Human Leucocyte Antigen Class II Risk and Protective Alleles in Women with Cervical Intraepithelial Neoplasia.

Background: Persistent human papillomavirus (HPV) infection is a necessary cause for development of cervical precancerous lesions and cervical cancer, however, only a small percentage of women progress to cervical cancer. The local immune response, determined, among other factors, by Human Leucocyte Antigen (HLA) genes, is thought to be significant. Still the results of genome studies are inconsistent and differ between ethnical populations. The aim of the study was to assess an association between HLA-DQA1*; DQB1*; DRB1* allele's genetic variants between women with cervical precancerous lesions and healthy controls in Latvia. Materials and methods: From January until April 2017 we enrolled 84 consecutive patients referred for colposcopy to Riga East University Hospital (Latvia) due to abnormal cervical cytology results. 57 women who came for a regular check-up and had normal cytology smears were included in the control group. Material from the cervix was taken for subsequent HLA genotyping of 13 DRB1*, 8 DQA1*, and 12 DQB1* alleles. Colposcopy was performed on all participants. In case of visual suspicion for CIN cervical biopsy was done. Results: There were 57 "no CIN" patients, 23 histologically proven CIN 1 and 61 CIN2+ cases in the study population. CIN2+ was more often associated with DQA1*0401 (OR 6.68, 95% CI 1.47-30.29, p=0.014), DRB*15 (OR 2.99, 95% CI 1.22-7.39, p=0.017), DQB1*0401 (OR 2.91, 95%CI 1.11-7.68, p=0.03), DQA1*0103 (OR 2.72, 95% CI 1.02-7.21, p=0.045), DRB1*11 (OR 2.42, 95% CI 1.10-5.33, p=0.029) and DQB1*0301 (OR 1.94, 95% CI 1.12-3.38, p=0.018). Women with "no CIN" more often had DQB1*0501 (OR 0.17, 95% CI 0.04-0.81, p=0.026), DRB1*16 (OR 0.21, 95% CI 0.06-0.78, p=0.019), DQA1*0301 (OR 0.35, 95% CI 0.14-0.87, p=0.024) and DRB1*14 (OR 0.59, 95% CI 0.01-0.46, p=0.007). Conclusions: In the current study we have demonstrated a strong association with risk and protective HLA class II alleles that are determined by the HLA-DRB1*; DQA1*; DQB1*.

A Narrative Review on the Clinical Utility of Electrical Impedance Spectroscopy for Diagnosing High-Grade Cervical Intraepithelial Neoplasia.

Colposcopy constitutes a pivotal step in the diagnosis and management of cervical intraepithelial neoplasia; nevertheless, the method has several inherent and external limitations. Electrical impedance spectroscopic (EIS) has been among the adjuncts that have been developed to increase the diagnostic accuracy of colposcopy. EIS is based on the principle that the trajectory of electrical current alters depending on the consistency of the tissues. In the present study, we investigate the diagnostic accuracy and clinical utility of EIS by means of searching the available evidence. Our search yielded 17 articles during the period 2005-2023. Subsequently, we focused on the performance metrics of the included studies. The general concept is that EIS, in combination with colposcopy, is a method with increased sensitivity and specificity in detecting high-grade cervical intraepithelial neoplasia as compared to colposcopy alone. However, we documented a heterogeneous distribution of these and other metrics, including the positive predictive value, the negative predictive value, and the area under the receiver operating characteristic curve (AUC). Additionally, we located potential confounders that might hamper the measurements of EIS and, as such, warrant further investigation in future research. We conclude that future studies should be directed towards randomized multicentric trials, whereas the advent of artificial intelligence might improve the diagnostic accuracy of the method by helping incorporate a large amount of data.

Does HPV-18 co-infection increase the risk of cervical pathology in individuals with HPV-16?

