Cervical Squamous Carcinoma Research Articles

Prognostic significance of poorly differentiated histology and impact of adjuvant chemotherapy in early squamous cell carcinoma of cervix uteri.

ObjectiveThis study is to determine whether the addition of cisplatin‐based chemotherapy after radical hysterectomy will improve the survival of low‐risk squamous cervical carcinoma with poor differentiation.MethodsPatients with low‐risk squamous cervical cancer (FIGO IA2–IIA, absent high‐ and intermediate‐risk factors after pathological evaluation) were eligible for this study. As first, the prognostic relevance of G3 versus G1/G2 among patients with low‐risk squamous cervical cancer was analyzed, then, the oncological results of postoperative chemotherapy among low‐risk squamous cervical cancer with poor differentiation was explored.ResultsTotally, there were 367 low‐risk squamous cervical cancer patients, of whom 161 were poor‐differentiated (47 in the chemotherapy group and 114 in the nonchemotherapy group), with a median follow‐up time of 56 months. Patients with G3 displayed a significantly worse overall survival (p = 0.035), and a higher recurrence rate (p = 0.014) than patients with G1/G2. Compared with the nonchemotherapy group, the hazard ratios (95%CI) for recurrence‐free survival in the chemotherapy group was 0.24 (0.06–0.93), (p = 0.038). No difference in overall survival was observed between the chemotherapy group and the nonchemotherapy group.ConclusionsThe addition of cisplatin‐based chemotherapy following surgery significantly improved recurrence‐free survival for low‐risk, poor differentiation, and early stage squamous cervical cancer patients.

Absence of EpCAM in cervical cancer cells is involved in slug induced epithelial-mesenchymal transition

BackgroundSlug (Snai2) is a pivotal player in initiating epithelial-mesenchymal transition (EMT) through its trans-suppression effect on E-cadherin in various normal and malignant cells. In this study, the positive effect of Slug on promoting cell motility and metastasis in cervical cancer was further confirmed in this study.MethodsRNA-Seq was performed to explore the potential molecules that participate in Slug-mediated EMT in cervical cancer cells. The negative correlation between Slug and EpCAM expression in cervical cancer cells was detected in this study, and linked them with in vitro migration and invasion assay, in vivo metastasis experiments, luciferase reporter assay and Chromatin immunoprecipitation.ResultsTranscriptome sequencing analysis revealed that epithelial cell adhesion molecule (EpCAM) was significantly decreased in Slug-overexpressing SiHa cells. Simultaneously, an absence of EpCAM expression was observed in Slug-overexpressing cells. Further studies revealed the trans-suppression effect of Slug on EpCAM through its binding to the E-boxes in the proximal promoter region of EpCAM in cervical cancer cells. Restoring EpCAM in Slug-overexpressing cells by transiently transfecting an EpCAM recombinant plasmid attenuated cell motility and promoted cell growth. Moreover, the negative correlation between Slug and EpCAM expression in human squamous cervical carcinoma (SCC) samples was verified by using Pearson correlation analysis.ConclusionsThese results demonstrated that the absence of EpCAM under Slug expression in cervical cancer cells probably participated in Slug-regulated EMT and further promoted tumor metastasis. Additionally, this study supports a potential way for Slug to initiate EMT progression in cervical cancer cells in addition to inhibiting E-cadherin.

Discovery and validation of FBLN1 and ANT3 as potential biomarkers for early detection of cervical cancer

BackgroundTo validate markers for cervical carcinoma (CC) and precancerous lesions related with HPV infections.MethodsThree different cervical cancer cell lines C-33A, SiHa and Caski were used for secretome profiling by label-free quantitative proteomics. Cervical exfoliated cells and matching serum samples were collected from 284 patients with normal control (n = 75, 26.41 %), precancerous lesions (n = 88, 30.99 %) and early stage cervical squamous carcinoma (n = 121, 42.61 %). HPV subtyping and quantification was performed by PCR and hybridization. 20 candidate proteins identified in previous screening studies (tissue, plasma, cells) were quantified by ELISA. Finally, highly quantitative parallel reaction monitoring mass spectrometry was used to assess the specificities and sensitivities of candidate serum markers.ResultsWhile CC was found to be associated with high-risk HPV subtypes, serum antibodies for high risk HPV were not significantly related to the progression of cervical cancer. Significant differences between patient groups were detected for the four proteins CLU, APOA4, APOE and MLH3, but none would allow clinical application due to insufficient sensitivity and specificity and large variability. Subsequent proteomic secretome analysis of cervical cancer cell lines identified a set of 729 common proteins. Cross referencing this dataset with ELISA measurements revealed six candidate proteins of which two, FBLN1 and ANT3, showed co-occurrence with HPV infection (75.7 % and 85 %, respectively) and had promising diagnostic ability in terms of sensitivity and specificity. After the loss of E6/E7 by using CRISPR/Cas9 gene editing, the content of ANT3 and FBLN1 in KoE6/E7 SiHa were downregulated, which indicated the expression of ANT3 and FBLN1 in cervical cancer may be affected by HPV infection.ConclusionsFBLN1 and ANT3 might be potential tumor- and HPV-associated serum markers.

