The International Journal of Biological Markers

Immunogenetic contribution of the fractalkine / CX3CR1 axis in oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is a malignant neoplasm with high mortality and recurrence. Its etiology is multifactorial and involves environmental factors such as smoking, alcohol, and human papilloma virus infection, as well as genetic factors such as single nucleotide polymorphisms. The fractalkine / CX3CR1 axis is key in the regulation of cell apoptosis, proliferation, migration, and invasion, which are fundamental processes in cancer development. The CX3CL1 gene, which encodes fractalkine, presents variants such as rs223815 (G > C) and rs682082 (G > A), associated with resistance to chemotherapy in ovarian cancer. In OSCC, its increased expression correlates with shorter survival. On the other hand, the CX3CR1 gene, which encodes its receptor, has variants such as T280M and V249I, which are associated with reduced cell adhesion and deficiencies in chemotaxis. These variants have been implicated in various diseases and in reduced immune response against cancer. Although the fractalkine / CX3CR1 axis may have protective or tumorigenic effects depending on the type of cancer, in OSCC its activation seems to favor tumor invasion and metastasis. Future studies could determine its impact on the development and treatment of this disease.

Impact of metabolism-related markers on outcomes in ovarian cancer patients: Findings of the MITO16A/MaNGO-OV2 trial

Introduction In ovarian cancer, expression of metabolism-related markers has been investigated in several studies focusing on individual markers; however, a parallel quantitative evaluation of markers mapping to distinct metabolic processes and their prognostic value in large patient cohorts is still lacking. Methods Here, by using immunohistochemistry followed by digital pathology, we investigated the expression of several markers related to glycolysis including monocarboxylate transporter 1 and 4 (MCT1, MCT4), glutamine metabolism (glutaminase, GLS) and hypoxia/acidosis (carbonic anhydrase 9, CA IX) in tissue microarrays of > 300 patients recruited in the MITO16A clinical trial, which involved treatment of ovarian cancer patients with carboplatin/taxol plus bevacizumab. Results Regarding the prognostic impact of these markers, results indicate that GLS expression correlated with progression-free survival, but this effect disappeared when data were corrected for multiple testing. All other markers showed no correlation with clinical outcome. Conclusion These results indicate marked heterogeneity of expression of metabolism-associated markers in ovarian cancer; however, there was a lack of association with clinical benefit after chemotherapy/anti-vascular endothelial growth factor treatment. Notwithstanding the lack of prognostic value, knowledge of the pattern of expression of these biomarkers in tumors can be useful for patient stratification purposes when new drugs targeting these metabolic pathways will be tested.

Clinicopathological role of Cyclin A2 in uterine corpus endometrial carcinoma: Integration of tissue microarrays and ScRNA-Seq

Background The comprehensive expression level and potential molecular role of Cyclin A2 (CCNA2) in uterine corpus endometrial carcinoma (UCEC) remains undiscovered. Methods UCEC and normal endometrium tissues from in-house and public databases were collected for investigating protein and messenger RNA expression of CCNA2. The transcription factors of CCNA2 were identified by the Cistrome database. The prognostic significance of CCNA2 in UCEC was evaluated through univariate and multivariate Cox regression as well as Kaplan–Meier curve analysis. Single-cell RNA-sequencing (scRNA-seq) analysis was performed to explore cell types in UCEC, and the AUCell algorithm was used to investigate the activity of CCNA2 in different cell types. Results A total of 32 in-house UCEC and 30 normal endometrial tissues as well as 720 UCEC and 165 control samples from public databases were eligible and collected. Integrated calculation showed that the CCNA2 expression was up-regulated in the UCEC tissues (SMD = 2.43, 95% confidence interval 2.23∼2.64). E2F1 and FOXM1 were identified as transcription factors due to the presence of binding peaks on transcription site of CCNA2. CCNA2 predicted worse prognosis in UCEC. However, CCNA2 was not an independent prognostic factor in UCEC. The scRNA-seq analysis disclosed five cell types: B cells, T cells, monocytes, natural killer cells, and epithelial cells in UCEC. The expression of CCNA2 was mainly located in B cells and T cells. Moreover, CCNA2 was active in T cells and B cells using the AUCell algorithm. Conclusion CCNA2 was up-regulated and mainly located in T cells and B cells in UCEC. Overexpression of CCNA2 predicted unfavorable prognosis of UCEC.

