HPV-related Cervical Disease Research Articles

Post-marketing study design to evaluate the effectiveness of the 9-valent and 4-valent HPV vaccines on serious HPV-related cervical disease in China.

The 4-valent (4 v) and 9-valent (9 v) human papillomavirus (HPV) vaccines are approved in China for females aged 9-45 years. However, the real-world impact of 4vHPV or 9vHPV vaccination for the prevention of high-grade cervical disease in Chinese women is lacking. Two post-marketing surveillance studies will be conducted to measure the occurrence of high-grade cervical lesions in Chinese women who had received ≥1 dose of the 4vHPV (aged 20-45 years) or 9vHPV (aged 16-26 years) vaccine in Ningbo, China. Vaccination data will be extracted from the Ningbo Regional Health Information Platform (NRHIP) from the date of the first 4vHPV (January 9, 2018) or the first 9vHPV (January 25, 2019) vaccination to March 31, 2021. The primary 4vHPV and 9vHPV vaccinated cohorts will include women vaccinated per protocol. The 4vHPV/9vHPV vaccinated test-negative (cervical HPV negative; ThinPrep cytology test negative) and corresponding matched unvaccinated HPV test-negative sub-cohorts will also be assessed. Outcomes will be the occurrence of new-onset cervical intraepithelial neoplasia grade 2/3, adenocarcinoma in situ, and invasive cervical cancer. This study aims to demonstrate that such a methodological approach is feasible and can be used to assess the impact of HPV vaccination in other regions across China.

HPV-related cervical diseases: Alteration of vaginal microbiotas and promising potential for diagnosis.

Vaginal microbiota is closely associated with women's health, however, the correlation between HPV-related cervical disease (HRCD) and vaginal microbiota is still obscure. In this study, patients with HRCD (n = 98) and healthy controls (n = 58) in Hangzhou were recruited, and their vaginal microbiota were collected and analyzed. The composition of the vaginal microbial community was explored, and a disease classification model was developed by random forest algorithm. The results suggested that the diversity of vaginal microbiota was significantly higher in HRCDs than that in healthy controls (p < 0.05). Firmicutes is the dominant phylum in vaginal microbiota, and Lactobacillus was identified as the most altered genus between two groups (p < 0.01). Kyoto Encyclopedia of Genes and Genomesanalysis suggested the difference in vaginal microbial community functions between two groups. Furthermore, we identified 10 biomarkers as the optimal marker sets for the random forest model and found a higher probability of disease values in HRCD group in discovery cohort (p < 0.0001), with an area under the receiver operating characteristiccurve reaching 89.7% (95% confidence interval: 78.3%-100%). We further validated the model in both validation and independent diagnosis cohorts, confirming its accuracy in the prediction of HRCD. In conclusion, this study revealed the community composition of vaginal microbiota in HRCDs and successfully constructed a diagnostic model for HRCD.

Current and future direction in treatment of HPV-related cervical disease.

Human papillomavirus (HPV) is the most common sexually transmitted virus in the world. About 70% of cervical cancers are caused by the most oncogenic HPV genotypes of 16 and 18. Since available prophylactic vaccines do not induce immunity in those with established HPV infections, the development of therapeutic HPV vaccines using E6 and E7 oncogenes, or both as the target antigens remains essential. Also, knocking out the E6 and E7 oncogenes in host genome by genome-editing CRISPR/Cas system can result in tumor growth suppression. These methods have shown promising results in both preclinical and clinical trials and can be used for controlling the progression of HPV-related cervical diseases. This comprehensive review will detail the current treatment of HPV-related cervical precancerous and cancerous diseases. We also reviewed the future direction of treatment including different kinds of therapeutic methods and vaccines, genome-editing CRISPR/Cas system being studied in clinical trials. Although the progress in the development of therapeutic HPV vaccine has been slow, encouraging results from recent trials showed vaccine-induced regression in high-grade CIN lesions. CRISPR/Cas genome-editing system is also a promising strategy for HPV cancer therapy. However, its safety and specificity need to be optimized before it is used in clinical setting.

Inside the pocket: Critical elements of HLA-mediated susceptibility to cervical precancerous lesions.

