Prevalence of human papillomavirus and cervical lesions among elderly women: an unignored challenge to cervical cancer prevention.

The prevalence of human papillomavirus (HPV) genotype and cervical neoplasia in women older than 64 years, who are outside the age demographic of cervical cancer screening in China, has been under-researched. This study conducts a retrospective analysis of women from a tertiary hospital in Guangzhou, with the aim to offer valuable insights for cervical cancer prevention and control in elderly women. The study incorporated 876 women, all aged 64 and above. In this age bracket, the prevalence rate of any HPV genotype was found to be 19.27%. The top six HR HPV genotypes were HPV 16, HPV 52, HPV 58, HPV 31, HPV 33, and HPV 18. The persistence rate of any HPV type over a 24-month period in this age group was as high as 33.33%. Among women over 64, around 16.47% of HPV-positive patients were diagnosed with cervical cancer. HPV 58 infection was the most substantial risk factor for histological CIN2+ (OR 3.556; 95% CI, 1.107-11.415; p = 0.032) in women over 64 years of age with HPV-positive/NILM status. In conclusion, the burden of HPV infection is significant among women over 64 years in Guangzhou. Re-evaluation of cervical cancer screening strategies for women after the age of 64 is imperative. Moreover, the HPV 16/18/52/58 genotype model could serve as an alternative triage approach to identify histological CIN2+ among elderly women with HPV-positive/NILM status.

Elderly women exhibit an elevated risk of contracting HPV infection and developing cervical lesions.HPV 58 is notably associated with the progression of CIN2+ among women aged above 64 years with HPV-positive/NILM status.HPV 16/18/52/58 genotype model presents an alternative triage approach for identifying CIN2+ among women aged above 64 years with HPV-positive/NILM status.

Impact of postsurgical vaginal microbiome on high-risk HPV infection and recurrence risk in patients with cervical cancer and intraepithelial neoplasia: A retrospective study.

Purpose: This study aimed to determine the effect of postsurgical vaginal microbiome (VM) on high-risk human papillomavirus (hrHPV) infection and the risk of disease recurrence in patients surgically treated for cervical cancer (CC) or intraepithelial neoplasia (CIN). Methods: 207 women who underwent surgical treatment for CC or CIN at the Department of Gynecologic Oncology of the First Affiliated Hospital of University of Science and Technology of China from November 2016 to October 2023 were included. The patients' clinical data, including age, surgical modality, and diagnosis at time of index surgery, were collected retrospectively and analyzed. Associations between postsurgical VM indices, hrHPV infection, cervical cytology, and recurrence were also evaluated. Results: Patient age, surgical modality (whether complete excision of the cervix was performed), and diagnosis at time of index surgery (cervical dysplasia vs. cervical carcinoma) showed no significant association with postsurgical hrHPV infection, cervical cytology, or disease recurrence. However, postsurgical VM imbalance was significantly associated with hrHPV infection status (OR = 4.640, 95 % CI = 2.085-10.460, P < 0.001), abnormal cervical cytology (OR = 3.994, 95 % CI = 1.154-13.826, P = 0.020), and disease recurrence (OR = 3.789, 95 % CI = 1.091-13.154, P = 0.026). Among the specific VM indices, a vaginal pH above 4.5 (OR = 4.570, 95 % CI = 1.640-12.690, P = 0.002), a lactobacilli proportion below 50 % (OR = 3.938, 95 % CI = 1.299-11.934, P = 0.010), and the presence of aerobic vaginitis (AV, OR = 2.425, 95 % CI = 0.996-5.901, P = 0.046) were risk factors for postsurgical recurrence. Conclusion: Postsurgical VM imbalance, especially abnormal indices, such as a pH above 4.5, a lactobacilli proportion below 50 %, and the presence of AV, was associated with an increased risk of postsurgical recurrence in patients who underwent surgical treatment for CIN and CC. Monitoring and potentially intervening in the VM may improve the prognosis of these patients.

