Low-grade Cervical Intraepithelial Neoplasia Research Articles

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

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. 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 2years. Micro-environmental factors such as vaginal pH, cleanliness, hydrogen peroxide (H2O2), β-glucuronidase (GUSB), leucocyte esterase (LE), and sialidase (SNA) were detected to evaluate their effect on the malignant prognosis of CIN1. 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 8months, and then stabilizing. 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.

Exposure to polycyclic aromatic hydrocarbons promotes the progression of low-grade cervical intraepithelial neoplasia: A population-based cohort study in China.

Low-grade cervical intraepithelial neoplasia (CIN1) is an early stage of cervical cancer development. Previously, we reported that exposure to polycyclic aromatic hydrocarbons (PAHs) increases the risk of cervical precancerous lesions, especially in females with a high-risk human papillomavirus (HR-HPV) infection. However, the effects of PAHs on CIN1 progression remain unclear. A community-based prospective cohort study was conducted to evaluate the role of exposure to PAHs in the progression of CIN1. A total of 564 patients diagnosed with CIN1 were followed-up at 6, 12, and 24 months, post-diagnosis, to determine CIN1 reversion, persistence, and progression. Exposure to PAHs was determined by the urine 1-hydroxipayrene (1-OHP) level. Our results showed that the 1-OHP level was significantly higher in patients with CIN1 persistence/progression than in those with reversion (P < .05). High exposure to PAHs increased the risk of CIN1 persistence/progression, with hazard ratios (HR), 95% confidence intervals (CI) of (1.62, 1.24-2.67), (1.98, 1.42-2.75), and (2.37, 1.61-3.49) at 6, 12, and 24 months, post-diagnosis, respectively. The effect was enhanced with HR-HPV positivity, as determined at 6 (1.82, 1.24-2.67), 12 (3.02, 1.74-5.23), and 24 (2.51, 1.48-4.26) months, post-diagnosis. Moreover, the predictive value of exposure to PAHs for CIN1 persistence/progression was higher in HR-HPV-positive patients than in HR-HPV-negative patients. The results revealed that exposure to PAHs facilitated the malignant progression of CIN1 and hindered its reversal, particularly in patients with HR-HPV infection. Our findings provide novel insights into early prevention and intervention targeting the initiation and progression of cervical neoplasia.

Cervicovaginal microbiota disorder combined with the change of cytosine phosphate guanine motif- tolllike receptor 9 axis was associated with cervical cancerization.

Convincing studies demonstrated that cervicovaginal microbiota disorder and toll-like receptor 9 (TLR9) high expression were related to cervical carcinogenesis. However, the effects of cervicovaginal microbiota integration TLR9 in cervical cancerization are unclear. Based on the biological basis that unmethylated cytosine-phosphate-guanine (CpG) motifs of bacteria could activate TLR9, we explored the effects of cervicovaginal microbiota disorder and CpG motif-TLR9 axis change in cervical carcinogenesis. A total of 341 participants, including 124 normal cervical (NC), 90 low-grade cervical intraepithelial neoplasia (CIN1), 78 high-grade cervical intraepithelial neoplasia (CIN2/3) and 49 squamous cervical cancer (SCC), diagnosed by pathology were enrolled in the study. Here, metagenomic shotgun sequencing was used to reveal cervicovaginal microbiota characteristics, and TLR9 protein was detected by western blotting. Our results showed that the diversity of cervicovaginal microbiota gradually increased along with the poor development of cervical lesions, showing the abundance of Lactobacillus crispatus and Lactobacillus iners decreased, while the abundance of pathogenic bacteria gradually increased. The level of TLR9 expression was gradually increased with cervicovaginal microbiota diversity increasing, the abundance of Lactobacillus decreasing, and we found a positive correlation dependency relationship (r = 0.384, P = 0.002) between TLR9 and GTCGTT motif content. Stratified analysis based on HPV16 infection, we found that the characteristics of cervicovaginal microbiota and increased TLR9 expression were also closely related to HPV16 infection. Cervicovaginal microbiota dysbiosis might lead to the CpG motif increased, which was closely associated with TLR9 high expression, and ultimately might promote the progression of cervical lesions.

