Overall Survival In Cervical Cancer Research Articles

Efficacy and safety of bevacizumab in neoadjuvant and concurrent chemoradiotherapy for refractory cervical cancer patients.

A platinum-based concurrent chemoradiotherapy (CCRT) is the standard treatment for refractory cervical cancer (CC). However, the recurrence of disease and the occurrence of metastasis remain prevalent. We observed the long-term efficacy and safety of bevacizumab combined with neoadjuvant chemotherapy (NACT) and CCRT in refractory CC. A total of 62 patients with refractory CC were enrolled in this study from January 2016 to December 2019. The NACT regimen included bevacizumab (7.5 mg/kg), docetaxel (75 mg/m2), and cisplatin (75 mg/m2), administered tri-weekly for 2 cycles. The CCRT regimen included bevacizumab (7.5 mg/kg) and cisplatin (75 mg/m2), administered tri-weekly for 2 cycles. A dose of 45-50 Gy was prescribed for external beam radiotherapy (EBRT), while 30-35 Gy in 4-5 fractions was prescribed for brachytherapy (BT). Among the patients, 21 patients (33.9%) were at stages IIB-IIIB, 8 patients (12.9%) were at stage IIIC1, 19 patients (30.6%) were at stage IIIC2, and 14 patients (22.6%) were at stage IVB. Pelvic, para-aortic, supraclavicular, and inguinal lymph node metastases were discovered in 41 patients (66.1%). The median follow-up was 49.8 months (12.3-82.7 months). The median tumor volumes pre-treatment, after NACT, and before BT were 84.64 ± 53.15 cm3, 1.64 ± 13.15 cm3, and 0 ± 1.5 cm3, respectively. Complete clinical response (cCR) rates after NACT and EBRT were 35.5% and 66.1%, respectively. Four years after the diagnosis, the overall survival (OS) rate was 78.6%, the local region-free survival (LRFS) rate was 91.3%, the disease-free survival (DFS) rate was 70.6%, and the distant metastasis-free survival (DMFS) rate was 81.4%. A total of 29 patients (46.8%) experienced grade 3/4 hematological toxicity, 3 patients (4.8%) experienced grade 3 gastrointestinal toxicities, and none experienced grade 5 adverse events. Bevacizumab combined with NACT and CCRT significantly improved cCR and OS in refractory CC with acceptable toxicity.

MiR-218-5p, miR-124-3p and miR-23b-3p act synergistically to modulate the expression of NACC1, proliferation, and apoptosis in C-33A and CaSki cells

BackgroundIn cervical cancer (CC), miR-218-5p, -124-3p, and −23b-3p act as tumor suppressors. These miRNAs have specific and common target genes that modulate apoptosis, proliferation, invasion, and migration; biological processes involved in cancer. MethodsmiR-218-5p, -124-3p, and −23b-3p mimics were transfected into C-33A and CaSki cells, and RT-qPCR was used to quantify the level of each miRNA and NACC1. Proliferation was assessed by BrdU and apoptosis by Annexin V/PI. In the TCGA and The Human Protein Atlas databases, the level of NACC1 mRNA and protein (putative target of the three miRNAs) was analyzed in CC and normal tissue. The relationship of NACC1 with the overall survival in CC was analyzed in GEPIA2. NACC1 mRNA and protein levels were higher in CC tissues compared with cervical tissue without injury. ResultsAn increased expression of NACC1 was associated with lower overall survival in CC patients. The levels of miR-218-5p, -124-3p, and −23b-3p were lower, and NACC1 was higher in C-33A and CaSki cells compared to HaCaT cells. The increase of miR-218-5p, -124-3p, and −23b-3p induced a significant decrease in NACC1 mRNA. The transfection of the three miRNAs together caused more drastic changes in the level of NACC1, in the proliferation, and in the apoptosis with respect to the individual transfections of each miRNA. ConclusionThe results indicate that miR-218-5p, -124-3p, and −23b-3p act synergistically to decrease NACC1 expression and proliferation while promoting apoptosis in C-33A and CaSki cells. The levels of NACC1, miR-218-5p, -124-3p, and −23b-3p may be a potential prognostic indicator in CC.

Serum squamous cell carcinoma antigen level and magnetic resonance imaging for the prognosis of locally advanced cervical cancer.