OBJECTIVE: We aimed to investigate differences between HPV-16 mono- and HPV-16/18 co-infections in terms of cervical dysplasia and invasive cancer. METHODS: This multicentre, retrospective study spanned from December 2017 to December 2020, involving women who visited gynaecological oncology clinics for colposcopy with either HPV-16 or HPV-16/18 positivity. A total of 736 patients, 670 in Group 1 (HPV-16 positivity) and 66 in Group 2 (HPV-16/18 positivity), were compared for the presence of CIN2+ lesions detected by colposcopic biopsy or endocervical curettage (ECC). Exclusions included hysterectomized patients, those with prior gynaecological cancers, and patients with HPV positivity other than types 16 and 18. RESULTS: Among the included patients, 42.4% had a diagnosis of CIN2+ lesions. The cytology results demonstrated abnormal findings in 45.3% in Group 1 and 42.2% in Group 2, with no significant difference between the groups. ECC revealed CIN2+ lesion in 49 (8.7%) patients in group 1, while only 1 (1.7%) patient had CIN2+ lesion in group 2. There was no difference between 2 groups in terms of ECC result (p = 0.052). In group 1, 289 (43.1%) patients had CIN2+ lesion, while 23 (34.8%) patients had CIN2+ lesions in group 2. There was no difference between group 1 and 2 in terms of diagnosis of CIN2+ lesions (p = 0.19). CONCLUSION: This multicentre retrospective study found no significant differences between HPV-16 mono- and HPV-16/18 co-infections regarding cervical pathologies. Larger studies are needed to validate and further explore these findings.

Immunohistochemistry staining of Eag1 and p16/Ki-67 can help improve the management of patients with cervical intraepithelial Neoplasia after cold knife conversion.

BACKGROUND: Immunohistochemistry (IHC) is widely used in the management of patients with cervical intraepithelial neoplasia (CIN) but still has many limitations in clinical practice. We analyzed the correlation of new biomarkers with the severity of CIN and follow-up outcomes in patients after conization to improve the management of patients with CIN. METHODS: IHC staining of Eag1 and p16/Ki-67 was performed on cervical tissue sections from 234 patients with suspected CIN2/3. After a series of follow-ups, including human papillomavirus (HPV) test and thinprep cytologic test (TCT) for 1-2 years, the outcomes were collected. IHC scores of biomarkers and follow-up results were used to analyze the correlation and assess the diagnostic efficiency of biomarkers. RESULTS: The IHC staining intensity of Eag1 and p16/Ki-67 was significantly different from that of the CIN1-3 groups (p < 0.05). Eag1 expression scores were significantly different in the distribution between the two follow-up groups (p < 0.001). ROC curves based on the correlations between the follow-up outcomes and the Eag1 scores and IS of p16/ki-67 showed that Eag1 had a greater AUC (0.767 vs. 0.666). Logistic regression analysis of the combination of biomarkers revealed a greater AUC value than any single biomarker. CONCLUSIONS: Eag1 expression was significantly correlated with CIN grade and follow-up outcomes after conization. IHC staining of combinations of biomarkers of Eag1, p16 and Ki-67 may help us to improve the ability to identify risk groups with abnormal follow-up outcomes after treatment for CIN.

Modified swede colposcopic index versus modified reid index in colposcopic screening for premalignant & malignant lesions of the cervix: a cross-sectional analysis.

BACKGROUND: Cervical cancer cases in India account for one-fourth of the worldwide burden. Colposcopy is used to evaluate the cervix of women with abnormal screening test results. For standardized reporting, various scores were introduced of those, Reid Colposcopic Index (RCI) and Swede score are the most commonly used. AIMS AND OBJECTIVES: This study is undertaken to determine the diagnostic efficacy and clinical relevance of the newly introduced MSCI and compare MSCI and Modified Reid Index. RESULTS: 225 women out of 237 were analyzed. MSCI score 9 perform best for colposcopic diagnosis of CIN 2 or higher lesions. The sensitivity, specificity, PPV, and NPV for threshold score 9 for CIN 2 or higher lesions were 94.92 %, 67.88 %, 51.38 %, and 97.39 % respectively. Modified Reid Index threshold 3 performed best for the detection of CIN 2 or higher lesions with a sensitivity, specificity, PPV, and NPV of 84.75 %, 44.85 %, 35.46 %, and 89.16 % respectively. On comparing the area under the curve (AUC) for MSCI and MRI, we found that the difference between the AUC of MSCI (0.854) and Modified Reid Index (0.657) was significant (P < 0.05). CONCLUSION: MSCI performs better than the modified reid index for the diagnosis of both HGL and LGL or higher. Also, the omission of impractical measurements and inclusion of easier and more practical parameters than the Swede score or Modified Reid Index makes MSCI a simple and effective screening tool.