Distribution of human papillomavirus genotypes in women with high-grade cervical intraepithelial lesions and cervical carcinoma and analysis of human papillomavirus-16 genomic variants

AimTo analyze the distribution of high-risk human papillomavirus (HR-HPV) genotypes and the diversity of HPV-16 genomic variants in Croatian women with high-grade squamous intraepithelial lesions (HSIL) and cervical carcinoma.MethodsTissue biopsy specimens were obtained from 324 women with histopathologically confirmed HSIL or cervical carcinoma, 5 women with low-grade SIL, and 49 women with negative histopathology. HR-HPV DNA was detected with Ampliquality HPV-type nucleic-acid hybridization assay, which identifies 29 different HPV genotypes. HPV-16 genomic variants were analyzed by an in-house sequencing.ResultsThe most common HPV type in women with HSIL was HPV-16, detected in 127/219 (57.9%) specimens. HPV-16 was also the dominant type in squamous cell cervical carcinoma (46/69 or 66.7%) and in adenocarcinoma (18/36 or 50.0%). Out of 378 patients, 360 had HR-HPV (282 single infections and 79 multiple infections), 3 (0.8%) patients had low-risk HPV, and 15 (4%) tested negative. HPV-16 variants were determined in 130 HPV-16 positive specimens, including 74 HSIL and 46 carcinoma specimens. In HSIL specimens, 41 distinct variants were found, 98.6% belonging to the European branch and 1.4% belonging to the African branch. In cervical carcinoma specimens, 95% isolates grouped in 41 variants belonging to the European branch, one isolate (2.5%) belonged to the North American, and one (2.5%) to the Asian-American branch.ConclusionHPV-16, mainly belonging to the European branch, was the most frequent HPV genotype in women from Croatia with histologically confirmed HSIL and cervical cancer.

PI3KCA Mutations in Uterine Cervix Carcinoma.

Background: Squamous cervical carcinoma represents an infection-associated malignancy that produces a high mortality when metastatic or recurrent after primary local treatment. There is an urgent need for new therapies for this cancer. Molecular lesions in cervical cancer may provide opportunities for targeted therapies development. Methods: Publicly available data from the Cancer Genome Atlas (TCGA) were analyzed to define the molecular landscape of squamous cervical carcinomas with and without mutations of PIK3CA, the gene encoding the alpha catalytic subunit of phosphatidylinositol 3 kinase (PI3K). Associations with alterations in other critical genes and pathways of cancer and the total mutation burden and copy number alteration burden of cervical cancers were examined. Results: Mutations in PIK3CA are observed in 27.1% of squamous cervical cancers. PIK3CA represents the most frequently mutated gene in these cancers. Mutations in PIK3CA are associated with higher rates of mutations in other genes of important cancer-associated pathways such as the tyrosine kinase receptors/K-Ras/BRAF/MAPK and the Wnt/β catenin pathway. In addition, PIK3CA mutated cervical cancers display a higher tumor mutation burden (TMB) than non-mutated cancers. Conclusion: Frequent mutations of PIK3CA gene in squamous cervical carcinomas may represent an opportunity for targeted therapies development both inhibiting the PI3K kinase and associated pathway defects. Increased TMB may additionally confer immunotherapy sensitivity.

Predictive value of microvessel features for the clinical response to neoadjuvant chemotherapy in cervical squamous carcinoma and the associations with prognosis.