Human papillomavirus (HPV) infection is a necessary cause for cervical cancer (CC), but it also depends on genetic factors, such as HLA polymorphism. However, few reports addressed the role of amino acids residues at the HLA peptide-binding cleft in HPV-related cervical disease. Therefore, we aimed to investigate the association between HLA-B, HLA-C, and HLA-DRB1 polymorphism and amino acid residues composing the pockets of the peptide-binding cleft of the respective polypeptide chains with cervical intraepithelial neoplasia (CIN II/III). HLA typing was performed by PCR-SSOP in 184 women with CIN II/III and 174 controls from South Brazil. Associations were estimated by multivariate logistic regression. FDR test was performed to correct the p-value for multiple comparisons. HLA-DRB1*13:01 was associated with protection against CIN II/III, while HLA-C*03:04 was associated with susceptibility. The amino acid residues isoleucine, tyrosine, and leucine at positions 95, 116, and 163 of HLA-C, respectively, were associated with CIN II/III susceptibility. In contrast, serine at positions 11 and 13 of HLA-DRB1 was associated with protection against the disease. Our results confirm previously reported associations between HLA and cervical diseases caused by HPV and suggest a role for amino acid residues at different positions of HLA-C and HLA-DRB1 in CIN II/III. This finding may be further explored to better understand the genetic risk and the influence of immune response to CC development.

Self-obtained vaginal samples for HPV DNA testing to detect HPV-related cervical disease.

To investigate if a self-obtained vaginal sample (SOVAS) contains sufficient DNA for a human papillomavirus (HPV) test and if the results are comparable to those obtained via cervical samples (CS) collected by a physician. One hundred and fifty-one women who had abnormal cervical smears or who were HPV-positive were enrolled. Self-sampling was done after reading instructions and watching a 2-min-long video, whereas CS was obtained with a cervical cytobrush during a gynecologic examination. A multiplex real-time polymerase chain reaction-based assay detected the prevalence of any type of HPV to be 67.5% in the SOVAS and 57.4% in the CS, and that of high-risk (HR-) HPV to be 58.7% in the SOVAS and 48.6% in the CS. The sensitivity of detection of HR-HPV in the SOVAS was 100% (95% confidence interval [CI] -0.09 to 0.32) for high-grade squamous intraepithelial lesion, 78% (95% CI -0.09 to 0.13) for atypical squamous cells of undetermined significance or worse, and 95% (95% CI -0.01 to 0.25) for low-grade squamous intraepithelial lesion or worse, which was statistically within the non-inferiority margin compared with that of CS. Our study shows that the collection of a SOVAS is feasible and it is comparable to a CS for HPV DNA testing. Future studies are required to investigate the feasibility and cost-effectiveness of a mail-delivered SOVAS for cervical cancer screening.

4553 An investigation into the use of curcumin, a topical herbal agent, for the treatment of cervical intraepithelial neoplasia

4553 An investigation into the use of curcumin, a topical herbal agent, for the treatment of cervical intraepithelial neoplasia

Gold Nanoparticles Enhanced Electrochemical Impedance Sensor (EIS) for Human Papillomavirus (HPV) 16 Detection E6 region

The persistent infection by high risk HPV is a necessary but not sufficient cause of this cancer which develops over a long period through precursor lesions which can be detected by electrochemical impedance sensor. The HPV driven molecular mechanisms underlying the development of cervical lesions have provided a number of potential biomarkers for both diagnostic and prognostic use in the clinical management of women with HPV related cervical disease and these biomarkers can also be used to increase the positive predictive value of current methods. The most influential methods for the detection and identification of HPV using gold nanoparticle (GNP) included electrochemical impedance sensor will visit their sensitivity, selectivity and characteristic detection on synthetic target which are complement of the DNA, non-complement of the DNA and mismatch of the DNA. In difference concentration of synthetic target, which stage can get the exactly value to determine the HPV in strain 16 was evaluated in this research studies.

