Efficacy and influencing factors of CO2 laser, topical photodynamic therapy versus therapy combined with CO2 laser pretreatment for vaginal low-grade squamous intraepithelial lesions with high-risk HPV infection.

BACKGROUND: Vaginal intraepithelial neoplasia (VaIN) is a group of diseases of squamous epithelial dysplasia and carcinoma in situ occurring in the vagina, which is associated with high-risk human papillomavirus (HR-HPV) infection. OBJECTIVES: To evaluate the efficacy and safety of Carbon dioxide (CO2) laser, 5-aminolevulinic acid photodynamic therapy (PDT) and PDT combined with CO2 laser pretreatment for VaIN1 with HR-HPV infection, and analyze the factors affecting the clearance of HR-HPV. METHODS: Patients with HR-HPV infection and pathological diagnosis of VaIN1 and received laser or PDT or PDT combined with laser pretreatment were recruited. A total of 45 patients received one to three times CO2 laser (laser Group), 15 patients received three times PDT (PDT Group) and 15 patients received CO2 laser once and PDT three times (laser + PDT Group). HPV testing, cytology and colposcopy examinations at 3-6 months and 9-12 months after treatment were analyzed to assess the outcomes of the treatment. RESULTS: There was no significant difference in regression rate of VaIN1 among the laser Group, the PDT Group and the laser + PDT Group (3-6 month follow-up: 57.78% vs 73.3% vs 80 %, 9-12 month follow-up: 68.89% vs 80% vs 86.67 %, P>0.05). HR-HPV remission rates were also similar in the three groups (3-6 month follow-up: 26.67% vs 46.67% vs 46.67 %, 9-12 month follow-up: 40 % in all groups, P>0.05). Compared to HR-HPV negative group, patients in the HR-HPV positive group were older and had more pregnancies. Menopause and multiple vaginal lesions were more common in the HR-HPV positive group. Adverse reactions were mild in the PDT Group. The laser Group and the laser + PDT Group had more adverse effects, such as increased vaginal secretion, vaginal bleeding, scarring and local pain. CONCLUSION: For patients with VaIN1 at risk of progression, ALA-PDT presents itself as a viable choice for those who are well-informed and can consent to its costs and benefits. The addition of CO2 laser pretreatment may not increase the benefit of ALA-PDT treatment of VaIN1. Older age, menopause, more times of pregnancies, and multiple vaginal lesions might affect HR-HPV regression.

Optimising cervical cancer screening during pregnancy: a study of liquid-based cytology and HPV DNA co-test.

This study assessed the efficacy of ThinPrep cytologic test and human papillomavirus (HPV) co-test in cervical cancer screening during pregnancy. A cohort of 8,712 pregnant women from Ren Ji Hospital participated in the study. Among them, 601 (6.90%) tested positive for high-risk HPV (HR-HPV) and 38 (0.44%) exhibited abnormal cytology results (ASCUS+). Following positive HR-HPV findings, 423 patients underwent colposcopy, and 114 individuals suspected of having high-grade squamous intraepithelial lesion and cervical cancer (HSIL+) underwent cervical biopsy. Histological examination revealed 60 cases of normal pathology (52.63%), 35 cases of low-grade squamous intraepithelial lesion (30.70%), 17 cases of HSIL (14.91%), and 2 cases of cervical cancer (1.75%). The incidence of HSIL+ in HPV 16/18 group was significantly higher than that in non-HPV16/18 group (10.53% vs. 6.14%, P < 0.05). Subsequent evaluation of the clinical performance of cytology alone, primary HPV screening, and co-testing for HSIL+ detection revealed that the HSIL+ detection rate was lowest with cytology alone. These findings suggest that HPV testing, either alone or combined with cytology, presents an efficient screening strategy for pregnant women, underscoring the potential for improved sensitivity in cervical cancer screening during pregnancy. The significantly higher incidence of HSIL+ in the HPV16/18 group emphasizes the importance of genotype-specific considerations.

The effects of 5-aminolevulinic acid photodynamic therapy on the local immune response of women with cervical intraepithelial neoplasia grade 2.