Genomic Characterization of Low and High Grade Cervical Intraepithelial Neoplasia in Comparison to Cervical Cancer

Screening reduces incidence of cervical cancer (CC) through identification and treatment of cervical intraepithelial neoplasia (CIN). Triage of CIN must balance between overtreatment versus progression as invasive therapies increase the risk of side effects including obstetric complications. The majority of CIN 1-2 lesions regress and a subset of CIN 3 lesions progress, however, due to inability to differentiate lesions likely to progress, the majority of CIN 2-3 lesions are treated with resection. Improved genomic and molecular identifiers of disease represent an urgent unmet clinical need. Using next generation sequencing of a targeted exome panel of 1109 genes (previously validated), we characterized somatic mutations in 36 CIN (14 CIN 1, 11 CIN 2, 11 CIN 3) and 13 CC samples. Sequencing of CIN samples was performed on exfoliated cervical cells. CIN diagnosis and grade was confirmed on biopsy. Mutation profiles between CIN grades and CC were compared to identify genomic patterns that distinguish these groups. Across the 49 samples sequenced, we identified a total of 5142 somatic mutations, including 2178 missense, 2522 synonymous, 171 nonsense, 62 splice site, 135 inframe indels, and 74 frameshift mutations. The mutation frequency was significantly higher in CC vs CIN1-3 (Table), p<0.01 (Wilcoxon signed-rank test). The difference in mutation frequency and type (Table) was not significant between CIN grades 1, 2 and 3 (p = 0.07, Kruskal-Wallis test). Cancer related pathway signatures were analyzed for the percentage of CC vs CIN samples with at least one altered variant as follows: RTK-RAS (92% vs 31%), PI3K (92% vs 17%), NOTCH (100% vs 39%), WNT (85% vs 14%) and cell cycle (53% vs 3%). Ninety percent of CC samples versus only 30% of CINs had nonsynonymous variants in the RTK-RAS and NOTCH pathways as well as the PI3K pathway which is implicated as a late event in cervical carcinogenesis. We observed recurrent missense variants in ABL1, IGF1R, TSC2 in the CIN2, CIN3 and CC samples, particularly in genes that belong to the RTK-RAS, PI3K, NOTCH pathway signatures. Potential driver mutations in EGFR, PIK3CA, ERBB4, MTOR, CSF1R genes were exclusive to CC samples. Our results show that there is a clear distinction of mutational burden and type between cervical cancer and CIN1-3. However, the pathologic grading of CIN is not consistently associated with dynamic changes in overall mutation burden, type, or specific genes with escalating CIN grade. This data supports the hypothesis that late genetic events in CIN accompany a transition to invasive cervical cancer.

MicroRNA expression associated with low-grade cervical intraepithelial neoplasia outcomes.

Only a fraction of low-grade cervical intraepithelial neoplasia (CIN) progresses to high-grade CIN; however, the biological processes that differentiate progressive CIN from CIN that resolves naturally are poorly understood. MicroRNAs (miRNAs) are important epigenetic regulators of gene expression and thus, miRNA expression profiling can reveal the dysregulated biology underlying disease processes. The purpose of this case-control study was to reveal miRNA expression patterns and predict the underlying biological pathways that are associated with clinical outcomes of low-grade CIN. Women with low-grade CIN diagnosis and definitive clinical outcomes (n = 51) were identified retrospectively using electronic clinical records. Comprehensive miRNA expression profiling was performed on the low-grade CIN diagnostic cervical biopsies retrieved from pathology archives. Differential miRNA expression was analyzed by comparing women with CIN that progressed to women with CIN that resolved naturally. Differential expression of 29 miRNAs was observed in low-grade CIN that progressed to high-grade compared to low-grade CIN that resolved. Of these, 24 were significantly downregulated in progressive CIN, including miR-638, miR-3196, miR-4488, and miR-4508, while 5 miRNAs, including miR-1206a, were significantly upregulated. Computational gene ontology analysis based on the discovered miRNAs and their putative mRNA targets revealed biological processes associated with oncogenic phenotypes. Distinct miRNA expression profiles are associated with clinical outcomes of low-grade CIN. The functional effects of the differentially expressed miRNAs may be biological determinants of CIN progression or resolution.

Significance of concurrent HPV testing with unsatisfactory Papanicolaou test for prediction of follow-up HPV, Papanicolaou test, and biopsy results.