The autophagy-related gene PEA15 is a potential prognostic biomarker for early-stage endometrial carcinoma

Background The Cancer Genome Atlas (TCGA) molecular classification has advanced risk stratification for endometrial carcinoma but has demonstrated comparable survival outcomes between the microsatellite instability (MSI) and copy-number low (CN-L) subtypes. In this study, we aimed to identify potential autophagy-related molecular signatures to increase the precision of TCGA-based prognostic stratification in early-stage endometrial carcinoma. Methods Univariate Cox regression analysis of the TCGA-Uterine Corpus Endometrial Carcinoma cohort was used to identify autophagy-related genes associated with survival outcomes in patients with endometrial carcinoma. The candidates were analyzed by the Kaplan–Meier method. Multivariate Cox regression was used to assess whether PEA15 served as an independent prognostic factor, especially for the MSI and CN-L subtypes. We examined the correlation between PEA15 protein expression and patient survival through immunohistochemical analysis of tissue microarrays from our institutional cohort of stage I endometrial cancer patients. Results Univariate analysis revealed that NRG3, PEA15, DNAJB1, BAK1, DRAM1, KLHL24, ATF6, CDKN2A, MBTPS2, and UVRAG were significantly associated with survival outcomes in early-stage endometrial carcinoma patients. Multivariate analysis established PEA15 as an independent prognostic factor. Immunohistochemical analysis of tissue microarrays revealed that elevated PEA15 expression was significantly correlated with poorer overall survival and disease-free survival. Both univariate and multivariate Cox regression confirmed high PEA15 expression as an independent prognostic factor for recurrence in patients with stage I endometrioid adenocarcinoma. Conclusions The autophagy-related gene PEA15 is an independent prognostic biomarker in early-stage endometrial carcinoma, improving risk stratification between the MSI and CN-L subtypes. Immunohistochemical detection has clinical potential for molecular classification, offering opportunities for personalized postoperative management strategies.

LRP1B mutation is associated with lymph node metastasis in endometrial carcinoma: A clinical next-generation sequencing study

Background This study aims to investigate the mutation status and protein expression of low-density lipoprotein receptor-related protein 1B (LRP1B) in endometrial cancer, and analyze its association with lymph node metastasis (LNM) in endometrial cancer. Methods Targeted next-generation sequencing (NGS) was conducted on both tumor tissues and paired blood DNA obtained from 94 endometrial cancer patients, followed by comprehensive analysis. Additionally, immunohistochemistry (IHC) was used to explore the correlation between LRP1B protein expression levels, its gene mutation status, and LNM. Results LRP1B mutation was observed in 19 patients (20.2%). Our results revealed that LRP1B mutation frequencies were significantly different between endometrial cancer with or without LNM ( P  = 0.038). Multivariate analysis indicated that LRP1B mutation was a favorable predictor (odds ratio 0.09; 95% confidence interval 0.01–0.95; P  = 0.045) for LNM in endometrial cancer. Further analysis revealed that combination of LRP1B mutation with clinical variants (LVSI and histological subtype) yielded a higher area under the curve value of 0.871) and patients harboring LRP1B mutated-type were less likely to develop LNM. On integrated analysis, the concordance between LRP1B NGS and LRP1B IHC was 73.3%. Conclusions This study utilizes targeted NGS to uncover the relationship between LRP1B mutation and LNM status, contributing to the development of primary prevention and proactive treatment strategies.