BackgroundNeoadjuvant chemotherapy (NACT) may help reduce the difficulty of surgery and eliminate tiny tumor metastatic foci. It has been reported that 69.4% to 95% of patients with cervical cancer respond to NACT. The aim of this study was to evaluate the value of microvessel features in the prediction of response of cervical carcinoma to NACT and its association with the prognosis.MethodsIn all, 106 patients (FIGO stage IB2 and IIA2) received NACT followed by radical hysterectomy. Pre-treatment biopsy specimens and post-treatment surgical specimens were stained by immunohistochemistry using CD31 and CD105 antibodies and were counted by quantitative stereology. The correlation between microvessel features [microvessel density (MVD) and volume density (Vv)] and the clinical response and prognosis were determined using the Mann-Whitney U-test and logistic multivariate analysis.ResultsOf the 106 patients, 74 (69.4%) responded to NACT. The chemotherapeutic response was more favorable in patients with poor pathological grades and tumors larger than 5 cm (P=0.047, P<0.010). According to the pretreatment tumor size and the pathological grade, the patients were divided into six subgroups. In the subgroup of patients with a pretreatment tumor size ≥5 cm and tumors of moderate pathologic grade, the pre-NACT CD31-Vv was higher in NACT nonresponders than in responders (P=0.028). The area under the ROC curve for CD31-Vv was 0.767. In the logistic multivariate analysis, CD31-Vv was not an independent factor that affected the clinical response. The survival analysis showed that although higher post-treatment CD31-Vv was associated with a worse prognosis, Cox proportional hazards regression analysis did not indicate that microvessel features are prognostic predictors (P>0.05). Both pathological grade and invasive depth were independent predictors of survival.ConclusionsPre-treatment CD31-Vv could be a predictor of chemosensitivity in one specific subgroup (pre-treatment tumor size ≥5 cm and moderate pathological grade). Post-treatment CD31-Vv is associated with a worse prognosis but is not an independent factor for overall survival.

A Prognostic Risk Score Based on Integration of 9-Gene Expression and 5-Microbial Abundance Improves the Power to Predict Overall Survival of Patients with Cervical Squamous Carcinoma

Background: Prognosis of cervical squamous cancer (CESC) patients varies widely. Therefore, it is urgent to identify a reliable prognostic biomarker to distinguish patients with poor prognosis. Methods: Transcriptionally altered genes in CESC were identified by GEO2R in NCBI GEO database. Kaplan-Meier and Cox regression analysis was used to assess association of gene expression, microbial abundance, and scores with overall survival (OS). The multivariate Cox regression with/without resampling method was used to identify a gene or microbe signature associated with OS. Prognostic scoring systems were developed. Findings: We found 308 genes both transcriptionally altered in CESC and significantly correlated to OS. Resampling 100 times, we identified a 9-gene prognostic signature (SLC25A28, RFC5, RNASEH2A, SLC39A14, APOBEC3B, MS4A7A, FAM20C, ERG and TFRC) in TCGA-CESC dataset. A 9-gene expression-based prognostic score (GPS) was created and externally validated to predict OS. Moreover, our GPS performed significantly better than five published gene prognostic signatures. Similarly, we identified a 5-microbe prognostic signature (Dermabacter, Sulfurovum, Nostoc, Thermacetogenium and Alphavirus) using TCGA-CESC microbiome. A 5-microbial abundance-based prognostic score (MPS) was created to predict OS. When integrated the 9-gene signature with 5-microbe signature, the gene and microbe prognostic score (GMPS) showed much better performance for predicting OS than GPS and MPS. Interpretation: Our study constructed a GPS, MPS and GMPS for robustly recognizing patients with poor prognosis, which could guide individualized treatment in the future. Funding: National Natural Science Foundation of China, Zhongnan Hospital of Wuhan University Science, Technology and Innovation Seed Fund. Declaration of Interest: The authors declare no conflict of interest.

Identification of significant genes signatures and prognostic biomarkers in cervical squamous carcinoma via bioinformatic data.

BackgroundCervical squamous cancer (CESC) is an intractable gynecological malignancy because of its high mortality rate and difficulty in early diagnosis. Several biomarkers have been found to predict the prognose of CESC using bioinformatics methods, but they still lack clinical effectiveness. Most of the existing bioinformatic studies only focus on the changes of oncogenes but neglect the differences on the protein level and molecular biology validation are rarely conducted.MethodsGene set data from the NCBI-GEO database were used in this study to compare the differences of gene and protein levels between normal and cancer tissues through significant pathway selection and core gene signature analysis to screen potential clinical biomarkers of CESC. Subsequently, the molecular and protein levels of clinical samples were verified by quantitative transcription PCR, western blot and immunohistochemistry.ResultsThree differentially expressed genes (RFC4, MCM2, TOP2A) were found to have a significant survival (P < 0.05) and highly expressed in CESC tissues. Molecular biological verification using quantitative reverse transcribed PCR, western blotting and immunohistochemistry assays exhibited significant differences in the expression of RFC4 between CESC and para-cancerous tissues (P < 0.05).ConclusionThis study identified three potential biomarkers (RFC4, MCM2, TOP2A) of CESC which may be useful to clarify the underlying mechanisms of CESC and predict the prognosis of CESC patients.

