Survival Of Cervical Cancer Patients Research Articles

Correction: Adverse effect of excess body weight on survival in cervical cancer patients after surgery and radiotherapy.

[This corrects the article on p. 48 in vol. 35.].

CCAR2 negatively regulates IL-8 production in cervical cancer cells.

Cell cycle and apoptosis regulator 2 (CCAR2) is a multifaceted protein that controls diverse cellular functions; however, its function in cancer is unclear. To better understand its potential role in cancer, we examined gene expression patterns regulated by CCAR2 in cervical cancer cells. Cytokine and chemokine production by CCAR2-deficient cells increased under oxidative conditions. In particular, H2O2-treated CCAR2-depleted cells showed a significant increase in interleukin-8 (IL-8) production, indicating a negative regulation of IL-8 by CCAR2. Upregulation of IL-8 expression in CCAR2-deficient cells occurred via activation of transcription factor AP-1. The negative correlation between CCAR2 and IL-8 expression was confirmed by examining mRNA and protein levels in tissues from cervical cancer patients. Furthermore, CCAR2-regulated IL-8 expression is associated with a shorter survival of cervical cancer patients. Overall, the data suggest that CCAR2 plays a critical role in controlling both the cancer secretome and cancer progression.

Prediction of 5\u2013year overall survival in cervical cancer patients treated with radical hysterectomy using computational intelligence methods

BackgroundComputational intelligence methods, including non-linear classification algorithms, can be used in medical research and practice as a decision making tool. This study aimed to evaluate the usefulness of artificial intelligence models for 5–year overall survival prediction in patients with cervical cancer treated by radical hysterectomy.MethodsThe data set was collected from 102 patients with cervical cancer FIGO stage IA2-IIB, that underwent primary surgical treatment. Twenty-three demographic, tumor-related parameters and selected perioperative data of each patient were collected. The simulations involved six computational intelligence methods: the probabilistic neural network (PNN), multilayer perceptron network, gene expression programming classifier, support vector machines algorithm, radial basis function neural network and k-Means algorithm. The prediction ability of the models was determined based on the accuracy, sensitivity, specificity, as well as the area under the receiver operating characteristic curve. The results of the computational intelligence methods were compared with the results of linear regression analysis as a reference model.ResultsThe best results were obtained by the PNN model. This neural network provided very high prediction ability with an accuracy of 0.892 and sensitivity of 0.975. The area under the receiver operating characteristics curve of PNN was also high, 0.818. The outcomes obtained by other classifiers were markedly worse.ConclusionsThe PNN model is an effective tool for predicting 5–year overall survival in cervical cancer patients treated with radical hysterectomy.

PBX3 is associated with proliferation and poor prognosis in patients with cervical cancer.

Pre-B-cell leukemia homeobox 3 (PBX3) is upregulated in various malignancies; however, the role of PBX3 in cervical cancer (CC) is unknown. The purpose of this study was to explore the expression characteristics, clinicopathological significance, and molecular biological function of PBX3 in CC. The expression levels of PBX3 were analyzed in CC cell lines and tumor specimens by real-time polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemical staining. The clinicopathological characteristics associated with PBX3 expression were evaluated. An RNA interference approach was employed to suppress PBX3 expression in CC in vitro and in vivo, determine its role in cell proliferation and analyze its molecular function. We found that PBX3 expression was significantly upregulated in CC cell lines and clinical specimens compared with normal cells and adjacent nontumorous cervical tissues. PBX3 was an independent predictive factor of poor prognosis, and its expression was correlated with tumor diameter, pathological grading, lymph node metastasis, invasion depth, vascular invasion, and clinical stage of CC. Multivariate analysis suggested that PBX3 expression may represent an independent prognostic indicator of the survival of CC patients. CC patients with high PBX3 expression exhibited reduced overall survival compared with those with low PBX3 expression. Additionally, stable downregulation of PBX3 expression in CC cell lines suppressed cell proliferation and decreased p-AKT protein expression levels in vitro. Similarly, in vivo assays demonstrated that PBX3 downregulation in CC cells markedly inhibited tumor size and weight. Overall, we demonstrated that PBX3 can promote CC cell proliferation via the AKT signaling pathway and that it may serve as a prognostic marker. Our data indicate that inactivation of PBX3 may be an effective clinical treatment for CC.