Effects of coagulation function indicators and tumor markers on diagnosis and clinicopathological characteristics of endometrial cancer

Background Endometrial cancer is currently the prevalent malignant cancer worldwide. Diagnostic efficiency of tumor markers is limited, and coagulation function indicators in endometrial cancer are less concerned. Methods This study attempted to evaluate the effects of coagulation function indicators and tumor markers on the clinical diagnosis and clinicopathological characteristics of patients with endometrial cancer. The retrospective analysis compared the differences in coagulation function indicators and tumor markers among 175 patients with endometrial cancer and 170 healthy women from January 2020 to October 2022. Results Compared to the healthy control, the levels of D-dimer, fibrinogen, human epididymis protein 4 (HE4), carbohydrate antigen 125 (CA125), CA153, and CA199 in patients with endometrial cancer were significantly higher ( P < 0.05). Univariate and multivariate regression analyses revealed that abnormal levels of D-dimer, fibrinogen, HE4, CA125, CA153, and CA199 were related risk factors affecting the incidence of endometrial cancer. Receiver operating characteristic curve analysis exhibited that the area under the curve (0.931) and accuracy (85.2%) of combined diagnosis of coagulation function indicators (D-dimer, fibrinogen) and tumor markers (HE4, CA125, CA153, CA199) were the highest, and its sensitivity (82.3%) and specificity (88.2%) were higher than any single or combined indicators of four tumor markers. Moreover, relative expression levels of the combined indicators were significantly different among clinicopathological characteristics that had the highest predictive value in the FIGO stage ( P < 0.001). Conclusions D-dimer and fibrinogen represent potential diagnostic factors for endometrial cancer. The combination of coagulation function indicators and tumor markers exhibited high diagnostic value in endometrial cancer, as well as predictive value for clinicopathological characteristics.

Development and validation of a nomogram involving immunohistochemical markers for prediction of recurrence in early low-risk endometrial cancer

Background The purpose of this study was to construct a nomogram based on classical parameters and immunohistochemical markers to predict the recurrence of early low-risk endometrial cancer patients. Methods A total of 998 patients with early low-risk endometrial cancer who underwent primary surgical treatment were enrolled (668 in the training cohort, 330 in the validation cohort). Prognostic factors identified by univariate and multivariate analysis in the training cohort were used to construct the nomogram. Prediction performance of the nomogram was evaluated using the calibration curve, concordance index (C-index), and the time-dependent receiver operating characteristic curve. The cumulative incidence curve was used to describe the prognosis of patients in high-risk and low-risk groups divided by the optimal risk threshold of the model. Results In the training cohort, grade ( P = 0.040), estrogen receptor ( P < 0.001), progesterone receptor ( P = 0.001), P53 ( P = 0.004), and Ki67 ( P = 0.002) were identified as independent risk factors of recurrence of early low-risk endometrial cancer, and were used to establish the nomogram. The calibration curve showed that the fitting degree of the model was good. The C-indexes of training and validation cohorts were 0.862 and 0. 827, respectively. Based on the optimal risk threshold of the nomogram, patients were split into a high-risk group and a low-risk group. The cumulative incidence curves showed that the prognosis of the high-risk group was far worse than that of the low-risk group ( P < 0.001). Conclusion This nomogram, with a combination of classical parameters and immunohistochemical markers, can effectively predict recurrence in early low-risk endometrial cancer patients.

The predictive value of miR-29b-2-5p on the prognosis of cervical cancer and its inhibitory effect on cervical cancer progression

Objective The poor prognosis of cervical cancer patients leads to an annual increase in mortality, while microRNAs are involved in various cancers, including cervical cancer. This study aimed to investigate the clinical value and possible effect of miR-29b-2-5p on the progression of cervical cancer. Methods The expression level of miR-29b-2-5p in cervical cancer tissues and cells was analyzed by polymerase chain reaction. The Kaplan–Meier curve was used to evaluate the role of miR-29b-2-5p in cervical cancer prognosis. The independent prognostic factors of cervical cancer were explored by the multivariate Cox regression analysis. The effect of miR-29b-2-5p on the proliferation, migration, and invasion of cervical cancer cells was determined by in vitro cell experiments. Results A significantly downregulated miR-29b-2-5p expression was observed in cervical cancer tumor tissues and cervical cancer cells compared with the adjacent tumor tissues (tissues of the negative surgical margin) and H8 cells, respectively. Higher miR-29b-2-5p expression correlated with a better 5-year progression-free survival of cervical cancer. MiR-29b-2-5p was also associated with the indicators (tumor size, tumor differentiation, FIGO (International Federation of Gynecology and Obstetrics) stage, and invasion depth) of the progression of cervical cancer tumors. And miR-29b-2-5p, along with tumor size, tumor differentiation, FIGO stage, histology type, and invasion depth, were independent prognostic factors for poor cervical cancer prognosis. MiR-29b-2-5p showed a suppressive effect on the proliferation, migration, and invasion of cervical cancer cells. Conclusions MiR-29b-2-5p was downregulated in cervical cancer tumor tissues and could serve as an independent prognostic factor for cervical cancer. The overexpressed miR-29b-2-5p could be considered a tumor suppressor to inhibit the progression of cervical cancer.

