical neoplasia.
Virology. 2014; 448:314-21 [PubMed] Related Publications
During progression of cervical cancer, human papillomavirus genomes and cellular tumor suppressor genes can become methylated. Toward a better understanding of these biomarkers, we studied 104 samples with HPV16, 18, 31, and 45 representing five pathological categories from asymptomatic infection to cancer. We grouped all samples by HPV type and pathology and measured the overall methylation of informative amplicons of HPV late genes and the cellular DAPK gene. Methylation of all four HPV types as well as of the DAPK gene is lowest in asymptomatic infection and increases successively in all four pathological categories during progression to cancer. 27 out of 28 cancer samples showed methylation both in the L2/L1 genes as well as in DAPK, but a much lower fraction in all other pathological categories. We discuss the problem to develop diagnostic tests based on complex methylation patterns that make it difficult to classify amplicons as "methylated" or "unmethylated".

Srivastava P, Mangal M, Agarwal SM
Understanding the transcriptional regulation of cervix cancer using microarray gene expression data and promoter sequence analysis of a curated gene set.
Gene. 2014; 535(2):233-8 [PubMed] Related Publications
Cervical cancer, the malignant neoplasm of the cervix uteri is the second most common cancer among women worldwide and the top-most cancer in India. Several factors are responsible for causing cervical cancer, which alter the expression of oncogenic genes resulting in up or down-regulation of gene expression and inactivation of tumor-suppressor genes/gene products. Gene expression is regulated by interactions between transcription factors (TFs) and specific regulatory elements in the promoter regions of target genes. Thus, it is important to decipher and analyze TFs that bind to regulatory regions of diseased genes and regulate their expression. In the present study, computational methods involving the combination of gene expression data from microarray experiments and promoter sequence analysis of a curated gene set involved in the cervical cancer causation have been utilized for identifying potential regulatory elements. Consensus predictions of two approaches led to the identification of twelve TFs that might be crucial to the regulation of cervical cancer progression. Subsequently, TF enrichment and oncomine expression analysis suggested that the transcription factor family E2F played an important role for the regulation of genes involve in cervical carcinogenesis. Our results suggest that E2F possesses diagnostic/prognostic value and can act as a potential drug target in cervical cancer.

Dittus JL, Dudley BS, Upender M, Endress GA
Cervical adenocarcinoma identification by testing for chromosomal abnormalities.
Arch Pathol Lab Med. 2013; 137(12):1829-31 [PubMed] Related Publications
We report on a case of cervical adenocarcinoma in situ in a 42-year-old woman with a history of human papillomavirus infection. Repeat cytology, human papillomavirus testing, and colposcopy failed to identify the lesion. Testing of the cervical cell DNA identified chromosomal abnormalities, prompting a cervical cone biopsy, which identified adenocarcinoma in situ.

Related: Cancer Screening and Early Detection

Ohayi SA, Ezugwu EC, Aderibigbe AS, Udeh EI
Angiosarcoma of the cervix: a case and literature review.
Niger J Med. 2013 Oct-Dec; 22(4):362-4 [PubMed] Related Publications
BACKGROUND: Generally, sarcomas of the female genital tract are rare and angiosarcomas are extremely rare. They usually have poor prognosis and pose serious diagnostic challenges requiring special techniques namely special stains and immunohistochemistry for proper elucidation.
METHOD: A case report of a 65 old para 8 (4 alive) widow, 17 years postmenopusal, who presented with history of foul smelling brownish vaginal discharge, progressive weight loss and cervical lesion. She had examination under anaesthesia and biopsy.
RESULT: Histopathological result showed features in keeping with angiosarcoma of the uterine cervix.
CONCLUSION: Although angiosarcoma of the cervix is very rare, it is occasionally seen in black women in Nigeria.

Shuaibu SI, Gidado S, Oseni-Momodu E
Endoscopic retrograde JJ-stenting of the ureter without fluoroscopy guidance--an appraisal of outcome.
Niger J Med. 2013 Oct-Dec; 22(4):348-50 [PubMed] Related Publications
BACKGROUND: JJ- ureteral stenting is a means of relieving ureteric obstruction. It is done as a retrograde or antegrade procedure, usually under fluoroscopy guidance. We reviewed our results in 2 independent tertiary health centers in Nigeria which lack fluoroscopy units.
METHODS: A 2 year retrospective review of data of patients who had retrograde JJ- ureteric stenting was done. Data relating to age, indication and outcome of procedure were retrieved and analysed.
RESULTS: 22 (71%) patients had successful retrograde JJ- ureteric stenting out of 31 patients who were taken for the procedure. These 22 patients had stenting of 27 ureteric units. Mean age was 48.5 years. Commonest indication was carcinoma of the cervix (31.8%). Commonest complication was irritative lower urinary tract symptoms (43.5%).
CONCLUSION: In spite of inherent complications, JJ-stenting is a simple and safe technique. Therefore, the decision to attempt JJ -stenting in carefully selected patients in the absence of fluoroscopy is acceptable.