Investigation of RIP140 and LCoR as independent markers for poor prognosis in cervical cancer.

IntroductionRIP140 (Receptor Interacting Protein) is involved in the regulation of oncogenic signaling pathways and in the development of breast and colon cancers. The aim of the study was to analyze the expression of RIP140 and its partner LCoR in cervical cancers, to decipher their relationship with histone protein modifications and to identify a potential link with patient survival.MethodsImmunohistochemical analyses were carried out to quantify RIP140 and LCoR expression in formalin-fixed paraffin-embedded tissue sections cervical cancer samples. Correlations of RIP140 and LCoR expression with histopathological variables were determined by correlation analyses. Survival rates of patients expressing low or high levels of RIP140 and LCoR were compared by Kaplan-Meier curves.ResultsRIP140 overexpression was associated with a significantly shorter overall survival of cervical cancer patients. This effect was significant in the squamous cell carcinoma subtype but not in adenocarcinomas. RIP140 is no longer a significant negative prognosticator for cervical cancer when LCoR expression is low.DiscussionRIP140 is an independent predictor of poor survival of patients with cervical cancer. Patients with tumors expressing low levels of both RIP140 and LCoR showed a better survival compared to patients expressing high levels of RIP140. Modulation of RIP140 and LCoR may represent a novel targeting strategy for cervical cancer prevention and therapy.

Tumour size, volume, and marker expression during radiation therapy can predict survival of cervical cancer patients: a multi-institutional retrospective analysis of KROG 16-01.

The aim of this multi-institutional study was to determine the prognostic impact of tumour parameters, such as tumour size (TS), tumour volume (TV), and marker expression, on survival during radiation therapy (RT) for cervical cancer patients. A total of 231 patients with histologically confirmed cervical cancer, classified as Federation of Gynecology and Obstetrics (FIGO) Ib2-IVa, were enrolled in this study. Pre- and mid-RT pelvic magnetic resonance imaging (MRI) and squamous cell carcinoma antigen (SCC-ag) analysis were performed twice, during RT and just before brachytherapy. The median follow-up time was 27.8months (range, 2-116months). Multivariate analysis revealed that stage (odds ratio [OR], 2.936 and 95% confidence interval [CI], 1.119-7.707; P=0.029), tumour volume reduction rate (TVRR) (OR, 3.435 and 95% CI, 1.062-11.106; P=0.039), and SCC-ag reduction rate (SCCRR) (OR, 5.104 and 95% CI, 1.769-14.727; P=0.003) were independently associated with overall survival (OS), while pre-RT TS (OR, 2.148 and 95% CI, 1.221-3.810; P=0.009), mid-RT TV (OR, 3.106 and 95% CI, 1.685-5.724; P<0.0001) and SCCRR (OR, 1.954 and 95% CI, 1.133-3.369; P=0.016) were associated with progression-free survival (PFS). Based on the prognostic factor analysis, patients with the highest prognostic risk score of 3 showed poorer overall survival and progression free survival than patients with lower prognostic risk scores. We identified that tumour parameters such as TVRR, SCCRR, pre-RT TS, and mid-RT TV areindependent and strong prognostic parameters for patients with cervical cancer receiving RT. This scoring system-based prognostic factor analysis could be used to help develop optimized treatment plans for cervical cancer patients during RT.

The association between diabetes/hyperglycemia and the prognosis of cervical cancer patients: A systematic review and meta-analysis.

The predictive roles of diabetes in the prognosis of many types of cancer have been well studied, but its role in predicting the prognosis of cervical cancer is still controversial. The aim of the study is to evaluate the association between diabetes/hyperglycemia and the prognosis of cervical cancer. We conducted a systematic review for peer-reviewed studies indexed in PubMed, Embase, Web of Science, and Wanfang published before December 2016. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were pooled in the meta-analysis. This systematic review identified 13 studies with a total of 11,091 cervical cancer patients, of which 11 studies were included in the meta-analysis. The study indicated that diabetes was related to poorer overall survival (HR = 1.59, 95% CI: 1.35-1.87, P < .001) and poorer recurrence-free survival (HR = 1.98, 95% CI: 1.47-2.66, P < .001) in cervical cancer patients. The meta-analysis of adjusted HRs also indicated that diabetes was independently associated with poor overall survival (HR = 1.69, 95% CI: 1.38-2.05, P < .001) and poor recurrence-free survival (HR = 1.98, 95% CI: 1.47-2.66, P < .001) in cervical cancer patients. Sensitivity analysis and subgroup analyses showed similar results. No significant heterogeneity was observed for the included studies. The meta-analysis suggests that diabetes is an important predictive factor for cervical cancer prognosis, and it is linked to poorer survival of cervical cancer patients. Diabetes can serve as a useful index in the prognostic evaluation for patients with cervical cancer.