A novel decision tree model based on chromosome imbalances in cell-free DNA and CA-125 in the differential diagnosis of ovarian cancer

Objective: CA-125 is widely used as biomarker of ovarian cancer. However, CA-125 suffers low accuracy. We developed a hybrid analytical model, the Ovarian Cancer Decision Tree (OCDT), employing a two-layer decision tree, which considers genetic alteration information from cell-free DNA along with CA-125 value to distinguish malignant tumors from benign tumors. Methods: We consider major copy number alterations at whole chromosome and chromosome-arm level as the main feature of our detection model. Fifty-eight patients diagnosed with malignant tumors, 66 with borderline tumors, and 10 with benign tumors were enrolled. Results: Genetic analysis revealed significant arm-level imbalances in most malignant tumors, especially in high-grade serous cancers in which 12 chromosome arms with significant aneuploidy ( P<0.01) were identified, including 7 arms with significant gains and 5 with significant losses. The area under receiver operating characteristic curve (AUC) was 0.8985 for copy number variations analysis, compared to 0.8751 of CA125. The OCDT was generated with a cancerous score (CScore) threshold of 5.18 for the first level, and a CA-125 value of 103.1 for the second level. Our most optimized OCDT model achieved an AUC of 0.975. Conclusions: The results suggested that genetic variations extracted from cfDNA can be combined with CA-125, and together improved the differential diagnosis of malignant from benign ovarian tumors. The model would aid in the pre-operative assessment of women with adnexal masses. Future clinical trials need to be conducted to further evaluate the value of CScore in clinical settings and search for the optimal threshold for malignancy detection.

SOX2 as a prognostic marker and a potential molecular target in cervical cancer: A meta-analysis

Background Sex determining region Y-box 2 (SOX2) has been reported as a potential therapeutic target for cancer. However, the role of SOX2 in cervical cancer remains largely undetermined. This study was performed to evaluate the correlation of SOX2 with clinical characteristics and prognosis in cervical cancer. Methods Multiple databases were systematically searched for eligible publications. The combined odds ratios (ORs) or hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs) were used to assess the effect sizes. Results A total of 17 studies with 1906 participants were identified. SOX2 expression was higher in cervical cancer than in the normal control group (OR = 10.83, 95% CI = 6.64–17.67, P < 0.001), while no significant difference was observed between cervical cancer and cervical intraepithelial neoplasia. SOX2 expression was not associated with age, tumor stage, and lymph node metastasis, but was correlated with tumor grade (grade 2–3 vs. grade 1: OR = 4.59, 95% CI = 2.76–7.62, P < 0.001) and tumor size (≥4 cm vs. ≤4 cm: OR = 1.66, 95% CI = 1.05–2.60, P = 0.028). Based on multivariate Cox analysis, SOX2 expression was not correlated with overall survival, but was closely associated with poor recurrence-free survival (HR = 5.83, 95% CI = 1.35–25.16, P = 0.018) and progress-free survival HR = 2.29, 95% CI = 1.01–5.19, P = 0.046). Conclusion SOX2 may serve as a novel prognostic factor and a promising molecular target for cervical cancer.

Signature involved in immune-related lncRNA pairs for predicting the immune landscape of cervical cancer

