Cervical Intraepithelial Neoplasia Patients Research Articles

The disease stage-associated imbalance of Th1/Th2 and Th17/Treg in uterine cervical cancer patients and their recovery with the reduction of tumor burden

BackgroundNearly all uterine cervical cancer (UCC) cases result from human papillomavirus (HPV) infection. After high-risk HPV infection, most HPV infections are naturally cleared by humoral and cell-mediated immune responses. Thus, cervical lesions of only few patients progress into cervical cancer via cervical intraepithelial neoplasia (CIN) and lead to persistent oncogenic HPV infection. This suggests that immunoregulation plays an instrumental role in the carcinogenesis. However, there was a few studies on the relation between the immunologic dissonance and clinical characteristics of UCC patients.MethodWe examined the related immune cells (Th1, Th2, Th17, and Treg cells) by flow cytometric analysis and analyzed their relations with UCC stages, tumor size, differentiation, histology type, lymph node metastases, and vasoinvasion. Next, we quantified the Th1, Th2, Th17, and Treg cells before and after the operation both in UCC and CIN patients.ResultsWhen compared with stage I patients, decreased levels of circulating Th1 cells and elevated levels of Th2, Th17, and Treg cells were detected in stage II patients. In addition, the imbalance of Th1/Th2 and Th17/Treg cells was related to the tumor size, lymph node metastases, and vasoinvasion. We found that immunological cell levels normalized after the operations. In general, immunological cell levels in CIN patients normalized sooner than in UCC patients.ConclusionsOur findings suggested that peripheral immunological cell levels reflect the patient’s condition.

Diagnostic Value of Albumin to Fibrinogen Ratio in Cervical Cancer.

Albumin to fibrinogen ratio (AFR) play a crucial role in the progression and prognosis of many malignant tumors. This study aimed to comprehensively assess the diagnostic value of AFR as single markers or in combination with squamous cell carcinoma antigen (SCC-Ag), cancer antigen 125 (CA-125) in cervical cancer. A total of 323 cervical cancer inpatients, 143 patients with cervical intraepithelial neoplasia (CIN) and 317 healthy controls were analyzed. Differences in laboratory parameters and clinicopathological features were calculated using the Mann-Whitney U or Kruskal-Wallis H test. The receiver operating characteristic (ROC) curve was used to evaluate the predicted value of AFR, alone or combined with SCC-Ag, CA-125 for the diagnosis of cervical cancer. The levels of AFR in patients with cervical cancer were significantly lower than those in the CIN patients and the control subjects. AFR were not only negatively correlated with the tumor stage, but also related to histology typing, lymph node metastasis, distant metastasis, depth of stromal infiltration, tumor size, and tumor stage; however, it was not associated with the blood group. AFR combined with SCC-Ag possessed a larger area under the curve (AUC; AUCAFR+SCC-Ag = 0.924, 95% confidence interval (CI) 0.900, 0.944) than AFR (P < 0.001), SCC-Ag (P < 0.001), or CA-125 (P < 0.001) did alone. The pretreatment levels of AFR, alone or combined with SCC-Ag, CA-125 could improve the diagnostic efficiency of cervical cancer.

Polymorphisms in endoplasmic reticulum aminopeptidase genes are associated with cervical cancer risk in a Chinese Han population