Molecular evolution of intestinal-type early gastric cancer according to Correa cascade.

Early screening is crucial for the prevention of intestinal-type gastric cancer. The objective of the current study was to ascertain molecular evolution of intestinal-type gastric cancer according to the Correa cascade for the precise gastric cancer screening. We collected sequential lesions of the Correa cascade in the formalin-fixed and paraffin-embedded endoscopic submucosal dissection-resected specimens from 14 Chinese patients by microdissection, and subsequently determined the profiles of somatic aberrations during gastric carcinogenesis using the whole exome sequencing, identifying multiple variants at different Correa stages. The results showed that TP53, PCLO, and PRKDC were the most frequently mutated genes in the early gastric cancer (EGC). A high frequency of TP53 alterations was found in low-grade intraepithelial neoplasia (LGIN), which further increased in high-grade intraepithelial neoplasia (HGIN) and EGC. Intestinal metaplasia (IM) had no significant correlation with EGC in terms of mutational spectra, whereas both LGIN and HGIN showed higher genomic similarities to EGC, compared with IM. Based on Jaccard similarity coefficients, three evolutionary models were further constructed, and most patients showed linear progression from LGIN to HGIN, ultimately resulting in EGC. The ECM-receptor interaction pathway was revealed to be involved in the linear evolution. Additionally, the retrospective validation study of 39 patients diagnosed with LGIN indicated that PRKDC mutations, in addition to TP53 mutations, may drive LGIN progression to HGIN or EGC. In conclusion, the current study unveils the genomic evolution across the Correa cascade of intestinal-type gastric cancer, elucidates the underlying molecular mechanisms of gastric carcinogenesis, and provides some evidence for potential personalized gastric cancer surveillance.

Ranking the attribution of high-risk genotypes among women with cervical precancers and cancers: a cross-sectional study in Ningbo, China.

BACKGROUND: The region-specific importance of carcinogenic HPV genotypes is required for optimizing HPV-based screening and promoting appropriate multivalent HPV prophylactic vaccines. This information is lacking for Ningbo, one of the first cities of China's Healthy City Innovation Pilot Program for Cervical Cancer Elimination. Here, we investigated high-risk HPV (HR-HPV) genotype-specific distribution and attribution to biopsy-confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+) before mass vaccination in Ningbo, China. METHODS: A total of 1393 eligible CIN2+ archived blocks (including 161 CIN2, 1107 CIN3, and 125 invasive cervical cancers [ICC]) were collected from 2017 to 2020 in Ningbo. HR-HPV DNA was genotyped using the SPF10-DEIA-LiPA25 version 1 detection system and the SureX HPV 25X Genotyping Kit. Genotype-specific attribution to CIN2+ was estimated using a fractional contribution approach. RESULTS: Ranking by the attributable proportions, HPV16 remained the most important genotype in both cervical precancers and cancers, accounting for 36.8% of CIN2, 53.2% of CIN3, and 73.3% of ICC cases. Among cervical precancers, HPV52 (17.3% in CIN2, 12.7% in CIN3) and HPV58 (13.9%, 14.9%) ranked second and third, while HPV33 (8.3%, 7.9%) and HPV31 (6.5%, 4.1%) ranked fourth and fifth, respectively. However, among ICCs, HPV18 (5.7%) accounted for the second highest proportion, followed by HPV33 (5.4%), HPV58 (4.0%), and HPV45 (3.2%). HPV18/45 together accounted for 46.8% of adenocarcinomas, which was slightly lower than that of HPV16 (47.7%). The remaining HR-HPV genotypes (HPV35/39/51/56/59/66/68) combined accounted for only 6.7% of CIN2, 2.9% of CIN3, and 4.2% of ICC. CONCLUSIONS: With Ningbo's strong medical resources, it will be important to continue HPV16/18 control efforts, and could broaden to HPV31/33/45/52/58 for maximum health benefits. However, different strategies should be proposed for other HR-HPV genotypes based on their lower carcinogenic risks.