Cervical intraepithelial neoplasia and fecundability: a prospective cohort study.

STUDY QUESTION: Is cervical intraepithelial neoplasia (CIN) associated with reduced fecundability, defined as the probability of conceiving per menstrual cycle? SUMMARY ANSWER: Overall, we observed no meaningful association between CIN and fecundability, regardless of surgical status, although a recent diagnosis of moderate or severe CIN might be associated with slightly reduced fecundability for 2 years after diagnosis. WHAT IS KNOWN ALREADY: About 15% of couples experience infertility. Few studies have examined the influence of CIN on fertility, and the results have been inconsistent. No study has investigated the association between fecundability and pathologist-reported CIN diagnoses, particularly with respect to the recency of the specific CIN diagnoses. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 9586 women trying to conceive. The women were enrolled from 1 June 2007 to 3 February 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women were invited to complete a baseline questionnaire and bimonthly follow-up questionnaires for up to 12 months or until pregnancy occurred. Data on cervical cytologies and biopsies were retrieved from The National Pathology Registry (DNPR), which holds records of all cervical specimens examined in Denmark. Women were categorized based on their most severe diagnosis of CIN: no lesion, other cervical changes, mild CIN (CIN1), or moderate/severe CIN (CIN2+) with or without surgery. To investigate the association between CIN and fecundability, we computed fecundability ratios (FR) and 95% confidence intervals (CI) using a proportional probabilities regression model. We adjusted for age at study entry, partner age, body mass index, smoking status, timing of intercourse, parity, education, number of sexual partners, and household income. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with no lesion, the adjusted FRs (95% CI) for the association between CIN and fecundability were: other cervical lesions, 0.97 (0.91-1.04); CIN1, 1.04 (0.96-1.13); CIN2+ no surgery, 1.00 (0.82-1.22); and CIN2+ with surgery 0.99 (0.89-1.10). The FRs (95% CI) for a recent diagnosis (<2 years) of CIN were 0.98 (0.86-1.11) for other cervical lesions; 1.13 (0.99-1.29) for CIN1; 0.89 (0.62-1.26) for CIN2+ no surgery and 0.91 (0.75-1.10) for CIN2+ with surgery compared with the no lesion group. LIMITATIONS, REASONS FOR CAUTION: In the analyses, we adjusted for several covariates related to the women. However, we had little information on the male partners which could lead to unmeasured confounding as fecundability is a couple-based measure of fertility. Furthermore, a CIN diagnosis may not be constant as it may regress or progress spontaneously; therefore, it is possible that we have misclassified some women, especially women categorized as having normal cells or CIN1. WIDER IMPLICATIONS OF THE FINDINGS: Our results contribute important knowledge to women who are concerned about their future fertility after receiving a CIN diagnosis. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by The Danish Cancer Society (R167-A11036-17-S2). The overall cohorts were funded by the National Institute of Child Health and Human Development (R01-HD086742 and R03-HD094117). The authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Risk of cervical high-grade squamous intraepithelial neoplasia in cytologic negative and persistently high-risk human papillomavirus positive patients according to genotypes: a retrospective single center analysis.

In January 2020, a different cervical cancer screening program started in Germany. Women above the age of 35 are recommended to have a combined HPV and cytology swab every three years. Showing persistent high-risk human papillomavirus (hrHPV), cytologic negative cervical samples at baseline and after 12 months, patients are referred to colposcopy. Entailing considerable additional workload due to the required colposcopies, we analyzed the risk of high-grade cervical intraepithelial neoplasia (CIN 3) in cytologic negative and persistent hrHPV women according to their hrHPV genotypes.Methods In this single center retrospective study, patients with persistent hrHPV, cytology negative cervical samples from our certified Colposcopy Unit in 2020 and 2021 were analyzed. Patient demographics, hrHPV types, biopsy rates and histological reports were collected.Results During the study, 69 patients were enrolled. Most frequent hrHPV genotypes were: hrHPV other 72.5%; HPV 16, 20.3% and HPV 18, 7.2%. Colposcopy showed no or minor changes in 92.7% and major changes in 7.2%. CIN 3 was found in 7 patients (10.1%). Prevalence of CIN 3 by hrHPV genotypes was 27.3% for HPV16, 20.0% for HPV18 and 7.1% for HPVO. A statistically significant dependency between hrHPV and cervical intraepithelial neoplasia was demonstrated (p = 0.048).Conclusion Within this single center study of persistent hrHPV, cytologic negative samples, patients with HPV 16 were more likely to have high-grade disease compared to other hrHPV subtypes. Larger prospective randomized trials are needed to substantiate our results and obtain adjusted cervical cancer screening time intervals according to the hrHPV genotypes.