BackgroundAntigen-processing machinery molecules play crucial roles in infectious diseases and cancers. Studies have shown that polymorphisms in endoplasmic reticulum aminopeptidase (ERAP) genes can influence the enzymatic activity of ERAP proteins and are associated with the risk of diseases. In the current study, we evaluated the influence of ERAP gene (ERAP1 and ERAP2) polymorphisms on susceptibility to cervical intraepithelial neoplasia (CIN) and cervical cancer.MethodsSix single nucleotide polymorphisms (SNPs) in ERAP1 and 5 SNPs in ERAP2 were selected and genotyped in 556 CIN patients, 1072 cervical cancer patients, and 1262 healthy control individuals. Candidate SNPs were genotyped using SNaPshot assay. And the association of these SNPs with CIN and cervical cancer was analysed.ResultsThe results showed that allelic and genotypic frequencies of rs26653 in ERAP1 were significantly different between cervical cancer and control groups (P = 0.001 and 0.004). The allelic frequencies of rs27044 in ERAP1 and rs2287988 in ERAP2 were significantly different between control and cervical cancer groups (P = 0.003 and 0.004). Inheritance model analysis showed that genotypes of rs27044, rs26618, rs26653 and rs2287988 SNPs may be associated with the risk of cervical cancer (P = 0.003, 0.004, 0.001 and 0.002). Additionally, haplotype analysis results showed that the ERAP1 haplotype, rs27044C-rs30187T-rs26618T-rs26653G-rs3734016C, was associated with a lower risk of cervical cancer (P = 0.001). The ERAP2 haplotypes rs2549782G- rs2548538A-rs2248374A-rs2287988G-rs1056893T (P = 0.009 and 0.006) and rs2549782T-rs2548538T-rs2248374G-rs2287988A-rs1056893T (P = 0.003 and 0.009) might be associated with cervical cancer and the development from CIN to cervical cancer.ConclusionOur results indicated that rs27044, rs26618 and rs26653 in ERAP1 and rs2287988 in ERAP2 influenced susceptibility to cervical cancer.

Socio-demographic Characteristics and Incidence of CIN of Uterine Cervix among VIA Positive Women attended at a Tertiary Care Hospital in Dhaka City

Background: Women in different socio-demographic are presented with VIA positivity.&#x0D; Objective: The purpose of the present study was to see the socio-demographic characteristics and incidence of CIN of uterine cervix among of VIA positive women.&#x0D; Methodology: This cross sectional study was conducted in the Department Of Pathology at Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh during the period of July 2007 to June 2008 for one (01) year. Patients who were colposcopically positive for cervical intraepithelial neoplasia and early invasive carcinoma or patients who are colposcopically negative but clinically suspicious for cervical neoplasia were included in this study. The clinical history was obtained by taking history with particular attention to age, age at marriage, parity, history of contraceptives, abnormal per vaginal discharge and post coital bleeding. The cervix was examined on naked eye by Cusco’s speculum to see whether it was healthy or not. Then it was examined by the colposcope after applying 3.0 to 5.0% acetic acid and colposcopic findings were collected. VIA positive cases were underwent colposcopy guided LEEP biopsy.&#x0D; Result: A total of 63 patients of different age group were recruited for this study. The mean with SD of age of this study population was 34.6±9.59 years. In this study, 41(65%) cases were diagnosed as cervical intraepithelial neoplasia (CIN). Incidence of CIN-I was 10 cases in age group 20 to 29 years. Most of the cases were in 30 to 39 (18 cases) years age group. Among 20 cases of high grade lesion (CIN-II/III) 9(45%) cases were in lower class, 8(40%) cases were in middle class and 3(15%) cases in upper class. Conclusion: In conclusion majority of the women were middle aged reproductive age group who are mostly in the lower class of socioeconomic class.&#x0D; Journal of Current and Advance Medical Research 2020;7(1): 7-11

Serum miR-638 Combined with Squamous Cell Carcinoma-Related Antigen as Potential Screening Biomarkers for Cervical Squamous Cell Carcinoma.

Aims: Cervical cancer is the second most common cause of cancer-related deaths in developing nations. Human papillomavirus prophylactic vaccines are not widely available, and there are shortages of gynecologists and cytologists in the already overburdened health care systems. The aim of this study was to identify circulating microRNAs (miRNAs) that could be used as feasible screening tests for cervical cancer in low-resource regions. Materials and Methods: Serum expression levels of five miRNAs were measured and validated by quantitative real-time polymerase chain reaction in cervical squamous cell carcinoma (CSCC) patients, cervical intraepithelial neoplasia patients, and healthy individuals. Squamous cell carcinoma-related antigen (SCC-Ag) was also measured in the serum. Results: Serum miR-638, miR-203a-3p, miR-1914-5p, and miR-521 levels were downregulated in the CSCC group (p < 0.05). Receiver operating characteristic (ROC) curve analysis indicated that the area under the ROC curve (AUC) values for miR-638 and miR-521 were 0.734 and 0.742, respectively, for discriminating CSCC patients from healthy controls. Furthermore, the combined use of miR-638 and SCC-Ag yielded the best screening performance and increased the AUC value, sensitivity, and specificity to 0.956, 94.87%, and 80.00%, respectively. Conclusion: This study suggested that miR-638 and miR-521 have independent screening value and that the combined measurement of miR-638 and SCC-Ag resulted in a better ability to discriminate patients with CSCC from healthy individuals.

