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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
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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).

Lee H, Lee H, Cho YK
Cytokeratin7 and cytokeratin19 expression in high grade cervical intraepithelial neoplasm and squamous cell carcinoma and their possible association in cervical carcinogenesis.
Diagn Pathol. 2017; 12(1):18 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: High risk human papillomavirus (HR HPV) infects cells at the squamocolumnar junction (SCJ) of the cervix, causing cancer. Cytokeratin (CK)7 is an SCJ marker, and stains cervical neoplasia. CK19 is a binding partner of CK7 and expressed in cervical cancer. Despite this possible association between CK7/CK19 and cervical cancer, not much is known about the mechanism of CK7/CK19 involvement in HR HPV-mediated cervical carcinogenesis.
METHODS: We analyzed the expression pattern of CK7, CK19, and p16 by using immunohistochemistry and HPV infection by in situ hybridization in 25 cases of high grade cervical intraepithelial neoplasia (CIN3) and in 30 cases of squamous cell carcinoma (SCC).
RESULTS: CK19, p16, and HPV expression was positive in all CIN3 and SCC cases. CK7 expression was positive in all CIN3 cases and in 20/30 (66%) SCCs. Each protein showed diffuse or patchy staining with topographic distinction. Patchy staining of CK7 and episomal HPV DNA overlapped in the upper layer of CIN3 and central portion of an invasive nest in the SCC, whereas patchy CK19 staining and integrated HPV DNA were usually noted in the lower layer of CIN3 and the periphery of the SCC nest. The p16 staining pattern coincided with that of CK19 in a subset of SCC.
CONCLUSION: These results suggest that CK7 may be more related with viral episomal replication and CK19 with viral integration, contributing to viral replication and malignant transformation in HR HPV infected cells. In addition, coordinate CK7/CK19 staining may be used as a valuable marker for predicting physical status of HR HPV and E7 oncoprotein level in cervical tumor.

Rathore R, Arora VK, Singh B
Lymphoepithelioma-like carcinoma of cervix: Cytological Features on Conventional Cervical Smear.
Diagn Cytopathol. 2017; 45(3):239-242 [PubMed] Related Publications
Lymphoepithelioma-like carcinoma (LELC) is a rare neoplasm of the cervix. The importance of distinguishing this undifferentiated carcinoma with a predominant lymphocytic infiltrate lies in the fact that despite being poorly differentiated they have a better prognosis. The diagnosis however becomes more challenging when the pathologist is provided with a small cervical biopsy or a Papanicolaou smear. While the reports describing histology and their relation to Epstein-Barr virus (EBV) are many, there are only few case reports describing the cytology of these tumors. We describe the cytological features of LELC of cervix on conventional smear and correlate it with the histopathological findings of the same. A 67-year-old multiparous Hindu woman presented to the gynecology outpatient department with the history of postmenopausal bleeding for the past six months. The cytological examination of the cervical smear (Papanicolaou stain) was done followed by cervical and endometrial biopsy. Based on Papanicolaou smear and biopsy suggestive of a poorly differentiated carcinoma a radical hysterectomy with pelvic lymphadenectomy was performed. Hysterectomy specimen showed the morphology of LELC and was then correlated with the cervical smears retrospectively. On review of cytological smears it was seen that the tumor cell clusters had an abundant lymphoid background, which was overlooked earlier. Immunohistochemistry for EBV was negative. We conclude that the presence of undifferentiated tumor cell clusters with ill-defined cell borders and large number of lymphoid cells in the background suggest the diagnosis of LELC on cervical cytology. Diagn. Cytopathol. 2017;45:239-242. © 2016 Wiley Periodicals, Inc.

Adepoju EG, Ilori T, Olowookere SA, Idowu A
Targeting women with free cervical cancer screening: challenges and lessons learnt from Osun state, southwest Nigeria.
Pan Afr Med J. 2016; 24:319 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: The study was conducted to determine the challenges and suggest solutions to conducting free cervical cancer screening among Nigerian women.
METHODS: Awareness was created among women groups and mass media in Osun State for women to undergo free cervical cancer screening programme. Consenting women had their socio-demographic characteristics, awareness and uptake of HPV vaccine documented and papanicolaou smear procedure done with adequate referral for treatment given where necessary.
RESULTS: A total of 287 women had cervical cancer screening. Mean (SD) age was 51.6 (14.3) years. Most participants were urban based (87.1%), married (63.1%), had secondary education (39%) and were traders (79.1%). None of the women were aware of the preventive HPV vaccine or had been vaccinated against HPV. About 6% were pre-invasive while 0.7% had invasive cervical cancer. The highest proportions of respondents affected were young, married and had lower education. Challenges identified included poor attendance, low risk perception and logistic issues.
CONCLUSION: Most participants were urban based. There is need to decentralize cancer of cervix screening through mobile clinics and establishment of screening centres in the rural areas. Neighbour to neighbour sensitization is essential. Also, HPV vaccine should be available and affordable to all girls before sexual maturity.

Damião PA, Oliveira-Silva M, Moreira MÂ, et al.
Human Papillomavirus types distribution among women with cervical preneoplastic, lesions and cancer in Luanda, Angola.
Pan Afr Med J. 2016; 24:268 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Cervical cancer is the leading cause of cancer deaths among females in Angola and human papillomavirus (HPV) is the main risk factor for the development of pre-cancerous squamous intraepithelial lesions. The diversity and frequency of HPV types in Angola has yet to be reported.
AIM: To determine the frequency of HPV among women with squamous intraepithelial lesions from women in Luanda, Angola.
METHODS: Study participants included women diagnosed with cytological abnormalities that voluntarily provided Pap smears (n = 64). Genomic DNA was extracted from the samples for use as templates in the PCR amplification of HPV sequences. PCR products were sequenced to determine HPV type.
RESULTS: HPV DNA was detected in 71.9% (46/64) in the samples. A higher diversity of HPV types was found in the cytological lesions, such as ASCUS and LSIL (HPV16, 6, 18, 31, 58, 66, 70 and 82, in order of frequency) than that detected for HSIL and SSC (HPV16, 18, 6 and 33). The most prevalent HPV type were: HPV16, HPV6 and HPV18.
CONCLUSION: This is the first report on HPV type diversity and frequency in woman of Angola. The results suggest that large-scale studies across Africa would improve our understanding of interrelationship between HPV infections and cervical cancer. More directly, the identification of the HPV types most prevalent suggests that women in Angola would benefit from currently available HPV vaccines.