Risk factors for residual lesions after total hysterectomy in patients with high-grade cervical intraepithelial neoplasia.

BACKGROUND: The purpose of this study was to predict the risk factors for residual lesions in patients with high-grade cervical intraepithelial neoplasia who underwent total hysterectomy. METHODS: This retrospective study included 212 patients with histologically confirmed high-grade cervical intraepithelial neoplasia (CIN2-3) who underwent hysterectomy within 6 months after loop electrosurgical excision procedure (LEEP). Clinical data (e.g., age, menopausal status, HPV type, and Liquid-based cytology test(LCT) type), as well as pathological data affiliated with endocervical curettage (ECC), colposcopy, LEEP and hysterectomy, were retrieved from medical records. A logistic regression model was applied to estimate the relationship between the variables and risk of residual lesions after hysterectomy. RESULTS: Overall, 75 (35.4%) patients had residual lesions after hysterectomy. Univariate analyses revealed that positive margin (p = 0.003), glandular involvement (p = 0.017), positive ECC (p < 0.01), HPV16/18 infection (p = 0.032) and vaginal intraepithelial neoplasia (VaIN) I-III (p = 0.014) were factors related to the presence of residual lesions after hysterectomy. Conversely, postmenopausal status, age ≥ 50 years, ≤ 30 days from LEEP to hysterectomy, and LCT type were not risk factors for residual lesions. A positive margin (p = 0.025) and positive ECC (HSIL) (p < 0.001) were identified as independent risk factors for residual lesions in multivariate analysis. CONCLUSIONS: Our study revealed that positive incisal margins and ECC (≥ CIN2) were risk factors for residual lesions, while glandular involvement and VaIN were protective factors. In later clinical work, colposcopic pathology revealed that glandular involvement was associated with a reduced risk of residual uterine lesions. 60% of the patients with residual uterine lesions were menopausal patients, and all patients with carcinoma in situ in this study were menopausal patients. Therefore, total hysterectomy may be a better choice for treating CIN in menopausal patients with positive margins and positive ECC.

Impact of human papillomavirus types on uterine cervical neoplasia.

Human papillomavirus (HPV) is a major cause of cervical cancer. As the natural history of HPV-associated cervical lesions is HPV genotype-dependent, it is important to understand the characteristics of these genotypes and to manage them accordingly. Among high-risk HPVs, HPV16 and 18 are particularly aggressive, together accounting for 70% of HPV genotypes detected in cervical cancer. Other than HPV16 and 18, HPV31, 33, 35, 45, 52, and 58 are also at a high risk of progression to cervical intraepithelial neoplasia (CIN)3 or higher. Recent studies have shown that the natural history of HPV16, 18, 52, and 58, which are frequently detected in Japan, depends on the HPV genotype. For example, HPV16 tends to progress in a stepwise fashion from CIN1 to CIN3, while HPV52 and 58 are more likely to persist in the CIN1 to CIN2 state. Among the high-risk HPVs, HPV18 has some peculiar characteristics different from those of other high-risk HPV types; the detection rate in precancerous lesions is much lower than those of other high-risk HPVs, and it is frequently detected in highly malignant adenocarcinoma and small cell carcinoma. Recent findings demonstrate that HPV18 may be characterized by latent infection and carcinogenesis in stem cell-like cells. In this context, this review outlines the natural history of HPV-infected cervical lesions and the characteristics of each HPV genotype.

The diagnostic accuracy of serum and plasma microRNAs in detection of cervical intraepithelial neoplasia and cervical cancer: A systematic review and meta-analysis.