Practices regarding human Papillomavirus counseling and vaccination in head and neck cancer: a Canadian physician questionnaire

BackgroundHuman papillomavirus (HPV) has recently been implicated as a causative agent in a rapidly growing number of oropharyngeal cancers. Emerging literature supports the hypothesis that HPV vaccination may protect against HPV-related head and neck cancer (HNC) in addition to HPV-related cervical and anogenital disease. While the association between HPV infection and cervical cancer is widely understood, its relation to HNC is less well known. The purpose of this study was to better understand HPV counseling practices for infection and vaccination in relation to HNC of primary care physicians (PCPs), Obstetricians/Gynecologists (OBGYNs), and Otolaryngology - Head and Neck Surgeons (OHNSs) in Canada.MethodsA Canada-wide electronic questionnaire regarding counseling practices on HPV infection, transmission, and vaccination was designed and distributed to PCPs, OBGYNs, and OHNSs across Canada through electronic and paper-based methods. Basic Descriptive statistics were used to analyze responses.ResultsIn total, 337 physicians responded (239 family physicians, 51 OHNSs, 30 OBGYNs, and 17 pediatricians). Three out of four PCPs reported routine counseling of their patients regarding HPV infection, transmission, and vaccination. Among this group, 68% reported “never” or “rarely” counseling patients that HPV can cause HNC. The most commonly reported reason that PCPs cited for not counseling was a lack of knowledge. The majority of OHNSs (81%) and OBGYNs (97%) counseled patients regarding HPV infection, transmission, and vaccination. However, very few OHNSs (10%) regularly counseled patients with HPV-related HNC about HPV-related anogenital cancer. Similarly, very few OBGYNs (18%) regularly counseled patients with HPV related cervical/anogenital cancer about HPV related HNC.ConclusionsThe rate of counseling on HPV infection, transmission, and vaccination in relation to HNC among PCPs is low. The most common reason is a lack of knowledge. Specialists rarely counsel patients with confirmed HPV-related cancer about other HPV-related malignancies. More research is needed on the relationship between different HPV-related cancers in order to better inform counseling practices.

Management of HPV-related cervical disease: role of p16INK4a immunochemistry. Review of the literature.

This systematic review of 43 studies aims to evaluate the absolute and relative sensitivity and specificity of p16INK4a with regard to uterine cervix lesions, describing innovations and techniques for the detection of high-grade cervical dysplasia and allowing correct treatment. Studies were identified in the PubMed database up to March 2015. The keywords hrHPV, p16INK4a gene, and uterine cervical disease (MeSH terms) were used. Only English-language articles were included. We considered retrospective and prospective studies that assessed p16INK4a or p16INK4a/Ki67 staining, with or without HPV-DNA testing (HC2/PCR) as a comparator test, in cytological/histological specimens for which the diagnosis of ASCUS, LSIL or HSIL was verified with a reference standard. The primary outcome for cervical lesions was evaluation of the absolute p16INK4a immunoreactivity; the secondary outcome was evaluation of the relative p16INK4a immunoreactivity versus HPV testing in those studies where comparator tests were available. p16INK4a was more specific than HPV-DNA test (median values of 56.1% vs. 52.25% in CIN grade ≥2 lesions; 82.5% vs. 53% in negative and CIN grade ≥1 lesions). The main limitation of this study is linked to both qualitative and quantitative p16INK4a levels of expression, while the second limitation is the lack of standardized scales. p16INK4a and HPV-DNA used together increased the sensitivity and negative predictive value for CIN detection. p16INK4a can be considered a biomarker of CIN2 or CIN3, indicating a high risk of relapse or evolution to invasive carcinoma. Also p16INK4a-negative CIN should be considered and further research should be performed.

A Single-Arm, Proof-Of-Concept Trial of Lopimune (Lopinavir/Ritonavir) as a Treatment for HPV-Related Pre-Invasive Cervical Disease