Objective: To evaluate and elucidate the effects and mechanism of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) on the local immune response of women with cervical intraepithelial neoplasia grade 2 (CIN2). Materials and methods: Immunofluorescence staining was used to compare immune cells infiltration before and after ALA-PDT in 23 patients with CIN2. The infiltration of immune cells into the cervical tissues of patients with different outcomes was also compared at the 6-month follow-up period. Immune cell counts in samples collected before and after treatment were compared. Results: We found an increased number of CD8+ T cell infiltration, an increased proportion of CD8+ T cells expressing Granzyme B (GrB), Chemokine receptor 3 (CXCR3), and CD8+ tissue-resident memory T (TRM) cells, and a decreased proportion of CD8+ T cells expressing PD-1 in patients with CIN2 compared to that before ALA-PDT. Moreover, at the 6-month follow-up, there was higher infiltration of CD8+ T and CD8+ TRM cells, higher expression of GrB and CXCR3, and lower expression of PD-1 on CD8+ T cells in the HPV clearance and CIN2 disappearance groups than in the HPV-positive and CIN2 regression groups. However, no significant difference was observed in the number of CD8+ TSCM following ALA-PDT. Conclusion: ALA-PDT could activate CD8+ T cell responses by modulating the expression of CXCR3 and PD-1 in CD8+ T cells and increasing the infiltration of CD8+ TRM cells. And the infiltration of CD8+ T cells is correlated with the prognosis of CIN2.

Exosomal NOX1 promotes tumor-associated macrophage M2 polarization-mediated cancer progression by stimulating ROS production in cervical cancer: a preliminary study.

BACKGROUND: Cervical cancer the fourth most frequently diagnosed cancer and the fourth leading cause of cancer death in women, with an estimated 604,000 new cases and 342,000 deaths worldwide in 2020 for high rates of recurrence and metastasis. Identification of novel targets could aid in the prediction and treatment of cervical cancer. NADPH oxidase 1 (NOX1) gene-mediated production of reactive oxygen species (ROS) could induce migration and invasion of cervical cancer cells. Tumor-associated macrophages (TAMs) play important roles in cervical cancer. Tumor cell-derived exosomes mediate signal transduction between the tumor and tumor microenvironment. Elucidation of the mechanisms of NOX1-carrying exosomes involved in the regulation of TAMs may provide valuable insights into the progression of cervical cancer. METHODS: Uniformly standardized mRNA data of pan-carcinoma from the UCSC database were downloaded. Expression of NOX1 in tumor and adjacent normal tissues for each tumor type was calculated using R language software and significant differences were analyzed. SNP data set were downloaded for all TCGA samples processed using MuTect2 software from GDC. Cell experiment and animal tumor formation experiment were used to evaluate whether exosomal NOX1 stimulating ROS production to promote M2 polarization of TAM in cervical cancer. RESULTS: NOX1 is highly expressed with a low mutational frequency in pan-carcinoma. Upregulation of NOX1 may be associated with infiltration of M2-type macrophages in cervical cancer tissues, and NOX1 promotes malignant features of cervical cancer cells by stimulating ROS production. Exosomal NOX1 promotes M2 polarization of by stimulating ROS production. Exosomal NOX1 enhances progression of cervical cancer and M2 polarization in vivo by stimulating ROS production. CONCLUSION: Exosomal NOX1 promotes TAM M2 polarization-mediated cancer progression through stimulating ROS production in cervical cancer.

Analysis of outcomes following loop electrosurgical excision and clinical features of patients with cervical high-grade squamous intraepithelial lesions with abnormal preoperative endocervical curettage.

OBJECTIVE: The purpose of this study was to identify the clinical characteristics of patients with high-grade squamous intraepithelial lesions (HSIL) with abnormal endocervical curettage (ECC) and to evaluate the efficacy of abnormal preoperative ECC in predicting recurrence after a loop electrosurgical excision procedure (LEEP). METHODS: We retrospectively analyzed a total of 210 cases of histological HSIL in female patients diagnosed using cervical biopsy and/or indiscriminating ECC, and these included 137 cases with normal ECC and 63 cases with abnormal ECC. We also collected preoperative information and data on postoperative human papillomavirus (HPV) and histological outcomes within 2 years. RESULTS: The additional detection rate of HSIL using indiscriminating ECC was 5%. Patients with abnormal ECC were older (P < 0.001), predominantly menopausal (P = 0.001), had high-grade cytology (P = 0.032), a type 3 transformation zone (P = 0.046), and a higher proportion of HPV type 16/18 infection (P = 0.023). Moreover, age (odds ratio [OR] = 1.078, 95% confidence interval [CI] = 1.0325-1.1333, P = 0.003) and HPV 16/18 infection (OR = 2.082, 95% CI = 1.042-4.2163, P = 0.038) were independent risk factors for abnormal ECC. With an observed residual lesion/recurrence rate of 9.5% over the 24-month follow-up, we noted a 9.3% higher rate in the abnormal ECC group when compared with the normal ECC group. Abnormal preoperative ECC (OR = 4.06, 95% CI = 1.09-15.14, P = 0.037) and positive HPV at the 12-month follow-up (OR = 16.55, 95% CI = 3.54-77.37, P = 0.000) were independent risk factors for residual disease/recurrence. CONCLUSION: Preoperative ECC was one of the risk factors for post-LEEP residual/recurrent HSIL, and detecting abnormal ECC when managing older patients or patients with HPV 16/18 infection during colposcopy is critical.