Studies suggest a need for new diagnostic approaches for cervical cancer including microRNA technology. In this review, we assessed the diagnostic accuracy of microRNAs in detecting cervical cancer and Cervical Intraepithelial Neoplasia (CIN). We performed a systematic review following the Preferred Reporting Items for Systematic Review and Meta-Analysis guideline for protocols (PRISMA-P). We searched for all articles in online databases and grey literature from 01st January 2012 to 16th August 2022. We used the quality assessment of diagnostic accuracy studies tool (QUADAS-2) to assess the risk of bias of included studies and then conducted a Random Effects Meta-analysis. We identified 297 articles and eventually extracted data from 24 studies. Serum/plasma concentration miR-205, miR-21, miR-192, and miR-9 showed highest diagnostic accuracy (AUC of 0.750, 0.689, 0.980, and 0.900, respectively) for detecting CIN from healthy controls. MicroRNA panels (miR-21, miR-125b and miR-370) and (miR-9, miR-10a, miR-20a and miR-196a and miR-16-2) had AUC values of 0.897 and 0.886 respectively for detecting CIN from healthy controls. For detection of cervical cancer from healthy controls, the most promising microRNAs were miR-21, miR-205, miR-192 and miR-9 (AUC values of 0.723, 0.960, 1.00, and 0.99 respectively). We report higher diagnostic accuracy of upregulated microRNAs, especially miR-205, miR-9, miR-192, and miR-21. This highlights their potential as stand-alone screening or diagnostic tests, either with others, in a new algorithm, or together with other biomarkers for purposes of detecting cervical lesions. Future studies could standardize quantification methods, and also study microRNAs in higher prevalence populations like in sub-Saharan Africa and South Asia. Our review protocol was registered in PROSPERO (CRD42022313275).

Emerging trends and hotspots in cervical intraepithelial neoplasia research from 2013 to 2023: A bibliometric analysis.

Background: Cervical intraepithelial neoplasia (CIN) encompasses a range of cervical lesions that are closely linked to cervical invasive carcinoma. Early detection and timely treatment of CIN are crucial for preventing the progression of the disease. However, no bibliometric analysis has been conducted in this area. This research aimed to employ bibliometric analysis to summarize the current research hotspots and estimate future research trends in the CIN field. Methods: Publications related to CIN (2013-2023) were retrieved from the Science-Citation-Index-Expanded-of-Web-of-Science-Core-Collection. CiteSpace, VOSviewer, and the bibliometric-Online-Analysis-Platform-of-Literature-Metrology were employed to analyze the yearly research output, collaborating institutions or countries, leading researchers, principal journals, co-referenced sources, and emerging keywords. Results: In total, 4677 articles on CIN that were published from 2013 to 2023 and met our criteria were extracted. Major publishing platforms were predominantly USA until 2017 when China emerged as the leading source of publications about CIN. The USA was the leading nation in international collaborations. The National-Cancer-Institute (NCI) was the institution with the most publications. Schiffman Mark produced the highest number of articles, with a total of 92. Ten major clusters were identified through co-cited keyword clustering, including prevalence, human papillomavirus, DNA methylation, p16, methylation, conization, HPV genotyping tests (VALGENT), deep learning, vaginal microbiome, and immunohistochemistry. Keyword burst analysis showed that photodynamic therapy and deep learning emerged as prominent research focal points with significant impact in resent three years. Conclusion: Global publications on CIN research showed a relatively stable trend over the past eleven years. Current research hotspots are deep learning and photodynamic therapy. This research offered organized data and insightful guidance for future studies, which may help better prevent, screen, and treat CIN.

Reproducibility of colposcopy quality indicators-A survey among members of the European Federation for Colposcopy.

INTRODUCTION: Colposcopy is an important part of the diagnostic work-up of women with an abnormal cervical screening test as it is used to guide the collection of biopsies. Although quality assurance has been used in the evaluation of screening programs, not much is known about quality indicators for the diagnostics and treatment of screen-positive women. Therefore, the European Federation for Colposcopy developed quality indicators aiming to support colposcopy practice across Europe. We performed a survey of colposcopy cases to determine if the quality indicators are understandable, relevant, and reproducible. MATERIAL AND METHODS: We conducted a survey among all members of the European Federation for Colposcopy Quality and Standards Group from November 2022 to March 2023. Members were asked to collect information on a total of 17 quality indicators for 50 women who had been newly referred for colposcopy due to an abnormal screening test between January 1, 2020 to December 31, 2021. Results were reported descriptively. RESULTS: We included data on 609 cases from 12 members across Europe. The majority of the quality indicators were either achieved or within reach of the agreed standard, often due to few countries with outlying data. One quality indicator had very low performance, although stratified results indicated that two countries had different clinical management of the patient type thereby skewing the results. In addition, discrepancies between the number of cases included in each quality indicator raised concerns regarding potential misunderstanding of the quality indicator and its objective. CONCLUSIONS: Quality indicators on colposcopy must be understandable to those collecting data, highlighting the importance of validating quality indicators before data collection.