Phosphatidyl Inositol-3 Kinase (PIK3CA) Mutational Status and Post-chemoradiation Therapy 18f-FDG-PET Imaging Response in Patients With Cervical Cancer

Previous studies have shown association between tumor PIK3CA mutation, cisplatin resistance, and worse survival in cervical cancer patients. To date, the relationship between tumor PIK3CA status and post-treatment imaging response has not been investigated. We hypothesized that tumors harboring a PIK3CA mutation, or multiple mutations, would have lower rates of complete metabolic response (CMR) on post-treatment 18F-FDG-PET imaging after radical CRT. After ethics approval, cervical cancer patients treated with radical, curative intent RT including CT/MR-based brachytherapy planning at a single academic center between 2010 and 2014 were identified retrospectively. Pre-treatment tumor FFPE specimens were obtained. Patient, tumor and treatment characteristics were collected from clinical and RT treatment records. Post-treatment 18F-FDG-PETs were reviewed and assessed for CMR. For next generation sequencing, tumor DNA was extracted and assayed for SNPs and Indels in 50 oncogene and tumor suppressor genes using the Ampliseq Cancer Hot Spot Panel v2 (CHPv2) on the Ion PGM instrument using a 316v2 chip. Bioinformatic analysis was performed using Torrent Suite Software version 5.05. All variants were manually reviewed using Broad Institute’s Integrative Genomics Viewer. Descriptive statistics were used to characterize the data. Seventy-nine patients with available pre-treatment tumor specimens were identified; 77/79 (97%) underwent full sequencing analysis. Median patient age was 52 years; 53/77 (69%) had FIGO stage I or II disease. Median tumor size was 5 cm. Sixty-nine (90%) patients received concurrent cisplatin chemotherapy. Median EQD2 to tumor was 80 (72-101) Gy. The most common mutations (n = 28, 36%) were in the PI3K/PTEN/AKT pathway, 25 (31%) were PIK3CA; 92% on exon 9. 3 (12%) PIK3CA mutations involved multiple exons. Other mutations were uncommon, including: p53 (4%); KRAS (4%); FBXW7 (4%). In tumors with other mutations, 10 (43%) also carried PIK3CA mutation. 54 (70%) patients had 18F-FDG-PET a median of 3 months post-treatment; 41 (76%) had CMR. 20/22 (91%) PIK3CA mutant and 21/32 (66%) wild-type tumors had CMR, (Fisher’s P = 0.05). CMR was associated with improved overall and progression-free survival (log-rank P = 0.05 and P = 0.04, respectively). For tumors with multiple mutations, 6/9 (67%) had CMR vs 35/45 (78%) for other tumors (Fisher’s P = 0.7). PIK3CA was the most commonly mutated gene in this cervical cancer cohort. The trend towards improved CMR rates on 18F-FDG-PET imaging after radical CRT in PIK3CA mutated tumors is unexpected. Evaluation of multiple mutations on CRT response may reflect the biologic behavior of these tumors. Further investigation within a larger patient cohort is warranted to follow-up these findings.

Repeating platinum/bevacizumab in recurrent or progressive cervical cancer yields marginal survival benefits