Ondič O, Kašpírková J, Májek O, Kinkorová I
HPV typing of high-grade dysplasia (CIN III) in cone biopsies of 38 HPV-vaccinated women.
Virchows Arch. 2014; 464(1):79-83 [PubMed] Related Publications
HPV-vaccinated women develop CIN III very rarely. We have identified a study group of 38 such patients and showed that a specific HPV genotype prevalence in those cases equals the prevalence of HPV genotypes in CIN III present in the general Czech population. In all cases, CIN III was diagnosed within 3 years after having completed the HPV vaccination. We conclude that dysplasia was present before the vaccination in those women. A history of abnormal pre-vaccination PAP smear result (present in 78 % of women in the study group) and age of over 17 by the time of vaccination completion (97 % of women in the study group) are identified as probable factors increasing the risk of CIN III development after HPV vaccination.

Holman DM, Benard V, Roland KB, et al.
Barriers to human papillomavirus vaccination among US adolescents: a systematic review of the literature.
JAMA Pediatr. 2014; 168(1):76-82 [PubMed] Related Publications
IMPORTANCE: Since licensure of the human papillomavirus (HPV) vaccine in 2006, HPV vaccine coverage among US adolescents has increased but remains low compared with other recommended vaccines.
OBJECTIVE: To systematically review the literature on barriers to HPV vaccination among US adolescents to inform future efforts to increase HPV vaccine coverage.
EVIDENCE REVIEW: We searched PubMed and previous review articles to identify original research articles describing barriers to HPV vaccine initiation and completion among US adolescents. Only articles reporting data collected in 2009 or later were included. Findings from 55 relevant articles were summarized by target populations: health care professionals, parents, underserved and disadvantaged populations, and males.
FINDINGS: Health care professionals cited financial concerns and parental attitudes and concerns as barriers to providing the HPV vaccine to patients. Parents often reported needing more information before vaccinating their children. Concerns about the vaccine's effect on sexual behavior, low perceived risk of HPV infection, social influences, irregular preventive care, and vaccine cost were also identified as potential barriers among parents. Some parents of sons reported not vaccinating their sons because of the perceived lack of direct benefit. Parents consistently cited health care professional recommendations as one of the most important factors in their decision to vaccinate their children.
CONCLUSIONS AND RELEVANCE: Continued efforts are needed to ensure that health care professionals and parents understand the importance of vaccinating adolescents before they become sexually active. Health care professionals may benefit from guidance on communicating HPV recommendations to patients and parents. Further efforts are also needed to reduce missed opportunities for HPV vaccination when adolescents interface with the health care system. Efforts to increase uptake should take into account the specific needs of subgroups within the population. Efforts that address system-level barriers to vaccination may help to increase overall HPV vaccine uptake.

Serdarevic N, Stanciu AE
Comparison of Architect i2000 for determination of Scc with IMX determination of SCC with different methods.
Clin Lab. 2013; 59(9-10):1129-33 [PubMed] Related Publications
BACKGROUND: SCC (squamous cell carcinoma) antigen (SSCA), a tumor marker, is already used for the diagnosis and follow-up of carcinoma of the cervix and lungs. The aim of our study was the determination of SCCA concentration in 96 serum samples using CMIA (chemiluminesecent microparticle immnoassay) on an Architect i2000 (Abbott Diagnostics) and MEIA (microparticle enzyme immnoassay) on an IMx Chemistry Analyzer (Abbott Diagnostics).
METHODS: In our investigation we used a CMIA (chemiluminesecent microparticle immnoassay) Architect i2000 and MEIA (microparticle enzyme immnoassay) Imx Chemistry Analyzer for SCCA determination.
RESULTS: All patients were hospitalized at the Department of Gynecologic Oncology and Department for Oncology at the University Clinics Center of Sarajevo. The normal serum range of SCCA should be < 0.1 microg/L. The quality control, precision and accuracy of the Architect i2000 were assessed. The quality control was done using quality control serums for low (X = 2.17 microg/L), medium (X = 10.23 microg/L), and high (X = 48.99 microg/L) range. The precision for the Architect i2000 has a CV of 3.44% to 4.44%. We established that the main difference between Architect i2000 and IMx was statistically significant at p < 0.05 according to Student's t-test. The correlation coefficient was r = 0.990. The some samples have higher concentrations on the Architect than on the IMx because the sensitivity of the Architect assay is high (< 0.1 microg/L).
CONCLUSIONS: The CMIA Architect technology is an applicable method significant in diagnostic of SCCA.