Reduced risk of CIN2+ recurrence in women immunized with a 9-valent HPV vaccine post-excision: Retrospective cohort study.

The main aim of our study was to investigate the specific contribution of a 9-valent human papillomavirus vaccine (9vHPV) to the recurrence risk of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in women vaccinated post-excision. Therefore, we conducted a retrospective monocentric cohort study in women aged 22-49 years undergoing conization between 2014 and 2023. The 9vHPV-vaccinated women were matched to unvaccinated women for age and follow-up duration in a 1:2 ratio to eliminate allocation bias. The risk of CIN2+ recurrence was estimated by the incidence rate ratio using Poisson regression with adjustment for comorbidities, smoking status, nulliparity, CIN grade, positive cone margin, and HPV genotypes. The CIN2+ recurrence rates in 147 women enrolled in the analysis were 18 and 2 cases per 100,000 person-days for unvaccinated and vaccinated women, respectively, during a mean follow-up period of 30 months (±22 months). A reduction in CIN2+ recurrences by 90% (95% confidence interval: 12-99%) was documented in 9vHPV-vaccinated participants compared to women undergoing only surgical excision. Moreover, vaccinated women with a positive cone margin showed a 42% (though non-significant) reduction in relapse (p = .661). Full post-conization vaccination with the 9vHPV contributed to an additional reduction in the risk of CIN2+ recurrence. This finding is consistent with current knowledge and suggests a high adjuvant effect of the 9vHPV vaccine.

Clinical vaginal-microecology testing using double-fluorescence staining in patients with high-risk human papillomavirus infection.

High-risk human papillomavirus (hrHPV) infection is associated with cervical cancer; imbalanced vaginal microecology may contribute to HPV progression. Currently used methods for clinical vaginal-microecology (CVM) testing are associated with several disadvantages, such as low accuracy and complicated operation. This retrospective study presents a novel testing method to examine vaginal microecology via double-fluorescence staining and explores the relationship between hrHPV and CVM. We analyzed 1242 patients who underwent hrHPV testing at our hospital over a two-month period; of these, 695 also underwent clinical vaginal-microecology testing (CVMT). Patients underwent routine leukorrhea detection (n=322), functional testing (n=277), and our novel double-fluorescence staining-based CVMT approach (n=376). Patients with hrHPV exhibited more epithelial cells, miscellaneous bacteria, and hyphae than those without hrHPV on double-fluorescence staining-based CVMT approach. Double-fluorescence staining was effective in identifying indicators of hrHPV infection and may serve as an auxiliary tool for clinical hrHPV screening.

Comparison of HPV-positive triage strategies combining extended genotyping with cytology or p16/ki67 dual staining in the Italian NTCC2 study.

BACKGROUND: Each high-risk HPV genotype has different oncogenic potential, and the risk of CIN3+ varies according to genotype. We evaluated the performance of different strategies of HPV-positivity triage combining cytology, p16/ki67 dual staining (DS), and extended genotyping. METHODS: Samples from 3180 consecutive women from the NTCC2 study (NCT01837693) positive for HPV DNA at primary screening, were retrospectively analyzed by the BD Onclarity HPV Assay, which allows extended genotyping. Genotypes were divided into three groups based on the risk of CIN3+. HPV DNA-positive women were followed up for 24 months or to clearance. FINDINGS: Combining the three groups of genotypes with cytology or DS results we identify a group of women who need immediate colposcopy (PPV for CIN3+ from 7.8 to 20.1%), a group that can be referred to 1-year HPV retesting (PPV in those HPV-positive at retesting from 2.2 to 3.8), and a group with a very low 24-month CIN3+ risk, i.e. 0.4%, composed by women cytology or DS negative and positive for HPV 56/59/66 or 35/39/68 or negative with the Onclarity test, who can be referred to 3-year retesting. INTERPRETATION: Among the baseline HPV DNA positive/cytology or DS negative women, the extended genotyping allows to stratify for risk of CIN3+, and to identify a group of women with a risk of CIN3+ so low in the next 24 months that they could be referred to a new screening round after 3 years. FUNDING: Italian Ministry of Health (grant number RF-2009-1536040). Hologic-Genprobe, Roche Diagnostics, and Becton & Dickinson provided financial and non-financial support.