Squamous cell carcinoma antigen (SCC-ag) and magnetic resonance imaging (MRI) were explored to serve as biomarkers to predict the prognosis of cervical cancer (CC) patients treated with neoadjuvant chemotherapy (NACT) prior to radical surgery, with the aim of identifying the subgroup that least benefits from the combined therapy. All patients were treated with NACT prior to radical surgery and received MRI and SCC-ag examinations before and after NACT. For these three cycles of NACT, patients were treated with intravenous paclitaxel at 150 mg/m2 over a period of 3 hours and carboplatin, with the area under the sera concentration-time curve of 5 over a period of 30 minutes on the first day of each cycle. Meanwhile, the blood pressure, ECG, and blood oxygen saturation of the patients were observed during the infusion. A discovery cohort and a validation cohort were applied to examine the prognostic performance of SCC-ag, MRI, and their combination. The endpoints of our study were overall survival (OS) and progression-free survival (PFS). A total of 384 patients diagnosed between August 2006 and December 2010 were enrolled in our research, with 206 patients in the discovery cohort and 178 patients in the validation cohort. The high-risk group identified by MRI had a worse OS [hazard ratio (HR), 3.567; 95% confidence interval (CI), 1.466-8.677; log-rank p=0.0027) and PFS (HR, 4.062; 95% CI, 2.171-7.6; log-rank p<0.0001) than the low-risk group. Meanwhile, the SCC-RC could serve as a strong prognostic factor to predict OS (HR, 5.614; 95% CI, 2.473-12.744; log-rank p<0.0001) and PFS (HR, 7.481; 95% CI, 4.194-13.344; log-rank p<0.0001) for CC. In addition, the combined MRI and SCC-ag had greater prognostic efficiency and were used to divide the whole patient population into three groups. Compared with patients in the low-risk group, patients in the high-risk group had a worse OS (HR, 8.216; 95% CI, 2.98-22.651; log-rank p<0.0001) and PFS (HR, 11.757; 95% CI, 5.735-24.104; log-rank p<0.0001). Multivariate analyses revealed that MRI, SCC-ag, and their combination were independent prognostic factors. SCC-ag and MRI, individually or in combination, were bound up with OS and PFS in CC. Additionally, the predictive efficiency improved when SCC-ag and MRI were combined in a risk model that predicted the OS and PFS of SCC compared with the predictive efficiency of either SCC-ag or MRI alone, revealing that the combination of these two biomarkers could help to ameliorate prognostic stratification and to guide personalized therapy for SCC patients.

Establishment of prediction models to predict survival among patients with cervical cancer based on socioeconomic factors: a retrospective cohort study based on the SEER Database

ObjectiveTo construct and validate predictive models based on socioeconomic factors for predicting overall survival (OS) in cervical cancer and compare them with the American Joint Council on Cancer (AJCC) staging...

CERVICAL CANCER INCIDENCE AND MORTALITY IN ALMATY IN 2005-2022

Relevance: In Kazakhstan, the standardized incidence rate of cervical cancer for 2022 was 19 per 100,000 women, and the mortality rate was 5.9 per 100,000 female population. The overall survival of cervical cancer in the Republic of Kazakhstan for 2022 was 59.6% (95% CI: 50.7-54.2). Since 2008, in Kazakhstan, there has been a National Screening Program for cervical cancer for women from 30 to 70 years old with an interval of 4 years. Almaty is the largest city in Kazakhstan, with a high incidence and mortality from all types of cancer.&#x0D; The study aimed to analyze the cervical cancer incidence and mortality in Almaty in 2005-2022.&#x0D; Methods: Epidemiological analysis of cervical cancer incidence in Almaty for 2005-2022 was provided with analyzing reporting forms of documentation. Statistical processing was carried out using the SPSS v. 23.0 software.&#x0D; Results: Over the past 18 years (2005 to 2022), there has been an increase in the incidence rate from 16 to 18.3 per 100,000 female population and a consistently high mortality rate, which was 6.6 per 100,000 female population in 2022. In 2005, 108 women with cervical cancer were&#x0D; identified, of which 70% were patients with the first and second stages. In 2022, 198 cases of cervical cancer were registered, where the first stage&#x0D; accounts for 56.5%. In recent years, there has been an increase in the frequency of registration of new cases of cervical cancer starting from 30-34&#x0D; years old, with a noticeable increase up to 40-44 years old.&#x0D; Conclusion: The results of this epidemiological study of cervical cancer incidence and mortality in Almaty indicate the need to improve and intensify screening among women of reproductive age, and introduce a vaccination and screening program using HPV testing.