Approximately 1% to 2% of routine cytologic specimens collected for Papanicolaou testing are unsatisfactory for evaluation. The American Society for Colposcopy and Cervical Pathology 2019 guidelines recommend repeat testing within 2 to 4 months of an unsatisfactory Papanicolaou test (UPT) result. We evaluated the utility of follow-up Papanicolaou testing, human papillomavirus (HPV) testing, and biopsy in 258 cases of UPTs. High-risk HPV testing was positive in 17.4% (n = 45) and negative in 82.6% (n = 213) of cases at the time of initial UPT; 8.1% (n = 21) of cases had discordant HPV test results. Similarly, 3.8% (n = 8) of initially HPV-negative cases were reported to be HPV-positive on follow-up; 28.9% (n = 13) of initially HPV-positive cases were reported to be HPV negative on follow-up. In total, 27.1% (n = 70) of cases underwent biopsy. Biopsies with significant findings were present in 40% (n = 12) of HPV-positive cases and 7.5% (n = 3) of HPV-negative cases. Low-grade squamous intraepithelial lesion (LSIL) (low-grade cervical intraepithelial neoplasia [CIN-1]) was the most significant finding in all 3 HPV-negative biopsies; 58.3% (n = 7) of HPV-positive biopsies showed LSIL (CIN-1), 13.3% (n = 4) showed HSIL (high-grade CIN), and 3.3% (n = 1) showed invasive carcinoma. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of concurrent HPV testing at the time of UPT for predicting follow-up HPV test result within 1 year of initial UPT are 80.0%, 94.0%, 71.1%, and 96.2%, respectively. The sensitivity, specificity, PPV, and NPV of initial HPV test results for predicting follow-up Papanicolaou test results are 67.7%, 89.7%, 48.8%, and 95.0%, respectively. Concurrent HPV testing in the setting of UPT can be a sensitive tool for predicting follow-up HPV status and significant findings of squamous intraepithelial lesions on follow-up Papanicolaou tests and biopsy.

Spectrum, Clinicopathologic Profile, and p16 Expression Pattern of Nonmalignant Cervical Tissues in Enugu, South-East Nigeria

Abstract Background p16 is a marker for p16-induced transformation of high-risk human papilloma virus (hrHPV)-infected cervical epithelium. HPV is a known etiologic agent of cervical cancer. Persistent hrHPV infection of cervical epithelium causes transformation of the infected epithelial cells resulting in increased proliferative potential of the cells and subsequent progression to frank malignancy. Early detection of transformation in cervical cells is crucial in reducing morbidity and mortality associated with cervical cancer. Materials and Methods We aimed to study the clinicopathologic profile of nonmalignant cervical lesions and their p16 staining pattern. Histopathology requisition forms, blocks, and slides of cases containing cervical tissue with nonmalignant diagnosis received into the morbid anatomy department of University of Nigeria Teaching Hospital, Enugu, from 2009 to 2018 were studied. Fresh sections from the blocks were immunohistochemically stained with p16 and examined. Results One-hundred and ninety-one cases were studied. Majority of the cases are normal cervical epithelium. Chronic nonspecific cervicitis was the major non-neoplastic lesion present and accounted for 33.3% of the biopsy and the mean age was 50.5 years. Other lesions were nabothian cyst (8.4%), cervical polyp (10.5%), low-grade and high-grade squamous intraepithelial lesion (LSIL and HSIL; 6.3 and 2.6%, respectively). The mean age for LSIL was 40.3 years, while that of HSIL was 45.2years. Four LSIL, two HSIL, one polyp, one chronic nonspecific cervicitis, and one lobular endocervical hyperplasia stained positively with p16. Conclusion The most common benign lesion of the cervix is cervicitis. Chronic cervicitis is negative to p16 immunoreactivity. There are more low-grade cervical intraepithelial neoplasia (CIN) than high-grade CIN. The low-grade CIN overexpress p16 in one-third of cases. There are more cases of p16-negative high-grade CIN in this study.

The characteristics and correlations of vaginal flora in women with cervical lesions

Objective: To explore the characteristics and correlations of vaginal flora in women with cervical lesions. Methods: A total of 132 women, including 41 women diagnosed with normal cervical (NC), 39 patients with low-grade cervical intraepithelial neoplasia (CIN 1), 37 patients with high-grade cervical intraepithelial neoplasia (CIN 2/3) and 15 patients with cervical squamous cell carcinoma (SCC), who came from the gynecological clinic of Second Hospital of Shanxi Medical University during January 2018 to June 2018, were enrolled in this study according to the inclusive and exclusive criteria strictly. The vaginal flora was detected by 16S rDNA sequencing technology. Co-occurrence network analysis was used to investigate the Spearman correlations between different genera of bacteria. Results: The dominant bacteria in NC, CIN 1 and CIN 2/3 groups were Lactobacillus [constituent ratios 79.4% (1 869 598/2 354 098), 63.6% (1 536 466/2 415 100) and 58.3% (1 342 896/2 301 536), respectively], while Peptophilus [20.4% (246 072/1 205 154) ] was the dominant bacteria in SCC group. With the aggravation of cervical lesions, the diversity of vaginal flora gradually increased (Shannon index: F=6.39, P=0.001; Simpson index: F=3.95, P=0.012). During the cervical lesion progress, the ratio of Lactobacillus gradually decreased, the ratio of other anaerobes such as Peptophilus, Sneathia, Prevotella and etc. gradually increased, and the differential bacteria (LDA score >3.5) gradually evolved from Lactobacillus to other anaerobes. The top 10 relative abundance bacteria, spearman correlation coefficient>0.4 and P<0.05 were selected. Co-occurrence network analysis showed that Prevotella, Peptophilus, Porphyrinomonas, Anaerococcus, Sneathia, Atopobium, Gardnerella and Streptococcus were positively correlated in different stages of cervical lesions, while Lactobacillus was negatively correlated with the above anaerobes. It was found that the relationship between vaginal floras in CIN 1 group was the most complex and only Peptophilus was significantly negatively correlated with Lactobacillus in SCC group. Conclusions: The increased diversity and changed correlations between vaginal floras are closely related to cervical lesions. Peptophilus is of great significance in the diagnosis, prediction and early warning of cervical carcinogenesis.

