The International Journal of Biological Markers

Preoperative estimation of microvascular invasion is of great significance for the clinical decision making in hepatocellular carcinoma. Neutrophil-lymphocyte ratio (NLR) has been reported to be correlated with the poor prognosis of hepatocellular carcinoma. However, the conclusions are conflicting on whether high preoperative NLR level is associated with the presence of microvascular invasion.

To evaluate the association between preoperative NLR level and the risk of microvascular invasion in hepatocellular carcinoma.

Relevant studies were identified by searching PubMed and Embase through February 2019. Fixed or random models were applied to analyze the data based on the heterogeneity. Subgroup, sensitivity, and publication bias analyses were performed. Review Manager 5.3 and STATA software were used for the meta-analysis.

A total of 15 studies were eventually included in this meta-analysis. Pooled data based on retrospective cohort studies showed there are more hepatocellular carcinoma patients with vascular invasion (OR 1.74; 95% Cl 1.42, 2.12; P < 0.001) and microvascular invasion (OR 1.62 95% Cl 1.39, 1.89; P < 0.001) in the high NLR group than in the low NLR group. Of case-control studies, a higher preoperative NLR level was found in the microvascular invasion positive group than in the microvascular invasion negative group (OR 0.62; 95% Cl 0.35, 0.90; P < 0.001). The subgroup, sensitivity, and publication bias analyses did not change the results.

A higher preoperative NLR level is positively correlated with the risk of microvascular invasion in hepatocellular carcinoma.

Salivary proteomic analysis has been extensively used in a wide range of cancer, but not in hepatocellular carcinoma. The aim of this study was to identify potential salivary biomarkers for hepatocellular carcinoma clinical screening.

In this study, we performed isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics analysis to detect differentially expressed proteins between saliva samples from 15 hepatocellular carcinoma patients and 15 healthy controls. Enzyme-linked immunosorbent assay (ELISA) verification was undertaken in saliva samples from 14 hepatocellular carcinoma patients and 14 healthy controls.

Overall, 133 proteins with significant differential expression level (ratio > 1.5 or < 0.67) were detected. Using bioinformatic analysis, two candidate proteins were selected and subsequently verified by ELISA. The increased expression of superoxide dismutase 2, mitochondrial (SOD2) in hepatocellular carcinoma patients was confirmed by ELISA, with an area under the curve value of 0.9082.

iTRAQ-based quantitative proteomics revealed that SOD2 might serve as a potential salivary biomarker for hepatocellular carcinoma detection. Our results indicated that a noninvasive and inexpensive salivary test might be established for hepatocellular carcinoma detection.

Since the diagnostic value of microRNAs for detecting glioma is contentious, we aimed to carry out a meta-analysis to synthetically evaluate the diagnostic significance of cell-free microRNAs in cerebrospinal fluid and blood in the detection of glioma.

A systematic document retrieval of public databases was performed to obtain eligible studies. Specificity was applied to draw the summary receiver operator characteristic (SROC) curve against sensitivity, and the pooled diagnostic efficiency was assessed by generating the area under the SROC curve. Meta-regression and subgroup analyses were utilized to explore the latent sources of heterogeneity. STATA 12.0, RevMan 5.3 and Meta-DiSc 1.4 were used to conduct all statistical analyses.

A total of 47 studies from 20 articles comprising 2262 glioma patients and 1986 controls were included in our meta-analysis. Cell-free microRNAs exhibited relatively good diagnostic efficiency in glioma detection, with a sensitivity of 0.83, a specificity of 0.87, and an area under the curve of 0.91. Cell-free miR-21 performed best with pooled area under the curve of 0.88, followed by miR-125 and miR-222. Subgroup analyses and meta-regression indicated that there was substantial heterogeneity existing among the studies, which was in part caused by sample size, World Health Organization grade, reference gene, microRNA origin (extracellular vesicles or non-extracellular vesicle-based-microRNA), microRNA profiling (single- or multiple-microRNA), specimen types, and ethnicity.

Cell-free microRNAs in cerebrospinal fluid and blood may play an important role as promising non-invasive biomarkers in the early diagnosis of glioma. Further comprehensive forward-looking research is required to validate their clinical significance in glioma diagnosis.

Bone metastasis remains critical for advanced stage non-small cell lung cancer (NSCLC)—a disease that is challenging to manage. Urinary markers present opportunities for non-invasive testing.

