Cervical Intraepithelial Neoplasia Research Articles

Associations Between Preoperative Inflammatory Indices and Residual or Recurrent Cervical Intraepithelial Neoplasia Post Loop Electrosurgical Excision Procedure

Associations Between Preoperative Inflammatory Indices and Residual or Recurrent Cervical Intraepithelial Neoplasia Post Loop Electrosurgical Excision Procedure

Risk of cervical intraepithelial neoplasia II/III with high-risk, HPV-negative, high-grade Pap smear cytology

Risk of cervical intraepithelial neoplasia II/III with high-risk, HPV-negative, high-grade Pap smear cytology

Preliminary results from a phase II clinical trial assessing the safety and efficacy of pembrolizumab in the treatment of high-grade cervical intraepithelial neoplasia

Preliminary results from a phase II clinical trial assessing the safety and efficacy of pembrolizumab in the treatment of high-grade cervical intraepithelial neoplasia

The cervical and tumor-associated microbiome among Botswanan women with HIV diagnosed with high-grade cervical dysplasia and squamous cell carcinoma of the cervix

The cervical and tumor-associated microbiome among Botswanan women with HIV diagnosed with high-grade cervical dysplasia and squamous cell carcinoma of the cervix

Cervical cancer screening in high-risk patients: Clinical challenges in primary care.

The risk of developing cervical cancer is not equal across populations-individual health history, economic, political, and societal factors influence cervical cancer risk. Certain health conditions, including human immunodeficiency virus (HIV) infection, immunosuppression, and history of high-grade cervical dysplasia, are associated with higher cervical cancer risk and warrant distinct screening, surveillance, and management guidelines. It is imperative for clinicians to recognize high-risk groups and apply appropriate corresponding guidelines. However, this can be difficult in practice, as recommendations regularly evolve. This review offers up-to-date guidance in a case-based format on cervical cancer screening, surveillance, and management for high-risk patients.

Outcomes of loop electrosurgical excision procedure versus cold knife conization for cervical dysplasia

Outcomes of loop electrosurgical excision procedure versus cold knife conization for cervical dysplasia

In the era of the HPV vaccine, what are the current HPV subtypes contributing to high-grade cervical dysplasia, adenocarcinoma in situ, and early cervical cancer?

In the era of the HPV vaccine, what are the current HPV subtypes contributing to high-grade cervical dysplasia, adenocarcinoma in situ, and early cervical cancer?

Investigation of the Efficacy of Nowarta110 in the Treatment of HPV-16 and HPV-18 Oncogenically-transformed Human Cells and Cancer-implanted Animal Models.

Cervical cancer is the third leading cause of cancer-related death in women worldwide. Nearly all cases of cervical cancer are due to infection with human papillomavirus (HPV). Nowata110 has shown breakthrough therapeutic efficacy in phase II clinical study against plantar warts, with no reported side effects. This study evaluated the effectiveness of Nowarta110 in killing cultured HPV-transformed cancer cells and its anti-cancer effects in mice, using both vaginally engrafted and subcutaneously implanted animal cancer models. Nowata110 is a novel compound composed of colloidal silver and fig extract. The cytotoxic properties of Nowarta110 were evaluated on HPV-16 and HPV-18-transformed human cancer cells (ARPE-19/HPV-16 and HeLa cells, respectively). The therapeutic potential of Nowarta110 in vivo was evaluated following the engraftment of ME-180 epidermoid carcinoma cells in the mouse vagina or their subcutaneous implantation. Nowarta110 treatment was initiated when the tumor reached an approximate volume of 65 mm3 Results: Our data showed that HPV16-expressing human retinal pigmented epithelial cells are susceptible to Nowarta110-induced cell death, with a reduction in cell viability observed at 1% Nowarta110 and a complete absence of viable cells at 5% Nowarta110. In HPV18-expressing HeLa cells, Nowarta110 caused significant and rapid cell death at a dose of 5%, whereas lower doses of 1% did not produce the same effects. The results from animal studies indicated that Nowarta110 effectively induced tumor regression in both the intravaginal and subcutaneous tumor models. Nowarta110 effectively induced cell death in HPV-16 and HPV-18-transformed human cancer cells. It also effectively induced tumor regression in mouse models with intravaginally engrafted or subcutaneously implanted cancer cells. Considering the high prevalence of HPV-induced cervical dysplasia and cancer and the lack of treatment, clinical studies to promote the implementation of Nowarta110 are warranted.