Identification of Circulating MicroRNAs as a Promising Diagnostic Biomarker for Cervical Intraepithelial Neoplasia and Early Cancer: A Meta-Analysis.

Background Cervical cancer (CC) is one of the most common female malignant tumors. And cervical intraepithelial neoplasia (CIN) is the precancerous lesion of CC, which can progress to invasive CC. MicroRNAs (miRNAs) have been found to be potential diagnostic biomarkers for CIN or CC. However, recently, the lack of sufficient studies about the diagnostic value of miRNAs for CIN made it challenging to separately investigate the diagnostic efficacy of miRNAs for CIN. Likewise, the conclusions among those studies were discordant. Therefore, we conducted this meta-analysis, aimed at evaluating the diagnostic efficacy of miRNAs for CIN and CC patients. Methods Literature search was performed in PubMed, Embase, and Web of Science databases. Pooled sensitivity, specificity, and other diagnostic parameters were calculated through Stata 14.0 software. Furthermore, subgroup analyses and metaregression analysis were conducted to explore the main sources of heterogeneity. Results Ten articles covering 50 studies were eligible, which included 5,908 patients and 4,819 healthy individuals. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were 0.81 (95% CI, 0.77-0.85), 0.86 (95% CI, 0.83-0.89), 5.9 (95% CI, 4.5-7.7), 0.22 (95% CI, 0.17-0.28), 27 (95% CI, 17-44), and 0.91 (95% CI, 0.88-0.93), respectively. Additionally, the ethnicity and internal reference were the main sources of heterogeneity. Conclusions Circulating miRNAs can be a promising noninvasive diagnostic biomarker for CIN and early CC, especially miR-9 and miR-205, which need to be verified by large-scale studies.

HLA-B*38:165N and HLA-B*51:309 alleles identified in two Chinese cervical intraepithelial neoplasia patients.

The new HLA-B*38:165N and HLA-B*51:309 alleles in two Chinese cervical intraepithelial neoplasia patients.

Discovery of candidate gene expression signatures in peripheral blood for the screening of cervical cancer.

Aim: To investigate whether cervical cancer (CC) and cervical intraepithelial neoplasia (CIN) can be screened by analyzing gene expression profiling of peripheral blood. Methods: RNA-sequencing analysis of blood was performed on 11 CC patients, 21 CIN patients and 19 healthy controls (H). Fifty-nine genes were validated by quantitative real-time PCR using blood samples from 46 H, 83 CC and 32 CIN patients. Results: There were significant differences in the expression levels of six genes between CC and H, five genes between CIN and H and four genes between CC and CIN (p < 0.05). Four genes discriminated cervical lesions from H with a sensitivity of 82.61%, a specificity of 87.83% and an area under the curve of 0.8981. Three genes discriminated CC from CIN with a sensitivity of 53.13%, a specificity of 96.39% and an area under the curve of 0.7786. Conclusion: Our findings provided a promising noninvasive quantitative real-time PCR diagnostic assay of CC and CIN.