Low-Grade Cervical Intraepithelial Neoplasia (CIN1) Evolution: Analysis of Opportunistic Preventive Vaccination Role.

Low-grade cervical lesions have a high percentage of clearance in young women, even if 71-82% of low-grade intraepithelial lesion/atypical squamous cells of undetermined significance (LSIL/ASCUS) reported a High-Risk Human Papillomavirus (HR-HPV) infection, which correlates with an increased risk of Cervical Intraepithelial Neoplasia (CIN)2+. The immunogenic effect of the anti-HPV vaccine appears to be significant. The aim of the study is to evaluate the effect, two years after the diagnosis, of the anti-HPV preventive vaccination on patients with low-grade cervical lesions. We collected clinical, colposcopic, histological, and virological data from patients aged 21-45 years who attended the colposcopy service of the department of Obsetrics and Gynecology of IRCCS Foundation Policlinico San Matteo, Pavia, Italy. In the 2005-2019 period and had a low-grade pap-smear. We enrolled 422 women consecutively, divided into two groups (vaccinated and not vaccinated) for the retrospective analysis. The rate of persistence and progression of CIN were higher in the not-vaccinated group (p = 0.019). The relative risk (RR) to develop CIN2+ during follow-up vs. the the CIN1 persistence was 1.005 (95% Confidence Interval-CI 0.961-1.051) vs. 0.994 (95% CI 0.994-1.018) for age, 3.472 (95% CI 1.066-11.320) vs. 1.266 (95% CI 0.774-2.068) for non-vaccinated, 0.299 (95% CI 0.088-1.018) vs. 0.518 (95% CI 0.242-1.109) for HIV status negative, respectively. Analyzing the time to negativity, the odds ratio (OR) was 1.012 (95% CI 1-1.024) for age and 1.591 (95% CI 1.223-2.069) for vaccination; on the other hand, considering the relationship between the time to negative and the HPV genotypes contained in the 9-valent HPV vaccines, the OR was 1.299 (95% CI 1.026-1.646) for at least one of these at recruitment and 0.631 (95% CI 0.471-0.846) at follow-up. Furthermore, the presence of at least one of the HPV genotypes targeted by the HPV nonavalent vaccine is a key indicator of the risk of progression to CIN2+: OR was 3.443 (95% CI 1.065-11.189) for the presence of at least one HPV genotype at enrollment and 5.011 (95% CI 1.899-13.224) for the presence of at least one HPV genotype at follow-up, respectively. We reported in a retrospective study the benefit of anti-HPV vaccination in promoting negativity and increasing low-grade cervical lesions regression.

Bovine Colostrum Treatment of Specific Cancer Types: Current Evidence and Future Opportunities.

Worldwide, the incidence of cancer is on the rise. Current cancer treatments include chemotherapy, radiation therapy, and surgery. Chemotherapy and radiation treatment are typically associated with severe adverse effects and a decline in patients' quality of life. Anti-cancer substances derived from plants and animals need to be evaluated therapeutically as it is cost-effective, have fewer side effects, and can improve cancer patients' quality of life. Recently, bovine colostrum (BC) has attracted the interest of numerous researchers investigating its anti-cancer potential in humans. Dressings loaded with BC are beneficial in treating chronic wounds and diabetic foot ulcers. Lactoferrin, a glycoprotein with potent anti-oxidant, anti-inflammatory, anti-cancer, and anti-microbial effects, is abundant in BC. The BC pills successfully promote the regression of low-grade cervical intraepithelial neoplasia when administered intravaginally. The biological, genetic, and molecular mechanisms driving BC remain to be determined. Oral BC supplements are generally well-tolerated, but some flatulence and nausea may happen. To evaluate the therapeutic effects, long-term safety, and appropriate dosages of BC drugs, well-designed clinical trials are necessary. The purpose of this article is to emphasize the anti-cancer potential of BC and its constituents.