Effect of topical 5-aminolevulinic acid photodynamic therapy versus therapy combined with CO2 laser pretreatment for patients with cervical high-grade squamous intraepithelial lesions.

OBJECTIVE: To evaluate the effect of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) combined with CO2 laser pretreatment (Laser+ALA-PDT) on patients with cervical high-grade squamous intraepithelial lesions (HSILs). METHODS: A total of 114 patients treated by ALA-PDT or Laser+ALA-PDT at 3 centers were retrospectively reviewed. The effective rate, cure rate of lesions as well as high-risk human papillomavirus (HR-HPV) regression rate and persistent infection rate in the 2 groups were compared according to 3-6 month and 9-12 months follow-ups. The characteristics and risk factors for ineffective cases were evaluated by regression analysis. RESULTS: At the 3-6month follow-up, the effective rate was significantly higher in the Laser+ALA-PDT group than in the ALA-PDT group (96.6% vs. 81.3%, p = 0.048). A total of 79.3% of the laser+ALA-PDT patients achieved cure rate compared with 61.3% of the ALA-PDT patients (p = 0.082). In the Laser+ALA-PDT group, the HR-HPV-negative rate was significantly higher (72.4% vs. 50.7%, p = 0.045), while the persistence rate was significantly lower (20.7% vs. 42.7%, p = 0.037). At the 9-12month follow-up, the cure rate was 83% in the ALA-PDT group, 17% lower than that in the Laser+ALA-PDT group (p = 0.055). A total of 20.8% of patients in the ALA-PDT group and 5.3% in the Laser+ALA-PDT group showed persistent HR-HPV infection (p = 0.120). Pretreatment HR-HPV type, multiple infections and treatment modality were relevant factors for PDT outcome. CONCLUSIONS: For patients with cervical HSIL, laser+ALA-PDT shows better efficiency and HPV regression compared with ALA-PDT. HPV16/18 and multi-infection may be risk factors for ineffective treatment with ALA-PDT.

Feasibility study of 5-aminolevulinic acid mediated photodynamic therapy of persistent vaginal high-risk HPV infection of post-hysterectomy patients.

BACKGROUND: Patients after hysterectomy are at higher risk for developing VaIN. However, there are no standard treatments for HPV infection and VaIN after hysterectomy and relative studies are limited. Thus we aim to evaluate the feasibility of 5-aminolevulinic acid photodynamic therapy (5-ALA-PDT) for the treatment of persistent vaginal infection with high-risk HPV (HR-HPV) in post-hysterectomy patients. METHODS: Thirty-eight patients aged 43-70 years old with persistent vaginal stump HR-HPV infection with or without histological vaginal intraepithelial neoplasia (VaIN1) during follow-up after hysterectomy were recruited. Twenty patients received three times of ALA-PDT (PDT Group). Eighteen patients did not receive any treatments (Control Group). HPV testing, cytology, and colposcopy were performed in all patients 4-6 months and 12 months after treatment. RESULTS: HR-HPV remission rates of the PDT Group were 40% (8/20) and 66.67% (12/18) at the 4-6 month and 12-month follow-up, respectively, both were significantly higher than that of the Control Group (11.11% (2/18) and 6.23% (1/16), respectively; P < 0.05). For the PDT Group, the regression rate of VaIN1 was 100% (7/7) at 4-6 months, while VaIN1 recurred in two cases (28.6%) at the 12-month due to persistent HR-HPV infection. No persistence or progression of VaIN1 was noted. For the Control group, the spontaneous regression rate of VaIN1 was 50% (3/6) at 4-6 months and one patient progressed into VaIN2. At the 12-month follow-up point, one patient reccurred and the disease regression, persistence and recurrence rates were 40% (2/5), 40% (2/5) and 20% (1/5), respectively. Adverse reactions were mild after PDT treatment. CONCLUSION: 5-ALA-PDT is a safe, non-invasive, and effective option for post-hysterectomy patients who have persistent HR-HPV infection.