Downregulated Expression of WWOX in Cervical Carcinoma: A Case-Control Study

Integration of human papilloma virus (HPV) in human genome is a random event, and fragile sites are one of the most susceptible sites for viral integrations. WWOX (WW-domain containing oxidoreductase) gene harbours the second most common fragile site, FRA16D, and can be an important candidate for HPV integration and cervical carcinogenesis. Our aim was to evaluate the potential role of WWOX in cervical carcinogenesis. Presence of HPV and its genotype was detected by PCR in normal cervix tissues and human cervical carcinoma. The expression of WWOX transcript and its protein was examined by RT-PCR, RNA in situ hybridization, and immunoblotting. Southern blotting and sequencing were used to determine the alternative transcripts of WWOX. Statistical analysis were performed by Mann Whitney U-test, Pearson correlation coefficient test at significance level of P value < 0.05. Prevalence of HPV was observed in cervicitis (40%), cervical intraepithelial neoplasia patients (50%), and invasive cervical carcinoma patients (89.6%). Clinicopathological findings suggested a correlation of reduced level of WWOX protein and progression of cervical carcinoma deciphering its role in tumorigenesis. Furthermore, we observed aberrant WWOX transcript having deleted exon 6-8 region in invasive cervical cancer tissues as well as normal cervix samples. More than 60% of cervical carcinoma samples showed reduced protein level with an increase in wild type transcript level suggesting the involvement of a negative regulator, pAck1 (activated Cdc42- associated kinase) which might ubiquitinate WWOX protein leading to its degradation. Also, nuclear retention of WWOX transcript in invasive cervical carcinoma tissues suggests its regulation at post-transcriptional level. Our findings suggest that WWOX acts as a tumor suppressor in cervical carcinoma and could act as a potential therapeutic target for the disease.

Application Value of Detection of High-Risk HPV Infection in Early Cervical Cancer Patients in Disease Diagnosis and Prognosis Evaluation.

To analyze the relationship between HPV infection and early cervical cancer and postoperative survival outcomes. A total of 556 women were recruited to receive TCT and HPV tests from October 2017 to October 2018. The type of disease was pathologically diagnosed. The HPV positive rate, HPV-DNA, and E6/E7 mRNA quantitative level were detected, and the diagnostic accuracy of the subjects was analyzed by the receiver operating characteristic (ROC). The cervical intraepithelial neoplasia (CIN) and early cervical cancer patients were radically cured and followed up for 12.0 months to analyze the recurrence rate. Seventy-two cases of chronic cervicitis, 54 cases of CIN, and 51 cases of cervical cancer patients were pathologically diagnosed (32 cases in early stage and 19 cases in middle and late stage). HPV positive rate increased gradually in chronic cervicitis, CIN, and cervical cancer group (p < 0.001) and HPV 16 + 18 subtype. The positive rate was significantly different (p = 0.009). HPV-DNA and E6/E7 mRNA quantification also showed significant differences (p < 0.001). ROC analysis indicated that the accuracy of HPV-DNA and E6/E7 mRNA quantitative diagnosis of malignant lesions (CIN+ cervical cancer) were 0.865 and 0.879, respectively. There were 4 cases (7.41%) of recurrence in CIN group and 5 cases (15.63%) in early cervical cancer group. There was no difference (p = 0.401) among all of the patients. All patients with recurrence were HPV positive. HPV detection is an indispensable screening method for early cervical cancer and precancerous lesions, and comprehensive HPV 16 and 18 subtypes. DNA and E6/E7 mRNA quantification assay would further improve the accuracy of screening.

The potential of ciRS-7 for predicting onset and prognosis of cervical cancer.

Considering the potency of circRNAs in manifesting neoplastic progression, we attempted to explore the feasibility of applying ciRS-7 for diagnosis and prognosis estimation of cervical cancer (CC). Here 352 CC patients, 204 cervical intraepithelial neoplasia (CIN) patients and 227 healthy controls were recruited. The Kaplan-Meier survival curves were fitted to estimate associations of ciRS-7 expression with CC prognosis, and we also adopted receiver operating characteristic (ROC) curves to assess the diagnostic performance of ciRS-7 for CC. Meanwhile, endometrial stromal cell line (ESC) and 4 human CC cell lines (i.e. Hela, CaSki, C33A and SiHa) were also gathered. After transfection of pcDNA3.1-ciRS-7, impacts of overexpressed ciRS-7 on proliferation, apoptosis, invasion and migration of CC cells were assessed through performing colony formation assay, flow cytometry, transwell assay and wound healing assay. The results demonstrated that CC patients that highly expressed ciRS-7 were associated with high odds of large tumor size, advanced FIGO stage, deep invasion, metastatic lymph nodes and HPV infection (p<0.05). Furthermore, ciRS-7 excelled in differentiating CC patients from healthy controls and CIN patients than CEA and CA125 (p<0.05), and ciRS-7 combined with CA125 and CEA generated an optimum efficacy in diagnosing CC patients and CIN patients from healthy controls (p<0.05). Concerning in vitro experiments, elevating ciRS-7 expression significantly intensified proliferation and epithelial-mesenchymal transition (EMT) of CC cells (p<0.05), and also markedly suppressed apoptosis of the cells (p<0.05). In conclusion, ciRS-7 possessed great potential in clinical diagnosis of CC, given its involvement in modulating the activity of CC cells.