CERVICAL CANCER INCIDENCE AND MORTALITY IN ALMATY IN 2005-2022

Relevance: In Kazakhstan, the standardized incidence rate of cervical cancer for 2022 was 19 per 100,000 women, and the mortality rate was 5.9 per 100,000 female population. The overall survival of cervical cancer in the Republic of Kazakhstan for 2022 was 59.6% (95% CI: 50.7-54.2). Since 2008, in Kazakhstan, there has been a National Screening Program for cervical cancer for women from 30 to 70 years old with an interval of 4 years. Almaty is the largest city in Kazakhstan, with a high incidence and mortality from all types of cancer.&#x0D; The study aimed to analyze the cervical cancer incidence and mortality in Almaty in 2005-2022.&#x0D; Methods: Epidemiological analysis of cervical cancer incidence in Almaty for 2005-2022 was provided with analyzing reporting forms of documentation. Statistical processing was carried out using the SPSS v. 23.0 software.&#x0D; Results: Over the past 18 years (2005 to 2022), there has been an increase in the incidence rate from 16 to 18.3 per 100,000 female population and a consistently high mortality rate, which was 6.6 per 100,000 female population in 2022. In 2005, 108 women with cervical cancer were&#x0D; identified, of which 70% were patients with the first and second stages. In 2022, 198 cases of cervical cancer were registered, where the first stage&#x0D; accounts for 56.5%. In recent years, there has been an increase in the frequency of registration of new cases of cervical cancer starting from 30-34&#x0D; years old, with a noticeable increase up to 40-44 years old.&#x0D; Conclusion: The results of this epidemiological study of cervical cancer incidence and mortality in Almaty indicate the need to improve and intensify screening among women of reproductive age, and introduce a vaccination and screening program using HPV testing.

Development and validation of radiomic signature for predicting overall survival in advanced stage cervical cancer

BackgroundThe role of artificial intelligence and radiomics in prediction model development in cancer has been increasing every passing day. Cervical cancer is the 4th most common cancer in women worldwide contributing to 6.5% of all cancer types. The treatment outcome of cervical cancer patients varies and individualized prediction of disease outcome is of paramount importance.PurposeThe purpose of this study is to develop and validate the digital signature for 5-year overall survival prediction in cervical cancer using robust CT radiomic and clinical features.Materials and MethodsPretreatment clinical features and CT radiomic features of 68 patients, who were treated with chemoradiation therapy in our hospital were used in this study. Radiomic features were extracted using an in-house developed python script and pyradiomic package. Clinical features were selected by the recursive feature elimination technique. Whereas radiomic feature selection was performed using a multi-step process i.e., step-1: only robust radiomic features were selected based on our previous study, step-2: a hierarchical clustering was performed to eliminate feature redundancy, and final step-3: recursive feature elimination was performed to select the best features for prediction model development. Four machine algorithms i.e., Logistic regression (LR), Random Forest (RF), Support vector classifier (SVC), and Gradient boosting classifier (GBC) were used to develop 24 models (six models using each algorithm) using clinical, radiomic and combined features. Models were compared based on the prediction score in the internal validation.ResultsThe average prediction accuracy was found to be 0.65 (95% CI: 0.60–0.70), 0.72 (95% CI: 0.63–0.81), and 0.77 (95% CI: 0.72–0.82) for clinical, radiomic, and combined models developed using four prediction algorithms respectively. The average prediction accuracy was found to be 0.69 (95% CI: 0.62–0.76), 0.79 (95% CI: 0.72–0.86), 0.71 (95% CI: 0.62–0.80), and 0.72 (95% CI: 0.66–0.78) for LR, RF, SVC and GBC models developed on three datasets respectively.ConclusionOur study shows the promising predictive performance of robust radiomic signature to predict 5-year overall survival in cervical cancer patients.

Treatment Toxicities, Response to Treatment and Overall Survival of Cervical Cancer in Women with and without HIV in Botswana: Ipabalele Study U54 CA190158-01

