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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.

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

Information Patients and the Public (22 links)

Information for Health Professionals / Researchers (12 links)

Latest Research Publications

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

Sowunmi AC, Ajekigbe AT, Alabi AO, et al.
Incidence of Hydronephrosis in Cervical Cancer Patients in A Tertiary Hospital Lagog, Nigeria.
Nig Q J Hosp Med. 2015 Jul-Sep; 25(3):171-6 [PubMed] Related Publications
BACKGROUND: Cervical cancer is still a global health challenge that affects women of reproductive age group and consequently causes a drawback on the social and economic stability of nations. Developing countries suffer a greater burden of the disease because of several factors such as poverty, multiple sexual partners, unbalanced diet, poor knowledge and attitude to prevention of diseases and late-presentation.
OBJECTIVE: The aim of this study is to evaluate the incidence of hydronephrosis in cervical cancer patients in Lagos University Teaching Hospital (LUTH), Lagos, Nigeria for the period of 3 years (2010-2012).
METHOD: This study is a cross sectional study carried out among cervical cancer patients seeking treatment in the Radiotherapy department of the Lagos University Teaching Hospital (LUTH), between the year 2010 and 2012, to find out the incidence of hydronephrosis using abdominopelvic ultrasonography.
RESULTS: The incidence of hydronephrosis during the 3years period studied was 43.7%. A rise in the incidence of hydronephrosis of 5.4% in 2011 and 13.3% in 2012 was noted. The mean age of the patients was 55.5 years. 122 (56.7%) were grand multiparous and 123 (57.2%) had multiple sexual partners. An increase of 8.3% in 2011 and 9.3% in 2012 was noted in the incidence of cervical cancer cases studied. 107 (49.8%) presented at stages III and IV.
CONCLUSION: Late presentation of patients is still a major challenge affecting treatment outcomes. The presence of hydronephrosis was noticed at staging, during or after treatment, resulting in the need to separate this population from current Stage IIIB classification. The presence of hydronephrosis may or may not be related to the disease and so adequate staging is important.

Tsikouras P, Zervoudis S, Manav B, et al.
Cervical cancer: screening, diagnosis and staging.
J BUON. 2016 Mar-Apr; 21(2):320-5 [PubMed] Related Publications
Purpose: Despite the widespread screening programs, cervical cancer remains the third most common cancer in developing countries. Based on the implementation of cervical screening programs with the referred adoption of improved screening methods in cervical cytology with the knowledge of the important role of the human papilloma virus (HPV) it's incidence is decreased in the developed world. Even if cervical HPV infection is incredibly common, cervical cancer is relatively rare. Depending on the rarity of invasive disease and the improvement of detection of pre-cancerous lesions due to the participation in screening programs, the goal of screening is to detect the cervical lesions early in order to be treated before cancer is developed. In populations with many preventive screening programs, a decrease in cervical cancer mortality of 50-75% is mentioned over the past 50 years. The preventive examination of vagina and cervix smear, Pap test, and the HPV DNA test are remarkable diagnostic tools according to the American Cancer Association guidelines, in the investigation of asymptomatic women and in the follow up of women after the treatment of pre-invasive cervical cancer. The treatment of cervical cancer is based on the FIGO 2009 cervical cancer staging.

Jha AK, Sharma V, Nikbakht M, et al.
Genetika. 2016; 52(2):255-9 [PubMed] Related Publications
Tumor-specific genetic or epigenetic alterations have been detected in serum DNA in case of various types of cancers. In breast cancer, the detection of tumor suppressor gene hypermethylation has been reported in several body fluids. Promoter hypermethylation of some genes like MYOD1, CALCA, hTERT etc. has also been detected in serum samples from cervical cancer. The present study is the first report on the comparison of promoter hypermethylation of tumor suppressor genes likep14, p15, p16, p21, p27, p57, p53, p73, RARβ2, FHIT, DAPK, STAT1 and-RB1 genes in paired biopsy and serum samples from cervical cancer patients among north Indian population. This is also the first report on the hypermethylation of these genes in serum samples from cervical cancer patients among north Indian population. According to the results of the present study, promoter hypermethylation of these genes can also be detected in serum samples of cervical cancer patients. The sensitivity of detection of promoter hypermethylation in serum samples of cervical cancer patients as compared to paired biopsy samples was found to be around 83.3%. It was observed that promoter hypermethylation was mainly observed in the serum samples in the higher stages and very rarely in the lower stages. The present study clearly showed that serum of patients with cervical cancer can also be used to study methylated genes as biomarkers.

Takahashi K, Yoshida H, Watanabe R, et al.
Metastasis of extra-ampullary duodenal adenocarcinoma to the uterine cervix.
Malays J Pathol. 2016; 38(1):45-8 [PubMed] Related Publications
Secondary metastatic tumours of the uterine cervix are rare. There have been no reports of duodenal cancer metastasizing to the uterine cervix. Here we present a rare case of an extra-ampullary duodenal adenocarcinoma that has metastasized to the uterine cervix. The patient was a 71-year-old woman who had surgery for an extra-ampullary duodenal adenocarcinoma five years previously. Follow-up examination revealed a suspicious right ovarian mass and nodules in the cervix and posterior fornix of the vagina. Biopsies suggested squamous cell carcinoma in the cervix and adenocarcinoma in the fornix. Intraoperatively, the right ovary was enlarged and peritoneal disseminations were found in the pouch of Douglas and the sigmoid colon mesentery. Histopathology of the subsequent hysterectomy and bilateral salpingo-oophorectomy specimen revealed a cervical squamous cell carcinoma categorized as pT1b1. Adenocarcinoma infiltration into the ovaries, uterine cervix and vagina, with vascular involvement was detected. Immunohistochemistry revealed the tumour in the cervix and ovaries to be positive for CK7, MUC5AC and MUC6, and immunonegative for CK20, CDX2, Pax8, ER, MUC2 and CD10, similar to the original duodenal adenocarcinoma. This case illustrates the difficulty in making a preoperative diagnosis of metastatic adenocarcinoma in the uterine cervix with a coexisting primary cervical squamous cell carcinoma. The absence of atypia in cervical glandular cells and immunohistochemical profiling of the adenocarcinoma clusters helped to reach a final diagnosis. This is the first report of an extra-ampullary duodenal adenocarcinoma metastasis to the uterine cervix.