The prevalence of VAIN, CIN, and related HPV genotypes in Japanese women with abnormal cytology.

Vaginal intraepithelial neoplasia (VAIN) is often found by chance. We investigated the prevalence of VAIN and related human papillomavirus (HPV) types in comparison with cervical intraepithelial neoplasia (CIN). This study enrolled 648 women who were referred to the outpatient clinic of Kanazawa Medical University Hospital for abnormal cytology from January 2009 to January 2019. HPV genotypes were determined using Genosearch-31 + 4, which can detect 35 different HPV types. Colposcopy was performed at the first visit by an experienced gynecological oncologist. Among 611 subjects with squamous cell lesions, 107 (17.5%) VAIN cases were identified, and 67 (11.0%) women had both VAIN and CIN. Ultimately, 72 VAIN1, 15 VAIN2/3, 203 CIN1, 249 CIN2/3, 32 cervical squamous cell carcinomas (SCC), and one vaginal SCC (Vag-SCC) were identified. The prevalences of VAIN1, VAIN2/3, and Vag-SCC were 35.5%, 6.0%, and 3.1% of equivalent cervical lesions, respectively. The VAIN patients were older than the CIN patients (P = .002). About half of the VAIN cases were diagnosed during the follow-up. Multiple HPV infections were found in 42.9% of the VAIN and CIN patients. HPV52, 16, 51, 53, and 56 were the most common types in VAIN, whereas HPV16, 52, 58, 51, and 31 predominated in CIN. HPV18 was rare in VAIN, HPV58 was more common in CIN than in VAIN, and HPV53 and HPV73 were more common in VAIN. In conclusion, VAIN1 was identified more frequently than we expected. Various HPV types were identified in the vagina, which is likely a reservoir for HPV.

LC/MS-Based Polar Metabolite Profiling Identified Unique Biomarker Signatures for Cervical Cancer and Cervical Intraepithelial Neoplasia Using Global and Targeted Metabolomics

Cervical cancer remains one of the most prevalent cancers among females worldwide. Therefore, it is important to discover new biomarkers for early diagnosis of cervical intraepithelial neoplasia (CIN) and cervical cancer, preferably non-invasive ones. In the present study, we aimed to identify unique metabolic signatures for CINs and cervical cancers using global and targeted metabolomic profiling. Plasma samples (69 normal, 55 CIN1, 42 CIN2/3, and 60 cervical cancer) were examined by ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-QTOF-MS) coupled with multivariate statistical analysis. Metabolic pathways were analyzed using the integrated web-based tool MetaboAnalyst. A multivariate logistic regression analysis was conducted to evaluate the combined association of metabolites and human papillomavirus (HPV) status with the risk of cervical carcinogenesis. A total of 28 metabolites exhibiting discriminating levels among normal, CIN, and cervical cancer patients (Kruskal–Wallis test p < 0.05) were identified in the global profiling analysis. The pathway analysis showed significantly altered alanine, aspartate, and glutamate metabolic pathways (FDR p-value < 0.05) in both the discovery and validation phases. Seven metabolites (AMP, aspartate, glutamate, hypoxanthine, lactate, proline, and pyroglutamate) were discriminated between CINs and cervical cancer versus normal (area under the curve (AUC) value > 0.8). The levels of these metabolites were significantly high in patients versus normal (p < 0.0001) and were associated with increased risk of developing CIN2/3 and cervical cancer. Additionally, elevated levels of the seven metabolites combined with positive HPV status were correlated with substantial risk of cancer progression. These results demonstrated that metabolomics profiling is capable of distinguishing CINs and cervical cancers from normal and highlighted potential biomarkers for the early detection of cervical carcinogenesis.

