UNASSIGNED: To investigate the relationship between the DNA methylation state of NRG1 promoter and its expression changes, and to analyze the clinical significance of its regulatory mechanism of DNA methylation in cervical carcinoma.
UNASSIGNED: This was a retrospective study. One-hundred and twenty patients from the Department of Gynecology of Cangzhou People\'s Hospital from September 2017 to September 2019 were selected, including 40 cases of cervical SCC, 40 cases of high grade squamous intraepithelial lesions(HSIL) and 40 cases of control cervical tissues. RT-qPCR, immunohistochemistry and DNA methylation-specific PCR(MSP) were used to detect the mRNA and protein expression of NRG1 and DNA methylation status in different tissue types.
UNASSIGNED: Immunohistochemical results showed that the positive protein expression rate of NRG1 gene in the SCC group was lower than that in both HSIL and Control groups. RT-qPCR results showed that the mRNA gene of NRG1 gradually decreased in expression with the increase of cervical tissue lesions, with a statistically significant difference. Similarly, it also found that the mRNA expression level of NRG1 in the SCC group was independent of patients\' age (p>0.05), but significantly correlated with tumor pathological staging, surgical pathology staging and lymphatic metastasis (p<0.05). Furthermore, methylation-specific PCR results revealed a significantly higher DNA methylation rate of NRG1 gene in the SCC group than in both HSIL and Control groups, with a statistically significant difference. Moreover, the methylation degree of NRG1 gene in SCC tissues was negatively correlated with its mRNA expression (p<0.05).
UNASSIGNED: Abnormal DNA hypermethylation of NRG1 gene inhibits the expression of mRNA and protein in the progression of cervical tissue from normal to cancerous state, which is involved in the occurrence and development of cervical carcinoma.

OBJECTIVE: Lactic acid metabolism, a hallmark of carcinogenesis, may play potential roles in cervical carcinoma, assisting the prognosis prediction.
METHODS: A regression analysis was conducted to identify the ones with the most frequent variation in mutations and CNV changes in lactate metabolism-related (L-related) genes, after which a prognostic nomogram was built based on selected genes and clinical features by machine learning methods.
RESULTS: EGLN1, IL1, IL12RB1, ENO1, and 10 other genes had the most frequent changes and prognostic differences in overall survival (OS). The lactated associated risk (LAR) score model can distinguish the patients in OS (p = 0.046, HR = 101.9, 95%CI 1.1-9447.6), and together with clinical features has a higher AUC (AUC = 0.839). Furthermore, CD8+ T, activated CD4+ memory T and resting mast cells were significantly negatively associated with the LAR score.
CONCLUSIONS: Lactic acid metabolism is closely related to the prognosis of cervical carcinoma, where the immune microenvironment may play an important role.

Genomic instability is an important biomarker in the progression of cervical carcinoma. DBD-FISH (DNA breakage detection-fluorescence in situ hybridization) is a sensitive method that detects strand breaks, alkali-labile sites, and incomplete DNA excision repair in cells of the cervical epithelium. This technique integrates the microgel immersion of cells from a vaginal lesion scraping and the DNA unwinding treatment with the capacity of FISH integrated into digital image analysis. Cells captured within an agarose matrix are lysed and submerged in an alkaline unwinding solution that generates single-stranded DNA motifs at the ends of internal DNA strand breaks. After neutralization, the microgel is dehydrated and the cells are incubated with DNA-labeled probes. The quantity of a hybridized probe at a target sequence corresponds to the measure of the single-stranded DNA produced during the unwinding step, which is equivalent to the degree of local DNA breakage. DNA damage does not show uniformly throughout the entire DNA of a cell; rather, it is confined to specific chromosomal sites. In this chapter, an overview of the technique is supplied, focusing on its ability for assessing the association between DNA damage in specific sequences and in the progressive stages of cervical carcinoma.

BACKGROUND: Papillary squamotransitional cell carcinoma (PSTCC) arising from the uterine cervix is a distinctive histomorphological subtype of squamous cell carcinoma (SCC) not otherwise specified (NOS) of cervical epithelial tumors.
OBJECTIVE: The present study was undertaken to study the histopathological features and immunoexpression of CK7, CK20, p53 and Ki-67 in PSTCC of the cervix.
METHODS: This study included 43 cases of PSTCC of cervix. A technique of manual tissue array was employed along with IHC staining of entire section in some cases. The expression pattern of CK7, CK 20, p53 and Ki67 in PSTCC was studied and clinico-pathological correlation of various parameters with IHC expression of CK7 and CK20 was observed. Results were subjected to statistical analysis and were considered significant when the p-value was less than 0.05.
RESULTS: Out of 43 PSTCC cases, there were 38 squamotransitional type and 5 papillary type. Histomorphologically, all the cases studied were having fused papillae with rounded contours and fibrovascular cores with highest number of cases having intermediate cell type morphology (86%). Stromal invasion was seen in 74.4% of cases. Koilocytosis were seen in 39.3% of cases. Thirty-two cases showed CK7 immunopositivity (+) and CK20 immunonegativity (-), nine cases were both CK7 and CK20 - and two cases were CK7- and CK20+. Among them 90.7% cases were p53 positive and all cases were positive for Ki67 immunostaining with highest number of cases showing moderate proliferative activity (74.4%); followed by nine cases showing high (20.93%) and two cases showing low proliferative activity (4.65%).
CONCLUSIONS: The distinct histomorphology and CK7/CK20 immnunoprofile of PSTCC along with Ki67 and p53 could help in arriving at an accurate diagnosis as well predicting its biological behavior.