Cheah PL, Koh CC, Nazarina AR, et al.
Correlation of p16INK4a immunoexpression and human papillomavirus (HPV) detected by in-situ hybridization in cervical squamous neoplasia.
Malays J Pathol. 2016; 38(1):33-8 [PubMed] Related Publications
Persistence and eventual integration of high-risk HPV (hrHPV) into the cervical cell is crucial to the progression of cervical neoplasia and it would be beneficial to morphologically identify this transformation in routine surgical pathology practice. Increased p16(INK4a) (p16) expression is a downstream event following HPV E7 binding to pRB. A study was conducted to assess the correlation between hrHPV detection using a commercial in-situ hybridization assay (Ventana INFORM HPV ISH) and p16 immunoexpression (CINtec Histology Kit) in cervical squamous intraepithelial lesions and squamous carcinoma. 27 formalin-fixed, paraffin-embedded cervical low-grade squamous intraepithelial lesions (LSIL), 21 high-grade squamous intraepithelial lesions (HSIL) and 51 squamous carcinoma (SCC) were interrogated. hrHPV was significantly more frequent in HSIL (76.2%) and SCC (88.2%) compared to LSIL(37.0%). p16 expression was similarly more frequent in HSIL (95.2%) and SCC (90.2%) compared to LSIL(3.7%). That the rates of hrHPV when compared with p16 expression were almost equivalent in HSIL and SCC while p16 was expressed in only 1 of the 10 LSIL with hrHPV, are expected considering the likelihood that transformation has occurred in HSIL and SCC but does not occur in majority of LSIL.

Drozd E, Gruber B, Marczewska J, et al.
Intracellular glutathione level and efflux in human melanoma and cervical cancer cells differing in doxorubicin resistance.
Postepy Hig Med Dosw (Online). 2016; 70:319-28 [PubMed] Related Publications
INTRODUCTION: Drug resistance continues to be a major problem in cancer treatment. Occurrence of this phenomenon is often associated with altered levels of glutathione (GSH) and GSH-related enzymes. The aim of the study was to evaluate the possible involvement of GSH and GSH-related enzymes in doxorubicin (DOX) resistance in two types of cancer cells of different etiology, from both parental and DOX-resistant sublines.
MATERIALS AND METHODS: The human melanoma (ME18 and ME18/R) and cervical cancer cells (HeLa and KB-V1) were tested in terms of their DOX sensitivity (EZ4U test), GSH level (HPLC) and its efflux (spectrofluorometrically). The effects of inhibition of the GSH-related enzymes γ-glutamylcysteine synthetase (γ-GCS) and glutathione S-transferase (GST) were also evaluated.
RESULTS: Exposure to DOX caused an increase of GSH levels in all tested cells except for HeLa cells. However, depletion of GSH did not have a significant influence on the sensitivity of the cells to DOX. Inhibition of the activity of GST also did not have a major effect on DOX sensitivity, although it caused changes of the GSH content. Our attempts to use the spectrofluorometric method for measurements of GSH efflux were not successful. It could be suggested that in ME18 and HeLa cells treated with DOX, GSH efflux does occur.
DISCUSSION: The obtained results seem to refute the hypothesis of a central role of GSH in DOX resistance of the tested cells. Despite observations of different effects related to GSH, they do not seem to be essential in terms of DOX resistance. The mechanisms underlying DOX resistance are highly cell-specific.

Voidăzan S, Tarcea M, Morariu SH, et al.
Human Papillomavirus Vaccine - Knowledge and Attitudes among Parents of Children Aged 10-14 Years: a Cross-sectional Study, Tîrgu Mureş, Romania.
Cent Eur J Public Health. 2016; 24(1):29-38 [PubMed] Related Publications
AIM: Romania ranks first in Europe in terms of mortality from cervical cancer, recording 6.3 times more deaths than the mean in EU countries. Although vaccination campaigns were launched by health officials in Romania, the acceptance rate remained insignificant and programmes were discontinued. A successful vaccination programme requires a high rate of acceptance and accurate information for health professionals and parents. The aim of the study was to evaluate the level of parental knowledge about human papilomavirus (HPV) infection and HPV vaccination including the information obtained from general practitioners and identification of barriers in implementing a vaccination strategy.
METHODS: We performed a cross-sectional study using a self-administered questionnaire for the parents of pupils in grades 5-8, in three randomly selected secondary schools in Tîrgu Mureş, Romania.
RESULTS: We surveyed 918 parents. Of the respondents, 85.8% have heard of HPV infection. Most reported an average level of knowledge about HPV infection and HPV vaccination. The two main sources of information were specialized healthcare professionals (42.8% for HPV infection, 39.1% for HPV vaccination) and the Internet browsing (42.3% and 42.9%, respectively). Based on current knowledge, only one third of parents would have their child vaccinated against HPV infection. According to most parents surveyed, the main reasons for not wanting to have their child vaccinated is the fear of side effects; the vaccine is new and insufficiently studied; or parents do not know details about the vaccine.
CONCLUSIONS: The parents showed the average level of knowledge about HPV infection and HPV vaccination. The implementation of an effective programme to increase the acceptance rate of HPV vaccination requires educational strategies aimed at involving parents and their children and supported by general practitioners and public health professionals.