Related: Lung Cancer

Lin Y, Chen Z, Kuang F, et al.
Evaluation of international federation of gynecology and obstetrics stage IB cervical cancer: comparison of diffusion-weighted and dynamic contrast-enhanced magnetic resonance imaging at 3.0 T.
J Comput Assist Tomogr. 2013 Nov-Dec; 37(6):989-94 [PubMed] Related Publications
OBJECTIVE: The objective of this study was to compare the diagnostic performance of diffusion-weighted (DW) imaging with that of dynamic contrast-enhanced (DCE) imaging in the evaluation of tumor extent in patients with stage IB cervical cancer.
METHODS: This retrospective study was approved by the institutional review board. Between June 2010 and March 2012, 46 consecutive patients with FIGO (International Federation of Gynecology and Obstetrics) stage IB who underwent preoperative DCE, DW (b = 0 and 800 s/mm), and T1- and T2-weighted imaging were included in this study. Two radiologists independently evaluated the extent of cervical cancer and made a diagnosis of tumor stage according to the revised FIGO staging system. The staging accuracy by DCE and DW for readers 1 and 2 was compared with the McNemar test, and κ statistics were used for reader agreement.
RESULTS: No statistical difference between the diagnostic performance of staging with DCE and with DW was observed in reader 1 (P = 1.000) or in reader 2 (P = 0.109). Interobserver agreement between the 2 readers for staging was both substantial with DCE (κ = 0.750, P < 0.001) and with DW (κ = 0.683, P < 0.001).
CONCLUSIONS: The diagnostic performance of DW in distinguishing the subdivision of stage IB cervical cancer was not statistically different from that of DCE. Diffusion-weighted imaging may be preferable to DCE for the preoperative evaluation of stage IB cervical cancer.

Yang L, Wang YL, Liu S, et al.
miR-181b promotes cell proliferation and reduces apoptosis by repressing the expression of adenylyl cyclase 9 (AC9) in cervical cancer cells.
FEBS Lett. 2014; 588(1):124-30 [PubMed] Related Publications
MicroRNAs are a class of small, endogenous, non-coding RNAs that function as post-transcriptional regulators. In this study, we found that miR-181b promoted cell proliferation and inhibited cell apoptosis in cervical cancer cells. And we validated a new miR-181b target gene, adenylyl cyclase 9 (AC9). miR-181b restricted cAMP production by post-transcriptionally downregulating AC9 expression. Phenotypic experiments indicated that miR-181b and AC9 exerted opposite effects on cell proliferation and apoptosis.

Related: Apoptosis

Brooks FJ, Grigsby PW
The effect of small tumor volumes on studies of intratumoral heterogeneity of tracer uptake.
J Nucl Med. 2014; 55(1):37-42 [PubMed] Related Publications
UNLABELLED: The number of studies in the literature involving quantification of the metabolic heterogeneity seen in (18)F-FDG PET images has increased sharply over recent years. We hypothesized that inclusion of very small regions of interest as unique data points will have deleterious effects on these studies.
METHODS: Using a combination of probability theory and clinical (18)F-FDG PET data, we numerically calculated the curve describing the probability a given tumor volume is large enough to adequately sample the underlying tumor biology assayed via a PET/CT scanner at a planar resolution of 4 mm and transaxial resolution of 4 mm (64 mm(3) voxel size). We then used a computer simulation to isolate the effects of tumor volume on the image local entropy.
RESULTS: We computed the underlying global intensity distribution for 70 cervical cancer tumors ranging from 4 to 248 cm(3)), which were ensemble-averaged over the same intensity scale. From this distribution, we determined that about 700 total voxels (45 cm(3)) are required to give 95% certainty that the global intensity distribution has been sufficiently sampled for common statistical comparisons of individual tumor intensity distributions to be made canonically. We demonstrated that one previously suggested measure of heterogeneity is dependent on tumor volume and that measurement of heterogeneity is about 5 times more sensitive to volume changes for volumes below the proposed minimum than for those above it.
CONCLUSION: Inclusion of tumor volumes below 45 cm(3) can profoundly bias comparisons of intratumoral uptake heterogeneity metrics derived from data from the current generation of whole-body (18)F-FDG PET scanners.