Aerobic Vaginitis: is Enterococcus faecalis Another Risk Factor in the Progression of Cervical Intraepithelial Neoplasia to Cervical Cancer—Literature Review

Objective: The aim of our review article is to show Enterococcus faecalis (E. faecalis) as a risk factor of cervical cancer. Mechanism: Aerobic vaginitis (AV) is the absence of a balance of vaginal flora containing aerobic and intestinal pathogens, varying degrees of vaginal inflammation and immature epithelial cells. The causes of AV responsible for inflammatory changes are: E. faecalis, Esherichia coli, group B streptococcus and Staphylococcus aureus. The pathogenic effect of aerobic microorganisms such as E. faecalis shows that it causes spontaneous abortion, premature birth, puerperal sepsis, abscesses, and urinary tract infections. Findings in Brief: AV caused by E. faecalis is more common in low-grade and high-grade cervical intraepithelial neoplasia (CIN) than in women with a normal Pap test and is thought to contribute to the progression of cervical cancer. E. faecalis produces hydrogen superoxide which causes chromosomal instability in intestinal epithelial cell infection, which is considered a key factor in the carcinogenic process. The presence of the Human papilloma virus (HPV) 16 gene and genome in E. faecalis in cervical cancer biopsy material leads to a specific link that may be a risk factor in the progression of CIN toward cancer. The presence of HPV in this bacteria can lead to persistent HPV infection, CIN development and progression to cervical cancer. Conclusions: Increased vaginal pH, lactobacilli deficiency, and the ability of E. faecalis to contain HPV-16 in episomal form in E. faecalis-induced AV could be key promoters of persistence and proliferation of cervical HPV as a risk factor in development of CIN and cervical cancer.

Evaluation of 5-aminolevulinic acid-mediated photodynamic therapy in postmenopausal women with persistent HPV infection with or without cervical and vaginal low-grade squamous intraepithelial lesions (CIN1/VaIN1)

ObjectiveTo analyze the efficacy and safety of photodynamic therapy (PDT) on postmenopausal women with persistent human papillomavirus (HPV) infection with or without low-grade cervical and vaginal intraepithelial neoplasia (CIN1 and VaIN1). Materials and methodsThe clinicopathological and follow-up data of 86 postmenopausal women with HPV infection (35 cases with chronic cervicitis and 51 cases with CIN1/VaIN1) were collected. All the women in this group met these criteria: menopausal time ≥ 1 year, HPV infection time ≥ 2 years, colposcopy and pathological diagnosis of biopsy ≤ CIN1/VaIN1 before PDT treatment, and 5-aminolaevulinic acid (5-ALA) as photosensitizer treating for 6 times with a week interval. The above patients were followed up 6 months and 12 months after PDT treatment, and the follow-up contents included HPV typing, cytology, colposcopy and pathological examinations. HPV negative conversion rate and lesion remission rate are the evaluation indicators of treatment efficacy. In addition, we also assessed the safety of PDT treatment. ResultsAt 12-month follow-up, the overall HPV clearance rate was 60% (45/75), of which the negative conversion rate of 16/18 HPV was 41.38% (12/29), and non-16/18 HPV was 71.74% (33/46) (p = 0.009). In patients without lesions, the HPV clearance rate was 51.72% (15/29), while in patients with CIN1/VaIN1 (n = 46), the HPV complete remission rate and lesion regression rate were 65.22% (30/46) and 89.13% (41/46), respectively. In addition, the clearance rate of HPV in lesion regression group was significantly higher than that in lesion persistence/progression group (0.00% vs. 73.17%, p = 0.003). The adverse reactions after PDT treatment were mild, mainly manifested as increased vaginal secretions or burning/tingling. ConclusionsPhotodynamic therapy can significantly enhance the elimination rate of persistent HPV infection in postmenopausal women and reduce the progression of CIN1/VaIN1. It could be an effective conservative treatment for persistent HPV infection and CIN1/VaIN1 in postmenopausal women.

Immunological substantiation of complex therapy in patients with mild HPV-associated cervical intraepithelial neoplasia