<h3>Purpose/Objective(s)</h3> Cervical cancer is the leading cause of cancer death among women in Botswana. It is well established that persistent human papillomavirus (HPV) infection is the primary risk factor for cervical cancer and that co-infection with human immunodeficiency virus (HIV) further increases the risk for cancer development. Standard of care for locally advanced disease is treatment with chemoradiation (CRT). This study aimed to characterize toxicities, response to treatment, and survival in patients with cervical cancer in Botswana. <h3>Materials/Methods</h3> Patients with histologically confirmed locally advanced cervical cancer eligible for CRT were prospectively enrolled between Jan 2015 and June 2019 to the <i>Ipabalele</i> study in Gaborone, Botswana. Clinical and treatment characteristics, on-treatment toxicities, and treatment response of patients were recorded. Biochemical response to treatment was characterized using SCC-Ag level <2.2ng/ml at the end of treatment and 3 months post treatment. Toxicities were measured during on treatment visits (OTVs) and evaluated using CTCAE 4.0 grading. All patients were followed every 3 months for 2 years. <h3>Results</h3> Of 293 women diagnosed with cervical cancer, 73.7% (n=216) were women living with HIV (WLWH). The mean age of diagnosis for cervical cancer was younger in WLWH vs those without HIV (44.9 vs. 47.5, p<0.001). There was no difference in stage at presentation by HIV status, with the most common stage at presentation among both populations as Stage II (46.3% WLWH, 58.84% without HIV, p=0.349). Median CD4 count among WLWH was 467 cells/μL. WLWH had a lower external beam radiation dose (45.76 Gy) compared to women living without HIV (47.09 Gy), p=0.002; however, HIV status did not impact total EQD2 (median 85.7 Gy). HIV status did not impact number of chemotherapy cycles received (median 4 cycles). Seventy three percent (n=106) of all patients had a complete response to treatment by clinical exam and imaging, 65% (n=82) of all patients had a complete response to treatment by SCC-Ag. HIV status did not impact response to treatment by either SCC-Ag or clinical evidence (p=0.718). Two-year overall survival (OS) probability for the cohort was 77.7%. There was no difference in survival by HIV status (OS 75.8% in WLWH; 82.05% in those without HIV, p=0.31). Treatment response by SCC-Ag was associated with OS. Factors associated with OS in a multivariate analysis included cycles of chemotherapy given and stage at presentation. HIV was not significantly related to overall survival. The most common Grade2+ toxicities included anemia (42.8%, n=125), leukopenia (34.6%, n=101), and radiation dermatitis (39.9%, n=101). Importantly, HIV did not impact prevalence of any of the toxicities measured. <h3>Conclusion</h3> HIV status impacted age of diagnosis of cervical cancer; however, did not impact stage, treatment received for cervical cancer, or OS. There was no difference seen in chemoradiation associated toxicities of treatment for locally advanced cervical cancer by HIV status.

A Randomized Phase III Trial of Debulking Macroscopic Lymph Nodes vs. Concurrent Chemoradiotherapy (CCRT) for Stage ⅢCr (FIGO2018) of Cervical Cancer

<h3>Purpose/Objective(s)</h3> In FIGO 2018, allowing assessment of retroperitoneal lymph nodes by imaging and/or pathological findings and, if deemed metastatic, the case is designated as stage IIIC (with r and p notations). External beam radiotherapy (EBRT) with concurrent chemotherapy followed by brachytherapy is still the standard treatment for stage IIICr of cervical cancer. Patients with lymph node metastases have lower overall survival (OS), progression free survival (PFS), and survival after recurrence, especially those who have unresectable macroscopically positive lymph nodes. Retrospective analysis suggests that there may be a benefit to debulk macroscopic nodes that would be otherwise difficult to sterilize with standard doses of radiation therapy. No prospective study reported that resecting macroscopic lymph nodes before CCRT would improve PFS or OS of cervical cancer. The CQGOG0103 study is a national, prospective, multicenter and randomized clinical study evaluating lymph node dissection on stage IIICr (FIGO2018) of cervical cancer. <h3>Materials/Methods</h3> Eligible patients are histologically confirmed cervical squamous cell carcinoma, adenocarcinoma, adeno-squamous cell carcinoma. Stage IIICr (confirmed by CT/MRI/PET/CT) and the short diameter of image-positive lymph node ≥15mm. 452 patients will be equally randomized to receive either CCRT (Pelvic EBRT/Extended-field EBRT + cisplatin (40mg/m2) or carboplatin (AUC=2) every week for 5 cycles + brachytherapy) or Open/minimally invasive pelvic and para-aortic lymph node dissection followed by CCRT. Randomization is stratified by status of para-aortic lymph node. The primary endpoint is PFS. Secondary endpoints are OS and surgical complications. The sample size calculation of 346 patients provides 80% power to detect a difference in survival at the two-sided 5% significance level using the log-rank test, considering a 20% reduction, a total of 452 patients are required. This study began in January 2021 and will be accrued within 4 years. Enrollment is ongoing. <h3>Results</h3> Enrollment is ongoing. <h3>Conclusion</h3> Enrollment is ongoing.

Identification and verification of a 4-gene signature predicting the overall survival of cervical cancer.