Polymorphisms in miRNA genes play roles in the initiation and development of cervical cancer.

MicroRNA deregulation is crucial for cancer development. Studies showed that polymorphisms in miRNA genes could affect miRNA expression, which might be associated with cancer development. In the current study, we investigated the association of seven single nucleotide polymorphisms (SNPs) in seven miRNA genes with the initiation and development of cervical cancer in a Chinese Han population. The SNPs of 358 cervical intraepithelial neoplasia (CIN) patients, 547 cervical cancer patients and 567 healthy individuals were genotyped using TaqMan assays. Moreover, we evaluated the association of the seven SNPs with the different stages of cervical cancer. Our results showed that rs4636297 in miR-126 was associated with susceptibility to CIN and cervical cancer (P=0.019 and 0.019, respectively) and that the T allele was associated with a higher risk of CIN (OR=1.334, 95% CI: 1.049-1.698) and cervical cancer (OR=1.296, 95% CI: 1.044-1.609). Similarly, rs11614913 in miR-125a was associated with CIN and cervical cancer (P=0.025 and 0.015, respectively), and the T allele might be the protective factor for CIN (OR=0.807, 95% CI: 0.669-0.974) and cervical cancer (OR=0.814, 95% CI: 0.689-0.961). Our results indicated that rs4636297 in miR-126 and rs11614913 in miR-196a2 play an important role only in the initiation of cervical cancer not in the development of CIN to cervical cancer.

TCR Repertoire as a Novel Indicator for Immune Monitoring and Prognosis Assessment of Patients With Cervical Cancer.

There is increasing evidence that deep sequencing-based T cell repertoire can sever as a biomarker of immune response in cancer patients; however, the characteristics of T cell repertoire including diversity and similarity, as well as its prognostic significance in patients with cervical cancer (CC) remain unknown. In this study, we applied a high throughput T cell receptor (TCR) sequencing method to characterize the T cell repertoires of peripheral blood samples from 25 CC patients, 30 cervical intraepithelial neoplasia (CIN) patients and 20 healthy women for understanding the immune alterations during the cervix carcinogenesis. In addition, we also explored the signatures of TCR repertoires in the cervical tumor tissues and paired sentinel lymph nodes from 16 CC patients and their potential value in predicting the prognosis of patients. Our results revealed that the diversity of circulating TCR repertoire gradually decreased during the cervix carcinogenesis and progression, but the circulating TCR repertoires in CC patients were more similar to CIN patients than healthy women. Interestingly, several clonotypes uniquely detected in CC patients tended to share similar CDR3 motifs, which differed from those observed in CIN patients. In addition, the TCR repertoire diversity in sentinel lymphatic nodes from CC patients was higher than in tumor tissues. More importantly, less clonotypes in TCR repertoire of sentinel lymphatic node was associated with the poor prognosis of the patients. Overall, our findings suggested that TCR repertoire might be a potential indicator of immune monitoring and a biomarker for predicting the prognosis of CC patients. Although functional studies of T cell populations are clearly required, this study have expanded our understanding of T cell immunity during the development of CC and provided an experimental basis for further studies on its pathogenesis and immunotherapy.

Abstract 720: Anti-OX-40 agonist antibody significantly increases therapeutic efficacy of TVGV-1 vaccine for HPV-positive cancers