Introduction. As is known, the development of invasive cervical cancer is preceded by cervical intraepithelial neoplasia of varying severity, which is a pathological process in which cells with varying degrees of atypia and impaired differentiation appear in the thickness of the stratified squamous epithelium of the cervix.Objective. To study the effect of complex therapy in patients with mild HPV-associated cervical intraepithelial neoplasia on the dynamics of local cytokine status and autoimmunity parameters.Materials and methods. The study included 86 patients aged 35 to 40 years with morphologically verified mild cervical intraepithelial neoplasia. The main group consisted of 52 patients who, along with radio wave destruction of the cervix, were prescribed an immunostimulating drug with antiviral activity “Groprinosin-Richter” 1000 mg 3 times a day for 10 days 10–14 days before destruction and similar 2 courses after 10–14 days after it. The comparison group included 34 patients who underwent only radio wave destruction of the cervix.Results. An analysis of the outcomes of low-grade squamous intraepithelial lesions after 6 months showed that in the main group, CIN I regression was observed in 92.3% of patients, persistence – in 7.7% of cases, while in the comparison group, CIN I regression was noted in 73,5% of cases, persistence – in 26.5% of patients.Conclusions. Conducting complex therapy, including radio wave destruction and the use of a drug with immunostimulating and antiviral activity “Groprinosin-Richter” in patients with low-grade HPV-associated cervical intraepithelial neoplasia, leads to the elimination of the initial imbalance of cytokines and normalization of autoantibody levels, helping to reduce the likelihood of HPV persistence and CIN progression to invasive cervical cancer uterus.

A nested case-control study on the relationship between red blood cell folate and the prognosis of low-grade cervical intraepithelial neoplasia

Objective: To evaluate the relationship between red blood cell folate (RBC folate) and the prognosis of low-grade cervical intraepithelial neoplasia (CIN 1). Methods: In the married women cohort established in 2014, 564 women with CIN 1 diagnosed by pathology were recruited. The demographic characteristics and factors of cervical intraepithelial neoplasia were collected. Meanwhile, the infection status of human papillomavirus (HPV) was detected by molecular diversion hybridization, and the level of RBC folate was measured by chemical photoimmunoassay. After 24 months of follow-up, pathological examination was performed again to observe the prognosis of participants. The women with reversal were taken as the control group,and those with continuous and progressive CIN 1 were taken as the case group respectively. The relationship between RBC folate and CIN 1 outcome was evaluated by logistic regression model. Results: 453 women completed the follow-up, aged (49.72±6.84) years old. CIN 1 was reversed in 342 women, continued in 58 cases and progressed in 53 cases. The RBC folate level M (Q1,Q3) were 399.01 (307.10, 538.97) ng/ml, 316.98 (184.74, 428.49) ng/ml and 247.14 (170.54, 348.97) ng/ml, respectively. With the decrease of RBC folate, the risk of continuous and progressive CIN 1 increased (all P<0.001), while the risk of reversal CIN 1 decreased gradually (P<0.001). Combined with high-risk human papillomavirus (HR-HPV) infection status, low level of RBC folate could increase the risk of CIN 1 progression regardless of HR-HPV infection (HR-HPV infection: OR=21.34, 95%CI: 3.98-114.54; HR-HPV uninfection: OR=11.15, 95%CI: 2.34-53.13). Conclusion: Low level of RBC folate could increase the risk of CIN 1 persistence and progression regardless of HR-HPV infection.

CD74 and HLA-DRA in Cervical Carcinogenesis: Potential Targets for Antitumour Therapy.

Background and Objectives: Abnormal expressions of CD74 and human leukocyte antigen-DR alpha (HLA-DRA) have been reported in various cancers, though their roles in cervical cancer remain unclear. This study aimed to evaluate the gene and protein expressions of CD74 and HLA-DRA in the progression from normal cervix to precancerous cervical intraepithelial neoplasia (CIN) and finally to squamous cell carcinoma (SCC). Materials and Methods: The gene expression profiles of CD74 and HLA-DRA were determined in formalin-fixed paraffin-embedded tissues, with three samples each from normal cervixes, human papillomavirus type 16/18-positive, low-grade CIN (LGCIN), high-grade CIN (HGCIN), and squamous cell carcinoma (SCC) using Human Transcriptome Array 2.0. Immunohistochemical expression of the proteins was semi-quantitatively assessed in another cohort of tissue microarray samples comprising 7 normal cervix cases, 10 LGCIN, 10 HGCIN, and 95 SCC. Results: The transcriptomics profile and proteins’ expression demonstrated similar trends of upregulation of CD74 and HLA-DRA from normal cervix to CIN and highest in SCC. There was a significant difference in both proteins’ expression between the histological groups (p = 0.0001). CD74 and HLA-DRA expressions were significantly associated with CIN grade (p = 0.001 and p = 0.030, respectively) but not with the subjects’ age or SCC stage. Further analysis revealed a positive correlation between CD74 and HLA-DRA proteins. Conclusions: CD74 appears to promote cervical carcinogenesis via oncogenic signalling mechanisms and may serve as a potential antitumour target. Additionally, the upregulation of HLA-DRA, often associated with stronger immunogenicity, could be a promising biomarker for developing immunotherapies.

Acceleration of cervical cancer diagnosis with human papillomavirus testing below age 30: Observational study.