Personalized Medicine and Cervical Screening: Development of Individualized Quantitative Risk Assessments for Cervical Adenocarcinoma and Adenocarcinoma in situ

Introduction: Cervical screening has decreased the incidence of cervical carcinoma around the world primarily by preventing cervical squamous carcinoma, with significantly less measurable protective benefits in prevention of cervical adenocarcinoma. In this study, we apply Bayesian modeling of cervical clinical, screening, and biopsy data from a large integrated health system to explore the feasibility of calculating personalized risk assessments on screened system patients for subsequent histopathologic diagnoses of invasive cervical adenocarcinoma (AdCa) or cervical adenocarcinoma in situ (AIS). Materials and Methods: Diagnoses of cervical AIS or AdCa rendered between 2005 and 2018 were identified in our large health system database with 1,053,713 cytology results, 354,843 high-risk (hr) human papillomavirus (HPV) test results, and 99,012 cervical histopathologic results. Using our continuously updated Bayesian cervical cancer screening model which includes clinical data, cervical screening results, and cervical biopsy results, we projected quantitative estimates of patients’ 5-year cumulative risk for cervical AIS or AdCa. Results: 161 patients were identified with AIS (ages 17–75, mean 37 years), and 99 patients had diagnoses of cervical AdCa (ages 26–91, mean 48 years). Quantitative Bayesian 5-year cumulative risk projections for diagnoses of cervical AdCa or AIS in patients with different cervical screening test and biopsy histories were determined. The highest patient risk projections for subsequent cervical AdCa and/or AIS histopathologic diagnoses were associated with prior cervical screening test results of HPV-positive atypical glandular cells. Prior squamous cytologic abnormalities were associated with lower risk estimates. Prior histopathologic diagnoses of squamous abnormalities also influenced quantitative risk. A prior histopathologic diagnosis of AIS was associated with a very low risk of subsequent AdCa, consistent with effective excisional treatment. AdCa risk was greatest in women aged 30–65 years with prior CIN3 biopsy results, whereas AIS risk was greatest in women <30. Conclusion: Prevention of cervical AdCa in screened patients remains a major challenge for cervical screening. Individualized risk projections for cervical glandular neoplasia reflecting patient age, prior cervical screening test results, and prior cervical biopsy history are feasible using Bayesian modeling of health system data.

Analysis Of Clinical Outcome, Toxicity And Prognosis On Locally Advanced Cervical Squamous Cell Carcinoma With Normal SCCAg Levels Receiving Intensity-Modulated Radiotherapy, Brachytherapy Combined With Concurrent Chemotherapy