Our objective was to assess overall survival of cervical cancer patients following prior platinum/bevacizumab chemotherapy, comparing retreatment with platinum/bevacizumab with alternative therapies.A retrospective analysis was performed of women who received platinum/bevacizumab (PB) chemotherapy for cervical cancer at Washington University between July 1, 2005 and December 31, 2015. Wilcoxon rank-sum exact test and Fisher's exact test were used to compare the treatment groups, and Kaplan Meier curves were generated. Cox regression analyses were performed, with treatment free interval and prior therapy response included as covariates.Of 84 patients who received PB chemotherapy, 59 (70%) received no second line chemotherapy, as they did not recur, progressed without further chemotherapy, were lost to follow up, or expired. Of the remaining 25 patients, 9 were retreated with the combination of platinum/bevacizumab (PB), 6 were retreated with a platinum regimen without bevacizumab (P), and 10 were retreated with neither (not-P). The only long-term survivor was in the not-P group and was treated with an immunotherapy agent. Median overall survival of all patients was 7.1months. There was a marginal difference in survival between women in the PB and not-PB groups (11.8 versus 5.7months; HR 3.02, 95% CI, 0.98–9.28). There was no difference in survival based on platinum interval (HR 0.81; 95% CI, 0.27–2.45).Outcomes are grim for women retreated after platinum/bevacizumab therapy and are only marginally improved by retreatment with a platinum/bevacizumab regimen. Rather than additional PB therapy, women with cervical cancer who recur after platinum/bevacizumab should consider supportive care or clinical trials.

MicroRNA-1297 inhibits metastasis and epithelial-mesenchymal transition by targeting AEG-1 in cervical cancer.

Accumulating evidence has demonstrated that aberrant miRNAs contribute to cervical cancer (CC) development and progression. However, the roles of various miRNAs in CC remain to be determined. In the present study, we confirmed that a decreased miR-1297 expression was present in CC tissues and cell lines. Our clinical analysis revealed that the downregulated miR-1297 expression was significantly correlated with poor prognostic features including lymph node metastasis and lymphovascular space invasion. Moreover, we confirmed that miR-1297 was a novel independent prognostic marker for predicting the 5-year survival of CC patients. The ectopic overexpression of miR-1297 inhibited cell migration, invasion and EMT progression, while downregulated miR-1297 reversed these effects. In addition, miR-1297 regulated AEG-1 by directly binding to its 3'-UTR. In clinical samples of CC, miR-1297 was inversely correlated with AEG-1, which was upregulated in CC. Alteration of AEG-1 expression at least partially abolished the migration, invasion and EMT progression effects of miR-1297 on CC cells. In conclusion, our results indicated that miR-1297 functioned as a tumor suppressor gene in regulating the EMT and metastasis of CC via targeting of AEG-1, and may represent a novel potential therapeutic target and prognostic marker for CC.

The predictive value of nadir neutrophil count during treatment of cervical cancer: Interactions with tumor hypoxia and interstitial fluid pressure (IFP)

Background and purposeHypoxia, high interstitial fluid pressure (IFP) and immune effects have individually been shown to modulate radiotherapy (RT) response in cervical cancer. The aim of this study was to investigate the interplay between hypoxia or IFP and circulating neutrophil levels, and their combined effect on survival following RT. Material and methodsA total of 287 FIGO stage IB to IIIB cervical cancer patients treated with RT or RT and cisplatin (RTCT) were included. Tumor hypoxia and IFP were measured at baseline prior to treatment. Absolute neutrophil count (ANC) was measured at baseline and weekly during treatment. Median follow up was 7.1years. ResultsHigh nadir ANC at the point of maximal myelosuppression was a stronger predictor of inferior survival than high baseline ANC after adjusting for clinical prognostic factors and treatment (RT vs. RTCT). The predictive effect of nadir ANC was most evident in patients with well-oxygenated tumors or tumors with high IFP at diagnosis. ConclusionsThis study provides new information about the combined influence of the tumor microenvironment and myeloid cells on the survival of cervical cancer patients treated with RT/RTCT to motivate the development of new treatments based on molecular targeting of immune–based radioresistance pathways.

The prognostic values of the expression of Vimentin, TP53, and Podoplanin in patients with cervical cancer