Accuracy of GynTect® Methylation Markers to Detect Recurrent Disease in Patients Treated for CIN3: A Proof-of-Concept Case-Control Study.

Post-treatment follow-up in women with CIN3 is mandatory due to relapse in up to 15% of patients within 2 years. Standard follow-up care based on hrHPV-DNA/cytology co-testing has high sensitivity but limited specificity. The aim of our proof-of-concept case-control study was to evaluate the performance of the methylation test GynTect® for the detection of recurrent CIN2/3 during follow-up. Residual clinical material from a recent, prospective, multicenter, observational study was available for further analysis. We studied a sample of 17 cases with recurrent CIN2/3 diagnosed within 24 months of follow-up and 31 controls without recurrence. DNA from cervical scrapes at baseline (immediately before CIN3 surgery) and up to three follow-up visits were analyzed for hrHPV and GynTect® methylation status. Cytology data were available from the previous study. Overall, 12 cases and 21 controls were GynTect-positive at baseline. In these subgroups, single test sensitivity at first follow-up was 67% (95% CI 39-87%) for GynTect® compared to 83% (95% CI 55-96%) for hrHPV (p = 0.50). Single test specificity was significantly higher for GynTect® (90%, 95% CI 71-98% vs. 62%, 95% CI 40-80%) (p = 0.03). In a co-testing setting, both hrHPV/cytology and GynTect®/cytology detected all recurrences. Specificity for GynTect®/cytology was higher than for hrHPV/cytology, but this difference was not statistically significant. In conclusion, for initially GynTect-positive patients, both hrHPV and GynTect® tests detected recurrent disease with similar sensitivity, but the GynTect® assay has a higher specificity. Incident hrHPV infection and/or persisting multifocal hrHPV infections without clinical disease are most likely responsible for the poorer specificity of the hrHPV test. A future prospective validation study will have to show whether GynTect®/cytology co-testing can outperform hrHPV/cytology co-testing in post-treatment surveillance.

Surgical, oncological and obstetric outcomes of the Shimodaira-Taniguchi conization method.

The present study aimed to investigate the surgical, oncological and obstetric outcomes of the Shimodaira-Taniguchi (S-T) conization method. A total of 858 cases of high-grade intraepithelial lesions treated with S-T conization were retrospectively reviewed, and the surgical, oncological and obstetric outcomes were analyzed. The χ2 test was used to compare the clinical characteristics between patients with and without cervical stenosis. The factors associated with recurrent/persistent disease were analyzed using univariate and multivariate analyses with a Cox hazards regression model. The obstetric outcomes after conization were also evaluated. Cervical stenosis and recurrent/persistent disease occurred in 2.2 and 4.9% of the patients, respectively. Older age [≥45 years; hazard ratio (HR), 3.22; 95% CI, 1.73-6.02] and surgical margin involvement (HR, 6.39; 95% CI, 3.44-11.8) were independently associated with recurrent/persistent disease. In particular, older patients with endocervical margin involvement showed a higher rate of recurrence (3-year recurrence rate, 28.1%). The proportion of patients who experienced cervical stenosis was significantly higher in older patients (0.95 vs. 5.7%; P<0.001). Among the 66 deliveries after conization, term delivery was observed in 62 cases (93.9%). The proportion of patients who experienced preterm delivery after conization was significantly higher in patients with a short interval from conization to conception (P=0.045). In conclusion, the S-T conization method was effective in terms of surgical, oncological and obstetric outcomes. A careful follow-up is required for older patients with positive surgical margins, particularly those with positive endocervical margins. In addition, a short interval of ≤3 months from conization to conception should be avoided to expect term pregnancy.

Potential mechanisms of ZiGongDing in treating HPV-induced cervical intraepithelial neoplasia: a network pharmacology and experimental verification study.