Evaluation of endocervical curettage (ECC) in colposcopy for detecting cervical intraepithelial lesions.

Diagnostic challenges in colposcopy arise especially in women aged 50 or older, with postmenopausal status and transformation zone type 3 (TZ3). Endocervical curettage (ECC) is a valuable tool for diagnosing intracervical lesions. The aim of this retrospective analysis was to evaluate the use of ECC in colposcopy for detecting cervical intraepithelial lesions. A retrospective study was carried out of colposcopies performed in the certified Dysplasia Unit at Erlangen University Hospital between July 2016 and June 2023. Pap and human papillomavirus (HPV) results were correlated with the histologic findings via ECC, obtained during examinations or surgery. The primary outcome was the rate of accuracy between the colposcopic and histologic findings with regard to cytology, age of patients, and type of transformation zone (TZ). A total of 429 colposcopies in 413 women with histologic samples obtained via ECC were included in the final analysis. In all, 355 women had TZ3. Among patients with TZ3, evidence of high-grade lesions and invasive carcinoma was also found in women with normal or low-grade abnormal cytology. For patients with normal colposcopic findings, cervical intraepithelial neoplasia (CIN) 2 and CIN3/adenocarcinoma in situ (AIS) were found in 56 patients (16%), and invasive carcinoma was found in four patients (0.1%). This analysis suggests that ECC is a valuable tool in the diagnosis of cervical intraepithelial neoplasia, especially for patients who present with a normal colposcopy of the cervix and vagina but have either recurrent abnormal cytologic findings or high-grade abnormal cytology indicating CIN2 + .

Genital infections in high-risk human papillomavirus positive Paraguayan women aged 30–64 with and without cervical lesions

Objective To determine the prevalence of genital infections (GIs), including sexual transmitted STIs: Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Trichomonas vaginalis, and opportunistic pathogens that generally do not cause STIs, non-classic STI: Ureaplasma urealyticum, Ureaplasma parvum and Mycoplasma hominis, in women with high-risk oncogenic human papillomavirus (hr-HPV) infection and their association with cervical lesions. Methods A cross-sectional study was carried out including 231 hr-HPV positive women. Of these, 46 has histologically confirmed cervical intraepithelial neoplasia 3 (CIN3) or more (including CIN3 and cervical cancer lesions-CIN3+). GIs were detected by multiplex real time PCR. Odds ratios (OR) were estimated to explore possible associations between GIs and the presence or absence of CIN3+ lesions. Additionally, we examined associations between sociodemographic, sexual, and clinical characteristics and the presence of GIs. Results In total, there were 174/231 cases of GIs corresponding to an overall prevalence of 75.3% (95%CI: 69.4–80.4), being non-classic STIs the most common (72.3%) compared to STIs (12.6%). The most prevalent non-classic STI and STI were U. parvum (49.8%) and C. trachomatis (7.4%), respectively. The odds of presenting GIs were 3 times higher in women under 46 years compared to older counterparts (OR: 3.32, 95%CI: 1.74–6.16), and in women with a normal Pap smear with inflammation compared to those without inflammation (OR: 3.31, 95%CI: 1.15–9.77). GIs were equally present in women with and without CIN3+ lesions. Conclusion We observed an association of GIs with inflammation in the Pap smear, but no association with CIN3+, as some of them are very common and likely part of the normal vaginal flora, suggesting that such infections do not appear to be cofactors in cervical carcinogenesis, although larger prospective studies are needed.

Human papillomavirus vaccine to prevent CIN3 or worse (CIN3+): A nationwide case-control study in Japan.