PurposeEpithelial–mesenchymal transition (EMT), TP53, and Podoplanin have been implicated in the tumorigenesis and metastasis of human cancers. Nevertheless, the clinical significance of these markers in cancer patients is still not clear. In this study, we sought to determine the prognostic values of Vimentin, TP53, and Podoplanin in patients with cervical cancer.MethodsQuantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis were performed to determine the messenger RNA and protein expression levels of Vimentin, TP53, and Podoplanin, respectively, in cervical squamous cell carcinoma and adjacent normal cervical tissues. Additionally, the expression levels of Podoplanin were also measured in 130 cervical cancer patients (FIGO stages Ib1–IIa2) using immunohistochemistry (IHC) staining.ResultsThe mRNA expression levels of Vimentin, TP53, and Podoplanin were considerably elevated in cervical cancer tissues, compared with those in the adjacent normal cervical tissues. Additionally, the protein expression levels of Vimentin were closely correlated with the age of onset (P = 0.007), lymph node metastasis (P = 0.007), lymphatic invasion (P = 0.024), disease recurrence (P < 0.001), and the clinical prognosis of patients with cervical cancer (P < 0.001). Our multivariate analysis also suggests that Vimentin is an independent marker for survival in cervical cancer patients. Furthermore, the expression levels of Vimentin are negatively correlated with the proliferation marker Ki67 expression.ConclusionsOur data show that Vimentin can serve as an independent prognostic marker for cervical cancer patients with primary surgery.Registration number ChiCTR-TRC-06000236 Registered 15 December 2006

Integrative miRNA analysis identifies hsa‐miR‐3154, hsa‐miR‐7‐3, and hsa‐miR‐600 as potential prognostic biomarker for cervical cancer

MicroRNAs, which can interfere with the translation of target mRNAs, caught a particular interest as their functions are related to human cancers. As the most common cancer in women, cervical cancer remains one of the leading cancer-related causes of death. In this study, we performed an integrative miRNA analysis to identify prognosis related miRNAs for cervical cancer. In addition, we developed an n-miRNA expression signature (risk score) to comprehensively assess the prognosis of cervical cancer, especially for survival time. Furthermore, we performed target predictions and functional enrichment analyses for the identified miRNAs to investigate their potential role in the development of disease. Univariate Cox regression models were used to assess the association between miRNAs and prognosis of cervical cancer. Three miRNAs were identified to be significantly associated with survival time of patients. Hsa-miR-3154 and hsa-miR-7-3 were significantly associated with shortened survival time and more death cases, whereas expression level of hsa-miR-600 was significantly associated with prolonged survival time. The function enrichment analysis showed the target genes of poor prognosis related miRNAs were mainly enriched in the mTOR pathway, whereas target genes of positive prognosis related miRNAs were mainly enriched in the AMPK pathway. In summary, a 3-miRNA expression signature was identified which can predict cervical cancer patient survival. The potential functions of this 3-miRNA expression signature and individual miRNAs as prognostic targets of cervical cancer were revealed by this study. Furthermore, these findings may have important implications in the understanding of the potential therapeutic method for the cervical cancer patients.

Aberrant Methylation of MEG3 Functions as a Potential Plasma-Based Biomarker for Cervical Cancer

Methylation alterations of specific genes have recently been identified as diagnostic biomarkers for human cancers. Although MEG3 has been proved to be a tumor suppressor in cervical cancer according to our previous study, the diagnostic value of MEG3 methylation in plasma is still unknown. Therefore, the aim of this study is to identify a novel epigenetic biomarker for cervical cancer. In the current study, the level of MEG3 methylation was evaluated using methylation-specific polymerase chain reaction. The results showed that the level of MEG3 methylation was significantly higher in cervical cancer tissues and patients’ plasmas than those in adjacent normal tissues and plasmas of healthy participants respectively. Moreover, the accuracy was good enough for MEG3 methylation in plasma to discriminate CIN III patients from healthy participants. In addition, MEG3 methylation in plasma also has high discriminating power to predict HR-HPV infection and lymph node metastasis. Furthermore, hypermethylation of MEG3 in plasma was associated with worse recurrence-free and overall survival in cervical cancer patients. In conclusions, MEG3 methylation in plasma can serve as a diagnostic and prognostic biomarker for cervical cancer, providing useful information for clinical management.

Meta-analysis showing that early response to neoadjuvant chemotherapy predicts better survival among cervical cancer patients.

This study was designed to identify the prognostic value of early response to neoadjuvant chemotherapy (NACT) for long-term survival of cervical cancer patients. We searched Pubmed and EMBASE for studies published through July 2016 on outcomes of cervical patients that received NACT. Eight studies involving 825 cervical cancer patients were ultimately included in our meta-analysis. We pooled the hazard ratios (HR) according to random-effects models and used funnel plots with Egger's and Begg's tests to explore potential publication bias. The HR between early response and 1-year overall survival (OS) was 3.60 (95% CI 1.93–6.72; I2 = 0). Similar results were found in the analysis of 3-year OS (HR 3.34; 95% CI 2.28–4.90; I2 = 0) and 5-year OS (HR 3.44; 95% CI 2.40–4.94; I2 = 0). Sensitivity analysis showed that all of the pooled results were robust, and all logHRs had confidence limits > 0. Our findings indicate that early response is associated with long-term survival, and responders achieved a higher survival rate than non-responders.