The onset of cervical intraepithelial neoplasia (CIN) is strongly associated with persistent infection caused by high-risk human papillomavirus (HPV). ZiGongDing (ZGD), a traditional Chinese medicine, has progressed to clinical application in HPV-induced CIN treatment, yet the underlying mechanism remains unclear. The objective of this paper is to explore the mechanism of ZGD in treating HPV-induced CIN by integrating a combination of network pharmacology and experimental validation. The active ingredients and targets of ZGD were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database. CIN-related targets were sourced from GeneCards and the Online Mendelian Inheritance in Man (OMIM) database. Protein-protein interaction (PPI) and functional enrichment analyses were conducted to determine the potential molecular mechanism. The herb-active ingredient-target network was constructed by Cytoscape software. To further validate the therapeutic mechanism, molecular docking and in vitro experiments were performed. In this study, we identified 60 active ingredients in ZGD and 46 common targets in of CIN treatment. The PPI network analysis revealed estrogen receptor 1 (ESR1) as a pivotal target in ZGD against CIN. Functional enrichment analysis showed that the estrogen signaling pathway was mostly enriched, and ESR1 was involved. The herb-active ingredient-target network and relative literature identified cnidimol B as the primary active ingredient. Molecular docking demonstrated a strong binding affinity between ESR1 and cnidimol B. Cellular experiments revealed that cnidimol B could significantly decrease the viability of HeLa and CaSki cells. Moreover, the expression of ESR1 was notably upregulated in HeLa and CaSki cells after treatment with cnidimol B. Our study proposes a novel mechanism underlying ZGD against CIN, which involves the modulation of ESR1. This insight lays a solid foundation for further exploring and optimizing ZGD's therapeutic potential.

Machine Learning Prediction of Residual and Recurrent High-Grade CIN Post-LEEP.

Purpose: This study aims to develop a machine learning (ML) model to predict the risk of residual or recurrent high-grade cervical intraepithelial neoplasia (CIN) after loop electrosurgical excision procedure (LEEP), addressing a critical gap in personalized follow-up care. Methods: A retrospective analysis of 532 patients who underwent LEEP for high-grade CIN at Cangzhou Central Hospital (2016-2020) was conducted. In the final analysis, 99 women (18.6%) were found to have residual or recurrent high-grade CIN (CIN2 or worse) within five years of follow-up. Four feature selection methods identified significant predictors of residual or recurrent CIN. Eight ML algorithms were evaluated using performance metrics such as AUROC, accuracy, sensitivity, specificity, PPV, NPV, F1 score, calibration curve, and decision curve analysis. Fivefold cross-validation optimized and validated the model, and SHAP analysis assessed feature importance. Results: The XGBoost algorithm demonstrated the highest predictive performance with the best AUROC. The optimized model included six key predictors: age, ThinPrep cytologic test (TCT) results, HPV classification, CIN severity, glandular involvement, and margin status. SHAP analysis identified CIN severity and margin status as the most influential predictors. An online prediction tool was developed for real-time risk assessment. Conclusion: This ML-based predictive model for post-LEEP high-grade CIN provides a significant advancement in gynecologic oncology, enhancing personalized patient care and facilitating early intervention and informed clinical decision-making.

Post-conization pathological upgrading and outcomes of 466 patients with low-grade cervical intraepithelial neoplasia.