BackgroundCervical cancer is the most common female malignancy in the developing nations and the third most common cancer in women globally. An effective, inexpensive and self-applied topical treatment would be an ideal solution for treatment of screen-detected, pre-invasive cervical disease in low resource settings.MethodsBetween 01/03/2013 and 01/08/2013, women attending Kenyatta National Hospital's Family Planning and Gynaecology Outpatients clinics were tested for HIV, HPV (Cervista®) and liquid based cervical cytology (LBC -ThinPrep®). HIV negative women diagnosed as high-risk HPV positive with high grade squamous intraepithelial lesions (HSIL) were examined by colposcopy and given a 2 week course of 1 capsule of Lopimune (CIPLA) twice daily, to be self-applied as a vaginal pessary. Colposcopy, HPV testing and LBC were repeated at 4 and 12 weeks post-start of treatment with a final punch biopsy at 3 months for histology. Primary outcome measures were acceptability of treatment with efficacy as a secondary consideration.ResultsA total of 23 women with HSIL were treated with Lopimune during which time no adverse reactions were reported. A maximum concentration of 10 ng/ml of lopinavir was detected in patient plasma 1 week after starting treatment. HPV was no longer detected in 12/23 (52.2%, 95%CI: 30.6–73.2%). Post-treatment cytology at 12 weeks on women with HSIL, showed 14/22 (63.6%, 95%CI: 40.6–82.8%) had no dysplasia and 4/22 (18.2%, 95%CI: 9.9–65.1%) were now low grade demonstrating a combined positive response in 81.8% of women of which 77.8% was confirmed by histology. These data are supported by colposcopic images, which show regression of cervical lesions.ConclusionsThese results demonstrate the potential of Lopimune as a self-applied therapy for HPV infection and related cervical lesions. Since there were no serious adverse events or detectable post-treatment morbidity, this study indicates that further trials are clearly justified to define optimal regimes and the overall benefit of this therapy.Trial RegistrationISRCTN Registry 48776874

Abstract CT131: HPV specific immunotherapy for cervical intraepithelial neoplasia using VGX-3100 induces regression of cervical lesions and potent T-cell responses: Results from a randomized, double-blind, placebo-controlled phase II study

Abstract The advent of an immunotherapy that imparts a significant impact on the clinical status of advanced cervical intraepithelial neoplasia (CIN) has the potential to provide physicians an important alternative to surgery to treat CIN 2/3 disease. Our previous two phase I studies of VGX-3100, a highly optimized DNA immunotherapy for HPV16/18 delivered using electroporation, drove seroconversion as gauged by ELISA to at least one HPV antigen (E6 or E7) in 100% of patients while 78% of patients mounted a Interferon Gamma (IFNg) ELISpot response. Moreover, all patients showed the presence of CD8 T cells exhibiting full HPV-specific cytolytic functionality, a readout thought to be informative of the ability of VGX-3100 to induce an immune response that may be important for the direct elimination of HPV infected cells. The phase II study, designated HPV-003, assessed the safety and efficacy of VGX-3100 in 167 women with biopsy-proven CIN 2 or CIN 3 with concurrent HPV16/18 infection. The randomized, placebo-controlled, double-blind study, was stratified by age and severity of CIN and evaluated cervical tissue changes after three 6 mg intramuscular doses of VGX-3100 followed by electroporation (EP) with Inovio's CELLECTRA® 2000 device at weeks 0, 4, and 12. Cervical tissue was examined before starting blinded treatment and 9 months later. The study met its primary efficacy endpoint; the percentage of patients who had regression of CIN 2 or CIN 3 to CIN 1 or no disease at 6 months post third dose was significantly higher in the VGX-3100 group compared to the placebo group (p = 0.017). In addition, the trial demonstrated the ability of VGX-3100 clear HPV infection concurrent with regression of CIN lesions. The study also explored cellular immune responses to VGX-3100 in blood samples taken prior to the first vaccine dose and periodically thereafter. IFN-γ ELISpot results revealed higher responses in the VGX-3100 treated group than in the placebo group, suggesting that VGX-3100 was able to robustly engage the cellular arm of the patients’ immune system. Altogether, the successful phase 2 results represent a significant milestone in the development of active immunotherapies to treat cancer and infectious diseases and have the potential to provide physicians an important alternative to surgery to treat CIN 2/3 disease. They illustrate the highly promising potential of therapeutic immunization with DNA using electroporation for the treatment of HPV-related precancerous cervical disease in women and present the possibility of treating other HPV-associated cancers. Citation Format: Matthew Morrow, Cornelia Trimble, Xuefei Shen, Michael Dallas, David Weiner, Jean Boyer, Jian Yan, Kimberly Kraynyak, Albert Sylvester, Mary Giffear, Kathleen Marcozzi-Pierce, Divya Shah, Kate Broderick, Amir Khan, Jessica Lee, Laurent Humeau, Niranjan Sardesai, Mark Bagarazzi. HPV specific immunotherapy for cervical intraepithelial neoplasia using VGX-3100 induces regression of cervical lesions and potent T-cell responses: Results from a randomized, double-blind, placebo-controlled phase II study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT131. doi:10.1158/1538-7445.AM2015-CT131