The Role of Traditional Chinese Medicine in the Management of Cervical Cancer.

Globally, cervical cancer poses a substantial public health challenge, with low and middle-income countries bearing the highest burden [Rajkhowa, P., D.S. Patil, S.M. Dsouza, P. Narayanan and H. Brand. Evidence on factors influencing HPV vaccine implementation in South Asia: a scoping review. Glob. Public Health 18: 2288269, 2023]. The incidence rate ranks second highest among female malignant tumors in China, following only breast cancer. The prognosis of advanced cervical cancer is extremely poor, with a 5-year progression-free survival (PFS) rate of only 15%, and the treatment of advanced recurrent or metastatic cervical cancer remains a huge challenge. An increasing amount of evidence suggests that traditional Chinese medicine (TCM) can significantly enhance sensitivity to chemotherapeutic drugs, strengthen antitumor effects, and notably improve adverse reactions associated with cancer such as fatigue and bone marrow suppression. In recent years, the therapeutic effects and mechanisms of Chinese herbal medicines, such as the Guizhi-Fuling-decoction, the compound Yangshe granule, Huangqi, and Ginseng, herbal monomers (e.g., Ginsenoside Rh2, Tanshinone IIA, and Tetrandrine), and the related extracts and compound formulations, have received extensive attention for the treatment of cervical cancer. This paper reviews the research progress of TCM in cervical cancer. In addition, we reported a case of an advanced cervical cancer patient with multiple abdominal and pelvic metastasis who initially received chemotherapy, was then treated with TCM alone, and subsequently survived for 22 years. The model of whole-process management with TCM can enable more cancer patients to obtain longer survival periods.

Efficacy and Safety of 5-Aminolevulinic Acid Photodynamic Therapy for Treating Cervical and Vaginal Intraepithelial Neoplasia.

Persistent HPV infections may cause cervical and vaginal intraepithelial neoplasia (CIN and VaIN). Traditional methods might destroy the structure and function of the cervix. 5-aminolevulinic acid photodynamic therapy (ALA-PDT) is a non-invasive targeted therapy. This study aims to evaluate the efficacy and safety of ALA-PDT for CIN and VaIN and the clearance of HPV. A retrospective study of 303 patients who confirmed CIN or VaIN and received ALA-PDT was conducted. All the patients were followed up at six and twelve months after treatment and then annually thereafter. The effect was evaluated through HPV genotyping, a cytology test, and colposcopy-directed biopsy if necessary. After ALA-PDT, the remission rates for CIN 2, CIN 3, VaIN 2, and VaIN 3 were 90.6%, 88.5%, 87.3%, and 77.8%. For CIN 1, the remission rate at the six-month follow-up was 93.1%. The total HPV clearance rates were 72.5% at the six-month follow-up and 85.7% at the 12-month follow-up. The most common adverse event was vaginal discharge. No severe adverse effect was observed. ALA-PDT is an effective and safe treatment for all grades of CIN and VaIN and is helpful in clearing HPV with minimal side effects. This treatment may not influence fertility and delivery.

Advancements in the Management of Cervical Intraepithelial Neoplasia: A Comprehensive Review.

Cervical intraepithelial neoplasia (CIN) represents a significant precursor to cervical cancer, posing a considerable threat to women's health globally. This comprehensive review examines recent advancements in the management of CIN, encompassing screening, diagnosis, and treatment modalities. The etiology and pathogenesis of CIN are explored alongside an analysis of traditional and emerging screening techniques, including liquid-based cytology and molecular biomarkers. Treatment options, from minimally invasive procedures to immunotherapy approaches, are evaluated for efficacy and potential impact on patient outcomes. Furthermore, this review highlights the implications of these findings for clinical practice, emphasizing the importance of staying abreast of evolving guidelines and integrating innovative strategies into routine care. Recommendations for future research and practice are provided, emphasizing personalized approaches, disparities in access to care, and the exploration of novel therapeutic avenues. By addressing these challenges and opportunities, this review aims to contribute to the ongoing efforts to mitigate the burden of CIN and cervical cancer, ultimately improving women's health outcomes worldwide.