Erastin enhances metastatic potential of ferroptosis-resistant ovarian cancer cells by M2 polarization through STAT3/IL-8 axis.

Erastin is a small molecule identified in chemical screen that is capable of inducing ferropotosis. There is collective evidence proving that erastin-induced ferroptosis exhibits anti-tumor potential within diverse caners, such as ovarian cancer (OC). However, most OC cells show relative resistance to ferroptosis induced by erastin. M2-polarized tumor-associated macrophages (TAMs) have an important effect on the OC tumor microenvironment (TME), which makes M2 polarization a noticeable part in the context of OC therapy. The immunomodulatory effects of erastin on ferroptosis-resistant OC cells remain poorly understood. Here, we found that low concentration of erastin greatly promoted ferroptosis-resistant OC cell invasion and migration via STAT3-mediated M2 polarization of macrophages. As revealed by in-vitro experimental results, erastin significantly increased metastases of ferroptosis-resistant OC, and the percentage of M2 macrophage infiltration was also raised after erastin treatment. Furthermore, erastin augmented IL-8 production of macrophages, and pharmacological blockage of IL-8 partially abrogated the stimulatory effect of erastin on ferroptosis-resistant OC cells. This study demonstrates a new mechanism undering the tumor-promoting activity of erastin and has implications for the STAT3/IL-8 axis as a potential target for ferroptosis-resistant OC cells to improve overall anti-tumor efficacy.

Sesamin exerts anti-tumor activity in esophageal squamous cell carcinoma via inhibition of TRIM44 and NF-κB signaling.

Tripartite motif-containing 44 (TRIM44) is known to play an oncogenic role in multiple human cancers, including esophageal cancer. Sesamin possesses potent anti-inflammatory and anti-cancer properties for various cancers. This study is designed to unravel the biological functions of sesamin and TRIM44 in esophageal cancer. TRIM44 expression in esophageal squamous cell cancer (ESCC) cell lines and tissues was determined by RT-qPCR assay and Western blot. The effects of sesamin and TRIM44 on ESCC cell growth in vivo and in vitro were assessed by the mouse model and CCK-8 assay, respectively. We found that TRIM44 was significantly upregulated in ESCC cell lines and tissues when compared to their counterparts. Sesamin treatment or depletion of TRIM44 markedly reduced ESCC cell proliferation. The nuclear factor kappa B (NF-κB) and toll-like receptor 4 (TLR4) signaling pathway may be involved in sesamin-mediated TRIM44 suppression. Finally, we showed that oral administration of sesamin dramatically inhibited tumor growth or ESCC in nude mice. Our results suggest that sesamin exerts anti-tumor activity in ESCC via inhibition of NF-κB signaling pathway, demonstrating its potential for the treatment of esophageal cancer.

Epidemiology and analysis of potential risk factors of high-risk human papillomavirus (HPV) in Shanghai China: A cross-sectional one-year study in non-vaccinated women.

Data regarding human papillomavirus (HPV) prevalence, its associated risk factors, and women's knowledge about this disease before the HPV vaccine was approved are limited in Shanghai, China. Therefore, we investigated these questions among females in Shanghai and aimed to provide comprehensive data to guide HPV vaccination and present the biopsychosocial risk factors that impact high-risk HPV infection, and evaluate the level of knowledge and awareness of this disease among women aged 21-65 years old. A total of 6619 (aged from 21 to 65) women from different communities volunteered to participate in the HPV screening and complete questionnaires from December 2016 to December 2017 in the Department of Obstetrics and Gynecology of nine hospitals in Shanghai. Data were analyzed using sample logistic regression to assess biopsychosocial risk factors that impact high-risk HPV infection and knowledge of HPV infection. A total of 632 (9.5%) cases were positive for high-risk HPV test, 22.6% of them were HPV 16/18 infection, 77.4% of them were non HPV 16/18 infection. 40 potential risk factors may be related to high-risk HPV infection, and there were 19 factors' p value < 0.1 from single factor logistic analysis. Finally, multivariable regression revealed education level, type of vaginitis, history of hyperlipidemias, family history of cancer, number of pregnancies, number of sex partners were independent risk factors for high-risk HPV infection (p < 0.05). When stratified by education level, women who finished graduate school had significantly greater knowledge of cervical cancer, cervical screening, and the relationship between HPV and cervical cancer than other groups (p < 0.05). The prevalence rate of high-risk HPV was a little lower than other regions in China and other countries, which may be related to regions, races, living habits, and economy. A less reported finding is that the history of vaginitis and the history of hyperlipidemias in our study were related to HPV infection. The majority of the participants had poor knowledge regarding cervical cancer, cervical screening, and the relationship between HPV and cervical cancer. Hence, these results should be served as a wake-up call for the government to increase knowledge and awareness via the media and doctors.