Introduction: The management of patients with low-grade cervical intraepithelial neoplasia (CIN1) remains controversial. We analyzed the pathological upgrading rates of patients with CIN1 undergoing conization, identifying influencing factors, and compared their outcomes to those of patients with CIN1 receiving follow-up only. Methods: This retrospective study included 466 patients with CIN1 confirmed by histopathology and treated with conization. Postoperative pathological upgrading was determined and its influencing factors were identified. We also analyzed post-conization outcomes, examining the rate of persistent/recurrent CIN1 and its influencing factors, and comparing these results to those of patients receiving follow-up only. Results: The pathological upgrading rate of patients with CIN1 after conization was 21.03% (98/466), and the influencing factors were preoperative high-risk human papillomavirus (HR-HPV) infection and cytological results. The upgrading rates of HR-HPV positive and negative patients were 22.05% and 0.00%, respectively (χ 2 = 5.03, P=0.03). The upgrading rate of patients with cytological results negative for intraepithelial lesion malignancy was 10.94%, while the upgrading rates of atypical squamous cells, cannot exclude high-grade lesion(ASC-H) and high-grade squamous intraepithelial lesion(HSIL) groups were 47.37% and 52.94%, respectively (χ 2 = 22.7, P=0.03). Persistent/recurrent CIN1 rates in the conization group were 21.24%, 15.97%, and 6.67% at 6, 12, and 24 months, respectively, significantly lower than those in the follow-up only group. The CIN2 progression rate in the conization group (0.26%) during the 24-month follow-up period was also significantly lower than that in the follow-up only group (15.15%; χ 2 = 51.68, P<0.01). The only factor influencing postoperative persistent/recurrent CIN1 was preoperative HR-HPV status. No patients who were HR-HPV negative preoperatively exhibited persistent/recurrent CIN1, compared with 25.55% of those who were HR-HPV positive preoperatively (χ 2 = 4.40, P=0.04). Discussion: The risk of progression to CIN2+ in the medium term is higher in patients with CIN1 receiving follow-up than in those undergoing conization. Doctors should refer to the guidelines but comprehensively consider age, fertility requirements, preoperative HR-HPV and cytological results, follow-up conditions, and other factors to select the most appropriate treatment strategy for patients with CIN1.

Intravaginal artesunate pessaries for treatment of cervical intraepithelial neoplasia 2/3 among HIV-positive and HIV-negative women in Kenya: Study protocol for a pilot trial.

Background: Cervical cancer disproportionately affects women in low- and middle-income countries (LMICs), which bear 90% of deaths. Current precancer treatments rely on healthcare workers who may be out of reach for many women. Development of a patient-controlled cervical precancer treatment can significantly improve access in remote areas and promote secondary prevention of cervical cancer. Methods: This is a phase I trial among 18 HIV-positive and HIV-negative women in Kenya, investigating use of artesunate vaginal pessaries as treatment for cervical precancer among women screening positive for cervical precancer who need excisional treatment. The primary objective will be the safety of self-administered artesunate pessaries. Participants will self-administer 200mg of artesunate vaginally daily for 5 days, followed by a drug-free week, repeated for a total of 4 cycles (artesunate self-administration on weeks 1, 3, 5, 7). The total study duration, including participant follow-up is 48 weeks. Safety and adherence will be assessed through review of symptom diaries and biweekly follow-ups during the treatment phase. Data analysis will include quantitative and qualitative methods. Figure 1 illustrates the study schema. Discussion: Considering the challenges associated with excisional treatments for cervical precancer in LMICs where access to care is limited, this study proposes an alternative approach using intravaginal Artesunate. This clinical trial will provide important safety and efficacy data on using artesunate as a topical therapy for both HIV-positive and HIV-negative women. Trial Registration: ClinicalTrials.gov identifier: NCT06165614.

HPV 16/18 E7 oncoprotein detection as a promising triage strategy for HPV 16/18-positive patients: A prospective multicenter study with a 2-year follow up.

OBJECTIVE: To explore the effectiveness of HPV 16/18 E7 oncoprotein in detecting high-grade cervical intraepithelial neoplasia (CIN) and predicting disease outcomes in HPV 16/18-positive patients. METHODS: The present study was a cross-sectional study with a 2-year follow up. We collected 915 cervical exfoliated cell samples from patients who tested positive for HPV 16/18 in gynecologic clinics of three tertiary hospitals in Beijing from March 2021 to October 2022 for HPV 16/18 E7 oncoprotein testing. Subsequently, 2-year follow up of 408 patients with baseline histologic CIN1 or below were used to investigate the predictive role of HPV 16/18 E7 oncoprotein in determining HPV persistent infection and disease progression. RESULTS: The positivity rate of the HPV 16/18 E7 oncoprotein assay was 42.06% (249/592) in the inflammation/CIN 1 group and 85.45% (277/324) in the CIN2+ group. For CIN2+ detection, using the HPV 16/18 E7 oncoprotein assay combined with HPV 16/18 testing, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 85.45%, 57.94%, 52.57%, and 87.95%, respectively. During the 2-year follow up, the sensitivity, specificity, PPV, and NPV for predicting persistent HPV infection were 48.44%, 58.21%, 34.64%, and 71.18% in the baseline inflammation and CIN1 group. CONCLUSIONS: As a triage method for high-grade CIN screening in HPV 16/18-positive patients, HPV 16/18 E7 oncoprotein demonstrated a relatively high NPV, making it suitable for clinical use in triaging HPV 16/18-positive cases and potentially reducing the colposcopic referral rate. HPV 16/18 E7 oncoprotein exhibited a preferably predictive value in determining HPV infection outcomes and disease progression.