Recurrent non-squamous cell carcinoma (non-SCC) of the uterine cervix is resistant to treatment and has a poor prognosis. The efficacy and safety of S-1/oxaliplatin (SOX) therapy in patients with recurrent non-SCC was examined in a phase II study. Fifteen patients were enrolled between August 2013 and March 2023. S-1 was administered orally at a daily dose of 80-120 mg for 14 days, and oxaliplatin was administered intravenously at a dose of 100 mg/m2 on day 1. Each treatment cycle lasted 21 days. The anti-tumor effects, adverse events, progression-free survival (PFS), and overall survival (OS) were investigated. The median patient age was 54 (41-74) years. The anti-tumor effect was rated as a partial response in five patients, stable disease in four, and progressive disease in 6. The overall response rate was 33% and the disease control rate was 60%. Regarding hematologic toxicities of grade 3 or more severity, leukopenia, neutropenia, anemia, and thrombocytopenia occurred in 26.6-40.0%. None of the patients discontinued the treatment because of adverse events. The median PFS and OS were 6 months (95% confidence interval [CI]: 2-11 months) and 22 months (95% CI: 11-23 months), respectively. No treatment-related deaths occurred. These results suggest that SOX therapy is useful for the treatment of recurrent non-SCC with promising anti-tumor effects and minimal adverse events.

BACKGROUND: Cervical cancer (CC) is associated with high morbidity and mortality rates in women. Members of the receptor-interacting protein kinase (RIPK) family are important regulators of inflammation and cell death. However, the characteristics, molecular functions, and expression mechanisms of RIPK1 in CC remain unclear.
METHODS: To determine whether RIPK1 can be used for targeted therapy of CC, we assessed the clinical importance, biological function, and potential impact of RIPK1 in CC in 50 patients with CC. We utilized immunohistochemical staining, transfection, western blotting, cell counting kit-8 assay, colony formation assay, and wound healing assays among others, to elucidate the role of RIPK1 in CC.
RESULTS: RIPK1 expression was higher in tumor tissues than in paracancerous tissues. Poor prognosis of CC was linked to RIPK1 upregulation. Furthermore, silencing RIPK1 significantly inhibited the proliferation, migration, and invasion of CC cells in vitro. We also established that RIPK1 increased cell migration, invasion, and multiplication by regulating nuclear factor kappa-B (NF-κB) and tumor necrosis factor (TNF).
CONCLUSIONS: RIPK1 activates NF-κB and regulates TNF release to enhance the proliferation and spread of CC cells while suppressing their apoptosis. Therefore, RIPK1 plays a key role in the formation and progression of CC and is a potential target for CC treatment.

OBJECTIVE: This study aims to identify prognostic factors associated with metastatic recurrence-free survival of cervical carcinoma (CC) patients treated with radical radiotherapy and assess the cure probability of radical radiotherapy from metastatic recurrence.
METHODS: Data were from 446 cervical carcinoma patients with radical radiotherapy for an average follow up of 3.96 years. We applied a mixture cure model to investigate the association between metastatic recurrence and prognostic factors and the association between noncure probability and factors, respectively. A nonparametric test of cure probability under the framework of a mixture cure model was used to examine the significance of cure probability of the definitive radiotherapy treatment. Propensity-score-matched (PSM) pairs were generated to reduce bias in subgroup analysis.
RESULTS: Patients in advanced stages (p = 0.005) and those with worse treatment responses in the 3rd month (p = 0.004) had higher metastatic recurrence rates. Nonparametric tests of the cure probability showed that 3-year cure probability from metastatic recurrence was significantly larger than 0, and 5-year cure probability was significantly larger than 0.7 but no larger than 0.8. The empirical cure probability by mixture cure model was 79.2% (95% CI: 78.6-79.9%) for the entire study population, and the overall median metastatic recurrence time for uncured patients (patients susceptible to metastatic recurrence) was 1.60 (95% CI: 1.51-1.69) years. Locally advanced/advanced stage was a risk factor but non-significant against the cure probability (OR = 1.078, p = 0.088). The interaction of age and activity of radioactive source were statistically significant in the incidence model (OR = 0.839, p = 0.025). In subgroup analysis, compared with high activity of radioactive source (HARS), low activity of radioactive source (LARS) significantly contributed to a 16.1% higher cure probability for patients greater than 53 years old, while cure probability was 12.2% lower for the younger patients.
CONCLUSIONS: There was statistically significant evidence in the data showing the existence of a large amount of patients cured by the definitive radiotherapy treatment. HARS is a protective factor against metastatic recurrence for uncured patients, and young patients tend to benefit more than the elderly from the HARS treatment.