Clinical evaluation of a real-time optoelectronic device in cervical cancer screening.

OBJECTIVE: Early screening and intervention are crucial for the prevention and treatment of cervical cancer. TruScreen is a real-time, intelligent, pathological diagnostic technology designed for cervical cancer screening. The aim of this study was to evaluate the clinical value of TruScreen in screening for cervical lesions. STUDY DESIGN: A total of 458 women aged between 25 and 65 years were recruited to receive cervical cancer screening, including human papillomavirus (HPV) testing, cytological testing using the ThinPrep cytology test (TCT), and TruScreen from December 2018 to January 2020. The clinical performance of TruScreen, alone and in combination with HPV testing, was evaluated to detect cervical intraepithelial neoplasia grade 2 or worse (CIN2+ or CIN3+). RESULTS: For detection of CIN2+, the sensitivity and specificity of TruScreen were 83.78% and 78.86%, respectively. The specificity of TruScreen was significantly higher than those of HPV testing (50.59%, P < 0.001) and TCT (55.58%, P < 0.001). In high-risk HPV-positive women, the specificity of HPV testing combined with TruScreen was significantly higher than that of HPV testing combined with TCT (50% vs 39.9%, P = 0.004). The sensitivity of HPV testing combined with TruScreen was comparable to that of HPV testing combined with TCT (93.94% vs 87.88%, P = 0.625). Similar patterns were also observed for CIN3+ cases. CONCLUSION: TruScreen has the potential for screening high-grade cervical precancerous lesions and may replace cytological tests as a cervical cancer screening method in China to avoid subjectivity in the interpretation of cytological tests and requirements by pathologists.

The effect of 5-Aminolaevulinic Acid Photodynamic Therapy versus CO2 laser in the Treatment of Cervical Low-grade Squamous Intraepithelial Lesions with High-Risk HPV Infection: A non-randomized, controlled pilot study.

BACKGROUND: There are insufficient studies comparing the efficacy of 5-aminolaevulinic acid (ALA) photodynamic therapy (PDT) against CO2 laser therapy in the treatment of cervical low-grade squamous intraepithelial lesion (LSIL) with high-risk human papillomavirus (HR-HPV), especially for long-term efficacy. METHODS: Patients with cervical LSIL and HR-HPV infection were divided into two treatment groups based on their own choice. All patients had a follow-up test including HPV testing, cytology and colposcopy at 4-6 months and 12 months after the treatment. RESULTS: (1) Among 277 patients, 176 patients received 5-ALA PDT and 101 patients received CO2 laser therapy. (2) 4-6 months after treatment, there was no significant difference between two groups in the complete remission (CR) rates of cervical LSIL and the clearance rate of HR-HPV infection. (3) 12 months after treatment, compared with the CO2 laser group, the CR rates of cervical LSIL in the 5-ALA PDT group was significantly higher than the CO2 laser group. There was no statistical difference in the clearance rate of HR-HPV infection between the two groups. (4) 12 months after treatment, the recurrence rate of cervical lesions and the reinfection rate of HR-HPV infection in 5-ALA PDT group were significantly lower than those in CO2 laser group. CONCLUSION: The effect of 5-ALA PDT is similar to CO2 laser at 4-6 months. The long-term efficacy of 5-ALA PDT appears better than CO2 laser. As a non-invasive treatment, 5-ALA PDT is a highly effective therapeutic procedure for cervical LSIL with HR-HPV infection.

Effectiveness of photodynamic therapy in women of reproductive age with cervical high-grade squamous intraepithelial lesions (HSIL/CIN2).