Cervical cancer (CC) is one of the most common gynecological malignancies, ranking fourth in both incidence and mortality in women worldwide. Early screening and treatment are of great significance in reducing the incidence and mortality of CC. Due to the complex molecular mechanisms of tumor progression, the predictive power of traditional clinical information is limited. In this study, an effective molecular model is established to assess prognosis of patients with CC and guide clinical treatment so as to improve their survival rate. Three high quality datasets (GSE138080, GSE52904, GSE67522) of expression profiling were obtained from gene expression omnibus (GEO) database. Another mRNA expression and clinicopathological data of CC were obtained from The Cancer Genome Atlas (TCGA) dataset. The bioinformatic analyses such as univariate analysis, multivariate Cox proportional-hazards model (Cox) analysis and lasso regression analysis were conducted to select survival-related differentially expressed genes (DEGs) and further establish a prognostic gene signature. Moreover, the performance of prognostic gene signature was evaluated based on Kaplan–Meier curve and receiver operating characteristic (ROC) curve. Gene set enrichment analysis (GSEA) and tumor immunity analysis were carried out to elucidate the molecular mechanisms and immune relevance. A 4-gene signature comprising procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), spondin1 (SPON1), secreted phosphoprotein 1 (SPP1), ribonuclease H2 subunit A (RNASEH2A) was established to predict overall survival (OS) of CC. The ROC curve indicated good performance of the 4-gene signature in predicting OS of CC based on the TCGA dataset. The 4-gene signature classified the patients into high-risk and low-risk groups with distinct OS rates of CC. Univariate analysis and multivariate Cox regression analysis revealed that the 4-gene signature was an independent factor affecting the prognosis of patients with CC. Our study developed a 4-gene signature capable of predicting the OS of CC. The findings may be beneficial to individualized clinical treatment and timely follow-up for patients with CC.

Prognosis Analysis and Validation of Fatty Acid Metabolism-Related lncRNAs and Tumor Immune Microenvironment in Cervical Cancer.

Cervical cancer (CC) is the third most common carcinoma and the fourth leading cause of cancer-associated mortality in women. The deregulation of fatty acid metabolism plays a crucial role in the progression of various tumors. This study is aimed at exploring the prognostic values of fatty acid metabolism- (FAM-) related long noncoding RNAs (lncRNAs) in CC. FAM-related differentially expressed genes (DEGs) and lncRNAs were screened in CC specimens based on TCGA datasets. Univariate analysis was carried out on differentially expressed lncRNAs to screen the survival-related lncRNAs. Multivariate assays were performed on the resulting lncRNAs to create a novel risk model. Survival assays were applied to examine the prognostic abilities of our model. Receiver operating characteristic (ROC) analysis was used to evaluate the accuracy of the new model. The association between risk model and immune responses was analyzed. In this study, we screened 9 differently expressed lncRNAs associated with the clinical outcome of CC patients. A nine-lncRNA signature comprising SCAT1, AC119427.1, AC009097.2, MIR100HG, AC010996.1, AL583856.2, MIAT, AP003774.2, and AC004540.2 was established to predict overall survival of CC. Survival assays revealed that patients' high risk score showed a shorter overall survival than those with low risk score. Multivariate assays demonstrated that the nine-gene signature was an independent prognostic factor in CC. In addition, we observed that APC_co_stimulation, CCR, and parainflammation were distinctly different between low-risk and high-risk groups. Our group observed a distinct difference in the expressions of CD44, TNFRSF8, CD276, LAG3, TNFRSF14, TMIGD2, VTCN1, TNFRSF25, CD80, NRP1, TNFRSF18, CD70, TNFSF9, and LGALS9 between the two groups of patients. Overall, our findings indicated that the 9 FAM-related lncRNA signature might be a promising prognostic factor for CC and can promote the management of FAM-related therapy in clinical practice.

MiR-218-5p/RUNX2 Axis Positively Regulates Proliferation and Is Associated with Poor Prognosis in Cervical Cancer.

The overexpression of miR-218-5p in cervical cancer (CC) cell lines decreases migration, invasion and proliferation. The objective was to identify target genes of miR-218-5p and the signaling pathways and cellular processes that they regulate. The relationship between the expression of miR-218-5p and RUNX2 and overall survival in CC as well as the effect of the exogenous overexpression of miR-218-5p on the level of RUNX2 were analyzed. The target gene prediction of miR-218-5p was performed in TargetScan, miRTarBase and miRDB. Predicted target genes were subjected to gene ontology (GO) and pathway enrichment analysis using the Kyoto Encyclopaedia of Genes and Genomes (KEGG). The miR-218-5p mimetic was transfected into C-33A and CaSki cells, and the miR-218-5p and RUNX2 levels were determined by RT–qPCR. Of the 118 predicted targets for miR-218-5p, 86 are involved in protein binding, and 10, including RUNX2, are involved in the upregulation of proliferation. Low miR-218-5p expression and a high level of RUNX2 are related to poor prognosis in CC. miR-218-5p overexpression is related to decreased RUNX2 expression in C-33A and CaSki cells. miR-218-5p may regulate RUNX2, and both molecules may be prognostic markers in CC.