Analysis of the correlation between cervical HPV infection, cervical lesions and vaginal microecology.

Background: Vaginal microbiota is involved in human papillomavirus (HPV) infection and cervical cancer (CC) progression, and the specific changes in vaginal microbial composition during this process remains uncertain. Objective: This study aimed to observe the changes in the specific composition of vaginal microorganisms in different cervical lesions and identify biomarkers at different stages of lesions. Methods: In this study we used the illumina high-throughput gene sequencing technology to determine the V4 region of 16SrRNA and observed the vaginal microbial composition in different cervical lesions. Results: The vaginal microbiota of patients with high-risk HPV infection and cervical lesions is significantly different from that of the normal population, but there is no significant difference in the richness of vaginal microbes. The diversity of vaginal species in CC patients is higher than that in high-risk HPV infection or CIN patients. The main manifestation is an increase in the diversity of vaginal microbes, a decrease in the relative abundance of cyanobacteria and Lactobacillus, and an increase in the relative abundance of dialister, peptonephila and other miscellaneous bacteria. There are characteristic vaginal biomarker in normal women, high risk HPV patients and CC patients. In detail, the biomarker in the normal group was varibaculum, the biomarker in the high-risk HPV group was saccharopolyspora, the biomarker of the CC group was the Proteobacteria, Corynebacterium, Coprococcus, Peptococcus and Ruminococcus. Conclusions: The study indicated that the compositions of vaginal microbes in different cervical lesions is different. The vaginal microbial composition has a certain diagnostic effect on healthy women, patients with high-risk HPV infection and cervical lesions. These microbes may serve as potential biomarkers for CC. It also provided an effective way for the treatment of HPV infections and cervical lesions.

The impact of Germany's human papillomavirus immunization program on HPV-related anogenital diseases: a retrospective analysis of claims data from statutory health insurances.

PURPOSE: Human papillomavirus (HPV) is the most common sexually transmitted infection, responsible for multiple HPV-related diseases, including almost all cervical cancers. The highly effective HPV vaccination has been recommended under the German HPV national immunization program (NIP) since 2007 and is reimbursed by health insurances. Vaccination uptake rates, however, remain suboptimal and data on the real-world impact of HPV vaccination in Germany are lacking. This study aims to demonstrate the population-level impact of Germany's NIP on HPV-related anogenital diseases among young women. METHODS: Retrospective claims data analysis using a classic impact study design comparing disease prevalence among 28- to 33-year-old women before and after introduction of the HPV-immunization program in Germany. Claims data representing approximately two thirds of German health insurances were used. HPV-related disease outcomes included cervical cancer and high grade precancers (cervical intraepithelial neoplasia (CIN) 2+), anogenital warts, as well as vulvar, vaginal, and anal precancer/cancer. RESULTS: Significant declines were seen for CIN2+, anogenital warts, and vaginal precancer/cancer. Prevalence of CIN2+ declined 51.1% from 0.92% (95% CI = 0.78%, 1.08%) to 0.45% (95% CI = 0.38%, 0.53%). There was a 38.6% decline in anogenital warts prevalence from 0.44% (95% CI = 0.36%, 0.54%) to 0.27% (95% CI = 0.22%, 0.32%) and 75.0% decline in vaginal precancer/cancer prevalence from 0.04% (95% CI = 0.02%, 0.07%) to 0.01% (95% CI = 0.00%, 0.02%). CONCLUSION: The German HPV-immunization program has led to significant declines in female anogenital disease among young women in Germany, highlighting the importance of the vaccination. Moreover, the data suggest that increasing vaccination coverage in Germany could further strengthen the public-health impact of its HPV-immunization program.