Ma DL, Li JY, Liu YE, et al.
Influence of continuous intervention on growth and metastasis of human cervical cancer cells and expression of RNAmiR-574-5p.
J Biol Regul Homeost Agents. 2016 Jan-Mar; 30(1):91-102 [PubMed] Related Publications
This study was carried out to acquire solid evidence that some common treatments could affect micro ribonucleic acids (miRNAs) by revealing the regulatory effect of genes, so as to provide a reference for further exploration of the prevention and treatment of cervical cancer. Nude mouse tumorigenicity assay was used to study the effect of inhibiting miR-574-5p on development and tumorigenic ability of Henrietta Lacks (HeLa) tumor. Cell wound scratch assay, flow cytometry and real-time quantitative polymerase chain reaction (RT-qPCR) were adopted to study the effects of anoxia and temperature, etc., on expression of miR-574-5p and QKI in HeLa as well as on the clone and migration ability of cells, to provide prevention and treatment of cervical cancer with new ideas and evidence. The results demonstrated that cervical cancer tissues had a significantly increased miR-574-5p expression compared with para-carcinoma tissues; conversely, Gomafu, overall QKI (pan-QKI) and QKI-5 messenger ribonucleic acid (mRNA) and protein expression all decreased. Part of the common nursing methods had a certain influence on miR-574-5p expression, HeLa reproduction and metastasis, and even cell cycle. For example, ultraviolet (UV) irradiation was effective in decreasing miR-574-5p expression of HeLa and inhibiting cell migration; severe hypoxia significantly decreased the survival rate of HeLa, leading to the increase of programmed death percentage and cell ratio in G2/M phase as well as the decrease of cell ratio in G1 phase. Incubation at different temperatures also affected miR-574-5p expression and cell proliferation. Thus, it can be known that miR-574-5p, Gomafu and QKI expression in cervical cancer tissues and para-carcinoma tissues are significantly up-regulated or down-regulated. Some treatments, such as UV irradiation, hypoxia, incubation temperatures, etc., can affect miR-574-5p expression and HeLa proliferation as well as metastases in different degrees. These findings provide a reference and basis for further study.

Zhiqiang L, Bin S, Min F, Yufang L
Leiomyosarcoma of cervical stump following subtotal hysterectomy: a case report and review of literature.
Eur J Gynaecol Oncol. 2016; 37(1):148-51 [PubMed] Related Publications
BACKGROUND: Leiomyosarcoma that arises in the uterine cervix stump after subtotal hysterectomy is exceedingly rare. Only one case has been documented. The authors report an unusual case of leiomyosarcoma that arose in the cervix stump.
CASE PRESENTATION: A 46-year-old female presented with a one-month history of vaginal bleeding. Vaginal and ultrasonography examination revealed a mass in the cervix. The patient underwent radical resection of the cervix, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy. Chemotherapy and radiotherapy was given after the operation. The patient suffered from severe menopausal symptoms and received hormone replacement therapy. She eventually committed suicide.
CONCLUSION: Given the rarity of cases of leiomyosarcoma of cervical stump, its proper treatment remains to be determined. In dealing with benign uterus diseases, we should pay adequate attention in retaining the cervix. If the cervix is retained, patients require appropriate follow-up. The authors hope that this work will benefit the fields of gynecology and oncology.

Anthuenis J, Baekelandt J, Bourgain C, De Rop C
Squamous cell carcinoma in situ lining the uterine cavity.
Eur J Gynaecol Oncol. 2016; 37(1):135-8 [PubMed] Related Publications
Cervical intra-epithelial neoplasia is a very common and well-known pathology. However superficial spreading of this lesion is very rare. The authors present a case of a 72-year-old woman with an abdominal mass, who had previously undergone a cervical conisation for a high-grade cervical intra-epithelial neoplasia. Anatomo-pathological examination of the mass showed a large distended fluid-filled uterus with the entire endometrium replaced by a high-grade squamous cell lesion. There were only micro-invasive foci found. The authors performed a literature search in PubMed with the following MeSH-terms: "squamous cell carcinoma" and "endometrium". Other articles were selected out of the references of previously found articles. Only 31 similar cases were found. The presentation of the cases is varies extremely and a long-term prognosis is not yet known.

Yao YY, Wang Y, Wang JL, et al.
Outcomes of fertility and pregnancy in patients with early-stage cervical cancer after undergoing neoadjuvant chemotherapy.
Eur J Gynaecol Oncol. 2016; 37(1):109-12 [PubMed] Related Publications
OBJECTIVE: To explore the outcomes of oncology, fertility, and pregnancy in patients after undergoing neoadjuvant chemotherapy (NACT) followed by fertility-sparing operations with cervical cancer, and its value in clinical treatment.
MATERIALS AND METHODS: A total of 11 patients from seven hospitals in Beijing with cervical cancer since August 2009 to December 2011, who had undergone fertility- sparing treatments were recruited in this study.
RESULTS: Among the 11 patients, there were nine cases of squamous cell carcinoma, two cases of adenocarcinoma, one case in Stage IA2, and ten cases in Stage IB1 (FIGO, 2009). All of the 11 patients were treated with NACT of one to two cycles before the operations, and then they underwent radical trachelectomy (RT) + retroperitoneal lymphadenectomy. Eleven patients had completed the follow-up (100%) and the mean follow-up was 24.4 months. The outcomes of the oncology and pregnancy are as follows: no patient recurred after fertility-sparing treatments; in seven patients seeking pregnancy after the treatments, three pregnancies occurred in two women.
CONCLUSIONS: NACT+RT, as a fertility-sparing treatment for young women with bulky early-stage cervical cancer and its outcomes in fertility and pregnancy are satisfactory, however its safety needs to be studied further.

Chen XP, Xu WH, Xu DF, et al.
G12V Kras mutations in cervical cancer under virtual microscope of molecular dynamics simulations.
Eur J Gynaecol Oncol. 2016; 37(1):69-74 [PubMed] Related Publications
Kras mutations and cancers are common and their role in the progression of cancer is well known and elucidated. The present work is searching for the most deleterious mutation of the four found at codon 12 and 13 of Kras in cervical cancers using prediction servers; different servers were used to look into different factors that govern the protein function. The in silico results predicted G12V to be the most devastating; this particular mutation was then subjected to molecular dynamics simulation (MDS) for further analysis. The authors' approach of MDSs helped them to place the native and mutant structure under virtual microscope and observe their dynamics over time. The results generated are enlightening the effect of G12V variation on the dynamics of Kras. The structural variation between the native and mutant Kras over 50 nanoseconds (ns) run varied at every parameter checked and the results are in excellent agreement with the available experimental data.