Prognostic value of systemic inflammatory response markers in cervical cancer

We investigated the association between preoperative ratios of inflammatory markers and the prognosis in patients with invasive cervical cancer (CC). In this single-centre study, we retrospectively enrolled 163 CC patients who underwent radical hysterectomy between February 2008 and October 2018. Among the evaluated ratios, a high neutrophil-to-lymphocyte ratio (N/L) was significantly associated with deep stromal invasion and tumour size larger than 2 cm, whereas a high M/L was significantly related to advanced-stage CC (IB3–IIIC2), lymphatic metastasis (total) and pelvic lymph node metastasis (p= .002, p= .046 and p= .046, respectively). The neutrophil count plus monocyte-to-lymphocyte ratio (NM/L) and platelet-to-lymphocyte ratio (P/L) were significantly higher in patients with deep stromal invasion, advanced stage and tumour size larger than 2 cm (p=.01, p=.044 and p=.007; p=.004, p=.005 and p=.003, respectively). In the multivariate analysis, high NM/L (>168) was associated with a statistically significant hazard ratio of 3.04 (95% CI: (1.38–6.72); p=.006) for recurrence and 9.05 (95% CI: (2.10–38.99); p=.003) for death. Both stage and NM/L are independent prognostic factors that are significantly associated with recurrence and overall survival in CC. Impact Statement What is already known on this subject? Previous studies suggested that there is a relationship between inflammation and the formation, development and progression of cancer. However, the relationship between cervical cancer (CC) and inflammatory blood parameters is incompletely understood. What do the results of this study add? This study investigated the relationship between systemic blood inflammatory ratios and clinicopathological patient characteristics and disease outcomes in CC. What are the implications of these findings for clinical practice and/or further research? According to this study, systemic blood inflammatory ratios may help predict the prognosis and survival of patients with CC.

Randomized controlled trial of the efficacy of lymph node dissection on stage IIICr of cervical cancer (CQGOG0103).

TPS5604 Background: In FIGO 2018, allowing assessment of retroperitoneal lymph nodes by imaging and/or pathological findings and, if deemed metastatic, the case is designated as stage IIIC (with r and p notations). Patients with lymph node metastases have lower overall survival (OS), progression free survival (PFS), and survival after recurrence, especially those who have unresectable macroscopically positive lymph nodes. Retrospective analysis suggests that there may be a benefit to debulking macroscopic nodes that would be otherwise difficult to sterilize with standard doses of radiation therapy. No prospective study reported that resecting macroscopic nodes before Concurrent chemoradiation therapy (CCRT) would improve PFS or OS of cervical cancer. The CQGOG0103 study is a national, prospective, multicenter and randomized clinical study evaluating lymph node dissection on stage IIICr of cervical cancer. Methods: Eligible patients are histologically confirmed cervical squamous cell carcinoma, adenocarcinoma, adeno-squamous cell carcinoma. Stage IIICr (confirmed by CT/MRI/PET/CT) and the short diameter of image-positive lymph node ≥15mm. 452 patients will be equally randomized to receive either CCRT (Pelvic EBRT/Extended-field EBRT + cisplatin (40mg/m2) or carboplatin (AUC = 2) every week for 5 cycles + brachytherapy) or Open/minimally invasive pelvic and para-aortic lymph node dissection followed by CCRT. Randomization is stratified by status of para-aortic lymph node. The primary endpoint is PFS. Secondary endpoints are OS and surgical complications. The sample size calculation of 346 patients provides 80% power to detect a difference in survival at the two-sided 5% significance level using the log-rank test, considering a 20% reduction, a total of 452 patients are required. This study began in January 2021 and will be accrued within 4 years. Enrollment is ongoing.

MRVI1 and NTRK3 Are Potential Tumor Suppressor Genes Commonly Inactivated by DNA Methylation in Cervical Cancer.

The abnormally methylated tumor suppressor genes (TSGs) associated with cervical cancer are unclear. DNA methylation data, RNA-seq expression profiles, and overall survival data were downloaded from TCGA CESC database. DMGs and DEGs were obtained through CHAMP and DESeq packages, respectively. TSGs were downloaded from TSGene 2.0. Candidate hypermethylated/down-regulated TSGs were further evaluated and pyrosequencing was used to confirm their difference in methylation levels of selected TSGs in cervical cancer patients. A total of 25946 differentially methylated CpGs corresponding to 2686 hypermethylated genes and 4898 hypomethylated genes between cervical cancer and adjacent normal cervical tissues were found in this study. Besides, 693 DEGs (109 up-regulated and 584 down-regulated) were discovered in cervical cancer tissues. Then, 192 hypermethylated/down-regulated genes were obtained in cervical cancer compared to adjacent tissues. Interestingly, 26 TSGs were found in hypermethylated/down-regulated genes. Among these genes, low expression of MRVI1 and NTRK3 was associated with poor overall survival in cervical cancer. Moreover, GEO data showed that MRVI1 and NTRK3 were significantly decreased in cervical cancer tissues. The expression levels of MRVI1 and NTRK3 were negatively correlated with the methylation levels of their promoter CpG sites. Additionally, elevated methylation levels of MRVI1 and NTRK3 promoter were further verified in cervical cancer tissues by pyrosequencing experiments. Finally, the ROC results showed that the promoter methylation levels of MRVI1 and NTRK3 had the ability to discriminate cervical cancer from healthy samples. The study contributes to our understanding of the roles of MRVI1 and NTRK3 in cervical cancer.