Clemente N, Alessandrini L, Vaccher E, et al.
Multiple preinvasive and invasive HPV-related lesions of the anogenital tract in a female patient with HIV infection: A case report.
Medicine (Baltimore). 2017; 96(4):e5948 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Patients with human immunodeficiency virus (HIV) infection have been shown to be at increased risk for high-risk human papillomavirus (HR-HPV) infection of the anogenital tract. Furthermore, in the last decades, the introduction of highly active antiretroviral therapy (HAART) has increased the longevity of these patients who now live long enough to develop HPV-related cancers; hence, the impact of HPV infection on HIV-positive patients is of increasing concern.
PATIENT CONCERNS: We reported the case of an HIV-positive female patient on HAART with a good virological and immunological response and with a long history of HPV-related intraepithelial and invasive lesions of the anogenital tract.
DIAGNOSES: From 1996 to 2016, this patient was diagnosed with a high grade cervical intraepithelial neoplasia; a HR-HPV positive inguinal lymph node metastasis from clinically undetectable primary squamous cell carcinoma; a HPV-related vulvar high-grade squamous intraepithelial lesion and an invasive squamous cell carcinoma of the anus.
INTERVENTIONS: All the intraepithelial and invasive lesions detected were properly treated, and subsequent follow up visits with gynecologic examination, anoscopy, pap smear and anal cytology were performed.
OUTCOMES: After a recurrence of the anal cancer and a subsequent salvage surgery with abdominoperineal resection, at the last available follow up visit no sign of disease recurrence was found.
LESSONS: This case stresses the importance of an accurate multidisciplinary follow-up in HIV-positive patients, including not only the routine medical, immunological, and virological evaluation, but also a periodical complete examination of the anogenital tract with cervicovaginal and anal cytology, colposcopy, high resolution anoscopy, and vulvar examination.

Panich T, Tragoolpua K, Pata S, et al.
Downregulation of Extracellular Matrix Metalloproteinase Inducer by scFv-M6-1B9 Intrabody Suppresses Cervical Cancer Invasion Through Inhibition of Urokinase-Type Plasminogen Activator.
Cancer Biother Radiopharm. 2017; 32(1):1-8 [PubMed] Related Publications
Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN) accelerates tumor invasion and metastasis via activation of matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (uPA) expression. The authors were interested in whether the scFv-M6-1B9 intrabody against EMMPRIN that retains EMMPRIN in endoplasmic reticulum could be a potential tool to suppress cervical cancer invasion through inhibition of uPA. The chimeric adenoviral vector Ad5/F35-scFv-M6-1B9 was transferred into human cervical carcinoma HeLa cells to produce the scFv-M6-1B9 intrabody against EMMPRIN. Cell surface expression of EMMPRIN, the membrane-bound uPA, the enzymatic activity of secreted uPA, and the invasion ability were analyzed. The scFv-M6-1B9 intrabody successfully diminished the cell surface expression of EMMPRIN and the membrane-bound uPA on HeLa cells. uPA activity from tissue culture media of EMMPRIN-downregulated HeLa cells was decreased. The invasion ability of HeLa cells harboring scFv-M6-1B9 intrabody was also suppressed. These results suggested that the scFv-M6-1B9 intrabody might represent a potential approach for invasive cervical cancer treatment. The application of scFv-M6-1B9 intrabody in animal experiments and preclinical studies would be investigated further.

Chen Y, Wang H, Lin W, Shuai P
ADAR1 overexpression is associated with cervical cancer progression and angiogenesis.
Diagn Pathol. 2017; 12(1):12 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: This study aimed to assess the role of RNA-dependent adenosine deaminase (ADAR1) in cervical squamous cell carcinoma occurrence and progression.
METHODS: ADAR1 expression levels in stage IA and stage IIA cervical squamous cell carcinoma (group A), cervical intraepithelial neoplasia (CIN) specimens (group B), as well as normal and inflamed cervical tissue samples (group C) were assessed by immunohistochemistry. Clinical and pathological data of cervical squamous cell carcinoma patients undergoing surgery were retrospectively evaluated. Chi-square test, comparative analysis of survival curve, disease-free survival and COX risk assessment method were used to understand the association of ADAR1 with the occurrence and progression and prognostic significance of cervical squamous cell carcinoma.
RESULTS: ADAR1 is expressed in the cytoplasm and nuclei. The expression level was high in squamous cell carcinoma tissues (81.18%), while relatively low in the CIN group (21.56%). And there was no expression in non-cancerous tissues. The differences between them were statistically significant using P < 0.05 as criterion. One-factor analysis revealed that ADAR1 was significantly correlated with tumor diameter, horizontal diffusion diameter, vascular invasion, parametrial invasion, vaginal involvement, and pathologically diagnostic criteria for perineural invasion (PNI). Meanwhile, the overall survival rate of ADAR1 positive patients was significantly lower compared with that of patients with no ADAR1 expression (P < 0.05). Analysis also showed that disease-free survival time of ADAR1 positive patients was shorter than that of ADAR1 negative patients, and the difference was significant (P < 0.01). Finally, COX risk assessment showed that parametrical invasion had independent prognostic factors for overall survival of squamous cell carcinoma.
CONCLUSIONS: Results indicated that ADAR1 might play an important role in the occurrence, progression and prognosis of cervical squamous cancer.