Background Cervical carcinoma is one of the most prevalent cancers affecting women worldwide. Studies on Ki-67 expression in cervical lesions had focused mainly on the intraepithelial lesions of the cervix and not much on invasive carcinomas. The few studies published so far on Ki-67 expression in invasive cervical carcinomas have shown inconsistent results on the association of Ki-67 with various clinicopathological prognostic factors. Aims and objectives To assess Ki-67 expression in cervical carcinomas and to compare it with various clinicopathological prognostic factors. Materials and methods Fifty cases of invasive squamous cell carcinoma (SCC) were included in the study. Histological patterns and grades were identified and noted in these cases after microscopic examination of the histological sections. Immunohistochemical (IHC) staining with anti-Ki-67 was done and scored from 1+ to 3+. This score was compared with clinicopathological prognostic factors like clinical stage, histological pattern, and grade. Result Among the 50 cases of SCC, 41 showed keratinizing pattern (82%) and nine showed non-keratinizing pattern (18%). Four were in stage I, 25 were in stage II, and 21 were in stage III. Overall, 34 (68%) cases had Ki-67 score 3+, 11 (22%) had Ki-67 score 2+, and five (10%) had Ki-67 score 1+. Ki-67 score of 3+ was the most common score in keratinizing SCC (75.6%), poorly differentiated carcinomas (76.2%), and stage III cases (81%). Conclusion We observed statistically significant correlation of Ki-67 expression with higher clinical stage, keratinizing tumours, and poorly differentiated tumours (p<0.05) indirectly implying the poor prognostic significance of this marker.

UNASSIGNED: Lymph node metastasis (LNM) accounts for the most important route of metastasis for cervical cancer. Yet, the status of LNM is different in patients with similar clinico-pathological variables. It has been revealed that microRNAs are widely involved in the occurrence and development of various malignancies, and the tumor-suppressive or promoting effects of microRNA-99 (miR-99) family have been previously reported. This study sought to investigate the predictive value of miR-99a for lymphogenous spread and its effect on the survival of patients with early-stage cervical squamous cell cancer (CSCC).
UNASSIGNED: Patients with stage IB squamous cervical cancer who were treated surgically between October 2015 and November 2018 were enrolled. A total of 21 formalin-fixed paraffin-embedded tissues of pathologically confirmed positive lymph nodes were retrieved, and an additional 21 tissues of negative lymph nodes from patients well-matched on baseline characteristics were collected as the control group. TaqMan real-time quantitative polymerase chain reaction was used to examine the expression levels of miR-99a in the samples. Differential expression levels of miR-99a were compared between the 2 groups using independent sample t-test. Furthermore, the associations between miR-99a expression level and clinico-pathological parameters of these 42 patients was evaluated by Chi-square test or Fisher\'s exact-probability method, and their effects on survival were assessed using Kaplan-Meier product-limit method.
UNASSIGNED: There were no significant differences in baseline clinico-pathological parameters between the 2 groups (P>0.05). The expression levels of miR-99a in the node-positive group and control group were 1.61±3.09 and 16.77±30.40, respectively (P=0.029). Downregulated expression of miR-99a was closely related to depth of invasion (DOI) and lymph-vascular space invasion (P<0.05). Univariate analysis revealed that downregulated miR-99a and deeper DOI were associated with worse 5-year disease-free survival, while multivariate analysis showed that only the expression level of miR-99a was an independent factor for disease-free survival (HR =0.120; 95% CI: 0.015-0.979; P=0.048). Patients with downregulated miR-99a tended to have more unfavorable overall survival, but the difference did not reach statistical significance.
UNASSIGNED: MiR-99a plays an inhibitory role in the pathogenesis of lymph node metastasis and may serve as a novel prognostic biomarker for patients with CSCC.

UNASSIGNED: Metabolic reprogramming has been identified as a hallmark of cancer, influencing the immunity in the tumor microenvironment. Because of the high-heterogeneity of cervical carcinoma, we aim to figure out the metabolic subtypes of cervical carcinoma indicating the prognosis.
UNASSIGNED: We profiled the distinct metabolic signatures using data from transcriptomes obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Bioinformatics analyses were conducted to identify the possible biomarkers of overall survival and chemotherapy resistance.
UNASSIGNED: Immune infiltration was closely related to metabolic pathways, especially in the carbohydrate pathway and the lipid and energy pathway. Two distinct clusters of differentially expressed genes were identified. Six genes were selected as possible indicators of prognosis, including ELK3, BIN2, MEI1, CCR7, CYP4F12, and DUOX1, relating to the immune status of tumor microenvironment. Under the risk score model based on metabolic genes, the high-risk group showed significantly lower survival (HR =6.802, with 95% CI: 3.637-12.721, P<0.0001), higher possibility of chemotherapy resistance, and higher infiltration of anti-tumor immune cells compared to the low-risk group.
UNASSIGNED: Metabolic reprogramming, especially in the carbohydrate pathway and the lipid and energy metabolic pathway, is associated with the immune cell microenvironment, which is crucial for the prognosis of Invasive cervical carcinoma (ICC), providing potential therapeutic targets in clinic.