Urine specimens were collected from patients prior to treatment. Urinary cell-free DNA was subsequently purified from these samples. To address the specificity of the test, driver mutations in epidermal growth factor receptor L858R and L861Q were analyzed. Clinical specificity was established by comparison with healthy volunteers. Regular monitoring was established during treatment with tyrosine kinase inhibitors. The overall survival of patients was correlated with changes in circulating tumor DNA (ctDNA).

Baseline clinical correlation of urinary ctDNA and matched tumor specimens achieved 89% concordance. The clinical specificity was 100%. The average background level of urinary ctDNA was 20.7 ng/mL. Comparing patients with and without bone metastasis, the latter had significantly lower baseline levels. During treatment, more pronounced decline in urinary ctDNA was observed in patients without bone metastasis. In our Kaplan–Meier estimator, we observed that patients with a more significant reduction in ctDNA had a better overall survival outcome.

Our study demonstrates clear benefits and allows better risk profiling for NSCLC patients with bone metastasis. The non-invasive specimen collection is attractive and complements existing cancer management tools.

The aim of the study was to evaluate the diagnostic value of soluble fragment of cytokeratin 19 (CYFRA21-1) tests in detecting non-small cell lung cancer (NSCLC), including squamous cell carcinoma, lung adenocarcinoma, and large cell carcinoma.

The relevant studies were identified from PubMed, Embase and the Cochrane Library before November 2018. Summary estimates for sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio of CYFRA21-1 tests for the diagnosis of NSCLC were calculated using the random effects model. A summary receiver operating characteristic (SROC) curve was used to assess the overall effectiveness of the test. Meta-DiSc 1.4 and Stata11.0 were applied to the statistical analysis. Publication bias was detected using Egger’s test.

A total of 22 studies consisting of 7910 NSCLC patients (squamous cell carcinoma/lung adenocarcinoma/large cell carcinoma) and 2630 benign lesions patients that met the inclusion criteria were included. The meta-analysis showed that CYFRA21-1 tests had a relatively high accuracy for squamous cell carcinoma detection and a lower accuracy for lung adenocarcinoma detection. The overall sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio of CYFRA21-1 tests for squamous cell carcinoma detection were 0.72 (95% confidence interval (CI) 0.70, 0.74), 0.94 (95% CI 0.92, 0.95), 9.73 (95% CI 7.06, 13.40), 0.37 (95% CI 0.29, 0.47), and 27.30 (95% CI 17.68, 42.16), respectively. The area under the SROC curve was 0.9171 (Q* = 0.8500). No publication bias was tested in the squamous cell carcinoma (P = 0.567) and lung adenocarcinoma (P = 0.378) groups.

CYFRA21-1 tests might be appropriate for detecting squamous cell carcinoma.

Aberrant expression of different tight junction proteins, including the junctional adhesion molecule-A (JAM-A), has been frequently reported in association with tumor progression of several malignancies. To our knowledge, this is the first study examining the clinical significance of JAM-A gene expression in epithelial ovarian cancer.

JAM-A expression levels in 44 epithelial ovarian cancer and 12 benign formalin-fixed paraffin-embedded samples were determined by reverse transcription quantitative polymerase chain reaction. Receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic and prognostic potential of JAM-A. Associations between JAM-A expression and clinicopathological characteristics of epithelial ovarian cancer were analyzed using Fisher’s exact test. The Kaplan–Meier method and univariate Cox regression analysis were used for the survival analysis. P ⩽ 0.05 was considered statistically significant.

ROC curve analyses showed that JAM-A gene expression exhibits both diagnostic and prognostic performance in epithelial ovarian cancer (area under the curve (AUC) 0.640, 95% confidence interval (CI) 0.488, 0.792, sensitivity 43.18%, specificity 100% and AUC 0.621, 95% CI 0.427, 0.816, sensitivity 52.63%, specificity 85%, respectively). JAM-A expression was significantly associated with International Federation of Gynecologists and Obstetricians (FIGO) stage (P =0.049) and the Kaplan–Meier method demonstrated that patients with high expression of JAM-A had significantly worse overall survival compared to patients with low JAM-A expression (P =0.004). Moreover, univariate Cox regression analysis showed that FIGO stage, peritoneal metastasis, residual tumor and JAM-A expression were significantly associated with reduced overall survival in epithelial ovarian cancer.

Our results indicate that high levels of JAM-A expression are associated with an advanced clinicopathological feature and may have diagnostic potential; also, it could be a predictor of poor overall survival in patients with epithelial ovarian cancer.

Several prognostic factors were proposed to improve early detection of recurrence after liver resection of metastases of colorectal cancer. Circulating tumor cell-related transcripts were evaluated in colorectal cancer patients with conflicting results. The aim of this study was to investigate usefulness of carcinoembryonic antigen CAM5, epidermal growth factor receptor, and ERCC1 transcripts in the bloodstream as predictive factors of recurrence in patients who underwent liver resection for metastases of colorectal cancer.