Background Immune-related long non-coding RNAs (irlncRNAs) are known to hold great promise as superior biomarkers for cervical cancer-related immunotherapeutic response and the tumor immune microenvironment. Here, we constructed a prognostic signature based on irlncRNA pairs (IRLPs). Methods The samples were downloaded from The Cancer Genome Atlas and the Genotype-Tissue Expression databases. The least absolute shrinkage and selection operator Cox regression was performed to construct the prognostic model. Receiver operating characteristic (ROC) curve and nomogram were plotted to validate accuracy of the model. Next, we estimated the immune cell infiltration and the correlation between risk score and the expression of genes related to immune checkpoint. Finally, we calculated the score of the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and the half maximal inhibitory concentration of the chemotherapeutic agent to evaluate the response to immunotherapy and chemotherapy. Results We constructed a prognostic signature that consisted of 11 irlncRNAs. The area under the curve values of the 1-, 3-, and 5-year ROC curves were 0.844, 0.891, and 0.871, respectively. The expression of CTLA-4, HAVCR2, IDO1, LAG3, and PDCD1 were negatively correlated with risk scores. The score of TIDE in the high-risk group was significantly higher than in the low-risk group ( P < 0.01). Patients in the low-risk subgroup were more sensitive to chemotherapeutic agents, such as axitinib and docetaxel, whereas patients in the low-risk subgroup were more sensitive to mitomycin C. Conclusion Our study highlighted the value of the 11 IRLPs signatures to predict the prognosis and the response to immunotherapy and chemotherapeutics for patients with cervical cancer.

Identifying tumor markers-stratified subtypes (CA-125/CA19-9/carcinoembryonic antigen) in cervical adenocarcinoma

Objective There is a lack of research evaluating the effect of tumor markers for prognosis in cervical adenocarcinoma. We aimed to develop and validate a preoperative tumor-marker-based model including clinicopathological factors to clarify the prognostic value of endocervical adenocarcinoma. Methods A total of 572 patients with cervical adenocarcinoma who were staged at the International Federation of Gynecology and Obstetrics (FIGO) IA–IIA were reviewed retrospectively. Preoperative serum carcinoembryonic antigen (CEA), carbohydrate antigen (CA)-125 and CA19-9 levels were measured. The survival and recurrence patterns were analyzed according to the tumor-marker-related stratification. The predictive values of biomarkers and clinical variables were assessed with Cox regression and competing risk models. Results Patients with elevated preoperative tumor markers had evidently poor overall survival and recurrence-free survival. The triple-elevated tumor marker (TETM) subgroup had the worst overall survival and progression-free survival than the triple-negative tumor marker (TNTM) subgroup and the single-elevated tumor marker (SETM) subgroup. The most important predictors for overall survival were elevated tumor markers, FIGO-stage, tumor differentiation, lymphovascular space invasion (LVSI) and lymph nodes metastasis. The most important predictors for recurrence-free survival were elevated tumor markers, FIGO-stage, tumor differentiation, LVSI and deep stromal invasion. Stratified analysis showed that elevated CA-125 and CA19-9 were significantly associated with postoperative distant metastasis. A decision curve analysis confirmed that a combination of tumor markers as predictors significantly outperformed the other common predictors used (FIGO-stage, intermediate and high-risk factors, tumor differentiation, lymph nodes). Conclusions Elevated preoperative serum CEA, CA-125, and CA19-9 levels exhibited poor overall survival and recurrence-free survival in cervical adenocarcinoma patients. Combined preoperative serum CA-125 and CA19-9 independently predicted distant metastasis in patients with endocervical adenocarcinoma.

ERCC1 expression and platinum chemosensitivity in patients with ovarian cancer: A meta-analysis

Objective: This study aimed to comprehensively investigate the correlation of ERCC1 expression and chemosensitivity of ovarian cancer. Methods: The literature on the relationship between the excision repair cross complementary gene 1 (ERCC1) and the chemosensitivity of ovarian cancer published in PubMed, Web of Science, EMBASE, CNKI, and the China Wanfang database from the establishment of the databases to June 2020 were searched. Chemosensitivity is evaluated by clinical effective rate (complete remission plus partial remission). Statistical analysis was carried out by using Stata 15.1 software. Results: A total of 11 articles met the inclusion criteria, consisting of 758 patients with ovarian cancer. The results showed a significant difference in chemosensitivity between the low expression group and the high expression group of ERCC1 (odds ratio 4.23; 95% confidence interval 2.96, 6.06; P < 0. 01). The same result was shown in the ethnicity subgroup. Conclusion: The chemosensitivity of ovarian cancer patients with a low expression of ERCC1 is better than that of patients with a high expression.