Several international cervical screening guidelines advise against using high-risk human papillomavirus (HR-HPV) testing in women younger than 30. The rationale for this in young women, lies in the potential for additional detection of both low-grade and high-grade cervical intraepithelial neoplasia (CIN) leading to unnecessary treatments without reducing the burden of cervical cancer. We studied 56 544 women screened at 24 to 29 with HR-HPV testing and 116 858 screened with liquid-based cytology (LBC) in the English HPV screening pilot. They were compared to 528 460 women screened at the age of 30 to 49. We studied the detection of cervical cancer and CIN2/3 across two consecutive screening rounds 3 years apart. At 24 to 29, a positive HR-HPV test detected more cases of cervical cancer in the prevalence round than did a positive LBC test (1.36/1000 screened vs 0.82/1000, ORadj : 1.61, 95% CI: 1.18-2.19). In women with a negative HR-HPV test, cervical cancer was diagnosed before or at the incidence round in 0.07/1000. After a negative LBC test, cancer detection reached 0.47/1000 and 40% of these cases were diagnosed at FIGO stage IB+. HR-HPV testing increased the detection of CIN2/3 diagnoses in two consecutive rounds combined by 30% (71.9/1000 vs 55.2/1000). The patterns of detection of cervical cancer and CIN2/3 were almost identical at older ages. These data support using HR-HPV testing for screening of women younger than 30, which not only accelerates the diagnosis of cervical cancer but leads to a similar relative increase in CIN2/3 diagnosis to that found in women aged 30 to 49.

The effect of red blood cell folate on the prognosis of high-risk human papillomavirus infection: a community-based cohort study

Objective: To investigate the effect of red blood cell folate on the prognosis of high-risk human papillomavirus (HR-HPV) infection. Methods: A total of 564 participants with low-grade cervical intraepithelial neoplasias (CINⅠ) were selected from the community-based married women cohort established in 2014. The general baseline information and factors related to HPV infection were collected. Meanwhile, HPV genotyping and levels of folate were measured. The subjects were divided into different levels of exposure group according to the folate levels and followed up for 24 months to observe the changes of HR-HPV infection status. There were four changes, including persistent infection, infection turned negative, from negative to positive and constant negative by comparing HR-HPV infection status at baseline and follow-up to 24 months. Results: 483 participators completed 24 months of follow-up observation, with a follow-up rate of 85.64% (483/564). The rates of persistent infection, infection turned negative, from negative to positive, and the constant negative were 52.45% (75/143), 47.55% (68/143), 19.71% (67/340), 80.29% (273/340), respectively. Our results demonstrated that the risk of persistent infection (aRR=2.50, 95%CI: 1.55-4.02) and from negative to positive (aRR=4.55, 95%CI: 2.52-8.23) in the low level of folate were significantly higher than that in the high level of folate, especially the risk of homotype persistent infection (aRR=2.72, 95%CI: 1.51-4.90). The risk of persistent infection (trend χ2=20.62, P<0.001), from negative to positive (trend χ2=31.76, P<0.001), persistent homotypic infection (trend χ2=20.09, P<0.001) increased with the decrease of red blood cell folate level. On the contrary, no similar results were found in persistent heterotypic infection. Conclusions: A low level of red blood cell folate could increase the risk of HR-HPV persistent infection and from negative to positive. In women with HR-HPV infection, the risk of persistent homotypic infection is higher.

Follow–up of females with atypical glandular cells on Pap smears

Purpose: Atypical glandular cells (AGC) are often associated with clinically significant lesions, but the interpretation of AGC and the associated lesions on Pap smears remains challenging, even for experienced cytopathologists. The frequency and histologic follow–up of AGC regardless of gland cell type were investigated.&#x0D; Methods: A retrospective review was conducted involving 199,265 cervicovaginal smears which were examined in the Department of Pathology and Cytology of Celje General Hospital between 1 January 2003 and 31 December 2008. We investigated the frequency of AGC on conventional Pap smears and evaluated the follow–up and correlation between cytology results and subsequent biopsy diagnoses over a 6–year period. The data were processed using the statistics program, SPSS. Statistical significance was set at a p&lt;0.05.&#x0D; Results: Between 1 January 2003 and 31 December 2008, a total of 745 women had AGC, representing 0.4% of all Pap smear results. One hundred seventy–two women (23.1%) with an average age of 41 years (range, 17–65 years) had a subsequent histologic examination. There were 79 patients (45.9%) with a clinically significant diagnosis, including 63 patients with high– grade cervical intraepithelial neoplasia, 4 patients with adenocarcinoma in situ, and 12 patients with invasive carcinoma (5 endometrial adenocarcinomas, 5 cervical squamous carcinomas, and 2 other types). Normal histologic findings were present in 65 patients (37.8%), 26 patients had low–grade cervical intraepithelial neoplasia, and 2 patients had low–grade glandular intraepithelial neoplasia.&#x0D; Conclusion: In subsequent biopsy specimens, cytologically AGC are not always glandular or even abnormal. The underlying abnormalities are often so serious that AGC findings require careful clinical and histologic follow–up.