An immune-associated ten-long noncoding RNA signature for predicting overall survival in cervical cancer.

BackgroundSeveral immune-associated long non-coding RNA (lncRNA) signatures have been reported as prognostic models in different types of cancers; however, the immune-associated lncRNA signature for predicting overall survival (OS) in cervical cancer is unknown.MethodsThe lncRNA expression profiles and clinical data of cervical cancer were acquired from The Cancer Genome Atlas (TCGA) dataset. Immune-associated genes were extracted from the Molecular Signatures Database (MSigDB), and the immune-associated lncRNAs were extracted for Cox regression analysis. Principal component analysis (PCA) was used to distinguish the high and low risk status of cervical cancer patients. Gene Set Enrichment Analysis (GSEA) was used for functional analyses.ResultsCox regression analyses and the least absolute shrinkage and selection operator (LASSO) Cox regression model were used to construct an immune-associated ten-lncRNA signature (containing AL021807.1, AL109976.1, LINC02446, MIR4458HG, AC004540.2, AC009065.8, AC083809.1, AC055822.1, AP000904.1, and FBXL19-AS1) for predicting OS in cervical cancer. The signature segregated the cervical cancer patients into 2 groups (high-risk group and low-risk group). The Kaplan-Meier survival curves of AL021807.1, AL109976.1, LINC02446, and MIR4458HG were statistically significant (P<0.05) and the others (including AC004540.2, AC009065.8, AC083809.1, AC055822.1, AP000904.1, and FBXL19-AS1) were not statistically significant (P>0.05). The Kaplan-Meier survival curves of the signature were statistically significant (P=1.134e-10), and the 5-year survival rate was 0.444 in the high-risk group [95% confidence interval (CI): 0.334 to 0.590] and 0.884 in the low-risk group (95% CI: 0.807 to 0.969). The area under curve (AUC) of the receiver operating characteristic (ROC) curve of the signature was 0.833. The concordance index (C-index) of the signature was 0.788 (95% CI: 0.730 to 0.846, P=1.884778e-22). The PCA successfully distinguished the high-risk group and low-risk group based on the signature. The GSEA showed that the signature-related protein coding genes (PCGs) may participate in immunologic biological processes and pathways.ConclusionsThis study revealed that the immune-associated ten-lncRNA signature is an independent factor for cervical cancer prognosis prediction, providing a bright future for immunotherapy of cervical cancer patients.

Fanconi Anemia Pathway Genes Advance Cervical Cancer via Immune Regulation and Cell Adhesion.

Fanconi anemia (FA) pathway is a typical and multienzyme-regulated DNA damage repairer that influences the occurrence and development of disease including cancers. Few comprehensive analyses were reported about the role of FA-related genes (FARGs) and their prognostic values in cancers. In this study, a comprehensive pan-cancer analysis on 79 FARGs was performed. According to the correlation analyses between HPV integration sites and FARGs, we found that FARGs played specific and critical roles in HPV-related cancers, especially in cervical cancer (CC). Based on this, a FARGs-associated prognostic risk score (FPS) model was constructed, and subsequently a nomogram model containing the FPS was developed with a good accuracy for CC overall survival (OS) and recurrence-free survival (RFS) outcome prediction. We also used the similar expression pattern of FARGs by consensus clustering analysis to separate the patients into three subgroups that exhibited significant differential OS but not RFS. Moreover, differential expressed genes (DEGs) between the two risk groups or three clusters were identified and immune pathways as well as cell adhesion processes were determined by functional enrichment analysis. Results indicated that FARGs might promote occurrence and development of CC by regulating the immune cells’ infiltration and cell adhesion. In addition, through the machine learning models containing decision tree, random forest, naïve bayes, and support vector machine models, screening of important variables on CC prognosis, we finally determined that ZBTB32 and CENPS were the main elements affecting CC OS, while PALB2 and BRCA2 were for RFS. Kaplan-Meier analysis revealed that bivariate prediction of CC outcome was reliable. Our study systematically analyzed the prognostic prediction values of FARGs and demonstrated their potential mechanism in CC aggressiveness. Results provided perspective in FA pathway-associated modification and theoretical basis for CC clinical treatments.