Kim TS, Lim MS, Hong YJ, et al.
Significance of "Not Detected but Amplified" Results by Real-Time PCR Method for HPV DNA Detection.
Biomed Res Int. 2016; 2016:5170419 [PubMed] Free Access to Full Article Related Publications
Human papillomavirus (HPV) infection is an important etiologic factor in cervical carcinogenesis. Various HPV DNA detection methods have been evaluated for clinicopathological level. For the specimens with normal cytological finding, discrepancies among the detection methods were frequently found and adequate interpretation can be difficult. 6,322 clinical specimens were submitted and evaluated for real-time PCR and Hybrid Capture 2 (HC2). 573 positive or "Not Detected but Amplified" (NDBA) specimens by real-time PCR were additionally tested using genetic analyzer. For the reliability of real-time PCR, 325 retests were performed. Optimal cut-off cycle threshold (CT ) value was evaluated also. 78.7% of submitted specimens showed normal or nonspecific cytological finding. The distributions of HPV types by real-time PCR were not different between positive and NDBA cases. For positive cases by fragment analysis, concordance rates with real-time PCR and HC2 were 94.2% and 84.2%. In NDBA cases, fragment analysis and real-time PCR showed identical results in 77.0% and HC2 revealed 27.6% of concordance with fragment analysis. Optimal cut-off CT value was different for HPV types. NDBA results in real-time PCR should be regarded as equivocal, not negative. The adjustment of cut-off CT value for HPV types will be helpful for the appropriate result interpretation.

Fu ZZ, Li K, Peng Y, et al.
Efficacy and toxicity of different concurrent chemoradiotherapy regimens in the treatment of advanced cervical cancer: A network meta-analysis.
Medicine (Baltimore). 2017; 96(2):e5853 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The aim of this study was to compare the efficacy and toxicity of different concurrent chemoradiotherapy (CCRT) regimens in the treatment of advanced cervical cancer (CC) by adopting a network meta-analysis.
METHODS: We searched PubMed and Cochrane Library from the inception of these databases to September 2016, and all cohort studies (CSs) related to different CCRT regimens in the treatment of CC were included. A network analysis was adopted to compare the combination of direct and indirect evidence, to analyze the odds ratio (OR), and to draw a surface under the cumulative ranking curve of the efficacy and toxicity of different CCRT regimens for CC. Cluster analyses were used to group each category based on similar treatment regimens.
RESULTS: Nineteen CSs were enrolled in this network meta-analysis, including 12 CCRT regimens (radiotherapy [RT], CCRT [cisplatin], CCRT [vinorelbine], CCRT [paclitaxel], CCRT [hydroxyurea], CCRT [cisplatin + FU], CCRT [cisplatin + gemcitabine], CCRT [cisplatin + docetaxel], CCRT [cisplatin + paclitaxel], CCRT [cisplatin + amifostine], CCRT [cisplatin + FU + hydroxyurea], and CCRT [cisplatin + vincristine + bleomycin]). The results of the network meta-analysis showed that regarding efficacy, the overall response rate of CCRT (cisplatin + docetaxel) was higher than RT, and the 5-year overall survival (OS) rate of CCRT (cisplatin + FU + hydroxyurea) was relatively higher than CCRT (hydroxyurea). As for toxicity, CCRT (cisplatin) had a lower incidence of leukopenia than CCRT (hydroxyurea), CCRT (cisplatin + FU) and CCRT (cisplatin + paclitaxel), and the incidences of diarrhea and vomiting in CCRT (cisplatin) were lower than those in CCRT (cisplatin + gemcitabine). Additionally, the cluster analysis showed that CCRT (cisplatin) had relatively lower incidences of both hematotoxicity and gastrointestinal toxicity, and CCRT (paclitaxel) had lower gastrointestinal toxicity than other regimens.
CONCLUSION: Our study demonstrated that CCRT (cisplatin + docetaxel) might be the best choice of CCRT regimens in the treatment of CC, and the 5-year OS rate of CCRT (cisplatin + FU + hydroxyurea) might be the highest among these different regimens. CCRT (cisplatin) might have the lowest toxicity among all the CCRT regimens.

Dang YZ, Zhang Y, Li JP, et al.
High VEGFR1/2 expression levels are predictors of poor survival in patients with cervical cancer.
Medicine (Baltimore). 2017; 96(1):e5772 [PubMed] Free Access to Full Article Related Publications
The aim of the study to evaluate the prognostic significance of vascular endothelial growth factor receptor 1 and 2 (VEGFR1/2) expression levels and to correlate these levels with clinicopathological parameters in patients with cervical cancer.Forty-two patients with International Federation of Gynecology and Obstetrics Stage IIB-IVB cervical cancer were analyzed between January 2011 and December 2012. RNA expression levels of VEGFR1/2 were assessed by branched DNA-liquidchip technology and immunohistochemistry. Associations between RNA expression levels, important clinicopathological parameters, and patient survival were statistically evaluated.Higher VEGFR1/2 expression levels were predictive of poor overall survival (P = 0.009 and P = 0.024, respectively). Patients with higher VEGFR1 expression levels were associated with poorer progression-free survival than those with lower VEGFR1 expression levels (P = 0.043). In addition, patients with higher VEGFR1 expression levels were more likely to develop distant metastases than those with lower VEGFR1 expression levels (P = 0.049). Higher VEGFR2 expression levels were associated with larger tumor size (P = 0.037).VEGFR1/2 expression levels were prognostic factors for patients with cervical cancer. Higher VEGFR1/2 expression levels were also predictive of poor overall survival.