COL5A1 overexpression correlates with poor prognosis in human cervical cancer

Background Cervical cancer is the most prevalent malignant tumor in women. This study aims to detect collagen type V α1 chain (COL5A1) expression and its clinical relevance in the prognosis of patients with cervical cancer. Methods Cervical cancer tissues and their paired adjacent normal tissues were prepared for tissue microarray. The expression of COL5A1 protein and the scores of the expression were evaluated by immunohistochemistry (IHC) staining. The prognostic value of COL5A1 was analyzed by R software version 4.2.1 with “survival, survminer, ggplot2” packages and Gene Expression Profiling Interactive Analysis (GEPIA). The cBioPortal database was utilized for the analysis of COL5A1 gene mutations. Results COL5A1 protein was overexpressed in human cervical cancer tissues compared to their paired adjacent normal tissues detected by IHC ( P < 0.001). High expression of COL5A1 tends to be in elderly patients with cervical cancer. Survival analyses of clinical data of patients with cervical cancer showed that a high level of COL5A1 expression was significantly correlated with shorter overall survival ( P = 0.031) and disease-free survival ( P = 0.042) of patients. Further analyses of The Cancer Genome Atlas-Cervical Squamous Cell Carcinoma and the GEPIA survival datasets confirmed the association of high COL5A1 expression with poor overall survival of patients ( P = 0.040 and P = 0.018, respectively). The analysis of genomic alterations of COL5A1 using the cBioPortal tool revealed that the COL5A1 gene was altered in 4% of cervical cancer patients and COL5A1 corresponding protein alterations with post-translational modifications were hydroxylation. Conclusion COL5A1 is a tissue biomarker correlated with the poor prognosis of patients with cervical cancer, which may lead to a new clinical application.

Immune checkpoints as potential theragnostic biomarkers for epithelial ovarian cancer

Background Epithelial ovarian cancer (EOC) is the leading cause of death associated with gynecologic tumors. EOC is asymptomatic in early stages, so most patients are not diagnosed until late stages, highlighting the need to develop new diagnostic biomarkers. Mediators of the tumoral microenvironment may influence EOC progression and resistance to treatment. Aim To analyze immune checkpoints to evaluate them as theranostic biomarkers for EOC. Patients and methods Serum levels of 16 immune checkpoints were determined in EOC patients and healthy controls using the MILLIPLEX MAP® Human Immuno-Oncology Checkpoint Protein Magnetic Bead Panel. Results Seven receptors: BTLA, CD40, CD80/B7-1, GITRL, LAG-3, TIM-3, TLR-2 are differentially expressed between EOC and healthy controls. Serum levels of immune checkpoints in EOC patients are positively significantly correlated with levels of their ligands, with a higher significant correlation between CD80 and CTLA4 than between CD28 and CD80. Four receptors, CD40, HVEM, PD-1, and PD-L1, are positively associated with the development of resistance to Taxol-platinum-based chemotherapy. All of them have an acceptable area under the curve (>0.7). Conclusion This study has yielded a first panel of seven immune checkpoints (BTLA, CD40, CD80/B7-1, GITRL, LAG-3, TIM-3, TLR-2) associated with a higher risk of EOC and a second panel of four immune checkpoints (CD40, HVEM, PD-1, PD-L1) that may help physicians to identify EOC patients who are at high risk of developing resistance to EOC chemotherapy.

Prognostic and predictive value of combined HE-4 and CA-125 biomarkers during chemotherapy in patients with epithelial ovarian cancer

Introduction: At present there is no predictive value univocally associated with the success of chemotherapy. Biomarkers produced by ovarian cancer (HE4 and Ca125) could have a good prognostic significance. The aim of this study is to prove the ability of biomarkers to identify patients with the highest risk of non-optimal response during the chemotherapy, and to predict which patients will most likely develop recurrence of disease. Methods: We analyzed 78 patients with epithelial ovarian cancers who underwent surgery in the biennium 2016–2017. All the patients underwent chemotherapy after surgery or interval debulking surgery following neoadjuvant therapy. Serum levels of HE4 and Ca125 were measured at diagnosis and at each cycle of chemotherapy. We established the degree of response to the treatment by computed tomography scan, and the patients were followed up (median: 10 months). The parameters of progression-free survival and disease-free survival were related to serum levels of biomarkers. Results: Both CA125 and HE4 values became negative at the fourth cycle in the patients with good response to chemotherapy. HE4 increased earlier than Ca125. The parameters that best correlated with a long progression-free survival were: negativization of the marker after the third cycle of chemotherapy (HE4: odds ratio (OR) 5.5; Ca125: OR 9.1) and biomarker serum levels lower than the mean value in the affected population at the time of diagnosis (HE4: OR 3.4; Ca125: OR 3.7). Conclusions: We can conclude that the monitoring of HE4 and Ca125 during chemotherapy, especially at the third cycle, is recommended, because their variation is a good prognostic factor.