Yang YC, Chang TY, Chen TC, et al.
Human leucocyte antigen-G polymorphisms are associated with cervical squamous cell carcinoma risk in Taiwanese women.
Eur J Cancer. 2014; 50(2):469-74 [PubMed] Related Publications
BACKGROUND: The mere presence of human papillomavirus (HPV) is not enough for cervical cancer development and immunogenetic background may play an important role. Human leucocyte antigen (HLA)-G acts as a negative regulator of immune responses and its expression in tumour cells may enable them to avoid immune attack. We aim to study if polymorphisms in the HLA-G gene are associated with cervical cancer risk in Taiwanese women.
METHODS: +1537 A/C, 14-bp deletion/insertion (Del/Ins), and +3142 G/C polymorphisms were genotyped in a hospital-based study of 317 women with cervical squamous cell carcinoma (CSCC) and 400 healthy control women frequency matched by age. The presence and genotypes of HPV in CSCC were determined.
RESULTS: We found the +3142 C/C genotype and C allele were associated with increased risk for CSCC (adjusted odds ratio [OR]=1.78, P=0.004; adjusted OR=1.31, P=0.014, respectively). In subgroup analysis based on HPV type 16 positivity, significant associations with higher adjusted ORs were found in +3142 C/C genotype and C allele (adjusted OR=2.19, P=0.001; adjusted OR=1.48, P=0.003, respectively) and +1537 C/C genotype and C allele frequencies increased significantly (adjusted OR=2.88, P=0.004; adjusted OR=1.69, P=0.0005, respectively). Furthermore, the C-Del-C haplotype conferred increased risk of both CSCC and HPV-16 positive CSCC women (adjusted OR=1.41, P=0.009; adjusted OR=1.94, P=0.0001, respectively).
CONCLUSION: These findings suggest that HLA-G gene is involved in the susceptibility to CSCC.

Related: Polymorphisms

Mazeron R, Gilmore J, Champoudry J, et al.
Volumetric evaluation of an alternative bladder point in brachytherapy for locally advanced cervical cancer.
Strahlenther Onkol. 2014; 190(1):41-7 [PubMed] Related Publications
PURPOSE: To evaluate an alternative dose point, so-called ALG (for Alain Gerbaulet), for the bladder in comparison to the International Commission on Radiation Units and Measurements (ICRU) point and D2cm(3) (minimal dose to maximally exposed 2 cm(3)) in a large cohort of patients with locally advanced cervical cancer treated with external beam radiotherapy followed by image-guided pulsed dose rate brachytherapy.
METHODS AND MATERIALS: For each patient, the ALG point was constructed 1.5 cm above the ICRU bladder, parallel to the tandem (coronal and sagittal planes). The dosimetric data from 162 patients were reviewed.
RESULTS: Average doses to ALG and bladder points were 19.40 Gy ± 7.93 and 17.14 ± 8.70, respectively (p=0.01). The 2 cm(3) bladder dose averaged 24.40 ± 6.77 Gy. Ratios between D2cm(3) and dose points were 1.37 ± 0.46 and 1.68 ± 0.74 (p<0.001) for ALG and ICRU points, respectively. Both dose points appeared correlated with D2cm(3) (p<0.001) with coefficients of determination (R(2)) of 0.331 and 0.399 respectively. The estimated dose to the ICRU point of the rectum was 12.77 ± 4.21 and 15.76 ± 5.94 for D2cm(3) (p<0.0001). Both values were significantly correlated (p<0.0001, R(2) = 0.485).
CONCLUSION: The ALG point underestimates the D2cm(3), but its mean on a large cohort is closer to D2cm(3) than the dose to ICRU point. However, it shows great variability between cases and the weak strength of its correlation to D2cm(3) indicates that it is not a good surrogate for individual volumetric evaluation of the dose D2cm(3).

Related: Brachytherapy France

Kim DY, Shim SH, Kim SO, et al.
Preoperative nomogram for the identification of lymph node metastasis in early cervical cancer.
Br J Cancer. 2014; 110(1):34-41 [PubMed] Article available free on PMC after 07/01/2015 Related Publications
BACKGROUND: The objective of this study is to construct a preoperative nomogram predicting lymph node metastasis (LNM) in early-cervical cancer patients.
METHODS: Between 2009 and 2012, 493 early-cervical cancer patients received hysterectomy and pelvic/para-aortic lymphadenectomy. Patients who were diagnosed during 2009-2010 were assigned to a model-development cohort (n=304) and the others were assigned to a validation cohort (n=189). A multivariate logistic model was created from preoperative clinicopathologic data, from which a nomogram was developed and validated. A predicted probability of LNM<5% was defined as low risk.
RESULTS: Age, tumour size assessed by magnetic resonance imaging, and LNM assessed by positron emission tomography/computed tomography were independent predictors of nodal metastasis. The nomogram incorporating these three predictors demonstrated good discrimination and calibration (concordance index=0.878; 95% confidence interval (CI), 0.833-0.917). In the validation cohort, the discrimination accuracy was 0.825 (95% CI, 0.736-0.895). In the model-development cohort, 34% of them were classified as low risk and negative predictive value (NPV) was 99.0%. In the validation cohort, 38% were identified as low risk and NPV was 95.8%. Integrating the model-development and validation cohorts, negative likelihood ratio was 0.094 (95% CI, 0.036-0.248).
CONCLUSION: A robust nomogram predicting LNM in early cervical cancer was developed. This model may improve clinical trial design and help physicians to decide whether lymphadenectomy should be performed.

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