Identifying a cervical cancer survival signature based on mRNA expression and genome-wide copy number variations.

Cervical cancer mortality is the second highest in gynecological cancers. This study developed a new model based on copy number variation data and mRNA data for overall survival prediction of cervical cancer. Differentially expressed genes from The Cancer Genome Atlas dataset detected by univariate Cox regression analysis were further simplified to six by least absolute shrinkage and selection operator (Lasso) and stepwise Akaike information criterion (stepAIC). The study developed a six-gene signature, which was further verified in independent dataset. Association between immune infiltration and risk score was investigated by immune score. The relation between the signature and functional pathways was examined by gene set enrichment analysis. Ninety-nine differentially expressed genes were detected, and C11orf80, FOXP3, GSN, HCCS, PGAM5, and RIBC2 were identified as key genes to construct a six-gene signature. The prognostic signature showed a significant correlation with overall survival (hazard ratio, HR = 3.45, 95% confidence interval (CI) = 2.08-5.72, p < 0.00001). Immune score showed a negative correlation with the risk score calculated by the signature (p < 0.05). Four immune-related pathways were closely associated with risk score (p < 0.0001). The six-gene prognostic signature was an effective tool to predict overall survival of cervical cancer. In conclusion, the newly identified six genes may be considered as new drug targets for cervical cancer treatment.

Predicting Tumor Budding Status in Cervical Cancer Using MRI Radiomics: Linking Imaging Biomarkers to Histologic Characteristics.

Simple SummaryTumor budding is a histopathologic characteristic which has led to a growing interest in the prognosis prediction of cancers of various sites. We aimed to evaluate whether imaging biomarkers could predict tumor budding status. Preoperative MRI radiomic features were used as imaging biomarkers. Four machine learning classifiers were applied to build prediction models using a training dataset. Internal validation was performed to validate the built models. As a result, radiomics-based models predicted tumor budding status with a mean area under the receiver operating characteristic value of 0.816 and a mean accuracy of 0.779 in the independent test dataset. Final selected features were mostly from filtered images, implying the importance of filtering methods in radiomics. Preoperative prediction of tumor budding status may help personalize treatment in cervical cancer patients.Background: Our previous study demonstrated that tumor budding (TB) status was associated with inferior overall survival in cervical cancer. The purpose of this study is to evaluate whether radiomic features can predict TB status in cervical cancer patients. Methods: Seventy-four patients with cervical cancer who underwent preoperative MRI and radical hysterectomy from 2011 to 2015 at our institution were enrolled. The patients were randomly allocated to the training dataset (n = 48) and test dataset (n = 26). Tumors were segmented on axial gadolinium-enhanced T1- and T2-weighted images. A total of 2074 radiomic features were extracted. Four machine learning classifiers, including logistic regression (LR), random forest (RF), support vector machine (SVM), and neural network (NN), were used. The trained models were validated on the test dataset. Results: Twenty radiomic features were selected; all were features from filtered-images and 85% were texture-related features. The area under the curve values and accuracy of the models by LR, RF, SVM and NN were 0.742 and 0.769, 0.782 and 0.731, 0.849 and 0.885, and 0.891 and 0.731, respectively, in the test dataset. Conclusion: MRI-based radiomic features could predict TB status in patients with cervical cancer.

Identification of autophagy-related risk signatures for the prognosis, diagnosis, and targeted therapy in cervical cancer

BackgroundTo rummage autophagy-related prognostic, diagnostic, and therapeutic biomarkers in cervical cancer (CC).MethodsThe RNA-sequence and clinical information were from the TCGA and GTEx databases. We operated Cox regression to determine signatures related to overall survival (OS) and recurrence-free survival (RFS) respectively. The diagnostic and therapeutic effectiveness of prognostic biomarkers were further explored.ResultsWe identified nine (VAMP7, MTMR14, ATG4D, KLHL24, TP73, NAMPT, CD46, HGS, ATG4C) and three risk signatures (SERPINA1, HSPB8, SUPT20H) with prognostic values for OS and RFS respectively. Six risk signatures (ATG4C, ATG4D, CD46, TP73, SERPINA1, HSPB8) were selected for qPCR. We screened five prognostic signatures(ATG4C, CD46, HSPB8, MTMR14, NAMPT) with diagnostic function through the GEO database. Correlation between our models and treatment targets certificated the prognostic score provided a reference for precision medicine.ConclusionsWe constructed OS and RFS prognostic models in CC. Autophagy-related risk signatures might serve as diagnostic and therapeutic biomarkers.