Diagnostic and prognostic values of MMP-9 expression in ovarian cancer: A study based on bioinformatics analysis and meta-analysis

This study aims to explore the expression of matrix metalloproteinase-9 (MMP-9) associated with both diagnostic and prognostic value in ovarian cancer by meta-analysis and bioinformatics analyses. We investigated the prognostic value of MMP-9 expression in ovarian cancer based on The Cancer Genome Atlas. Five databases were used to collect records about MMP-9 expression related to diagnostic and prognostic values in ovarian cancer from inception to June 2022. Using Stata 15.0 software, hazard ratio (HR) and odds ratio (OR) were calculated as the effect index of prognosis. We chose the pooled sensitivity, specificity, and area under the curve (AUC) to judge the diagnostic utility of MMP-9 for ovarian cancer. A total of 23 studies on prognosis, and five studies on diagnosis were entered into the meta-analysis. These suggest that high MMP-9 expression was detrimental to the overall survival of patients with ovarian cancer (HR = 1.34; 95% confidence interval (CI) 1.08∼1.66; P<0.01). High MMP-9 expression increased the risk of tumor stage (OR = 3.66; 95% CI 1.89∼7.07), but was not related to the tumor grade of ovarian cancer ( P>0.05). The pooled analysis of serum MMP-9 diagnosing for ovarian cancer gave the pooled sensitivity, specificity, and AUC the values of 0.72 (95% CI 0.61∼0.81), 0.81 (95% CI 0.77∼0.85), and 0.84 (95% CI 0.81∼0.87), respectively. High MMP-9 expression can increase the tumor stage, and a correlation exists between high MMP-9 expression and poor prognosis in patients with ovarian cancer. Also, serum MMP-9 has a good diagnostic value for ovarian cancer.

Diagnostic Value of Albumin to Fibrinogen Ratio in Cervical Cancer

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

Immunoscore system combining CD8 and PD-1/PD-L1: A novel approach that predicts the clinical outcomes for cervical cancer

Purpose: Immunoscore was established to evaluate the prognosis of cancer patients. However, the feasibility of Immunoscore for the prognosis of cervical cancer remains unknown. To find other prognostic markers that contribute to immunological importance, immune checkpoint inhibitors targeting programmed cell death protein (PD-1), or its ligand, PD-L1, are of enormous interest. Our purpose is to investigate the expression of CD8 and PD-1/PD-L1 and their potential role in Immunoscore, supplementing the tumor/node/metastasis (TNM) classification of cervical cancer. Methods: Immunoscore was assessed according to the density of PD-1, PD-L1, and CD8 by immunohistochemistry. The association with overall survival and disease-free survival was assessed by the Kaplan–Meier method. To evaluate the effect of Immunoscore, a Cox proportional hazard regression classification was conducted. To compare the prognostic accuracies of Immunoscore and TNM staging, receiver operating characteristic curves were plotted. Results: Patients with PD-L1positive and PD-1high in immune cells had poorer overall survival and disease-free survival; however, PD-L1positive in tumor cells that infiltrated more CD8+ T cells were related to better overall survival and disease-free survival. These immune factors can be independent predictors for prognoses. According to these factors, a new Immunoscore system with priority in predicting prognoses was established. In receiver operating characteristic analysis for predictions of overall survival (the area under curve (AUC) = 0.833 vs. 0.766) and disease-free survival (AUC = 0.861 vs. 0.729), Immunoscore is more accurate than TNM staging. Conclusions: Thus, this Immunoscore system is an accurate predictive marker, which can be an important supplement to TNM staging for cervical cancer.