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

Li XS, Fang H, Song Y, et al.
The stratification of severity of acute radiation proctopathy after radiotherapy for cervical carcinoma using diffusion-weighted MRI.
Eur J Radiol. 2017; 87:105-110 [PubMed] Related Publications
OBJECTIVE: To determine whether diffusion-weighted imaging (DWI) can be used for quantitatively evaluating severity of acute radiation proctopathy after radiotherapy for cervical carcinoma.
MATERIALS AND METHODS: One hundred and twenty-four patients with cervical carcinoma underwent MR examination including DWI before and after radiotherapy. Acute radiation proctopathy was classified into three groups (grade 0, grade I-II and grade III-IV) according to Toxicity Criteria of the Radiation Therapy Oncology Group (RTOG). The pretreatment ADC (ADCpre), ADC after treatment (ADCpost) and ADC change (ΔADC) were compared among three groups. In addition, acute radiation proctopathy was classified into good-prognosis group and poor-prognosis group. ADCpre, ADCpost and ΔADC were compared between two groups. For DWI parameter that had significant difference, discriminatory capability of the parameter was determined using receiver operating characteristics (ROC) analysis.
RESULTS: ADCpost and ΔADC were higher in grade I-II group than in grade 0 group (p<0.05), yielding a sensitivity of 79.3% and specificity of 69.4% for ADCpost, and 85.1%, 72.3% for ΔADC for discrimination between two groups. ADCpost and ΔADC were higher in grade III-IV group than in grade I-II group (p<0.05), yielding a sensitivity of 80.3% and specificity of 72.5% for ADCpost, and 84.1%, 74.5% for ΔADC for discrimination between two groups. ADCpost and ΔADC were higher in poor-prognosis group than in good-prognosis group (p<0.05), yielding a sensitivity of 79.5% and specificity of 73.4% for ADCpost, and 87.2%, 78.3% for ΔADC for discrimination between two groups.
CONCLUSION: Diffusion-weighted MRI can be used for quantitative stratification of severity of acute radiation proctopathy, which serves as an important basis for appropriate timely adjustment of radiotherapy for cervical carcinoma in order to maximally reduce the radiation injury of rectum.

Ahmad I, Chufal KS, Bhargava A, Bashir I
Primitive neuroectodermal tumour of the cervix: a rare diagnosis.
BMJ Case Rep. 2017; 2017 [PubMed] Related Publications
A 48-year-old woman presented with symptoms of lower abdominal pain and vaginal discharge for 6 months. Clinical examination and pelvic ultrasound scan suggested a diagnosis of infected Gartner's cyst, for which she underwent vaginal cystectomy. However, histopathology and immunohistochemistry revealed a diagnosis of primitive neuroectodermal tumour of the cervix. Further investigations revealed the stage to be FIGO IIIB, which was inoperable. She received neoadjuvant chemotherapy (vincristine, adriamycin, cyclophosphamide alternating with ifosfamide, cisplatin and etoposide, every 21 days), but the tumour did not respond to treatment and she was started on radiotherapy with definitive intent (55.8 Gray in 31 fractions over 6.2 weeks). A PET-CT performed 2 months after completion of radiotherapy showed complete response, and she is now receiving adjuvant chemotherapy.

Joura EA, Pils S
Vaccines against human papillomavirus infections: protection against cancer, genital warts or both?
Clin Microbiol Infect. 2016; 22 Suppl 5:S125-S127 [PubMed] Related Publications
Since 2006, three vaccines against infections and disease caused by human papillomavirus (HPV) became available in Europe-in 2006 a quadrivalent HPV 6/11/16/18 vaccine, in 2007 a bivalent HPV 16/18 vaccine and in 2015 a nonavalent HPV 6/11/16/18/31/33/45/52/58 vaccine. HPV 16 and 18 are the most oncogenic HPV strains, causing about 70% of cervical and other HPV-related cancers, HPV 6 and 11 cause 85% of all genital warts. The additional types of the polyvalent vaccine account for about 20% of invasive cervical cancer and >35% of pre-cancer. The potential differences between these vaccines caused some debate. All three vaccines give a robust and long-lasting protection against the strains in the various vaccines. The promise of cross-protection against other types (i.e. HPV 31/33/45) and hence a broader cancer protection was not fulfilled because these observations were confounded by the vaccine efficacy against the vaccine types. Furthermore, cross-protection was not consistent over various studies, not durable and not consistently seen in the real world experience. The protection against disease caused by oncogenic HPV strains was not compromised by the protection against low-risk types causing genital warts. The most effective cancer protection to date can be expected by the nonavalent vaccine, data indicate a 97% efficacy against cervical and vulvovaginal pre-cancer caused by these nine HPV types.

Li C, Ge X, Wang L
Construction and comparison of different nanocarriers for co-delivery of cisplatin and curcumin: A synergistic combination nanotherapy for cervical cancer.
Biomed Pharmacother. 2017; 86:628-636 [PubMed] Related Publications
PURPOSE: Co-delivery of two or more drugs into the same cancer cells or tissues in the same nanocarriers provides a new paradigm in cancer treatment. In this study, two kinds of nanocarriers: lipid-polymer hybrid nanoparticles (LPNs) and polymeric nanoparticles (PNPs) were constructed and compared for co-delivery of cisplatin (DDP) and curcumin (CUR).
METHODS: DDP and CUR loaded LPNs (D/C/LPNs) and PNPs (D/C/PNPs) were prepared. Two kinds of nanocarriers were characterized in terms of particle size, zeta potential, drug encapsulation efficiency (EE), and drug release. Their in vitro cytotoxicity and in vivo anti-tumor efficacy was studied on human cervix adenocarcinoma cell line (HeLa cells) and mice bearing cervical cancer model.
RESULTS: Compared with D/C/PNPs, D/C/LPNs showed significantly higher cytotoxicity in vitro. D/C/LPNs also displayed the best antitumor activity than other formulations tested in vivo.
CONCLUSIONS: The results demonstrated that LPNs could improve the anticancer efficacy of drugs to higher levels than PNPs and free drugs, thus could serve as an effective drug system for targeted and synergistic co-delivery nanomedicine for cervical cancer chemotherapy.