The Prostaglandin EP3 Receptor Is an Independent Negative Prognostic Factor for Cervical Cancer Patients.

We know that one of the main risk factors for cervical cancer is an infection with high-risk human papillomavirus (HR-HPV). Prostaglandins and their receptors are very important for the tumour growth and tumour-associated angiogenesis. Little is known about the expression of the Prostaglandin E receptor type 3 (EP3) or the Prostaglandin (PG)E2-EP3 signalling in cervical cancer, so the aim of the study was to analyse the expression of the EP3 receptor in cervical cancer and find prognostic factors in relation to survival; EP3 immunohistological staining of 250 cervical cancer slides was performed and analysed with a semi-quantitative score. The statistical evaluation was performed with Statistical Package for the Social Sciences (SPSS) to evaluate the staining results and the survival analyses of the cervical cancer cases. A significant difference was observed in EP3 expression in Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) stadium I versus FIGO stadium II–IV cases. High expression of EP3 (IRS ≥ 1.5) in cervical cancer patients was correlated with poor prognosis in overall survival rates. Survival in adenocarcinoma (AC) of the cervix was lower than in squamous cell carcinoma (SCC). Cox regression analysis shows that EP3 is an independent prognosticator. In this study we could show that the membrane-bound prostaglandin receptor EP3 is an independent prognosticator for cervical cancer patient survival. Targeting the EP3 receptor seems to be an interesting candidate for endocrine therapy. Therefore, more research is needed on the influence of the receptor system and its influence on cervical cancer growth.

The ratio of serum Angiopoietin-1 to Angiopoietin-2 in patients with cervical cancer is a valuable diagnostic and prognostic biomarker.

ObjectivesAngiopoietins have been found to play essential roles in tumor angiogenesis. The present study was aimed at investigating the diagnostic and prognostic values of serum angiopoietin 1 and 2 (sAng-1 and sAng-2) in cervical cancer.MethodsThe sAng-1 and sAng-2 concentrations were analyzed in 77 women with cervical cancer, 44 women with cervical intraepithelial neoplasia (CIN) and 43 women without cervical lesions by enzyme-linked immunosorbent assay. The diagnostic values of sAng-1, sAng-2 and sAng-1/sAng-2 were evaluated by receiver operating characteristic (ROC) curves. The Ang-1 and Ang-2 expression in cervical cancer tissues as well as microvessel density (MVD), were assessed by immunohistochemistry.ResultsThe concentration of sAng-2 gradually increased and the sAng-1/Ang-2 ratio was gradually decreased from normal control to CIN, then to squamous cell cancer, and the sAng-1/sAng-2 ratio was also significantly decreased in adenocarcinoma. The area under ROC curves of sAng-2 and sAng-1/sAng-2 ratio for discriminating cervical cancer from normal were 0.744 and 0.705, respectively. Decreased sAng-1/sAng-2 was significantly associated with advanced tumor stage, poor differentiation, lymph-vascular space invasion and high MVD. sAng-2 was positively correlated with the Ang-2 expression in cervix epithelia. A high sAng-1/sAng-2 ratio was associated with a longer progression-free survival and a longer overall survival in cervical cancer patients.ConclusionsThese findings suggest that sAng-2 and the sAng-1/sAng-2 ratio may be valuable diagnostic and prognostic biomarkers for cervical cancer.

A randomized phase II study of chemoradiation and pembrolizumab for locally advanced cervical cancer.