Exploring serum trace element shifts: Implications for cervical intraepithelial neoplasia.

BACKGROUND: Cervical intraepithelial neoplasia (CIN) represents a premalignant state presumably related to perturbations in circulating levels of trace elements. MATERIALS AND METHODS: Employing inductively coupled plasma mass spectrometry (ICP-MS), we quantified essential and toxic trace elements in the sera of 60 women diagnosed with CIN and 60 age-matched healthy counterparts. RESULTS: Our investigation revealed a noteworthy higher levels in serum of Mn, Zn, and Pb, as well as lower levels in Ni, Se, Rb, and Mo levels within the CIN cohort. Levels of Mn, Zn, and Pb were higher by approximately 5.5-fold, 3.0-fold, and 7.5-fold, respectively, while Mo levels exhibited an approximate 4.5-fold reduction in CIN sera compared to the control group. While the study provided valuable insights into trace element variations, it's important to note that the adult Serbian population is considered Zn-deficient, so the Zn data should be interpreted with caution. Age stratification (30-40 vs. 40-50 vs. 50-60 years), smoking status (smokers vs. nonsmokers), and CIN severity (CIN 2 vs. CIN 3) yielded no significant disparities in elemental profiles. Among the 10 proposed ratios, 5 demonstrated a significant surge in CIN sera relative to controls: Mn/Se, Mn/Mo, Zn/Se, Zn/Mo, and Se/Mo. Correlation analysis of trace element levels revealed a predominantly consistent pattern between CIN cases and healthy subjects, except for Zn and its negative correlations (antagonistic interactions) with other analyzed trace elements. CONCLUSION: Our findings underscore differences in serum levels of specific trace elements in CIN cases versus controls, implicating their potential involvement in the underlying pathophysiological cascades culminating in cervical neoplasms.

Serum levels of stearic and dihomo-γ-linolenic acids can be used to diagnose cervical cancer and cervical intraepithelial neoplasia.

Despite widespread cervical cancer (CC) screening programs, low participation has led to high morbidity and mortality rates, especially in developing countries. Because early-stage CC often has no symptoms, a non-invasive and convenient diagnostic method is needed to improve disease detection. In this study, we developed a new approach for differentiating both CC and cervical intraepithelial neoplasia (CIN)2/3, a precancerous lesion, from healthy individuals by exploring CC fatty acid metabolic reprogramming. Analysis of public datasets suggested that various fatty acid metabolizing enzymes were expressed at higher levels in CC tissues than in normal tissues. Correspondingly, 11 free fatty acids (FFAs) showed significantly different serum levels in CC patient samples compared with healthy donor samples. Nine of these 11 FFAs also displayed significant alterations in CIN2/3 patients. We then generated diagnostic models using combinations of these FFAs, with the optimal model including stearic and dihomo-γ-linolenic acids. Receiver operating characteristic curve analyses suggested that this diagnostic model could detect CC and CIN2/3 more accurately than using serum squamous cell carcinoma antigen level. In addition, the diagnostic model using FFAs was able to detect patients regardless of clinical stage or histological type. Overall, the serum FFA diagnostic model developed in this study could be a powerful new tool for the non-invasive early detection of CC and CIN2/3.

RAP1-GTPase immunostaining is altered in human precancerous and cancerous cervical lesions.