OBJECTIVE: To evaluate the histologic response rate of high-grade squamous intraepithelial lesion (HSIL)/cervical intraepithelial neoplasia 2 (CIN2) of the cervix after photodynamic therapy (PDT) treatment in women with fertility requirements. MATERIALS AND METHODS: A retrospective study was carried out comprising 31 female patients aged 20-38 years with histologically confirmed HSIL/CIN2 with high-risk human papillomavirus (hrHPV) infection. Patients were treated with three sessions of 20% 5-aminolevulinic acid (5-ALA) PDT at intervals of 7-14 days. All patients had a follow-up including cytology, HPV testing and colposcopy-directed biopsy after PDT treatment at the 6-month and 12-month follow-up points. The main outcome measure was efficacy, defined as complete histologic remission 12 months after PDT. Secondary outcomes were the remission of HPV infection and the adverse effects of PDT treatment. RESULTS: At the 12-month follow-up, 21 out of 27 patients (77.78%) and 4 out of 27 patients (14.81%) showed histologic disappearance and histologic regression, respectively. Only 7.41% (2/27) patients persisted with HSIL/CIN2. In addition, no patients progressed to CIN3 or carcinoma. The total baseline HPV remission rate was 62.96% (17/27). The remission rate of HPV16/18 was statistically significant compared to the other hrHPV (57.14% vs. 100%, p = 0.016) in the group with HISL/CIN2 disappearance. Adverse events were mild, with increased vaginal secretion and abdominal pain being the most common complaints. There was no report of adverse events such as vaginal bleeding, colporrhagia, ulcer, or abdominal pain after PDT treatment. CONCLUSIONS: 5-ALA-PDT shows a favorable efficacy and safety profile and represents a promising alternative to observation and surgical procedures in patients with HSIL/CIN2 who have fertility requirements.

Effectiveness of photodynamic therapy with 5-aminolevulinic acid on HPV clearance in women without cervical lesions.

BACKGROUND: High-risk HPV (hrHPV) not only increases the risk of cervical precancerous lesions and cervical cancer, but also adds psychological burden to HPV-positive women. 5-aminolevulinic acid photodynamic therapy (ALA-PDT) is a non-invasive and highly tissue-selective therapy. We aim to investigate the clinical efficacy of ALA-PDT for elimination of cervical hrHPV infection in HPV-positive women without cervical lesions. METHODS: A total of 57 hrHPV-positive women without pathologically proved cervical lesions received three treatments of ALA-PDT in total. HPV DNA testing and pap cytology were performed in all patients. Patients with positive HPV16/18 or abnormal TCT results received colposcopic biopsy during the follow-up. RESULTS: hrHPV clearance rate was 56.1 % (32/57) at 3-month follow-up and 68.1 % at 6-month follow-up. 100 % of HPV 18 and 87.5 % of HPV16 infections were cleared while the clearance rate was 48.8 % among those positive for 12 other high-risk types. Multivariate analysis showed HPV16/18 infection was associated with significantly higher clearance rate. HPV clearance rate in patients with multiple-type HPV infection was significantly lower than that in patients with single-type HPV infections. CONCLUSIONS: ALA-PDT is effective on treating hrHPV infection in patients with no cervical lesions. HPV16/18 positive cases can benefit most from ALA-PDT. Multitype-infected women need more sessions of 5- ALA-PDT to eradicate hrHPV infection.

The effect of local photodynamic therapy with 5-aminolevulinic acid for the treatment of cervical low-grade squamous intraepithelial lesions with high-risk HPV infection: A retrospective study.