Vaginal micro-environment disorder promotes malignant prognosis of low-grade cervical intraepithelial neoplasia: a prospective community cohort study in Shanxi Province, China.

PURPOSE: Emerging evidence suggests that vaginal micro-environment disorder is closely related to the development of cervical lesions. Low-grade cervical intraepithelial neoplasia (CIN1), as an early stage of cervical lesions, exhibits a high risk of progressing to high-grade lesions or even cervical cancer. However, the effect of vaginal micro-environment on the malignant prognosis of CIN1 remains uncertain. METHODS: A total of 504 patients diagnosed with CIN1 by pathology, who were from the population-based cohorts established in Shanxi Province, China, were enrolled and followed up for 2 years. Micro-environmental factors such as vaginal pH, cleanliness, hydrogen peroxide (H2O2), ß-glucuronidase (GUSB), leucocyte esterase (LE), and sialidase (SNA) were detected to evaluate their effect on the malignant prognosis of CIN1. RESULTS: Abnormal vaginal pH (HR = 1.472, 95%CI 1.071-2.022), cleanliness (HR = 1.446, 95%CI 1.067-1.960), H2O2 (HR = 1.525, 95%CI 1.155-2.013), GUSB (HR = 1.739, 95%CI 1.235-2.448), LE (HR = 1.434, 95%CI 1.038-1.981), and SNA (HR = 1.411, 95%CI 1.065-1.870) could promote a higher incidence of CIN1 malignant prognosis, and the combined effects of these micro-environmental factors resulted in a nearly twofold increased risk (HR = 2.492, 95%CI 1.773-3.504) compared to any single factor alone, especially under the high-risk human papillomavirus (HR-HPV) infection. Notably, the cumulative incidence of malignant prognosis for CIN1 gradually increased during the early follow-up period, reaching its peak at approximately 8 months, and then stabilizing. CONCLUSION: Vaginal micro-environment disorder could promote CIN1 malignant prognosis, particularly in HR-HPV-infected women. Taking micro-environmental factors as the breakthrough, our study provides a feasible vision for preventing early stage cervical lesions.

Prevalence of cervical intraepithelial lesions and associated factors among women attending a cervical cancer clinic in Western Uganda; results based on Pap smear cytology.

Introduction: There are high incidence and mortality rates of cervical cancer among females in East Africa. This is exacerbated by limited up-to-date data on premalignant lesions and associated factors in this setting. In this study, we determined the prevalence of cervical intraepithelial lesions and associated factors among women attending the Mbarara Regional Referral Hospital cervical cancer clinic in Southwestern Uganda. Methods: In this cross-sectional study, 364 participants were recruited from among women attending the Mbarara Regional Referral Hospital cervical cancer clinic from 1 April to 30 June 2023. On consent, the study nurse collected demographic data and Pap smears, which were microscopically examined and reported by a laboratory scientist and a pathologist following the Bethesda grading system (2014). Statistical analyses were done in STATA version 17, using proportions, Chi-square, bivariate, and multivariate logistic regression analysis to determine associated factors at ⩽0.05 significance level. Results: The mean age of participants was 41.9 years. A third of all study participants (37.6%, 132/351) were contraceptive users, mostly hormonal contraceptives (87.1%, 115/132). Almost 88% (307/351) had an unknown Human Papilloma Virus status. The prevalence of cervical intraepithelial lesions among our study participants was 6.6% (23/351), of which 73.9% (17/23) were low-grade squamous intraepithelial lesions. More than half (9/17, 52.9%) of low-grade squamous intraepithelial lesions were active hormonal contraceptive users. Use of hormonal contraceptives (OR: 3.032, p: 0.0253), use of intrauterine devices (OR: 6.284, p: 0.039), and any family history of cervical cancer (OR: 4.144, p: 0.049) were significantly associated with cervical intraepithelial lesions. Conclusion: The prevalence of cervical intraepithelial lesions was 6.6%, lower than global estimates. Use of hormonal and intrauterine device contraceptives, as well as family history of cervical cancer, were significantly associated with cervical intraepithelial lesions among our study population. Prospective studies are recommended to further understand associations between different types of intrauterine devices and hormonal contraceptives, and cervical lesions.