Though SCCAg could be a useful marker in squamous cell carcinoma, rising of SCCAg is not demonstrated in some patients with squamous cell cancer. This study aimed to assess the clinical outcome, toxicity and prognosis on locally advanced cervical squamous carcinoma with normal SCCAg levels receiving concurrent chemoradiotherapy. A total of 294 patients of locally advanced cervical squamous cell carcinoma with normal SCCAg levels before treatment, FIGO 2018 staging from IB to IIIC2 with a median age of 54 years old, who received concurrent chemoradiotherapy from 2007 to 2016 were evaluated in this study. All patients received intensity-modulated external radiotherapy, high-dose-rate brachytherapy and cisplatin-based concurrent chemotherapy. 57 patients (19.39%) were diagnosed with pelvic lymph node metastasis before treatment, 32 (10.88%) of which were unilateral pelvic lymph node metastasis, and 25 (8.5%) were bilateral pelvic lymph node metastasis. The median survival time was 69.1 months, with 5-year OS, DFS, LCR and DMFS 83.6%, 80.6%, 90.3% and 88.1% respectively. 28 patients (9.52%) had local recurrence and 35 (11.9%) had distant metastasis. 11.56% and 1.02% patients had Grade III acute and late adverse effects in urinary system with 8.16% and 1.02% in gastrointestinal tract. The occurrence of the above for Grade IV were only 0%, 0%, 0% and 0.34%. Grade III acute hematological adverse events in leukocytes and neutrophils, lymphocytes, hemoglobin and platelets were 46.26%, 54.42%, 26.87%, 4.76% and 4.08%. Those of grade IV were 3.06%, 30.95%, 3.40%, 0.68% and 0.00%. Grade III late hematological toxicity, leukocytes, neutrophils, hemoglobin and platelets were 2.72%, 0.68%, 3.06% and 0.34%. Those of grade IV all show as 0.34%. As for prognostic factors, EQD2≥8500cGy (P = 0.001 and 0.008) and the courses of concurrent chemotherapy ≥4 cycles (P = 0.024 and 0.018) substantially improve OS and DFS. The performance of brachytherapy (P = 0.000) effectively improved LCR. While the courses of concurrent chemotherapy ≥ 4 cycles (P = 0.024) acted as an independent prognostic factor for DMFS, pelvic lymph node metastasis was an independent prognostic factor for OS, DFS, LC and DMFS, with metastasis of bilateral pelvic lymph nodes leading to worse prognosis than that of unilateral one. Intensity-modulated radiation therapy combined with brachytherapy and at least 4 courses of concurrent chemotherapy could significantly improve the prognosis including local recurrence and distant metastasis of locally advanced cervical squamous cell carcinoma with normal SCCAg level, and substantially reduce incidence of acute and late adverse effects above grade III. Most importantly, metastasis of pelvic lymph nodes acted as a significant prognosis factor. Among metastases of pelvic lymph nodes, bilateral metastases had a worse prognosis than unilateral ones.

Hyperthermia Combined with Concurrent Radiochemotherapy for 373 Patients with Cervical Cancer Stage IB-IV

Hyperthermia (HT) is a commonly used approach in tumor patients, but the efficacy was still uncertain on cervical cancer (CC) treatment. This study was to evaluate if HT combined with concurrent radiochemotherapy (RCT) could render a better survival in CC patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB-IV, and did not increase treatment related toxicity. This study was conducted between 2009 and 2013 in CC patients. Patient eligibility criteria included: (1) age between 25-70 years old; (2) Karnofsky ≥ 70; (3) FIGO stages IB-IV; (4) no prior RT, CT or surgery; (5) histologically confirmed cervical squamous carcinoma; (6) no RT and CT contraindications, no HT contraindications (no cardiac pacemaker, no body metal); (7) normal blood routine, liver and renal function, no vital organ function failure; (8) no double primary cancer (no malignancy except cervical cancer). Patients were randomly assigned into two treatment groups according to a computer-generated random number list: RCT and RCT+HT (RCHT). All patients were treated with external beam radiotherapy (EBRT), 1.8–2.0Gy/fraction per day, 5 days per week, to a total dose of 50.4 or 50Gy. A High-Dose-Rate intracavitary brachytherapy (HDRICB) application delivering a further dose of 5Gy/fraction, 4 or 5 fractions, twice every week, to a total dose of 20∼25Gy to point A. One week after the first EBRT, all patients were treated with cisplatin (PDD) and 5-fluorouracil (5-Fu) regimen (PF): PDD 30 mg/m2, d1-3; 5-Fu 350mg/m2, d1-5. HT was delivered after PF regimen in RCHT group using Radio Frequency HT machine. Temperature was controlled above average 40.5°C (range from 39.5∼41.5°C) for 60 minutes, twice a week, to a total of 6 fractions. Primary end points were 5-year overall survival (OS) and late toxicity. Secondary end points included local-regional relapse (LRFS) and acute toxicity. Analysis was done by per protocol approach. 373 patients completed treatment and were analyzed. 5-year overall survival (OS) in RCHT group (81.9%) was better than that in RCT group (72.3%) and the log-rank test showed statistically significant difference (p = 0.040). Univariate and multivariate COX regression analysis for 5-year OS showed statistically significant difference (p = 0.043, p = 0.045, respectively). 5-year local relapse-free survival (LRFS) in RCHT (86.8%) was also better than that in RCT (82.7%), but the difference was not significant. Acute or late toxicity was not significantly different between two groups. Advanced FIGO stage and larger tumor size showed higher risk of death and relatively poor prognosis in univariate and multivariate analysis. HT combined to RCT yielded a better 5-year OS in CC without increasing treatment related toxicity. Therefore, hyperthermia will be one of the most effective additional treatments. FIGO stage and tumor size were independent prognostic factors in CC.