BACKGROUND: High-risk HPV infection is the main cause of cervical cancer and pre-cancerous lesions. The current principle of clinical management of cervical low-grade squamous intraepithelial lesion is observation for 2 years. Progression to high-grade squamous intraepithelial lesion warrants intervention. Primary treatment option is surgical excision which may have a negative impact on fertility. Topical photodynamic therapy is a non-invasive and targeted therapy. We investigated the clinical efficacy of this therapy for cervical low-grade squamous intraepithelial lesion with high-risk HPV infection. METHODS: A retrospective study consisting of 258 female patients aged 21-69 years with a histologically confirmed cervical low-grade squamous intraepithelial lesion with high-risk HPV infection was carried out. Subjects were treated with three sessions of 20 % 5-aminolevulinic acid photodynamic therapy at intervals of 7-14 days. Three months after treatment, the effect was evaluated through HPV typing, Thinprep cytology and colposcopy directed biopsy. Six months after treatment, the photodynamic therapy effect was evaluated by HPV genotyping and Thinprep cytology first, the pathological examination would be performed at the 6-month follow-up point if the cytological results indicated the risk of high-grade squamous intraepithelial lesions. RESULTS: Three months after treatment, among 258 low-grade squamous intraepithelial lesion with high-risk HPV infection patients, total baseline HPV remission rates was 64.34 % (166/258). The remission rate of HPV16/18 group was not statistically significant compared to the HPV non-16/18 group (73.13 % vs 61.26 %, p = 0.081).The remission rates of the <50 age group was significantly higher than the >50 age group (67.28 %vs46.34 %, p = 0.001). The total lesion regression rate wa treatment, among 258 low-grade squamous intraepithelial lesion with high-risk HPV infection patients, total baseline HPV remission rates was 64.34 % (166/258). The remission rate of HPV16/18 group was not statistically significant compared to the HPV non-16/18 group (73.13 % vs 61.26 %, p = 0.081).The remission rates of the <50 age group was significantly higher than the >50 age group (67.28 %vs46.34 %, p = 0.001). The total lesion regression rate was 84.88 % (219/258). 12.8 % (33/258) of patients did not progress. Only 2.33 % (6/258) patients progressed to high-grade squamous intraepithelial lesion and accepted loop electrosurgical excision procedure. The patients >50 age group had significant higher progression rate than the patients ＜50 age group (p＜0.05). Six months after treatment, except for 6 patients who progressed to high-grade squamous intraepithelial lesion and underwent surgical treatment, the total baseline HPV remission rates was up to 82.54 % (208/252). CONCLUSION: 5-aminolevulinic acid photodynamic therapy was highly effective and did not appear to create cervical damage.. It might be an ideal treatment for cervical low-grade squamous intraepithelial lesion with high-risk HPV infection, but this requires additional clinical trials.

Clinical Evaluation of DNA Ploidy for the Triage of HPV-Positive Chinese Women During Cervical Cancer Screening.

Quantification of DNA aneuploidy has great potential as a prognostic marker of cervical precancerous lesions. We aim to evaluate the performance of DNA ploidy analysis for the triage of HPV-positive women. 523 HPV-positive women ages 25-64 undergoing HPV and pap cytology testing with valid cervical biopsies in Renji Hospital were enrolled in a prospective observational study from June 2018 to June 2019. The clinical performances of DNA ploidy, with or without HPV16/18 genotyping, were evaluated for all HPV-positive women to detect histologic high-grade squamous intraepithelial lesion or worse (HSIL+). For HSIL+ detection, DNA ploidy had statistically higher specificity (83.89%) than Pap cytology (75.50%, P = 0.002) and HPV16/18 genotyping (77.92%, P = 0.023). Although the sensitivity of DNA ploidy (58.57%) remained similar with pap cytology (65.71%, P = 0.461) and HPV16/18 genotyping (55.71%, P = 0.734). A comparable sensitivity (84.29% vs. 84.29%, P = 1.000) and a higher specificity (66.00% vs. 58.94%, P < 0.001) compared with combination with Pap cytology. DNA ploidy triage strategy required fewer colposcopies per detection of HSIL+ compared with pap cytologic testing, with a 13.1% (34 of 258) reduction of colposcopies compared with routine triage strategy of HPV screening with Pap cytologic testing. HPV16/18-negative women with negative DNA ploidy results had the lowest risk of HSIL+ among HPV-positive women (3.55%). Automated DNA ploidy analysis, alone or in combination with HPV16/18 genotyping, shows the potential as a triage strategy of cervical cancer screening for HPV-positive women. PREVENTION RELEVANCE: Results from this study indicate that DNA ploidy analysis has good performance in early detection of high-grade precancerous and cancerous lesions of the cervix. This strategy could be used in the triage of HPV-positive women in cervical cancer screening.

Evaluation of p16/Ki-67 Dual-Stained Cytology in Triaging HPV-Positive Women during Cervical Cancer Screening.