Wesoła M, Jeleń M
Morphometric differentiation of squamous cell carcinoma and adenocarcinoma of the cervix.
Pol J Pathol. 2015; 66(4):410-3 [PubMed] Related Publications
The aim of the study was to define the morphometric characteristics of squamous cell carcinoma (SCC) and adenocarcinoma (AC) cells and identify opportunities to differentiate these tumors based on determination of the morphometric characteristics in order to use the results of research in the diagnosis of cervical cancer. Pap smears with two histopathologically confirmed cervix cancers were used for testing. For the morphometric assessment of cancer cells the dotSlide program was used. The mean nucleus area for AC cells was 126.62 × 10(-6) m(2), while this value for SCC was 145.07 × 10(-6) m(2) (p = 0.000132). The mean circumference of AC cells was 42.43 × 10(-6) m, while for SCC cells it was 46.67 × 10(-6) m (p = 0.00). AC cell diameter was 13.83 µm, whereas for SCC cells it was 15.36 × 10(-6) m. On average the AC cell surface area was 195.72 × 10(-6) m(2), while for SCC cells it was 249.94 × 10(-6) m(2) (p = 0.00565). The mean AC cell circumference was 54.90 μm, whereas for SCC cells it was 65.23 × 10(-6) m (p = 0.00607). The research shows that, despite the presence of statistically significant differences for each morphometric parameter, determination of cancer type cannot be used in the diagnosis.

Bacalbaşa N, Bălescu I, Braşoveanu V
Total Pelvic Supralevator Exenteration with Ileo-Colic Orthotopic Neobladder for Locoregional Recurrence after Cervical Cancer - A Case Report.
Chirurgia (Bucur). 2016 Jan-Feb; 111(1):80-6 [PubMed] Related Publications
Pelvic exenteration is one of the most aggressive surgical interventions in gynaecologic surgical oncology, but, in the same time, is the only potentially curative treatment of locoregional recurrence after cervical cancer. Due to improvements in surgical technique and postoperative management, the overall survival increased signifficantly in the last decades. Trying to improve the quality of life, multiple models of reconstruction of urinary and digestive tract have been developed. In this report we present the case of a 51 years old female who underwent a total supralevator exenteration with ileo colic neobladder reconstruction with good oncologic and functional outcomes.

Stratton KL, Culkin DJ
A Contemporary Review of HPV and Penile Cancer.
Oncology (Williston Park). 2016; 30(3):245-9 [PubMed] Related Publications
Human papillomavirus (HPV) is a widespread sexually transmitted infection. In both men and women, HPV infection can result in a spectrum of genitourinary manifestations ranging from genital warts to cancer. Cervical cancer is nearly always associated with high-risk HPV infection. For men, penile cancer can develop following or independently of HPV infection. Basaloid and warty subtypes of penile squamous cell carcinoma are most frequently associated with HPV infection. Further research into the molecular alterations caused by HPV infection may provide prognostic markers and future treatment targets. Until an effective treatment for HPV infection is developed, prevention will remain the focus of disease control. For women, vaccination is increasingly utilized to prevent HPV infection and subsequent cervical cancer development. New recommendations for routine male vaccination may further reduce cancers for both men and women.

Boers A, Wang R, van Leeuwen RW, et al.
Discovery of new methylation markers to improve screening for cervical intraepithelial neoplasia grade 2/3.
Clin Epigenetics. 2016; 8:29 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Assessment of DNA promoter methylation markers in cervical scrapings for the detection of cervical intraepithelial neoplasia (CIN) and cervical cancer is feasible, but finding methylation markers with both high sensitivity as well as high specificity remains a challenge. In this study, we aimed to identify new methylation markers for the detection of high-grade CIN (CIN2/3 or worse, CIN2+) by using innovative genome-wide methylation analysis (MethylCap-seq). We focused on diagnostic performance of methylation markers with high sensitivity and high specificity considering any methylation level as positive.
RESULTS: MethylCap-seq of normal cervices and CIN2/3 revealed 176 differentially methylated regions (DMRs) comprising 164 genes. After verification and validation of the 15 best discriminating genes with methylation-specific PCR (MSP), 9 genes showed significant differential methylation in an independent cohort of normal cervices versus CIN2/3 lesions (p < 0.05). For further diagnostic evaluation, these 9 markers were tested with quantitative MSP (QMSP) in cervical scrapings from 2 cohorts: (1) cervical carcinoma versus healthy controls and (2) patients referred from population-based screening with an abnormal Pap smear in whom also HPV status was determined. Methylation levels of 8/9 genes were significantly higher in carcinoma compared to normal scrapings. For all 8 genes, methylation levels increased with the severity of the underlying histological lesion in scrapings from patients referred with an abnormal Pap smear. In addition, the diagnostic performance was investigated, using these 8 new genes and 4 genes (previously identified by our group: C13ORF18, JAM3, EPB41L3, and TERT). In a triage setting (after a positive Pap smear), sensitivity for CIN2+ of the best combination of genes (C13ORF18/JAM3/ANKRD18CP) (74 %) was comparable to hrHPV testing (79 %), while specificity was significantly higher (76 % versus 42 %, p ≤ 0.05). In addition, in hrHPV-positive scrapings, sensitivity and specificity for CIN2+ of this best-performing combination was comparable to the population referred with abnormal Pap smear.
CONCLUSIONS: We identified new CIN2/3-specific methylation markers using genome-wide DNA methylation analysis. The diagnostic performance of our new methylation panel shows higher specificity, which should result in prevention of unnecessary colposcopies for women referred with abnormal cytology. In addition, these newly found markers might be applied as a triage test in hrHPV-positive women from population-based screening. The next step before implementation in primary screening programs will be validation in population-based cohorts.