TPS5601 Background: The standard of care for patients with LACC is concurrent chemoradiation therapy (CRT) with weekly cisplatin. Five-year disease overall survival after contemporary CRT for LACC is only 66%. Human Papillomavirus (HPV) DNA is detected in virtually all cervical cancers, and HPV specific CD4+ helper and CD8+ cytotoxic T cells are found in cervical tumors, indicating the inherent immunogenicity of these tumors. The failure of the immune system to eradicate HPV DNA integration is thought to be associated with the cancer cells’ acquisition of mechanisms to avoid cytotoxic T cells, including, but not limited to, the expression of checkpoint inhibitory molecules such as PD-L1 and the recruitment of FoxP3+ immunosuppressive regulatory T cells. Low ratios of CD8+ T cells: regulatory T cells are associated with poor survival for cervical cancer patients, suggesting that strategies to enhance immune response would be effective. Additionally, in cervical cancer, PD-1 is expressed by the majority of infiltrating CD8+ T cells, suggesting that blocking of PD-1 could have therapeutic potential, inducing tumor-specific immunity in cervical cancer patients. We hypothesized that CRT may increase tumor responsiveness to anti-PD-1 therapy by enhancing antigen availability and disrupting immune-regulatory networks. However, it is unclear how treatment with cisplatin and/or ionizing radiation could influence the quality and quantity of the immune response. Methods: A randomized Phase II open-label multi-center study was designed in which 88 eligible subjects with LACC will be treated with standard CRT plus the PD-1 monoclonal antibody pembrolizumab. The primary objectives in the study are to estimate the safety and immune response to pembrolizumab given either sequentially or concurrently with CRT. Secondary objectives will evaluate the metabolic response and rates of distant metastases following treatment with pembrolizumab given sequentially or concurrently with CRT. The study design also affords the opportunity to characterize the effect of treatment on immune response pathways by estimating the effects of treatment on specific immune markers. Clinical trial information: NCT02635360.

Prognostic Parameters for Patients with Cervical Cancer FIGO Stages IA2-IIB: A Long-Term Follow-Up

Objective: We assessed the prognostic factors related to 10-year overall survival and disease-free survival in cervical cancer patients that underwent primary surgical protocols in 1 institution. Materials and Methods: A total of 102 patients with uterine cervical cancer at FIGO stages IA2-IIB that underwent a Piver type III radical hysterectomy and pelvic lymphadenectomy between 1998 and 2001 were included. Univariate and multivariate analyses of 10-year overall survival and 10-year disease-free survival were performed. Results: Univariate analysis revealed that only lymphovascular space invasion significantly affected 10-year overall survival (p = 0.04), but it had no effect on the 10-year disease-free survival rate. Multivariate analysis demonstrated that survival rates were significantly affected by FIGO stage (p = 0.02, 95% CI: 1.18-5.55, for 10-year overall survival; p = 0.03, 95% CI: 1.07-6.12, for 10-year disease-free survival) and metastases to the pelvic lymph nodes (p = 0.0005, 95% CI: 1.81-8.53, for 10-year overall survival; p = 0.01, 95% CI: 1.26-7.24, for 10-year disease-free survival). Conclusions: The only independent prognostic factors for 10-year survival rates in patients with cervical cancer at FIGO stages IA2-IIB were clinical stage and presence of metastases to the pelvic lymph nodes. The presence of lymphovascular space invasion adversely affected 10-year overall survival.

MicroRNA-106a promotes cell migration and invasion by targeting tissue inhibitor of matrix metalloproteinase 2 in cervical cancer.

Increasing evidence has demonstrated that miRNAs play a critical role in tumor development and progression. Previous studies have revealed that miR-106a is abnormally expressed in various cancers. However, its function and underlying mechanism in cervical cancer (CC) remains unknown. In this study, we confirmed that the expression of miR-106a was significantly upregulated in both CC cell lines and tissues by qRT-PCR. The increased expression of miR-106a was obviously associated with adverse prognostic features. Moreover, we demonstrated that miR-106a was a novel independent prognostic marker for predicting the 5-year survival of CC patients. The ectopic overexpression of miR‑106a promoted cell migration, invasion and invasion-related gene expression, while downregulated miR-106a reversed the effect. In addition, miR-106a regulated tissue inhibitor of metalloproteinase (TIMP)2 by directly binding to its 3'-UTR, leading to the indution of the expression of matrix metalloproteinases (MMPs). In clinical samples of CC, miR-106a was inversely correlated with TIMP2, which was downregulated in CC. Alteration of TIMP2 expression at least partially abolished the migration, invasion and MMP expression of miR-106a in CC cells. In conclusion, our data indicated that miR-106a promoted the migration, invasion and MMP expression of CC by targeting TIMP2, and may represent a novel potential therapeutic target and prognostic marker for CC.