Abstract Background: Human papillomavirus 16 (HPV16) E7 protein is a potential target antigen for HPV-positive cancers due to its interaction with pRb tumor suppressor protein. The clinical-stage therapeutic vaccine, TVGV-1, comprises of the PE-E7-K3 fusion protein and the adjuvant GPI-0100, has shown therapeutic effect preclinically by stimulating T cell response targeting HPV16 E7 protein. TVGV-1 was well tolerated clinically in more than 30 HPV+ cervical intraepithelial neoplasia (CIN) patients. Agonistic antibodies targeting OX40 (CD134) have shown remarkable single agent anti-tumor effect by modulating T cell response surrounding tumor environment, as well as the ability to combine with other immunotherapies in several mouse tumor models. Here we evaluated the synergistic therapeutic potential of TVGV-1 vaccine combined with anti-OX-40 agonist antibody for HPV-positive cancer therapy. Methods: Therapeutic and immune efficacy of TVGV-1 in combination with anti-OX-40 agonist antibody was tested in E7 antigen expressing TC-1 tumor mouse model. Mice with various treatments were assessed for tumor growth and survival. Peripheral and tumor-infiltrating immune cell profiles with various treatments were also assessed by flow cytometry. Results: Our results revealed that both the HPV16 E7-specific humoral and cell-mediated immunities solely elicited by TVGV-1 vaccination was synergistically enhanced more than two-fold by concomitant anti-OX-40 agonist antibody treatment. In a TC-1 tumor model, tumor growth and overall survival was not protected by OX-40 antibody treatment alone, and mice was protected with prolonged survival benefit when treated in combination of TVGV-1 and OX-40 antibody. In TC-1 tumor bearing mice, about 10% decrease of peripheral CD3+ T cell was observed upon TC-1 tumor development, and restoration was only observed when mice were treated with combined TVGV-1 and OX-40 antibody. When tumor infiltrating lymphocytes recognizing HPV E7 antigen were prepared from these mice, the amount of tumor-infiltrating mononuclear cells and CD3+ T cells were dramatically increased with combination treatment when compared to control group or to treatment alone groups. Conclusions: We demonstrated efficacy with combination approach between TVGV-1 vaccine and anti-OX-40 agonistic antibody in a pre-clinically mouse model. This enhanced activity is likely due to modulation of T-cell population in tumor and in periphery. This result will guide to a better design to perform clinical studies in order to obtain better outcome with TVGV-1 cancer vaccine intended for treating HPV E7 bearing tumors. Citation Format: Yin-Ching Lin, Yi-Tsui Chiu, Yi-Chia Lin, Jiun-Ming Wu, Chien-Hung Chen, Wen-Fang Cheng, Chia-Mao Wu. Anti-OX-40 agonist antibody significantly increases therapeutic efficacy of TVGV-1 vaccine for HPV-positive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 720.

Efficacy and safety of photodynamic therapy for cervical intraepithelial neoplasia and human papilloma virus infection: A systematic review and meta-analysis of randomized clinical trials.

We sought to conduct a systemic review and meta-analysis of randomized clinical trials to assess the efficacy and safety of photodynamic therapy (PDT) in cervical intraepithelial neoplasia (CIN) and cervical human papilloma virus (HPV) infection. The Medline, EMBASE, and Cochrane Central Register databases were searched using relevant keywords for entries up to May 1, 2017, irrespective of year of publication. The language was restricted to English. Randomized clinical trials and qualitative studies comparing PDT and placebo for CIN or HPV-positive patients were included. We assessed the evidence quality using a risk of bias graph in RevMan V5.3 and the Grading of Recommendations Assessment, Development, and Evaluation scoring system. Of the 168 studies identified, only 4 RCTs met the inclusion criteria for meta-analysis. In all, 292 and 141 patients received PDT or placebo, respectively. PDT significantly increased the complete remission rate (CRR) among those with CIN (odds ratio [OR]: 2.51 [1.23-5.12]; P = .01) and HPV infection (OR: 3.82 [1.91-7.65]; P = .0002). The adverse events rate (AER) for PDT was greater than that for placebo (OR: 13.32 [4.44, 40.02]; P < .00001). The overall evidence quality was very low. Similarly, in a systematic review including 21 qualitative records, the CRRs for CIN patients with PDT and cervical HPV infection patients with PDT were 82.0% and 77.5%, respectively. The AER for PDT was 31.6%, which was lower than that observed in our meta-analysis (74.6%). PDT that targets CIN or cervical HPV infection improves the CRR, but slightly compromises safety. Further studies are necessary to identify the most effective and least toxic photosensitizer.

Plasma miR-145 as a novel biomarker for the diagnosis and radiosensitivity prediction of human cervical cancer.