Rossi P, Borghi L, Ferro R, Mencarelli R
A population of 1136 HPV DNA-HR positive women: expression of p16(INK4a)/Ki67 Dual-Stain Cytology and cytological diagnosis. Histological correlations and cytological follow up.
Pathologica. 2015 Sep-Dec; 107(3-4):185-91 [PubMed] Related Publications
OBJECTIVE: The objectives of this study were to evaluate, in a selected HR-HPV positive population, the clinical performance of the p16/ki67 immunostaining in all the cytological diagnoses, as a reflex test of triage HPV-cytology, and assess the usefulness of p16/ki67-staining to classify CIN1 according to its risk of progression/regression in order to plan a personalized follow-up.
METHODS: Our analysis was in consecutive cases of 1136 women aged 25-64 years, asymptomatic, HR-HPV DNA HC2 tested positive in a HPV-screening program, from February to December 2011. All the women had a cervical sample, in the Thin Prep, used for cytological diagnosis and for pI6/Ki67 dual- staining. Histological correlations were 442. We studied the follow-up of two years of 387 cases, especially the biological behaviour of 316 low-grade lesions.
RESULTS: pI6/Ki67 dual-staining increases the VPP CIN2+ and NPV CIN2+, especially in atrophy/dystrophy, in ASC-US and LSIL. In follow-up of 387 cases, 71 CIN2+ and 316 CIN1, 69 CIN2+, after surgical treatment, had a negative follow up; two cases of CIN2 (p16/ki67-) without invasive treatments, had a spontaneous regression. Among the 316 CIN1, progression was observed in 10 women (4 pI6/Ki67 + and 6 pI6/Ki67 -); regression in 260 women (64 p16/Ki67 + and 196 p16/Ki67-); 46 women had a persistent LSIL (9 pI6/Ki67 + and 37 p16/Ki67-). It seems no significant differences in the biological behaviour in relation to the expression of the two biomarkers.
CONCLUSIONS: pI6/Ki67 immunostaining increases sensitivity of cytology in some diagnostic categories. After follow up of two years, a personalized and adequate treatment does not seem still possible. Further studies and trials are required to improve the management of the cervical lesions in HPV-based screening strategies.

Milanti A, Metsälä E, Hannula L
Reducing psychological distress in patients undergoing chemotherapy.
Br J Nurs. 2016 Feb 25-Mar 9; 25(4):S25-30 [PubMed] Related Publications
Psychological distress is a common problem among patients with cancer, yet it mostly goes unreported and untreated. This study examined the association of a psycho-educational intervention with the psychological distress levels of breast cancer and cervical cancer patients undergoing chemotherapy. The design of the study was quasi-experimental, pretest-posttest design with a comparison group. One hundred patients at a cancer hospital in Jakarta, Indonesia, completed Distress Thermometer screening before and after chemotherapy. Fifty patients in the intervention group were given a psycho-educational video with positive reappraisal, education and relaxation contents, while receiving chemotherapy. Patients who received the psycho-educational intervention had significantly lower distress levels compared with those in the control group. Routine distress screening, followed by distress management and outcome assessment, is needed to improve the wellbeing of cancer patients.

Hassan SJ, Dunphy E, Navin E, et al.
Screening for Chlamydia is acceptable and feasible during Cervical Screening in General Practice.
Ir Med J. 2016; 109(1):326-7 [PubMed] Related Publications
The incidence of Chlamydia trachomatis (CT) & Neisseria gonorrhoeae (NG) are rising in Ireland. Both are often undiagnosed and may cause infertility amongst other complications. CT/NG screening is not routinely offered during cervical cancer screening. This study aimed to ascertain the feasibility and acceptability of screening for CT/NG at time of smear and to measure the diagnostic yield. Screening was offered to women aged 25-40 years attending four participating general practices as part of Cervical Check. A retrospective review of the three months preceding the study period, indicated that out of 138 smears, CT/NG testing was performed in 10 (7%) of cases. 236 (93%) patients consented to screening for CT/NG. The detection rate for Chlamydia was 6 (2.4%), with no positive results for NG. Feedback from patients was positive. Interestingly, 42 (18%) of participants who completed the questionnaire believed STI screening was already part of the routine smear.

Rao J, Escobar-Hoyos L, Shroyer KR
Unmet clinical needs in cervical cancer screening.
MLO Med Lab Obs. 2016; 48(1):8, 10, 14; quiz 15 [PubMed] Related Publications
Cancer rates worldwide are expected to increase disproportionally in coming decades relative to the projected increase in population, especially in the developing world. The general unavailability of the Pap test and the cost of the HPV test in the developing world have precluded the deployment of effective cervical cancer screening programs in many developing countries. Recent improvements in testing technology arise from a need to overcome the significant limitations of the Pap test and HPV test, but results require first-world technology and validation. Developing countries, where cervical cancer remains one of the most important causes of cancer death, have the greatest need for an affordable, easy-to-use, and highly reliable cancer screening method that can return a diagnosis through efficient laboratory analysis or, more easily, at a woman's point of care. While research, testing, and vaccine improvements in recent years continue to lower the incidence of cervical cancer in some developed countries such as the U.S., HPV testing research needs to do more than test for the presence of virus. The tests must determine the presence and progression of cervical disease. Tests should be more sensitive and specific than Pap tests and Pap-related tests, and should be accurate in more than 90 percent of cases. Tests also need to be low-cost, objective, and easy to perform so screening programs can be widely implemented in developing countries where the need for a better cervical cancer screening test is highest. Such tests may be available through the recent advances in specific biomarkers of cervical cancer and multiplex detection technologies. Development of the next generation of cervical cancer tests that are more specific, sensitive, and informative than the traditional Pap or HPV test will make a significant impact on the reduction of cervical cancer worldwide.