Serum lncRNAs (CCAT2, LINC01133, LINC00511) with Squamous Cell Carcinoma Antigen Panel as Novel Non-Invasive Biomarkers for Detection of Cervical Squamous Carcinoma.

BackgroundWe screened long non-coding RNAs (lncRNAs) specifically expressed in the serum of cervical squamous carcinoma (CESC) patient samples and investigated the role of these specific lncRNAs in the diagnosis of CESC and cervical intraepithelial neoplasia (CIN).MethodsThe expression levels of the lncRNAs CCAT2, LINC01133, and LINC00511 in the serum of normal controls and patient with CESC and CIN were measured using reverse transcription–quantitative polymerase chain reaction (RT-qPCR). Next, we analyzed the correlation between the serum lncRNAs levels and the clinical characteristics of CESC. Thereafter, we estimated their combined diagnostic value by receiver operating characteristic (ROC) curve analysis.ResultsThe results showed that CCAT2, LINC01133, and LINC00511 were highly expressed in the serum of patients with CESC. When these lncRNAs and squamous cell carcinoma (SCC) antigen were combined, the area under the ROC curve (AUC) value reached 0.94. We also found that the AUC value of the diagnostic model combining CCAT2 and LINC01133 reached 0.894.ConclusionThe serum lncRNAs (CCAT2, LINC01133, and LINC00511) and SCC may be new non-invasive biomarkers for the diagnosis of CESC.

Sentinel lymph node biopsy versus pelvic lymphadenectomy in early-stage cervical cancer: a multi-center randomized trial (PHENIX/CSEM 010)

BackgroundThere is no accepted strategy for applying sentinel lymph node (SLN) biopsy as an alternative to pelvic lymphadenectomy in cervical cancer. It is unclear whether and when pelvic lymphadenectomy can...

A Preoperative Nomogram for Predicting Chemoresistance to Neoadjuvant Chemotherapy in Patients with Locally Advanced Cervical Squamous Carcinoma Treated with Radical Hysterectomy.

PurposeThis study aimed to investigate the factors associated with chemoresistance to neoadjuvant chemotherapy (NACT) followed by radical hysterectomy (RH) and construct a nomogram to predict the chemoresistance in patients with locally advanced cervical squamous carcinoma (LACSC).Materials and MethodsThis retrospective study included 516 patients with International Federation of Gynecology and Obstetrics (2003) stage IB2 and IIA2 cervical cancer treated with NACT and RH between 2007 and 2017. Clinicopathologic data were collected, and patients were assigned to training (n=381) and validation (n=135) sets. Univariate and multivariate analyses were performed to analyze factors associated with chemoresistance to NACT. A nomogram was built using the multivariate logistic regression analysis results. We evaluated the discriminative ability and accuracy of the model using a concordance index and a calibration curve. The predictive probability of chemoresistance to NACT was defined as > 34%.ResultsMultivariate analysis confirmed menopausal status, clinical tumor diameter, serum squamous cell carcinoma antigen level, and parametrial invasion on magnetic resonance imaging before treatment as independent prognostic factors associated with chemoresistance to NACT. The concordance indices of the nomogram for training and validation sets were 0.861 (95% confidence interval [CI], 0.822 to 0.900) and 0.807 (95% CI, 0.807 to 0.888), respectively. Calibration plots revealed a good fit between the model-predicted probabilities and actual probabilities (Hosmer-Lemeshow test, p=0.597). Furthermore, grouping based on the nomogram was associated with progression-free survival.ConclusionWe developed a nomogram for predicting chemoresistance in LACSC patients treated with RH. This nomogram can help physicians make clinical decisions regarding primary management and postoperative follow-up of the patients.

Coinfection of High-Risk Human Papillomavirus and Lower Genital Tract Pathogens in the Development of High-Grade Cervical Lesions.