An increase in cervical cancer incidence has been reported in Japan. The Ministry of Health, Labor, and Welfare of Japan has resumed the active recommendation of regular HPV vaccines in 2022. In Japan, the preventive effect of CIN3+ in the real world has not yet been demonstrated in age-adjusted cohort or case-control studies. This study aimed to estimate the effect of the HPV vaccine against CIN3+ in Japanese women. This nationwide case-control study from April 2013 to March 2020 targeted women aged 20-26 years old at the time of cervical screening. We compared HPV vaccination exposure between those with abnormal and those with normal cytology. Abnormal cytology was classified into cervical intraepithelial neoplasia (CIN)1+, CIN2+, and CIN3+. We calculated the odds ratio (OR) and 95% confidence interval (CI) of the above endpoints and vaccination exposure using the conditional logistic regression model and estimated vaccine effectiveness using the formula (1 -OR) × 100. A total of 2790 cases and 13,990 controls (one-to-five matching) were eligible in 37 municipalities in Japan. In this study, 61 CIN3 (2.2%) and 10 squamous cell carcinomas (SCC) (0.4%) were found. The OR for CIN3+ versus controls was 0.14 (95% CI, 0.03-0.75), equating to a vaccine effectiveness of 86%. Of the 10 patients who had SCC none were vaccinated. This nationwide case-control study in Japan demonstrated a substantial risk reduction in CIN3+ among women who did versus those who did not receive HPV vaccination.

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.

Germline variants of homology-directed repair or mismatch repair genes in cervical cancer.

While cervical cancer is associated with a persistent human papillomavirus (HPV) infection, the progression to cancer is influenced by genomic risk factors that have remained largely obscure. Pathogenic variants in genes of the homology-directed repair (HDR) or mismatch repair (MMR) are known to predispose to diverse tumour entities including breast and ovarian cancer (HDR) or colon and endometrial cancer (MMR). We here investigate the spectrum of HDR and MMR germline variants in cervical cancer, with particular focus on the HPV status and histological subgroups. We performed targeted next-generation sequencing for 5 MMR genes and 12 HDR genes on 728 German patients with cervical dysplasia or invasive cancer. In total, 4% of our patients carried a pathogenic germline variant, based on ClinVar classifications and additional ESM1b and AlphaMissense predictions. These included 15 patients with truncating variants in HDR genes (BARD1, BRCA1, BRCA2, BRIP1, FANCM, RAD51D and SLX4). MMR-related gene variants were less prevalent and mainly of the missense type. While MMR-related gene variants tended to associate with adenocarcinomas, HDR gene variants were commonly observed in squamous cancers. While one patient with HPV-negative cancer carried a pathogenic MMR gene variant (in MSH6), the HDR germline variants were found in patients with HPV-positive cancers and tended to associate with HPV18. Taken together, our study supports a potentially risk-modifying role of MMR and HDR germline variants in cervical cancer but no association with HPV-negative status. These variants may be exploitable in future therapeutic managements.

Effects of religion, politics and distance to providers on HPV vaccine attitudes and intentions of parents in rural Utah.

Human papillomavirus (HPV) causes an estimated 300,000 high grade cervical dysplasias and 36,000 preventable cancers each year in the United States alone. Despite having a safe, effective and long lasting vaccine since 2006, the rate of uptake has been suboptimal, particularly in rural areas. In 2020, Utah ranked near last in teenage HPV vaccination rates with rural areas trailing urban areas by about 18 percent. In this study, we identified factors that affect the intent of rural Utah parents to vaccinate their children against HPV. A survey was distributed electronically to Utah residents in rural areas. Recruitment was carried out through targeted advertising, community organizations, and professional survey panels. The survey was open from Nov. 15, 2022 to April 15, 2023. A total of 410 respondents were used for analysis. Survey results were analyzed using exploratory factor analysis, confirmatory factor analysis, and structural equation modeling. Distance to care was shown to negatively influence direct intent to vaccinate, while trust in government, general vaccine attitudes, and HPV knowledge positively influence intent to vaccinate. It was found that religious practice decreased vaccine hesitancy while cautious sexual attitudes, distance to care, and general negative vaccine attitudes increased vaccine hesitancy. Conservative political identity and high income were both shown to decrease vaccine hesitancy as covariates.

Validation of the 2019 American Society of Colposcopy and Cervical Pathology Online Cervical Cancer Screening Program via 9 Large-Cohort Data of Chinese Women.