Korkidakis A, Bryson P, Jamieson MA
Outcomes of a Decade of Routine Cervical Screening in a Canadian Adolescent Obstetrics Clinic.
J Obstet Gynaecol Can. 2016; 38(1):51-5 [PubMed] Related Publications
OBJECTIVE: New recommendations from the Ontario Cervical Cancer Screening Program indicate that initiation of screening should be delayed to age 21. However, there is sparse evidence pertaining to pregnant adolescents. Our objective was to determine whether early cervical cancer screening in pregnant adolescents confers an advantage over delayed screening in the prevention of cervical carcinoma.
METHODS: We conducted a retrospective cohort study of cervical cancer screening in all pregnant adolescents receiving antenatal care through an obstetrics clinic for adolescents between 2000 and 2010. Clinic attendees had an antenatal and/or postpartum Pap smear, with follow-up according to standard recommendations. Results were recorded together with information on regression, persistence, or progression of abnormal cytology, colposcopy referrals, and cervical biopsies. There is a single regional colposcopy clinic.
RESULTS: At least one Pap smear result was documented in 365 of the 388 patients. Of these 365 smears, 88 had abnormal cytology, 76 (86.4%) of which were reported as atypical cells of undetermined significance/low-grade squamous intraepithelial lesion, 11 (12.5%) high-grade squamous intraepithelial lesion (HSIL), and one atypical glandular cells (1.1%). Follow-up cytology was available for 78 patients. No patient lost to follow-up had subsequent referrals for colposcopic assessment in the region. Overall, cytologic abnormalities regressed in 75 (96.1%), persisted in two (2.6%), and progressed in one patient (1.3%). Twenty-three patients (of 365) required a total of 68 colposcopy visits and 17 biopsies, but ultimately only three loop electrosurgical excision procedures (LEEPs) and one laser vaporization were performed. Only one LEEP in a 20-year-old demonstrated HSIL.
CONCLUSION: This population of pregnant adolescents had a high incidence of low-grade cervical abnormalities with a high rate of regression. Routinely screening these pregnant adolescents resulted in numerous repeat visits, repeat Pap smears, and colposcopy referrals, and led to patient anxiety and systemic costs. Not a single case of cervical cancer was prevented that would not otherwise have been identified by adherence to the new guidelines.

Salazar-Piña DA, Pedroza-Saavedra A, Cruz-Valdez A, et al.
Validation of Serological Antibody Profiles Against Human Papillomavirus Type 16 Antigens as Markers for Early Detection of Cervical Cancer.
Medicine (Baltimore). 2016; 95(6):e2769 [PubMed] Free Access to Full Article Related Publications
Cervical cancer (CC) is the second most frequent neoplasia among women worldwide. Cancer prevention programs around the world have used the Papanicolaou (Pap) smear as the primary diagnostic test to reduce the burden of CC. Nevertheless, such programs have not been effective in developing countries, thus leading to research on alternative tests for CC screening. During the virus life cycle and in the process toward malignancy, different human papillomavirus (HPV) proteins are expressed, and they induce a host humoral immune response that can be used as a potential marker for different stages of the disease. We present a new Slot blot assay to detect serum antibodies against HPV16 E4, E7, and VLPs-L1 antigens. The system was validated with sera from a female population (n = 485) aged 18 to 64 years referred to the dysplasia clinic at the General Hospital in Cuautla, Morelos, Mexico. To evaluate the clinical performance of the serological markers, the sensitivity, specificity, positive, and negative predictive values and receiver-operating characteristic curves (for antibodies alone or in combination) were calculated in groups of lesions of increasing severity. The results showed high prevalence of anti-E4 (73%) and anti-E7 (80%) antibodies in the CC group. Seropositivity to 1, 2, or 3 antigens showed associations of increasing magnitude with CC (odds ratio [OR] = 12.6, 19.9, and 58.5, respectively). The highest association with CC was observed when the analysis was restricted to only anti-E4+E7 antibodies (OR = 187.7). The best clinical performance to discriminate CC from cervical intraepithelial neoplasia 2 to 3 was the one for the combination of anti-E4 and/or anti-E7 antibodies, which displayed high sensitivity (93.3%) and moderate specificity (64.1%), followed by anti-E4 and anti-E7 antibodies (73.3% and 80%; 89.6% and 66%, respectively). In addition, the sensitivity of anti-E4 and/or anti-E7 antibodies is high at any time of sexual activity (TSA), which suggests they can be biomarkers for the early detection of CC. The sensitivity of anti-E4 antibodies was low (<10%) when the TSA was <10 years, and it increased up to 100% in relation to the TSA, suggesting that anti-E4 antibodies can be useful as HPV exposure markers at early stages of the disease.

Wang J, Andrae B, Sundström K, et al.
Risk of invasive cervical cancer after atypical glandular cells in cervical screening: nationwide cohort study.
BMJ. 2016; 352:i276 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: To investigate the risks of invasive cervical cancer after detection of atypical glandular cells (AGC) during cervical screening.
DESIGN: Nationwide population based cohort study.
SETTING: Cancer and population registries in Sweden.
PARTICIPANTS: 3,054,328 women living in Sweden at any time between 1 January 1980 and 1 July 2011 who had any record of cervical cytological testing at ages 23-59. Of these, 2,899,968 women had normal cytology results at the first screening record. The first recorded abnormal result was atypical glandular cells (AGC) in 14 625, high grade squamous intraepithelial lesion (HSIL) in 65 633, and low grade squamous intraepithelial lesions (LSIL) in 244 168.
MAIN OUTCOME MEASURES: Cumulative incidence of invasive cervical cancer over 15.5 years; proportion of invasive cervical cancer within six months of abnormality (prevalence); crude incidence rates for invasive cervical cancer over 0.5-15.5 years of follow-up; incidence rate ratios compared with women with normal cytology, estimated with Poisson regression adjusted for age and stratified by histopathology of cancer; distribution of clinical assessment within six months after the abnormality.
RESULTS: The prevalence of cervical cancer was 1.4% for women with AGC, which was lower than for women with HSIL (2.5%) but higher than for women with LSIL (0.2%); adenocarcinoma accounted for 73.2% of the prevalent cases associated with AGC. The incidence rate of invasive cervical cancer after AGC was significantly higher than for women with normal results on cytology for up to 15.5 years and higher than HSIL and LSIL for up to 6.5 years. The incidence rate of adenocarcinoma was 61 times higher than for women with normal results on cytology in the first screening round after AGC, and remained nine times higher for up to 15.5 years. Incidence and prevalence of invasive cervical cancer was highest when AGC was found at ages 30-39. Only 54% of women with AGC underwent histology assessment within six months, much less than after HSIL (86%). Among women with histology assessment within six months, the incidence rate of cervical cancer after AGC was significantly higher than that after HSIL for up to 6.5 years.
CONCLUSIONS: AGC found at cervical screening is associated with a high and persistent risk of cervical cancer for up to 15 years, particularly for cervical adenocarcinoma and women with AGC at age 30-39. Compared with the reduction in risk of cancer seen after HSIL management, management of AGC seems to have been suboptimal in preventing cervical cancer. Research to optimise management is needed, and a more aggressive assessment strategy is warranted.