Purpose This study investigated the infection status and relationship between other common lower genital tract infectious pathogens and high-risk human papillomavirus (HR-HPV) in the high-grade cervical lesions. Methods Overall, 882 patients were enrolled in this retrospective study, of which 339 patients (≥HSIL group) were confirmed with high-grade squamous intraepithelial lesions (HSIL) or cervical squamous cell carcinoma (SCC), while 543 patients (≤LSIL group) were diagnosed with low-grade squamous intraepithelial lesions (LSIL) or normal cervical pathology diagnosis. Cervical swab specimens were tested for HPV, pathogenic bacteria (PB), U. urealyticum (UU), M. hominis (MH), and C. trachomatis (CT) in both groups. Results The infection rates of HR-HPV, PB, UU (at high density), and CT were higher in the ≥HSIL group than in the ≤LSIL group (P < 0.001); however, higher infection rates with MH were not observed (P > 0.05). PB, UU, and CT were associated with HR-HPV infection (P < 0.001). The PB and UU infection rates in the ≥HSIL group were significantly different from those in the ≤LSIL group, regardless of whether there was an HR-HPV infection at the same time (P < 0.05). However, this was not the case for the CT (P > 0.05). Furthermore, 259 pathogenic bacterial strains were detected in 882 cases. The difference in the distribution of pathogenic bacterial flora in the different grades of cervical lesions had no statistical significance, which was prioritized over Escherichia coli (P > 0.05). Conclusion PB, UU, and CT infection is associated with susceptibility to HR-HPV, HR-HPV coinfection with these pathogens might increase the risk of high-grade cervical lesions, and PB and UU might be independent risk factors for cervical lesions.

SOX1 Promoter Hypermethylation as a Potential Biomarker for High-Grade Squamous Intraepithelial Neoplasia Lesion and Cervical Carcinoma: A Meta-Analysis With Trial Sequential Analysis.

Background: DNA methylation has been widely assessed as a potential biomarker for the early detection of cervical cancer (CC). Herein, we assessed the associations of SOX1 promoter hypermethylation with squamous intraepithelial lesion and CC.Methods: Published studies and genome-wide methylation datasets were searched from electronic databases (up to April 2019). The associations of SOX1 hypermethylation with high-grade squamous intraepithelial lesion (HSIL) and CC risks were evaluated by odds ratios (ORs) and 95% confidence intervals (CIs). The summary receiver operator characteristic test was used to assess the diagnostic value of the SOX1 promoter hypermethylation of CC and intraepithelial neoplasia type III or worse (CIN3+). Trial sequential analysis (TSA) was performed to evaluate the stability of results and estimate the required information size (RIS).Results: In this meta-analysis of 17 published studies, the SOX1 methylation rates increased among low-grade SIL (LSIL, 27.27%), HSIL (40.75%), and CC (84.56%) specimens. Compared with control specimens, SOX1 promoter hypermethylation progressively increased the risk of HSIL by 4.20-fold (p < 0.001) and CC by 41.26-fold (p < 0.001). The pooled sensitivity of SOX1 methylation was estimated to be 0.85 (95% CI: 0.81–0.88) in differentiating patients with CC, corresponding to a specificity of 0.72 (95% CI: 0.69–0.75) and an area under the curve (AUC) of 0.93. Furthermore, the pooled sensitivity of SOX1 methylation was estimated to be 0.75 (95% CI: 0.72–0.78) in differentiating patients with CIN3+, corresponding to a specificity of 0.71 (95% CI: 0.69–0.73) and an AUC of 0.84. The pooled results of TCGA and GEO datasets showed that all CpG sites in SOX1 were associated with CC and 16 of 19 CpG sites were associated with HSIL. The results of TSA illustrated that the size was sufficient and significant associations were observed.Conclusion: This meta-analysis indicated that SOX1 promoter hypermethylation might have a potential value in the clinical diagnosis of CC and CIN3+.

STAT1 expression and HPV16 viral load predict cervical lesion progression.

Cervical cancer is the fourth leading cause of cancer-associated mortality worldwide. However, its underlying molecular mechanisms are unclear. It is important to explore these mechanisms in order to identify novel diagnostic and prognostic biomarkers. The present study determined the association between STAT1 and human papillomavirus (HPV)16 in cervical lesions. STAT1 expression was detected by immunohistochemistry. Quantitative PCR was used to detect HPV16 viral load and STAT1 expression in cervical lesions. The potential associations among STAT1 expression, HPV16 viral load and the severity of cervical lesions in patients were analyzed using receiver operating characteristic (ROC) curves. The Cancer Genome Atlas database was used to analyze STAT1 expression and survival. High STAT1 expression was observed in 10.71 (3/28), 41.18 (14/34), 53.06 (26/49) and 90.00% (27/30) of normal tissue, low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL) and cervical squamous cell carcinoma samples, respectively. The HPV16 copy number gradually increased with the progression of cervical lesions, with the highest copy number observed in cervical cancer samples. In addition, STAT1 expression was positively correlated with HPV16 viral load. Furthermore, ROC curve analysis demonstrated that the combination of STAT1 expression and HPV16 viral load was able to differentiate between LSIL/HSIL and cervical cancer samples. Bioinformatics analysis revealed that STAT1 expression was associated with improved survival in cervical cancer. Additionally, STAT1 expression was positively associated with the progression of cervical lesions, and HPV16 viral load may affect STAT1 expression. Overall, these findings indicate that STAT1 may be an indicator of the status of cervical lesions.