Potential impact of a 9-valent HPV vaccine in HPV-related cervical disease in 4 emerging countries (Brazil, Mexico, India and China)

BackgroundWe estimated the potential impact of an investigational 9-valent human papillomavirus (HPV) vaccine (HPVs 6/11/16/18/31/33/45/52/58) in HPV-related cervical disease in Brazil, Mexico, India and China, to help to formulate recommendations on cervical cancer prevention and control. MethodsEstimations for invasive cervical cancer (ICC) were based on an international study including 1356 HPV-positive cases for the four countries altogether, and estimations for precancerous cervical lesions were extracted from a published meta-analysis including 6 025 HPV-positive women from the four mentioned countries. Globocan 2012 and 2012 World Population Prospects were used to estimate current and future projections of new ICC cases. ResultsCombined proportions of the 9 HPV types in ICC were 88.6% (95%CI: 85.2–91.3) in Brazil, 85.7% (82.3–88.8) in Mexico, 92.2% (87.9–95.3) in India and 97.3% (93.9–99.1) in China. The additional HPV 31/33/45/52/58 proportions were 18.8% (15.3–22.7) in Brazil, 17.6% (14.2–21.2) in Mexico, 11.3% (7.5–16.1) in India and 11.9% (7.5–17.2) in China. HPV6 and 11 single types were not identified in any of the samples.Proportion of the individual 7 high risk HPV types included in the vaccine varied by cytological and histological grades of HPV-positive precancerous cervical lesions. HPV 16 was the dominant type in all lesions, with contributions in low grade lesions ranging from 16.6%(14.3–19.2) in Mexico to 39.8% (30.0–50.2) in India, and contributions in high grade lesions ranging from 43.8% (36.3–51.4) in Mexico to 64.1% (60.6–67.5) in Brazil. After HPV 16, variations in other majors HPV types were observed by country, with an under representation of HPV 18 and 45 compared to ICC. ConclusionThe addition of HPVs 31/33/45/52/58 to HPV types included in current vaccines could increase the ICC preventable fraction in a range of 12 to 19% across the four countries, accounting the 9-types altogether 90% of ICC cases. Assuming the same degree of efficacy of current vaccines, the implementation of the 9-valent HPV vaccine in Brazil, Mexico, India and China would substantially impact on the reduction of the world cervical cancer burden.

HPV-related cervical disease and oropharyngeal cancer

Human papillomavirus (HPV), especially HPV 16, is associated with the development of both cervical and oral cancer. We show the case of a woman affected by HPV-related cervical disease and oropharyngeal squamous cell carcinoma (OPSCC). A 41-year-old woman arrived at our Colposcopy Center following an abnormal Pap smear result (ASC-H) and a diagnosis of moderate cervical dysplasia obtained by a cervical biopsy. She underwent a colposcopy that showed a cervical abnormal transformation zone grade 2. A laser conization was performed in November 2010. Histology reported a moderate/severe dysplasia. The cone resection margins were free. Follow-up colposcopy and cytology were negative. The HPV testing showed an infection by HPV 16. In October 2012, the patient presented to the Head-Neck ER after episodes of hemoptysis; a lesion was found in the left tonsillar lodge. A biopsy was performed with a result of squamous cell carcinoma with low-grade differentiation. The HPV testing detected a high-risk HPV and the immunohistochemical analysis was positive for p16. She was treated by chemotherapy and brachytherapy. She was followed at the head-neck center with monthly visits with oral visual inspection that showed complete absence of mucosal abnormalities. HPV-related OPSCC and cervical precancerous/cancerous lesions have significant similarities in terms of pathogenesis. They are both caused largely by HPV 16, as in the present case. In conclusion, because of this association found in literature and in our case, we think that women with HPV cervical lesions should have regular surveillance for oropharyngeal cancer, whereas women with OPSCC should be encouraged to have diligent cervical screening.