Effects of polycyclic aromatic hydrocarbons exposure on prognosis of high risk human papillomavirus infection: a prospective cohort study

Objective: To investigate the effects of polycyclic aromatic hydrocarbons (PAHs) exposure on the prognosis of high risk human papillomavirus (HR-HPV) infection. Methods: In this prospective study, 564 patients with low-grade cervical intraepithelial neoplasia confirmed by pathology were selected from the natural cohort population established by our research group in Shanxi province in 2014. Based on the baseline data of demographic characteristics and factors related to HPV infection, the concentrations of 1-hydroxypyrene in urine samples of the patients were determined by high performance liquid chromatography to define the exposure level of PAHs. At baseline survey and follow-up after 24 months, flow-through hybridization was used to detect HPV infection types, and to evaluate the prognosis of HR-HPV (persistent infection, negative conversion, positive conversion and persistent negative status). Results: Of the 564 subjects, 483 completed the follow-up, with a follow-up rate of 85.6% (483/564). Among them, the persistent infection rate was 52.4% (75/143), the persistent homotype infection rate was 35.7% (51/143), the negative conversion rate was 47.6% (68/143), the positive conversion rate was 19.7% (67/340), and the persistent negative rate was 80.3% (273/340). The follow-up results showed that the persistent infection rate (aRR=3.22, 95%CI: 1.85-5.62) and positive conversion rate (aRR=2.84, 95%CI: 1.64-4.94) of HR-HPV in high PAHs exposure group were higher than those in low PAHs exposure group, while the persistent negative rate (aRR=0.55, 95% CI: 0.43-0.70) of HR-HPV in high PAHs exposure group were lower than those in low PAHs exposure group. Based on restrictive cubic spline analysis, the results showed that the effects of PAHs exposure on persistent HR-HPV infection and persistent homotype infection showed an ascending linear dose-response relationship, while on HR-HPV positive conversion and persistent negative status showed an ascending and declining nonlinear dose-response relationship respectively (P<0.01). Conclusions: High PAHs exposure could promote persistent HR-HPV infection and persistent homotypic infection. Reducing PAHs exposure might conducive to HR-HPV continuous negative maintenance. Active prevention and control of PAHs exposure is of great significance to prevent HR-HPV infection and persistent infection.

The optimal model of diagnosis to low-grade cervical intraepithelial neoplasia by combined detecting vaginal micro-environmental factors, based on the high-risk HPV infection

Objective: To investigate the diagnostic value of different vaginal micro-environmental factors in low-grade cervical intraepithelial neoplasia (CIN Ⅰ) and determine the optimal model in high-risk human papillomavirus (HR-HPV) infection. Methods: A total of 926 women, including 623 with normal cervical (NC) condition and 303 CINⅠ patients, had undergone pathological examinations, and were enrolled in the study. All the women were from a community previously established cohort. Vaginal cleanliness, pH, H2O2, β-glucuronidase, coagulase, sialidase, and leukocyte esterase (LE) were detected by the combined detection method aerobic vaginitis/bacterial vaginosis in vaginal secretions. HPV genotyping was performed by using the flow-through hybridization technology. The data were analyzed by SAS 9.2 and SPSS 23.0. Results: The vaginal cleanliness, pH, sialidase, and LE were determined as the representative vaginal micro-environment factors by principal component analysis. Based on logistic regression theory to analyze the ROC curve, the results showed that the highest sensitivity was with pH value (76.2%), and the highest specificity was with sialidase (90.9%). The area under ROC curve were higher in combination detection modes of sialidase+LE (0.714), pH+sialidase+LE (0.719), vaginal cleanness+sialidase+LE (0.713) and pH+vaginal cleanness+sialidase+LE (0.709). According to HR-HPV infection status, the TOPSIS method was used to analyze the combined detection optimal model. Specifically, we found that the best diagnostic model was pH+sialidase +LE (Ci=0.585) in the HR-HPV positive group and vaginal cleanness+sialidase+LE (Ci=0.641) in the negative group. Conclusions: The combined detection of vaginal microenvironment factors could be used for auxiliary diagnosis for CINⅠ. It would be more effective when detecting pH, sialidase, and LE in HR-HPV positive women while vaginal cleanness, sialidase, and LE in HR-HPV negative women at the same time.