The aim of the study is to validate the applicability and performance of the 2019 US risk-based guideline for Chinese women. We analyzed 10,055 cases with data on human papillomavirus testing, cytology, and pathologically confirmed diagnosis (analysis-set). According to the 2019 US risk-based guideline, we recorded the risk value and triage recommendations for each case. Then, we assessed the concordance of the guideline triage recommendations with pathology diagnosis for the relevant case from the real-world projects. Among the analysis-set, 9,495 cases with an estimated risk value were identified as analysis cohort while the remaining 560 cases were cataloged as "special cases." Among the analysis cohort, 960 and 526 cases were pathologically confirmed as cervical intraepithelial neoplasia (CIN) 2+ and CIN3+, respectively. The US risk-based guideline recommended colposcopy or more aggressive interventions (Colp+) for 86.8% (833/960) of the CIN2+ and 95.8% (504/526) of the CIN3+ cases, with 87.1% sensitivity and 82.5% specificity for CIN3+ cases (AUC = 0.926, p < .0001). The US risk-based recommended no-Colp for 98.0% (6,142/6,269) of the pathologically confirmed CIN1 or benign cases. In addition, 97.3% (545/560) of the "special cases" cases were recommended as Colp+. The 2019 US risk-based guideline works well with satisfied clinical sensitivity for CIN2+ and CIN3+ and seems applicable for cervical cancer screening in China.

Research Progress of Immune Mechanisms Related to Persistent HPV Infection in CIN after Cervical Conization

Persistent human papillomavirus (HPV) infection is associated with the grading of cervicalintraepithelial neoplasia (CIN), high-risk HPV infection, multiple HPV infections, high HPV load,HPV infection of surgical margin, and age in CIN after conization. The immune mechanism iscomplex and is primarily related to vaginal microecology disorders, immune escape, immuneresponse impairment, and the release of regulatory cytokines. Currently, the treatment methods forpostoperative persistent HPV infection include surgical treatment, antiviral treatment, vaccination,and other approaches.

An integrated approach to secondary prevention of cervical intraepithelial neoplasia

Secondary prevention of cervical precancer is aimed at preventing recurrence of cervical intraepithelial neoplasia (CIN) after excisional treatment. Recurrence of CIN after surgical treatment occurs in 8.1–14.4% of cases, which increases the risk of developing cervical cancer (CC). Despite the high effectiveness of local surgical treatment of patients with high-grade intraepithelial lesions (HSIL), an increased risk of late diagnosis of cervical cancer has been proven in comparison with the risk in the general population. The review article presents current data on factors that increase the potential risk of recurrence of precancer. Human papillomavirus (HPV) persistence is considered one of the leading predictors of relapse of CIN2+, regardless of the type of excision treatment. The combination of persistent high-risk (HR) HPV and a positive sectional margin significantly increases the risk of persistent/recurrent CIN2+. A negative co-test after conization during follow-up contributes to a favorable prognosis and the development of HSIL is observed less frequently than in the population. Only an integrated approach, including detection of cervical HPV HR infection after excisional treatment of CIN, assessment of the radicality of resection and timely measures to eliminate ineffective treatment, as well as subsequent active monitoring of patients, allows avoiding its recurrence and progression of cervical precancer

Nationwide study on development and validation of a risk prediction model for CIN3+ and cervical cancer in Estonia

Transitioning to an individualized risk-based approach can significantly enhance cervical cancer screening programs. We aimed to derive and internally validate a prediction model for assessing the risk of cervical intraepithelial neoplasia grade 3 or higher (CIN3+) and cancer in women eligible for screening. This retrospective study utilized data from the Estonian electronic health records, including 517,884 women from the health insurance database and linked health registries. We employed Cox proportional hazard regression, incorporating reproductive and medical history variables (14 covariates), and utilized the least absolute shrinkage and selection operator (LASSO) for variable selection. A 10-fold cross-validation for internal validation of the model was used. The main outcomes were the performance of discrimination and calibration. Over the 8-year follow-up, we identified 1326 women with cervical cancer and 5929 with CIN3+, with absolute risks of 0.3% and 1.1%, respectively. The prediction model for CIN3 + and cervical cancer had good discriminative power and was well calibrated Harrell’s C of 0.74 (0.73–0.74) (calibration slope 1.00 (0.97–1.02) and 0.67 (0.66–0.69) (calibration slope 0.92 (0.84–1.00) respectively. A developed model based on nationwide electronic health data showed potential utility for risk stratification to supplement screening efforts. This work was supported through grants number PRG2218 from the Estonian Research Council, and EMP416 from the EEA (European Economic Area) and Norway Grants.