Aim: This study investigated RAP1 immunostaining variation in different cell types during CC progression.Methods: Paraffin-embedded cervical tissues from 101 patients were categorized into control, pre-neoplastic and neoplastic groups. RAP1 immunolocalization, HPV detection and genotyping were performed. A semiquantitative immunoreactive score was employed to compare labeling intensity, cellular localization, nuclear labeling, percentage and distribution of reactive cells.Results: 73% (72/99) of cervical specimens were HPV+. RAP1 was localized in the nucleus and cytoplasm of all samples. Cytoplasmic RAP1 immunoscore was higher than nuclear score in all CC groups. RAP1 intensity increased with lesion severity. SCC samples exhibited predominantly intense RAP1 immunostaining.Conclusion: RAP1 is an efficient biomarker for detecting invasive CC lesions but has limited utility in distinguishing SCC grades.

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Clinical validation of the Roche cobas HPV test on the Roche cobas 5800 system for the purpose of cervical screening.

This study assessed the relative clinical sensitivity and specificity, as well as reproducibility, for high-risk HPV types of the Roche cobas HPV test when processed using the Roche cobas 5800 system. The results from this study demonstrate that the cobas HPV test using the cobas 5800 system fulfils the Meijer criteria for use in population-based cervical screening. This clinical validation study also examines the clinical sensitivity and specificity based on partial genotyping, with separate detection of HPV16 and HPV18, compared with the Roche cobas 4800 HPV test, a second-generation standard comparator assay. The cobas HPV test has a relative clinical sensitivity of 1.000, when compared with the cobas 4800 HPV test to detect histologically confirmed CIN2+ lesions in woman aged 30 years or older, with a relative clinical specificity of 0.995. The general intra- and inter-laboratory agreement for the cobas HPV test on the cobas 5800 system for finding a HPV positive result were 99.1% and 99.6%, respectively.IMPORTANCEThis study demonstrates, for the first time, the clinical performance of the Roche cobas HPV test when processed using the new cobas 5800 system [cobas (5800)]. This study shows that the cobas (5800) demonstrates relative clinical sensitivity and specificity, when compared with a standard comparator HPV test, which meets the international HPV test validation requirements. Intra- and inter-laboratory reproducibility also fulfills these criteria. The current study demonstrates that the cobas (5800) can be used for primary HPV-based cervical screening on cervical specimens.

Acvr1b Loss Increases Formation of Pancreatic Precancerous Lesions From Acinar and Ductal Cells of Origin.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma can develop from precursor lesions, including pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm (IPMN). Previous studies indicated that loss of Acvr1b accelerates the Kras-mediated development of papillary IPMN in the mouse pancreas; however, the cell type predominantly affected by these genetic changes remains unclear. METHODS: We investigated the contribution of cellular origin by inducing IPMN associated mutations (KRASG12D expression and Acvr1b loss) specifically in acinar (Ptf1aCreER;KrasLSL-G12D;Acvr1bfl/fl mice) or ductal (Sox9CreER;KrasLSL-G12D;Acvr1bfl/fl mice) cells in mice. We then performed magnetic resonance imaging and a thorough histopathologic analysis of their pancreatic tissues. RESULTS: The loss of Acvr1b increased the development of pancreatic intraepithelial neoplasia and IPMN-like lesions when either acinar or ductal cells expressed a Kras mutation. Magnetic resonance imaging, immunohistochemistry, and histology revealed large IPMN-like lesions in these mice that exhibited features of flat, gastric epithelium. In addition, cyst formation in both mouse models was accompanied by chronic pancreatitis. Experimental acute pancreatitis accelerated the development of large mucinous cysts and pancreatic intraepithelial neoplasia when acinar, but not ductal, cells expressed mutant Kras and lost Acvr1b. CONCLUSIONS: These findings indicate that loss of Acvr1b in the presence of the Kras oncogene promotes the development of large and small precancerous lesions from both ductal and acinar cells. However, the IPMN-like phenotype was not equivalent to that observed when these mutations were made in all pancreatic cells during development. Our study underscores the significance of the cellular context in the initiation and progression of precursor lesions from exocrine cells.