Improving Diagnostic Capability for HPV Disease Internationally Within the NIH-NIAID Division of AIDS Clinical Trial Networks

To evaluate an external quality assurance (EQA) program for the laboratory diagnosis of human papillomavirus (HPV) disease that was established to improve international research capability within the Division of AIDS at the National Institute of Allergy and Infectious Disease-supported Adult AIDS Clinical Trials Group network. A three-component EQA scheme was devised comprising assessments of diagnostic accuracy of cytotechnologists and pathologists using available EQA panels, review of quality and accuracy of clinical slides from local sites by an outside expert, and HPV DNA detection using a commercially available HPV test kit. Seven laboratories and 17 pathologists in Africa, India, and South America participated. EQA scores were suboptimal for EQA proficiency testing panels in three of seven laboratories. There was good agreement between the local laboratory and the central reader 70% of the time (90% confidence interval, 42%-98%). Performance on the College of American Pathologists' HPV DNA testing panel was successful in all laboratories tested. The prequalifying EQA round identified correctable issues that will improve the laboratory diagnosis of HPV-related cervical disease at the participating international study sites and will provide a mechanism for ongoing education and continuous quality improvement.

High-risk human papillomavirus load and biomarkers in cervical intraepithelial neoplasia and cancer

The purpose of this study was to examine the implication of high-risk human papillomavirus (HPV) load in cervical intraepithelial neoplasia (CIN) and cancer, and to detect biomarkers in cervical disease. We conducted high-risk HPV DNA load and cervical cytology tests in 343 women, cervical tissue biopsy in 143 women, and immunohistochemistry for p16(INK4A), cyclin D1, p53, cyclooxygenase-2, Ki-67, GLUT1, hPygopus2, and beta-catenin. As a result, HPV load [relative light units (RLU) value] was correlated with the histological severity of cervical disease (p < 0.05). In the 'atypical squamous cells of undetermined significance' cytology group, 2.385 of HPV load seemed to be the cut-off value at which 'benign' or CIN I can be differentiated from 'CIN II or more severe' (AUC = 0.712), but not statistically significant. The relative risk (odds ratio) of p16(INK4A) and GLUT1 overexpression increased gradually according to the histological severity of cervical disease. The p16(INK4A) showed statistically significant odds ratios in CIN II, CIN III, and cancer; GLUT1, in CIN II and CIN III; hPygopus2, in CIN III; and beta-catenin, in CIN III and cancer. Conclusively, HPV load, p16(INK4A) , and GLUT1 can be instrumental in predicting the severity of HPV-related cervical disease. The beta-catenin/hPygopus2 signaling may be involved in proceeding to CIN III.

Association of KIR genes and HLA‐C alleles with HPV‐related uterine cervical disease in Korean women

This study investigated whether killer-cell immunoglobulin-like receptor (KIR) genes and human leukocyte antigen (HLA)-C alleles, receptors and ligands of natural killer cells are associated with the development of human papillomavirus (HPV)-related cervical disease in Korean women. Blood samples from 132 women with HPV-related cervical disease and 159 women without HPV infection were collected for genotyping of KIR genes and HLA-C alleles. Although no relationship was found between KIR genes and HPV-related cervical disease, a significant relationship was found between HLA-C alleles as ligands of KIR and HPV-related cervical disease. Women with HPV-related cervical disease were found to be significantly more likely to carry HLA-C*0303, particularly those with HPV 16 or 18 infection, and less likely to carry HLA-C*01 compared to women without HPV infection. HLA-C*0303 was found to confer susceptibility to HPV-related cervical disease, whereas HLA-C*01 was found to confer a protective effect against HPV-related cervical disease.

The Association of the Immune Response Genes to Human Papillomavirus-Related Cervical Disease in a Brazilian Population

The genetic variability of the host contributes to the risk of human papillomavirus (HPV)-related cervical disease. Immune response genes to HPV must be investigated to define patients with the highest risk of developing malignant disease. The aim of this study was to investigate the association of polymorphic immune response genes, namely KIR, HLA class I and II, and single-nucleotide polymorphisms (SNPs) of cytokines with HPV-related cervical disease. We selected 79 non-related, admixed Brazilian women from the state of Paraná, southern region of Brazil, who were infected with high carcinogenic risk HPV and present cervical intraepithelial neoplasia grade 3 (CIN3), and 150 HPV-negative women from the same region matched for ethnicity. KIR genes were genotyped using an in-house PCR-SSP. HLA alleles were typed using a reverse sequence-specific oligonucleotide technique. SNPs of TNF −308G>A, IL6 −174G>C, IFNG +874T>A, TGFB1 +869T>C +915G>C, and IL10 −592C>A −819C>T −1082G>A were evaluated using PCR-SSP. The KIR genes were not associated with HPV, although some pairs of i(inhibitory)KIR-ligands occurred more frequently in patients, supporting a role for NK in detrimental chronic inflammatory and carcinogenesis. Some HLA haplotypes were associated with HPV. The associations of INFG and IL10 SNPs potentially reflect impaired or invalid responses in advanced lesions.