The Level of Serum Selenium in Patients with Cervical Intraepithelial Neoplasia in Medical City/ Baghdad Teaching Hospital

Introduction: Selenium is an essential trace element involved in different physiological functions of the human body. An inverse relationship between serum selenium levels and cervical intraepithelial neoplasia has been reported. cervical intraepithelial neoplasia is regarded as a potentially premalignant transformation of squamous cells of the cervix. Objectives: To evaluate the relationship between the serum level of selenium and cervical intraepithelial neoplasia. Methods: A case-control study was conducted at Baghdad Teaching Hospital and Iraqi National Cancer Research Center in the University of Baghdad during the period from July 2021 to July 2022. A convenient sample of 100 women was enrolled in the current study and included case group which consisted of 50 women who were diagnosed with cervical intraepithelial neoplasia and control group which consisted of 50 women who did not have cervical intraepithelial neoplasia as confirmed through histological examination after punch biopsy by colposcopy. Results: The serum level of the selenium was significantly lower in the case groups compared to the control groups (P-value=0.001). In addition, the proportion of the participant with abnormal levels of selenium was significantly higher in the case group compared to the control group (P-value=0.001). In the case group, there was a significant difference between the cervical intraepithelial neoplasia grade regarding the serum level of selenium, the level of selenium significantly decreased with the progression of the disease (P-value=0.001). Conclusions: Selenium deficiency may significantly increase the incidence of cervical intraepithelial neoplasia. In addition, it significantly impacts the transformation to a higher degree as there was a significant difference between cervical intraepithelial neoplasia I, II, and III regarding the level of serum selenium.

Age-specific 3-year risk of cervical precancer among HPV-positive women attending screening: a post hoc analysis from a retrospective cohort

This post hoc analysis explored the age-specific risk of cervical precancer in women infected with human papillomavirus (HPV), using data from a cohort of 7263 participants aged 21-71years undergoing cervical screening. We found a slightly varied prevalence of high-risk HPV (hrHPV) in different age, with highest in women under 30 years old (9.28% for 13 hrHPVs tested by HC2-HPV, 10.82% for 14 hrHPVs tested by DH3-HPV). However, the prevalence of cytology abnormalities peaked in age 30–39 years (~ 3.6%). A total of 5840 women completed 3-year follow-up. Among them, 558 were positive for HC2 assay and 583 were positive for DH3-HPV at baseline. Of note, the 3-year cumulative risks for cervical intraepithelial neoplasia grade 2+ (CIN2+) or grade 3+ (CIN3+) in women infected with high-risk HPV did not increase with age but declined (e.g., 41.67%, 27.78%, 26.42%, 15.98%, and 18% for CIN2 + risk in HC2-positive women at year 25–29, year 30–39, year 40–49, year 50–59, and year 60–71, respectively). If stratified by the median age, younger women (25–48 years) positive with HC2-HPV at baseline had a higher 3-year CIN2+/CIN3 + risk than older women (49–71 years) [26.55% (95%CI = 21.8-31.92%) vs. 18.28% (95%CI = 14.11-23.34%), P = 0.019; 15.52% (95%CI = 11.81-20.14%) vs. 9.7% (95%CI = 6.71-13.83%), P = 0.039]. Similarly, for women positive with DH3-HPV at baseline, younger group had a higher 3-year CIN2+/CIN3 + risk than older group [26.44% (95%CI = 21.73-31.75%) vs. 17.01% (95%CI = 13.11-21.78%), P = 0.006; 15.25% (95%CI = 11.6-19.8%) vs. 9.03% (95%CI = 6.24-12.9%), P = 0.021]. These findings indicate the potential value of age-specific risk assessment in cervical cancer screening.