Wang F, Li L, Liu B, et al.
Hyaluronic acid decorated pluronic P85 solid lipid nanoparticles as a potential carrier to overcome multidrug resistance in cervical and breast cancer.
Biomed Pharmacother. 2017; 86:595-604 [PubMed] Related Publications
This work aimed to develop hyaluronic acid (HA) decorated pluronic 85 (P85) coated solid lipid nanoparticles (SLN) loaded with paclitaxel (HA-PTX-P85-SLN) and to evaluate its potential to overcome drug resistance and to increase antitumor efficacy in mice bearing cervical and breast tumor. P85-Distearoyl Phosphoethanolamine (DSPE) was synthesized from P85 and DSPE by coupling in the presence of 1,10-carbonyldiimidazole (CDI) as a catalyst. The SLN were prepared by the hot homogenization technique and electrostatic interaction. PTX-loaded SLN was characterized for mean diameter, zeta potential, morphology, entrapment efficiency (EE), drug loading capacity (LC) and in vitro drug release. In vivo animal evaluation containing antitumor effect, pharmacokinetics and biodistribution were conducted in mice bearing cervical and breast tumor. The HA-PTX-P85-SLN showed a mean diameter of 160.3nm, negative zeta potential (-31.6mV), EE of 88.2%, and LC of 4.9%. PTX from HA-PTX-P85-SLN exhibited greater sustained drug release profiles compared free PTX. Pharmacokinetics results indicated that HA-PTX-P85-SLN exhibited a 5.5-fold increase in AUC in comparison to free PTX. Biodistribution results revealed that HA-PTX-P85-SLN exhibited higher tumor drug concentration compared with free PTX.

Rizou N, Moris D, Pikoulis E, et al.
Minimally Invasive Lymphadenectomy in Uterine Cervical Cancer: A Systematic Review.
Anticancer Res. 2017; 37(1):335-342 [PubMed] Related Publications
BACKGROUND/AIM: The aim of this study was to review the current literature on the role of minimally invasive lymphadenectomy in the treatment of cervical cancer.
MATERIALS AND METHODS: Non-randomized control trials published between January 2007 to May 2016 were identified by searching the Pubmed, EMBASE and Cochrane Library databases. Primary endpoints included operative outcomes (operative time, intraoperative blood loss, number of transfused patients and conversion rates), postoperative outcomes (length of postoperative hospital stay, postoperative morbidity and postoperative in-hospital mortality), and oncological outcomes (number of harvested lymph nodes, tumor recurrence, disease-free rates and overall survival rates).
RESULTS: A total of 17 studies with a total of 1,676 patients were included in the review. Compared to the open approach, minimally invasive lymphadenectomy demonstrated a significantly larger number of harvested lymph nodes, longer operative time, lower intraoperative blood loss and shorter postoperative hospital stay. No significant differences were observed between groups treated with an open, laparoscopic or robotic approach for the following criteria: lymph node metastasis, postoperative morbidity, tumor recurrence and postoperative mortality.
CONCLUSION: Although a technically demanding and time-consuming procedure, minimally invasive lymphadenectomy appears to be safe and feasible and may offer an alternative approach in staging and treatment of cervical cancer. Multicentre randomized controlled trials investigating its long-term oncological outcomes and its cost-effectiveness are required to determine the advantages of this procedure over the open approach in cervical cancer.

Cho O, Noh OK, Oh YT, et al.
Clinical Impact of Escalating Relative High-dose-rate Intracavitary Brachytherapy Dose in Stage IIB Cervical Cancer.
Anticancer Res. 2017; 37(1):327-334 [PubMed] Related Publications
BACKGROUND/AIM: To investigate whether high-dose-rate (HDR) intracavitary brachytherapy (IBT) dose ratios can predict treatment outcomes in patients with stage IIB cervical cancer.
PATIENTS AND METHODS: Ninety-three patients treated with weekly cisplatin-based concurrent chemoradiotherapy and HDR IBT were analyzed. Potential prognostic factors and treatment outcomes were compared between low-HDR-IBT-ratio (≤0.43) and high-HDR-IBT-ratio (>0.43) groups, and univariate and multivariate analyses were performed.
RESULTS: Five-year disease-specific survival (DSS) and progression-free survival (PFS) rates were significantly shorter in the low-compared to the high-HDR-IBT-ratio group. A high HDR IBT ratio was confirmed as an independent prognostic factor for DSS and PFS.
CONCLUSION: A high HDR IBT dose ratio improves DSS and PFS in patients with stage IIB cervical cancer. Therefore, active administration of HDR IBT beyond previously accepted levels may be necessary for the treatment of locally advanced cervical cancer.

Murakami T, Murata T, Kawaguchi K, et al.
Cervical Cancer Patient-Derived Orthotopic Xenograft (PDOX) Is Sensitive to Cisplatinum and Resistant to Nab-paclitaxel.
Anticancer Res. 2017; 37(1):61-65 [PubMed] Related Publications
BACKGROUND: Cervical cancer is a world-wide problem that requires transformative therapeutic strategies. We have previously developed patient-derived orthotopic xenograft (PDOX) nude-mouse models of this disease. In the present report, we demonstrate that the standard drug, cisplatinum (CDDP), is highly-effective while the new, highly-touted agent, nab-paclitaxel (NAB-PTX) is ineffective.
MATERIALS AND METHODS: Cervical PDOX tumors were grown on the cervix of nude mice for 4 weeks after surgical orthotopic implantation (SOI). Tumors were treated with CDDP or NAB-PTX.
RESULTS: H&E staining demonstrated that the PDOX tumor recapitulated the original patient tumor. CDDP was highly-effective. One tumor that was treated with CDDP completely regressed. CDDP-treated tumors were smaller (tumor volume ratio: 0.42±0.36) than the control group (tumor volume ratio: 3.47±1.66) (p<0.01). In contrast, NAB-PTX did not show significant efficacy on the cervical cancer PDOX model (tumor volume ratio: 2.85±1.45) (p=0.47). CDDP-treated tumor weight (50±50 mg) was significantly less than control (238±114 mg) (p<0.01). NAB-PTX-treated tumors were not reduced in weight (246±136 mg) compared to control (p=0.91). There were no significant differences in mouse body weight between groups. Histological evaluation demonstrated that CDDP-treated tumors were fibrotic with scattered squamous cell nests compared to control or NAB-PTX-treated tumors.
CONCLUSION: The results of the present study demonstrate the power of PDOX models of cervical cancer to distinguish efficacy of potential therapeutics for individual patients with this disease.