Grover S, Harkenrider MM, Cho LP, et al.
Image Guided Cervical Brachytherapy: 2014 Survey of the American Brachytherapy Society.
Int J Radiat Oncol Biol Phys. 2016; 94(3):598-604 [PubMed] Related Publications
PURPOSE: To provide an update of the 2007 American brachytherapy survey on image-based brachytherapy, which showed that in the setting of treatment planning for gynecologic brachytherapy, although computed tomography (CT) was often used for treatment planning, most brachytherapists used point A for dose specification.
METHODS AND MATERIALS: A 45-question electronic survey on cervical cancer brachytherapy practice patterns was sent to all American Brachytherapy Society members and additional radiation oncologists and physicists based in the United States between January and September 2014. Responses from the 2007 survey and the present survey were compared using the χ(2) test.
RESULTS: There were 370 respondents. Of those, only respondents, not in training, who treat more than 1 cervical cancer patient per year and practice in the United States, were included in the analysis (219). For dose specification to the target (cervix and tumor), 95% always use CT, and 34% always use MRI. However, 46% use point A only for dose specification to the target. There was a lot of variation in parameters used for dose evaluation of target volume and normal tissues. Compared with the 2007 survey, use of MRI has increased from 2% to 34% (P<.0001) for dose specification to the target. Use of volume-based dose delineation to the target has increased from 14% to 52% (P<.0001).
CONCLUSION: Although use of image-based brachytherapy has increased in the United States since the 2007 survey, there is room for further growth, particularly with the use of MRI. This increase may be in part due to educational initiatives. However, there is still significant heterogeneity in brachytherapy practice in the United States, and future efforts should be geared toward standardizing treatment.

Pötter R, Federico M, Sturdza A, et al.
Value of Magnetic Resonance Imaging Without or With Applicator in Place for Target Definition in Cervix Cancer Brachytherapy.
Int J Radiat Oncol Biol Phys. 2016; 94(3):588-97 [PubMed] Related Publications
PURPOSE: To define, in the setting of cervical cancer, to what extent information from additional pretreatment magnetic resonance imaging (MRI) without the brachytherapy applicator improves conformity of CT-based high-risk clinical target volume (CTVHR) contours, compared with the MRI for various tumor stages (International Federation of Gynecology and Obstetrics [FIGO] stages I-IVA).
METHODS AND MATERIALS: The CTVHR was contoured in 39 patients with cervical cancer (FIGO stages I-IVA) (1) on CT images based on clinical information (CTVHR-CTClinical) alone; and (2) using an additional MRI before brachytherapy, without the applicator (CTVHR-CTpre-BT MRI). The CT contours were compared with reference contours on MRI with the applicator in place (CTVHR-MRIref). Width, height, thickness, volumes, and topography were analyzed.
RESULTS: The CT-MRIref differences hardly varied in stage I tumors (n=8). In limited-volume stage IIB and IIIB tumors (n=19), CTVHR-CTpre-BT MRI-MRIref volume differences (2.6 cm(3) [IIB], 7.3 cm(3) [IIIB]) were superior to CTVHR-CTClinical-MRIref (11.8 cm(3) [IIB], 22.9 cm(3) [IIIB]), owing to significant improvement of height and width (P<.05). In advanced disease (n=12), improved agreement with MR volume, width, and height was achieved for CTVHR-CTpre-BT MRI. In 5 of 12 cases, MRIref contours were partly missed on CT.
CONCLUSIONS: Pre-BT MRI helps to define CTVHR before BT implantation appropriately, if only CT images with the applicator in place are available for BT planning. Significant improvement is achievable in limited-volume stage IIB and IIIB tumors. In more advanced disease (extensive IIB to IVA), improvement of conformity is possible but may be associated with geographic misses. Limited impact on precision of CTVHR-CT is expected in stage IB tumors.

Sawaya GF, Smith-McCune K
Cervical Cancer Screening.
Obstet Gynecol. 2016; 127(3):459-67 [PubMed] Related Publications
Recent changes in cervical cancer screening and management guidelines reflect our evolving knowledge about cervical carcinogenesis. In the pursuit of precision, however, decision-making has become complicated. We provide an overview of cervical cancer screening with a focus on what clinicians can do to maximize screening benefits while minimizing screening harms. The approach relies on categorizing women at each step in the screening process by their estimated risk of high-grade precancerous lesions and cervical cancer. Current screening guidelines are designed to find a reasonable balance between benefits and harms by recommending less screening in most women. Current management guidelines are designed to assure consistent decisions regarding referral to colposcopy. After initial colposcopy, we outline three major management options based on risk assessment. For treatment, we recommend ablational procedures when appropriate because they are similarly effective, less costly, and potentially safer than excisional procedures. We advise caution in adopting new screening strategies until they demonstrate cost-effective patient-centered improvements compared with current strategies. Clinicians can maximize their effect on cervical cancer prevention by being attentive to guidelines, assuring that women have access to appropriate human papillomavirus vaccination and providing low-cost, high-quality screening and treatment.

Hou LJ, Zhai JJ
Aberrant expression profile of translationally controlled tumor protein and tumor-suppressive microRNAs in cervical cancer.
J BUON. 2015 Nov-Dec; 20(6):1504-9 [PubMed] Related Publications
PURPOSE: Invasive and recurrent cervical cancer accounts for major mortality among women. The activity of biomarkers in cervical cancer varies with different pathological stages. The purpose of the present study was to evaluate the expression of 2 biomarkers in cervical cancer and their possible contribution to novel therapeutic strategies.
METHODS: In this study, we assessed the expression of translationally controlled tumor protein (TCTP) using immunohistochemistry and Western blot analysis. The expression pattern of miR-143 was also evaluated using Northern blot analysis.
RESULTS: HeLa cells and mice were used for tumor induction. A group of mice injected with HeLa cells and incubated for 6 weeks developed initial tumor, while a different group of mice injected with HeLa cells and incubated for about 10 weeks developed advanced stage cervical cancer. Histological analysis revealed higher proliferation of cells resulting in complex forms of tumor in advanced cervical cancer, whereas cell clustering was not found to be initiated in the initial stage. The results of immunohistochemistry and Western blot analysis indicated less variation in the expression of TCTP, but significant difference was observed in advanced stage. Expression of Bax apoptotic protein was higher in the initial stage of the tumor than in the advanced cervical cancer. Similar pattern of marginal downregulation of miR-143 was observed between control and initial tumor stages, but striking reduction in miR-143 expression was observed in advanced stages of tumor development.
CONCLUSION: The results of this study reveal a new aspect of altered expression of biomarkers in different pathological stages that could help identify novel therapeutic strategies for cervical cancer treatment.