ObjectivesThe objective of this study was to evaluate levels of plasma miR-145 in patients with cervical cancer (CC) and investigate its biomarker potential.MethodsUsing qRT-PCR, we compared plasma miR-145 levels in 120 patients with CC, 120 patients with cervical intraepithelial neoplasia (CIN), and 120 healthy volunteers. The association between plasma miR-145 expression and clinicopathological factors, including radiation response, was also analyzed.ResultsPlasma miR-145 levels were lower in CC patient than in CIN patients and healthy controls. Low levels were significantly associated with poor cancer differentiation, lymph node metastasis, HPV, and advanced FIGO stage. CC patients who achieved complete response to radiotherapy had higher plasma miR-145 levels than incomplete responders. ROC analysis confirmed that plasma miR-145 is a candidate biomarker for detecting CC and differentiating complete responders from incomplete responders.ConclusionsPlasma miR-145 is reduced in CC and is a novel candidate biomarker for diagnosing CC and predicting radiosensitivity.

The Neutrophil-Lymphocyte Ratio Predicts Recurrence of Cervical Intraepithelial Neoplasia.

OBJECTIVE: The purpose of the present study was to determine the prognostic significance of the neutrophil-lymphocyte ratio (NLR) in recurrence of cervical intraepithelial neoplasia (CIN).METHODS: We evaluated the NLR as a prognostic marker in the entire cohort of 230 patients who had undergone surgical resection and were diagnosed with CIN. Subjects were categorized into two different groups based on the NLR (NLR-high and NLR-low) using cutoff values determined by receiver operating characteristic (ROC) analysis. The primary research objective for this study was to validate the impact of the NLR on recurrence-free survival (RFS) in patients with CIN. The secondary objective was to evaluate the impact of other hematologic parameters on RFS in CIN patients.RESULTS: Using the entire cohort, the most appropriate NLR cut-off value for CIN recurrence selected on the ROC curve was 2.1. The NLR-low and NLR-high groups included 167 (72.6%) and 63 patients (27.4%), respectively. According to Kaplan-Meier analysis, RFS rates during the entire follow-up period were considerably lower in the NLR-high group than in the NLR-low group (P = 0.0125). In multivariate survival analysis using Cox proportional hazard model, we identified the NLR, absolute eosinophil count (AEC), hemoglobin concentration, and mean corpuscular volume (MCV) as valuable prognostic factors that impact RFS.CONCLUSIONS: The NLR is an independent prognosticator for RFS following surgical resection in CIN patients. We also found that the AEC, hemoglobin level, and MCV were strongly associated with RFS, as determined by multivariate analysis using a Cox model. These hematological parameters might provide additional prognostic value beyond that offered by standard clinicopathologic parameters.

Sensitization of immune cells following hexylaminolevulinate photodynamic therapy of cervical intraepithelial neoplasia

BackgroundEffects of photodynamic therapy (PDT) were tested with respect to immune cell stimulation in cervical intraepithelial neoplasia (CIN). MethodsA patient with CIN received hexaminolevulinate (HAL) and subsequent PDT. These data were compared to a placebo PDT patient and a healthy HPV16-vaccinated donor. Isolation of peripheral blood mononuclear cells (PBMC) was performed before PDT and at 4 different time points after PDT. The proliferation of these PBMC was tested by [3H]thymidine incorporation following stimulation with control or HPV16-L1 peptides. Potential effects on the CD4+ and CD8+ cell subsets were analysed. ResultsThe data revealed an unchanged or decreased proliferation of HPV16-L1 peptide-stimulated PBMC as compared to placebo patient. HPV16-L1 peptide incubation of PBMC from the HAL patient demonstrated significant proliferative capacity after PDT. The CD4+ and CD8+ T cell populations in placebo patient were slightly increased after HPV16-L1 peptide administration at each time point. Mixed results were obtained for CD4+ cells as compared to controls and nearly unchanged amounts of CD8+ cells were detectable following HPV16-L1 peptide exposure of PBMC from the HAL/PDT-treated patient. ConclusionsThese findings suggest a T cell reaction from CIN patients during repeated HAL/PDT treatment. However, further immune cell populations might be involved during PDT.