Li H, Lu Y, Pang Y, et al.
Propofol enhances the cisplatin-induced apoptosis on cervical cancer cells via EGFR/JAK2/STAT3 pathway.
Biomed Pharmacother. 2017; 86:324-333 [PubMed] Related Publications
OBJECTIVE: The main purpose of this study was to evaluate propofol and its combined effect with cisplatin on apoptosis of cervical cancer cells and molecular mechanisms of this phenomenon.
METHODS: The effects of propofol and cisplatin on cell viability and apoptosis were detected by cell counting kit-8 (CCK-8) assay, colony formation assay and flow cytometry assay. Besides, protein expression of EGFR/JAK2/STAT3 pathway was determined by western blot. STAT3 was over-expressed in cervical cancer cells by STAT3 cDNA. Expression of EGFR and STAT3 protein of human tissues was evaluated by immunohistochemistry (IHC) assay.
RESULTS: In this study, we found that not only propofol alone could inhibit cervical cancer cells viability but also could increase the inhibitory effect of cisplatin on cervical cancer cells growth. Meanwhile, propofol sensitized cervical cancer cells to cisplatin-induced apoptosis but not affected normal cervical cells. In genetic level, propofol could enhance the anti-tumor effect of cisplatin through EGFR/JAK2/STAT3 pathway. Further studies indicated that overexpression of EGFR and STAT3 is related to poor prognoses in cervical cancer patients, which contributed to confirm the clinical role of combined application of propofol and cisplatin.
CONCLUSION: Propofol enhances the cisplatin-induced cell apoptosis cervical cancer cells via EGFR/JAK2/STAT3 pathway and may be developed as a potential therapeutic agent to treat cervical cancer.

de Matos LG, Cândido EB, Vidigal PV, et al.
Association between Toll-like receptor and tumor necrosis factor immunological pathways in uterine cervical neoplasms.
Tumori. 2017; 103(1):81-86 [PubMed] Related Publications
INTRODUCTION: The immune system plays a critical role in the defense against human papillomavirus (HPV) infection and its persistence. Toll-like receptors (TLRs) are membrane receptors responsible for activation of the innate immune response, and an association between TLR expression and uterine cervical cancer has been shown. Tumor necrosis factors (TNFs) are among the main mediators of skin and mucosa inflammation. The aim of this study was to demonstrate the association between TLR and TNF immune expression and cervical cancer and premalignant cervical lesions.
METHODS: A total of 64 embedded tissues were obtained from gynecological procedures, including 35 specimens with cervical intraepithelial neoplasia (CIN) and 10 specimens with cervical squamous cell carcinoma (CSCC) as well as 19 normal cervical samples. The expression of TLR2, TLR3, TLR4, TNF-α and TNF-β was measured by immunohistochemistry and graded into low and high levels of expression.
RESULTS: There was an association between the expression levels of TLR2 and those of TNF-α and TNF-β (p = 0.01 and p = 0.021, respectively) in the cervical cancer and CIN groups. TLR4 expression was associated with TNF-α and TNF-β expression (p = 0.016 and p = 0.025, respectively) in these 2 groups. By contrast, TLR3 was not statistically associated with TNF-α or TNF-β in any of the groups.
CONCLUSIONS: There might be an association of the TLR2 and TLR4 pathways with the immunological response of TNF-α and TNF-β in cervical cancer. These markers are also expressed at higher levels in cervical cancer and premalignant lesions compared to normal controls.

Damian A, Lago G, Rossi S, et al.
Early Detection of Bone Metastasis in Small Cell Neuroendocrine Carcinoma of the Cervix by 68Ga-DOTATATE PET/CT Imaging.
Clin Nucl Med. 2017; 42(3):216-217 [PubMed] Related Publications
The neuroendocrine small cell carcinoma of the cervix is a rare malignancy that has a poor prognosis due to early lymphatic and hematogenous spread. We herein report a case of a 27- year-old woman who was referred for initial staging of a neuroendocrine small cell carcinoma with previous unremarkable structural imaging. Ga-DOTATATE PET/CT revealed focal uptake at the primary tumor and in a solitary pelvic bone lesion suggestive of metastases that was further confirmed by CT-guided biopsy. Somatostatin receptor PET/CT may be a useful image modality for early detection of metastases to guide treatment in these patients.

Sui M, Pei Y, Li D, et al.
Misdiagnosis Analysis of Cervical Minimal Deviation Adenocarcinoma: a Report of Three Rare Cases and Literature Review.
Ann Clin Lab Sci. 2016; 46(6):680-690 [PubMed] Related Publications
Cervical minimal deviation adenocarcinoma (MDA) is a rare variant of cervical adenocarcinoma that is difficult to diagnose due to the deep location, endogenous growth pattern, deceptively benign appearance of tumor cells, and lack of connection to human papillomavirus (HPV). Cytological evaluation and biopsies offer suboptimal detection and transvaginal sonography or Magnetic Resonance Imaging (MRI) only reveal multiple lesions that mimic multiple benign nabothian cysts. Besides, standard screening, diagnostic tools, and treatments are not established. Thus, MDA tends to be misdiagnosed with other gynecological diseases. In this study, we examine three cases with extensive abdominal metastasis and adhesions, which are not initially associated clinically with HPV and cervical malignancies. All cases were misdiagnosed as nabothian cysts, endometrial adenocarcinoma or ovarian cancer, though finally diagnosed as MDA by postoperative pathology. Delay in diagnosis and treatment can result in irreversible outcomes. Misdiagnoses are analyzed and suggestions for improving early detection are discussed with a brief review of the literature.