ERBB2 mRNA Expression and Response to Ado-Trastuzumab Emtansine (T-DM1) in HER2-Positive Breast Cancer.

Trastuzumab emtansine (T-DM1) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (BC) and for residual disease after neoadjuvant therapy; however, not all patients benefit. Here, we hypothesized that the heterogeneity in the response seen in patients is partly explained by the levels of human epidermal growth factor receptor 2 gene (ERBB2) mRNA. We analyzed ERBB2 expression using a clinically applicable assay in formalin-fixed paraffin-embedded (FFPE) tumors (primary or metastatic) from a retrospective series of 77 patients with advanced HER2+ BC treated with T-DM1. The association of ERBB2 levels and response was further validated in 161 baseline tumors from the West German Study (WGS) Group ADAPT phase II trial exploring neoadjuvant T-DM1 and 9 in vitro BC cell lines. Finally, ERBB2 expression was explored in 392 BCs from an in-house dataset, 368 primary BCs from The Cancer Genome Atlas (TCGA) dataset and 10,071 tumors representing 33 cancer types from the PanCancer TCGA dataset. High ERBB2 mRNA was found associated with better response and progression-free survival in the metastatic setting and higher rates of pathological complete response in the neoadjuvant setting. ERBB2 expression also correlated with in vitro response to T-DM1. Finally, our assay identified 0.20–8.41% of tumors across 15 cancer types as ERBB2-high, including gastric and esophagus adenocarcinomas, urothelial carcinoma, cervical squamous carcinoma and pancreatic cancer. In particular, we identified high ERBB2 mRNA in a patient with HER2+ advanced gastric cancer who achieved a long-lasting partial response to T-DM1. Our study demonstrates that the heterogeneity in response to T-DM1 is partly explained by ERBB2 levels and provides a clinically applicable assay to be tested in future clinical trials of breast cancer and other cancer types.

Neoadjuvant chemotherapy followed by radical surgery versus concurrent chemoradiotherapy in patients with FIGO stage IIB cervical cancer: the CSEM 006 study

BackgroundConcurrent chemoradiotherapy is the first-line treatment for FIGO stage IIB cervical cancer. Neoadjuvant chemotherapy followed by radical surgery may provide another treatment option.Primary objectiveTo compare the therapeutic outcomes of neoadjuvant...

Loss of MHC Class I Expression in HPV-associated Cervical and Vulvar Neoplasia

Tumor cell expression of major histocompatibility complex (MHC) class I is required for antigen presentation and adaptive immune recognition. Absent or diminished MHC class I expression is thought to contribute to immunotherapeutic resistance in some epithelial tumors but has not been previously studied in cervical and vulvar carcinoma. Given that anti-programmed cell death 1 (PD-1) checkpoint inhibition is deployed for programmed cell death ligand 1 (PD-L1)-positive recurrent and metastatic cervical squamous carcinomas, identifying tumors with loss of MHC class I is of clinical interest to optimize the selection of immunotherapeutic candidates. Immunohistochemistry for PD-L1 and MHC class I combined A, B, and C heavy chains (MHC class I) was assessed in 58 human papillomavirus-associated cervical and vulvar lesions, including 27 squamous intraepithelial lesions (SILs) and 31 invasive squamous cell carcinoma (SCC). Although 84% of SCC and 22% of SIL were PD-L1-positive, 35.5% (11/31) of SCC and 18.5% (5/27) of SIL also showed clonal or complete loss of MHC class I. Loss of MHC class I expression was more common in PD-L1-positive (10/26, 38%) versus PD-L1-negative SCC (1/5, 20%). In summary, over one third of human papillomavirus-associated cervical and vulvar SCC show clonal or complete loss of MHC class I expression, including many PD-L1-positive cases. This suggests that the efficacy of checkpoint inhibitors targeting the PD-1/PD-L1 axis may be limited in a subset of cervical and vulvar squamous neoplasms due to an impaired ability to engage with the adaptive immune system related to loss of MHC class I expression.