BACKGROUND: We aimed to evaluate the utility of p16/Ki-67 dual-stained cytology for triaging human papillomavirus (HPV)-positive women. METHODS: HPV-positive women ages ≥ 21 years were recruited in a multicenter prospective observational study between May 2016 and May 2017. The clinical performance of dual-stained cytology, with or without HPV16/18 genotyping, was evaluated for all HPV-positive women to detect cervical intraepithelial neoplasia grade 2 or worse (CIN2+). RESULTS: 846 HPV-positive women ages ≥ 21 years with valid cervical biopsies were enrolled for this study. For CIN2+ detection, dual-stained cytology showed statistically higher specificity (85.28%) than Pap cytology (80.00%, P < 0.001) and HPV16/18 genotyping (72.36%, P < 0.001), while the sensitivity of dual-stained cytology (63.49%) remained comparable with that of Pap cytology (61.90%, P = 0.832) and HPV16/18 genotyping (61.90%, P = 0.897). HPV16/18 genotyping in combination with dual-stained cytology was more specific (62.50% vs. 58.06%, P < 0.001), while it showed similar sensitivity (86.51% vs. 85.71%, P = 1.000), as compared with HPV16/18 genotyping in combination with Pap cytology. Similar patterns were also observed for CIN3+. CONCLUSIONS: p16/Ki-67 dual-stained cytology, either alone or in combination with HPV16/18 genotyping, showed a good stratification with high specificity and comparable sensitivity for HPV-positive women. IMPACT: This is one of the few studies that has evaluated the performance of dual-stained cytology for triaging HPV-positive women in China. The higher specificity and comparable sensitivity of dual-stained cytology in comparison with Pap cytology in the detection of CIN2+ or CIN3+ is of vital importance to developing countries, where Pap cytology faces many challenges.

Association between the vaginal microbiome and high-risk human papillomavirus infection in pregnant Chinese women.

BACKGROUND: In this study, the association between high-risk human papillomavirus (hrHPV) infection and the vaginal microbiome in pregnant women was evaluated in Chinese cohorts. METHODS: The vaginal bacterial composition of four groups, 38 hrHPV-infected pregnant women (PHR, n = 38), pregnant women without HPV infection (PN, n = 48), nonpregnant women with hrHPV infection (NPHR, n = 19) and nonpregnant women without HPV infection (NPN, n = 30), was characterized by deep sequencing of barcoded 16S rRNA gene fragments (V3-4) using Illumina MiSeq. RESULTS: The results revealed that both pregnancy and HPV infection can increase vaginal bacterial microbial richness and diversity, with the bacterial composition being most influenced by pregnancy. Lactobacillus was the most dominant genus among all samples. NPN samples were dominated by CST (community state type) III, mainly composed of Lactobacillus iners. Both pregnancy and hrHPV infection were accompanied by an increased proportion of CST I (dominated by Lactobacillus crispatus), as opposed to CST III. Bifidobacterium, Bacillus, Megasphaera, Sneathia, Prevotella, Gardnerella, Fastidiosipila and Dialister were found to be biomarkers for hrHPV-infected women, though different genera (Bifidobacterium, Megasphaera, Bacillus, Acidovorax, Oceanobacillus and Lactococcus) were associated with hrHPV-infected pregnant women. CONCLUSIONS: This work uncovered a probable synergistic effect of hrHPV infection and pregnancy on the vaginal microbial composition. HPV infection in pregnant women was associated with a more complex and diverse microbial environment.

Suppressive effect of microRNA-449a on the NDRG1/PTEN/AKT axis regulates endometrial cancer growth and metastasis.

Database screening indicated that microRNAs (miRNAs) are involved in pathogenesis of endometrial cancer. Among these miRNAs, miR-449a might be involved in tumorigenesis and lower expression of miR-449a was associated with poor prognosis. However, the role of miR-449a and its underlying molecular mechanism in endometrial cancer (EC) has not been investigated. In this study, our analysis found that miR-449a expression is inversely correlated with the stage of EC. Downregulation of miR-449a was correlated with tumor progression and poor prognosis in the EC patients. Results of functional analyses revealed that overexpression of miR-449a in human EC cells alleviated cell proliferation, invasion and metastasis. Conversely, loss of miR-449a in EC cancer cells facilitated all these cellular activities. Moreover, we identified N-myc downstream-regulated gene 1 (NDRG1) as a direct and functional target gene of miR-449a in EC cells, and the expression of NDRG1 in 87 EC specimens were inversely correlated with that of miR-449a. Additionally, further studies show that the down-regulation of NDRG1 expression inhibited proliferation and metastasis of EC cells through the PTEN/AKT pathway. Therefore, these results suggest that miR-449a suppresses the growth and metastasis of EC by directly targeting the NDRG1 gene and that the activation of miR-449a may represent an effective therapeutic strategy in EC.