Zhang QH, Xu P, Lu YX, Dou HT
Acidic and basic fibroblast growth factor expression levels in cervical cancer and their effects on tumor cell proliferation.
Genet Mol Res. 2016; 15(4) [PubMed] Related Publications
Fibroblast growth factors (FGFs) play important roles in angiogenesis, wound healing, embryonic development, and endocrine signaling pathways. Increasingly, recent studies have reported aberrant FGF expression in various malignancies. However, the involvement of FGFs in cervical carcinoma pathogenesis remains unclear. We aimed to investigate expression of acidic (aFGF) and basic FGF (bFGF) in patients with this disease, and assess their effects on cervical cancer cell proliferation. Twenty cervical cancer patients and 10 cervical intraepithelial neoplasia (CIN) patients were recruited, and 10 cancer-free individuals were included as controls. Reverse transcription-polymerase chain reaction and western blotting were employed to detect FGF mRNA and protein levels, respectively. Furthermore, HeLa cells were treated with FGFs and subjected to thiazolyl blue tetrazolium bromide assays to quantify proliferation. Compared with CIN and normal cervical tissues, aFGF and bFGF mRNA and protein levels were significantly elevated in cervical carcinomas (P < 0.05). CIN tissues exhibited higher expression of these FGFs than normal tissues (P < 0.05). Moreover, their mRNA levels were increased in advanced cancer stages (P < 0.05), although no significant difference was detected between tumors of different differentiation grades in this regard (P > 0.05). HeLa cell proliferation increased in an aFGF- and bFGF-dose-dependent manner (P < 0.05), the latter exerting a more potent proliferative influence, with its effect peaking at 75 ng/mL. aFGF and bFGF were highly expressed in cervical cancer tissues and their levels positively correlated with clinical stage. Both facilitate proliferation of cervical carcinoma cells and are implicated in cancer pathogenesis and progression.

Boussios S, Seraj E, Zarkavelis G, et al.
Management of patients with recurrent/advanced cervical cancer beyond first line platinum regimens: Where do we stand? A literature review.
Crit Rev Oncol Hematol. 2016; 108:164-174 [PubMed] Related Publications
BACKGROUND: Cervical cancer is the fourth most common cancer affecting women worldwide. Despite advances in screening and human papillomavirus (HPV) vaccination, a significant number of women present with or develop advanced disease. Palliative platinum-based chemotherapy (CT) is the standard first-line treatment for metastatic/recurrent cervical cancer. The prognosis remains poor and effective second line options are urgently needed.
METHODS: We searched the English-language medical literature as well as relevant guideline databases, published from January 1981 to December 2015 and identified publications related to cervical cancer and its therapies. Our effort was to highlight the available treatment options in the setting of recurrent/metastatic disease.
RESULTS: Although there have been important advances in the management of women with cervical cancer, the optimal treatment for patients with locally recurrent and metastatic disease after platinum failure is still problematic. Overall, there is a trend in terms of longer overall survival (OS) and better quality of life for the combination of cisplatin/paclitaxel (PC) as compared to the doublets of cisplatin/topotecan (TC), cisplatin/vinorelbine (VC), and cisplatin/gemcitabine (GC). Currently available single agents beyond first-line platinum-based therapy have limited efficacy in this setting and include topoisomerase inhibitors, vinca alkaloids, taxanes, alkylating agents and antimetabolites. Several targeted therapies have demonstrated activity in advanced cervical cancer. Bevacizumab has been evaluated in a phase III trial using doublets of cisplatin with paclitaxel or topotecan and has been approved in the first-line setting by the U. S. Food and Drug Administration. Selective targeting of angiogenic kinases by tyrosine kinase inhibitors (TKIs) may represent a novel therapeutic tool in this setting, but its use alone or in combination with CT is still investigational. Early reports have implicated PI3KCA somatic mutations suggesting that mTOR-targeted agents should be explored in this disease. Development of the immune checkpoint programmed cell death 1 (PD-1) and T-lymphocyte-associated molecule-4 (CTLA-4) inhibitors have been of considerable interest, leading to ongoing phase II studies in patients with advanced cervical cancer.
CONCLUSIONS: Progress in the management of recurrent and advanced cervical cancer patients has been slow and restricted to palliative intent. These patients should be considered for clinical trials of novel targeted agents and/or immunotherapy.

Kassem L, Abdel-Rahman O
Targeting mTOR pathway in gynecological malignancies: Biological rationale and systematic review of published data.
Crit Rev Oncol Hematol. 2016; 108:1-12 [PubMed] Related Publications
BACKGROUND: mTOR inhibitors are widely used in different malignancies with several trials testing their efficacy and safety in gynecological malignancies. We aimed to review the current evidence that support the expansion of using such drugs in the treatment of advanced gynecological cancers.
METHODS: A comprehensive systematic review of literature has been conducted to include prospective trials that used everolimus, temsirolimus or ridaforolimus in the management of gynecological cancers and have available efficacy and toxicity results.
RESULTS: A total of 23 studies including 980 patients were considered eligible for our review. Our review included 16 phase II and 7 phase I studies with the majority of patients having uterine cancers. Regarding Endometrial cancer, the CBR ranged from 21% to 60% and median PFS from 2.8 months to 7.3 months. In Ovarian cancers, CBR ranged from 24% to 50% and median PFS from 3.2 months to 5.9 months. In the single phase II study in cervical cancer the CBR was 61% and median PFS was 3.5 months. The toxicity profile was consistent with what was observed previously in other malignancies with fatigue, mucositis, and hematological toxicities being the most common adverse events observed.
CONCLUSION: mTOR inhibitors seem to be a promising option in the second line management of advanced gynecological cancers with best safety and efficacy outcomes when given as a single agent or in combination with hormonal treatment. More research is needed for better patient selection.