TLR4 May Accelerate Hypoxia Reaction to Promote the Occurrence and Progress of Cervical Lesions by Infected Pathogenic Microorganisms Other than HPV

Objective: To explore what role the inflammatory immune response is playing in the occurrence and development of HPV related cervical disease. Methods: To detect the expression of TLR4, HIF-1α and HPV16 E7 in the specimens of HPV related cervical lesions, for example normal cervix, cervicitis, cervical intraepithelial neoplasia and cervical cancer by RT PCR methods. Results: The expression of TLR4 and HIF-1α ascent from normal cervix to cervicitis, then to CIN tissue, and then to cervical cancer (P 0.05). The expression of HPV16 E7 was higher in cervicitis than that in normal cervix (P 0.05) while there was no significant ascendance from cervicitis to CIN tissue, either from CIN tissue to cervical cancer although it seemed ascending (P > 0.05). Conclusion: TLR4 may promote the occurrence and progress of cervical lesions by accelerating the hypoxia reaction. And the natural immune reaction mediated by TLR4 may be correlated to other pathogenic microorganisms infecting the cervical tissue, rather than HPV.

Prognostic Significance of Immunohistochemical Phenotypes in Patients Treated for High-Grade Cervical Intraepithelial Neoplasia

Strong evidence exists that the host's immune system plays a crucial role for the development of human papillomavirus-related cervical premalignant and malignant lesions. In particular, effective cell-mediated immunity (CMI) promotes spontaneous infection clearance and cancer precursors regression in healthy subjects, while immunosuppressed individuals are more likely to experience infection persistence, cervical intraepithelial neoplasia (CIN) lesions, and cervical cancer. In this study, the prognostic significance of immunohistochemical profiling of CD4+ T-cells, CD8+ T-cells, dendritic cells (CD11c+), T-bet+, and GATA-3+ transcription factors has been studied in surgical specimens of 34 consecutive women affected by high-grade cervical intraepithelial neoplasia (CIN2-3) submitted to cervical conization. Results have been correlated with the clinical outcomes at 24 months after treatment and statistically analyzed. Higher rates of CD4+ T-cells, CD11c+ dendritic cells, and T-bet+ transcription factor positivity showed a strong statistically significative correlation with favourable clinical outcomes (P ≤ 0.0001). These data reinforce the evidence of the relevance of the host's immune status in the natural history of HPV-related cervical disease and add a prognostic significance of the cervical immunological profile in terms of predicting significant lower recurrence rates.

A review of methods for detect human Papillomavirusinfection

Human Papillomavirus (HPV) is the most common sexually transmitted virus. Worldwide, the most common high-risk (HR)-HPV are -16/18, and approximately 70% of cervical cancers (CC) are due to infection by these genotypes. Persistent infection by HR-HPV is a necessary but not sufficient cause of this cancer, which develops over a long period through precursor lesions, which can be detected by cytological screening. Although this screening has decreased the incidence of CC, HPV-related cervical disease, including premalignant and malignant lesions, continues to be a major burden on health-care systems. Although not completely elucidated, the HPV-driven molecular mechanisms underlying the development of cervical lesions have provided a number of potential biomarkers for both diagnostic and prognostic use in the clinical management of women with HPV-related cervical disease, and these biomarkers can also be used to increase the positive predictive value of current screening methods. In addition, they can provide insights into the biology of HPV-induced cancer and thus lead to the development of nonsurgical therapies. Considering the importance of detecting HPV and related biomarkers, a variety of methods are being developed for these purposes. This review summarizes current knowledge of detection methods for HPV, and related biomarkers that can be used to discriminate lesions with a high risk of progression to CC.