Zhang Y, Wang T, Huang HQ, et al.
Human MALAT-1 long non-coding RNA is overexpressed in cervical cancer metastasis and promotes cell proliferation, invasion and migration.
J BUON. 2015 Nov-Dec; 20(6):1497-503 [PubMed] Related Publications
PURPOSE: Long non-coding RNAs (lncRNAs) have been shown to play a crucial role in the development as well as the prognosis of various human cancers, particularly in human metastasis associated lung adenocarcinoma transcript-1 (MALAT-1), which has been shown to be upregulated in some tumors. However, the role of MALAT-1 in cervical cancer (CC) is yet to be elucidated. This study aimed to establish a correlation between MALAT-1 and its role in CC progression and prognosis.
METHODS: The expression of MALAT-1 was examined in tissue samples of 30 CC patients and was compared with the adjacent non-cancerous tissues. The relationship between MALAT-1 levels and clinicopathological parameters from the CC patients was analyzed. Cell migration and invasion assays were performed with quantification of the expression levels of MALAT-1 in 4 CC cell lines using RT-PCR.
RESULTS: Our results demonstrate that MALAT-1 is upregulated in CC. We found higher expression of MALAT-1 in all the 4 CC cell lines, especially in SiHa and ME-180 CC cell lines. After analysis of the relationship between MALAT-1 levels and clinicopathological parameters from CC patients, a robust correlation could be obtained between MALAT-1 overexpression with lymph node metastasis, tumor differentiation and clinical stage. Furthermore, the ectopic expression of MALAT-1 increased cell proliferation and contributed directly to invasion and migration.
CONCLUSION: Taken together, this study suggests an indispensible role played by MALAT-1 in CC progression, which may act as a potential prognostic indicator for CC and also could be a novel potential target for diagnosis of CC.

Yu EY, Zhao RY, Wang DS
Inhibitory effect of Aphidicolin - a tetracyclic diterpene - on the proliferation and apoptotic induction in human cervical cancer (HeLa) cells.
J BUON. 2015 Nov-Dec; 20(6):1480-6 [PubMed] Related Publications
PURPOSE: The objective of the present work was to investigate the antitumor and apoptotic effect of aphidicolin against human cervical cancer (HeLa) cells.
METHODS: Flow cytometry was performed to detect alterations in the mitochondrial membrane potential loss (ΔΨm) after aphidicolin treatment. Cell viability was assessed by the MTT assay while the apoptotic effects of the compound were examined by fluorescence microscopy and flow cytometry.
RESULTS: Aphidicolin induced dose-dependent as well as time-dependent cytotoxic effects in HeLa cells. Chromatin condensation and formation of apoptotic bodies were observed by Hoechst 33258 staining after drug treatment. Aphidicolin induced both early and late apoptosis in HeLa cells which were correlated with strong concentration of the compound. ΔΨm was also observed following aphidicolin treatment at varying doses.
CONCLUSION: Aphidicolin is a potent antitumor and apoptotic agent against human cervical carcinoma and its effects are mediated via chromatin condensation and mitochondrial membrane potential loss.

Marnitz S, Martus P, Köhler C, et al.
Role of Surgical Versus Clinical Staging in Chemoradiated FIGO Stage IIB-IVA Cervical Cancer Patients-Acute Toxicity and Treatment Quality of the Uterus-11 Multicenter Phase III Intergroup Trial of the German Radiation Oncology Group and the Gynecologic Cancer Group.
Int J Radiat Oncol Biol Phys. 2016; 94(2):243-53 [PubMed] Related Publications
PURPOSE: The Uterus-11 trial was designed to evaluate the role of surgical staging in patients with cervical cancer before primary chemoradiation therapy (CRT). The present report provides the toxicity data stratified by the treatment arm and technique.
METHODS AND MATERIALS: A total of 255 patients with carcinoma of the uterine cervix (International Federation of Gynecology and Obstetrics stage IIB-IVA) were randomized to either surgical staging followed by CRT (arm A) or clinical staging followed by CRT (arm B). Patients with para-aortic metastases underwent extended field radiation therapy (RT). Brachytherapy was mandatory. The present report presents the acute therapy-related toxicities stratified by treatment arm and radiation technique.
RESULTS: A total of 240 patients were eligible (n=121 in arm A; n=119 in arm B). Of the 240 patients, 236 (98.3%) underwent external beam RT with a median total dose of 50.4 Gy. The mean treatment duration was 53 days. Of the patients, 60% underwent intensity modulated RT (IMRT). A total of 234 patients (97.5%) underwent chemotherapy, and 231 (96.3%) underwent brachytherapy, with a median single dose of 6 Gy covering the tumor to a median nominal total dose of 28 Gy. Treatment was well tolerated, with 0% grade ≥3 genitourinary and gastrointestinal toxicity, 6% grade 3 nausea, 3% grade 3 vomiting, and <2% grade 3 diarrhea. More patients after surgical staging experienced grade 2 anemia (54.3% in arm A vs 45.3% in arm B; P=.074) and grade 2 leukocytopenia (41.4% vs 31.6%; P=.56). Of the patients who received IMRT versus a 3-dimensional technique, 65.3% versus 33.7% presented with grade 2 anemia. Grade 3 gastrointestinal and grade 2 bladder toxicity were significantly reduced with the use of IMRT.
CONCLUSIONS: The incidence and severity of acute therapy-related toxicity compared favorably with those from other randomized trials. Excellent adherence to treatment and treatment quality was achieved compared with patterns of care analyses. Surgical staging led to a doubled number of patients treated with extended field RT. The question of whether surgical staging is beneficial in the context of primary CRT requires further study.

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