Liu S, Gu X, Zhu L, et al.
Effects of propofol and sevoflurane on perioperative immune response in patients undergoing laparoscopic radical hysterectomy for cervical cancer.
Medicine (Baltimore). 2016; 95(49):e5479 [PubMed] Free Access to Full Article Related Publications
The aim of this study is to compare the effects of propofol and sevoflurane anesthesia on perioperative immune response in patients undergoing laparoscopic radical hysterectomy for cervical cancer.Sixty patients with cervical cancer scheduled for elective laparoscopic radical hysterectomy under general anesthesia were randomized into 2 groups. TIVA group received propofol induction and maintenance and SEVO group received sevoflurane induction and maintenance. Blood samples were collected at 30 min before induction (T0); the end of the operation (T1); and 24 h (T2), 48 h (T3), and 72 h (T4) after operation. The T lymphocyte subsets (including CD3+ cells, CD4+ cells, and CD8+ cells) and CD4+/CD8+ ratio, natural killer (NK) cells, and B lymphocytes were analyzed by flow cytometry.After surgery, all immunological indicators except CD8+ cells were significantly decreased in both groups compared to basal levels in T0, and the counts of CD3+ cells, CD4+ cells, NK cells, and the CD4+/CD8+ ratios were significantly lower in the SEVO groups than that in the TIVA group. However, the numbers of B cells were comparable at all the time points between 2 groups.Laparoscopic radical hysterectomy for cervical cancer is associated with postoperative lymphopenia. In terms of protecting circulating lymphocytes, propofol is superior to sevoflurane.

Magnani B, Harubin B, Katz JF, et al.
See, Test & Treat: A 5-Year Experience of Pathologists Driving Cervical and Breast Cancer Screening to Underserved and Underinsured Populations.
Arch Pathol Lab Med. 2016; 140(12):1411-1422 [PubMed] Related Publications
CONTEXT: - See, Test & Treat is a pathologist-driven program to provide cervical and breast cancer screening to underserved and underinsured patient populations. This program is largely funded by the CAP Foundation (College of American Pathologists, Northfield, Illinois) and is a collaborative effort among several medical specialties united to address gaps in the current health care system.
OBJECTIVE: - To provide an outline for administering a See, Test & Treat program, using an academic medical center as a model for providing care and collating the results of 5 years of data on the See, Test & Treat program's findings.
DESIGN: - Sources include data from patients seen at Tufts Medical Center (Boston, Massachusetts) who presented to the See, Test & Treat program and institutional data between 2010 and 2014 detailing the outline of how to organize and operationalize a volunteer cancer-screening program.
RESULTS: - During the 5-year course of the program, 203 women were provided free cervical and breast cancer screening. Of the 169 patients who obtained Papanicolaou screening, 36 (21.3%) had abnormal Papanicolaou tests. In addition, 16 of 130 patients (12.3%) who underwent mammography had abnormal findings.
CONCLUSIONS: - In general, women from ethnic populations have barriers that prevent them from participating in cancer screening. However, the CAP Foundation's See, Test & Treat program is designed to reduce those barriers for these women by providing care that addresses cultural, financial, and practical issues. Although screening programs are helpful in identifying those who need further treatment, obtaining further treatment for these patients continues to be a challenge.

Lee YY, Jeon HK, Lee J, et al.
Dynamin 2 Inhibitors as Novel Therapeutic Agents Against Cervical Cancer Cells.
Anticancer Res. 2016; 36(12):6381-6388 [PubMed] Related Publications
AIM: We investigated the feasibility of dynamin 2 as a potential treatment target in cervical cancer cells.
MATERIALS AND METHODS: We performed tissue microarray for dynamin 2 expression in 208 patients with early cervical cancer and in vitro in HeLa cells with dynamin 2 inhibitors MiTMAB, OcTMAB, Dynasore, and DD-6.
RESULTS: Tumor size greater than 2 cm or tumor invasion of more than half of the entire cervix was associated with expression of dynamin 2 compared to no expression (p=0.013, and p=0.045, respectively). All dynamin 2 inhibitors significantly reduced proliferation, increased apoptotic activity, and reduced matrix metallopeptidase 9 expression in HeLa cells. Dynasore and DD-6 reduced migration of HeLa cells on laminin 1-coated plates and DD-6 most strongly reduced migration performance on fibronectin-coated plates.
CONCLUSION: Targeting dynamin 2 may be a promising new approach for the treatment of cervical cancer.

Zhang D, Sun G, Zhang H, et al.
Long non-coding RNA ANRIL indicates a poor prognosis of cervical cancer and promotes carcinogenesis via PI3K/Akt pathways.
Biomed Pharmacother. 2017; 85:511-516 [PubMed] Related Publications
Accumulating evidence suggests that long non-coding RNAs (lncRNAs) are playing critical roles in tumorgenesis. LncRNA ANRIL has been reported to promote tumor progression in types of cancers. However, the expression and function of ANRIL in cervical cancer are still largely unclear. We measured the expression of ANRIL in cervical cancer tissues and cell lines and analyzed its association with clinicopathological features and prognosis. Loss-of-function experiments were used to identify the biological function of ANRIL. Our results showed that the expression of lncRNA ANRIL was significantly increased both in cervical cancer tissues and cell lines. Patients with high ANRIL expression had advanced FIGO stage, lymph node metastasis and poor overall survival than those with low ANRIL expression. Multivariable Cox proportional hazards regression analysis suggested that high ANRIL expression was an independent prognostic factor of prognosis. Loss-of-function experiments showed that decreased expression of ANRIL inhibited cell proliferation, migration and invasion of cervical cancer. Finally, western blot indicated that the PI3K/Akt pathway was found to be inactivated in cervical cancer cells after ANRIL inhibition. These results indicated that lncRNA ANRIL might play an important role in cervical cancer progression and could serve as a novel prognostic biomarker and therapeutic target in cervical cancer.

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