Peripheral blood was collected from 29 patients at the time of the colorectal cancer liver metastasis resection, and from 25 normal controls. Follow-up draws (FUDs) were also performed at 30 days, and 3 and 12 months since surgery. On each sample, carcinoembryonic antigen CAM5, ERCC1, and GAPDH mRNAs were examined by quantitative reverse transcription (qRT).

Carcinoembryonic antigen transcript levels were linearly correlated to the number of spiked cells (qRT analytical limit = five cells). Among 29 patients (20 M/9 F; mean age 63 years (range 32–79), highly significant levels of carcinoembryonic antigen, if compared to the baseline, were detected in those relapsing after surgery (P <0.05). The main differences were between the 1st- and 12th-month FUDs. Significantly higher levels of carcinoembryonic antigen were also detected in patients who died from disease progression during the follow-up (as evaluated at 30 days and 90 days FUDs).

Blood carcinoembryonic antigen-mRNA absolute copy number overtime variation can represent a valid early predictor of relapse after liver resection in colorectal liver metastases patients. Prospective studies, in the context of large clinical trials, will provide further data to also qualify ERCC1 as a predictive biomarker for decisions on therapeutic strategies.

The aim of this study was to evaluate the clinicopathological significance and prognostic role of programmed death-1 ligand 2 (PD-L2) expression in colorectal cancer according to intratumoral components.

We used immunohistochemical analysis to investigate the impact of PD-L2 expression on clinicopathological characteristics and survival in 264 human colorectal cancer tissues. We also evaluated the correlation between PD-L2 expression and PD-L1 expression.

PD-L2 was expressed in 17.4% of the tumors (T-PD-L2) and in 19.3% of the immune cells (I-PD-L2) of the 264 CRC tissues. I-PD-L2 expression was significantly correlated with favorable tumor behaviors, including lower pathologic tumor stage, less lymph node metastasis, less distant metastasis, and lower pathologic tumor node metastasis stage. There was no significant correlation between I-PD-L2 expression and T-PD-L2 expression (P = 0.091). However, I-PD-L2 expression was correlated with PD-L1 expression in the immune cells (P < 0.001). There was also a significant correlation between high Immunoscore and I-PD-L2, but not T-PD-L2 (P < 0.001 and P = 0.190, respectively). The prognosis was better for patients who expressed I-PD-L2 than for patients who did not. In patients who expressed I-PD-L2, there was a significant difference in the survival rate between subgroups according to the presence or absence of T-PD-L2 expression.

Our results suggest that I-PD-L2 expression is significantly correlated with favorable tumor behaviors and better survival rates. There is also a significant correlation between PD-L2 expression and PD-L1 expression in immune cells.

Aberrant expression of circular RNAs (circRNAs) is implicated in tumorigenesis and disease progression. However, the underlying molecular mechanisms and physiological functions of hsa_circ_0005075 in human colorectal cancer are still poorly understood.

Quantitative real-time PCR (qRT-PCR) was performed to detect the expression level of hsa_circ_0005075 in colorectal cancer. Correlations of hsa_circ_0005075 expression with pathological parameters and overall survival were assessed. CCK-8 and Transwell invasion assays were utilized to determine the effect of hsa_circ_0005075 on proliferation and invasion of colorectal cancer cells.

Hsa_circ_0005075 was overexpressed in colorectal cancer tissues compared with paracancerous tissues and intestinal polyps. Its expression level was associated with distal metastasis, invasion, tumor node metastasis stage, and tumor diameter in colorectal cancer, and was negatively correlated with overall survival of patients with colorectal cancer. Moreover, enforced expression of hsa_circ_0005075 potentiated the proliferation and invasive behavior of colorectal cancer cells.

Our findings suggested that hsa_circ_0005075 expression was increased in colorectal cancer and might serve as a promising diagnostic mark and therapy target of colorectal cancer.

Tissue inhibitor of metalloproteinases 1 (TIMP-1) and matrix metalloproteinase 7 (MMP-7) were reported to have potent growth promoting activity. Lack of balance between MMPs and TIMPs is an important factor in the development of gastrointestinal malignancies.

We collected serum samples from 97 patients with metastatic colorectal cancer and 79 samples from healthy controls. Serum levels of TIMP-1 and MMP-7 were measured immunochemically and compared with standard tumor markers carcinoembryonic antigen and CA19-9.

Serum levels of TIMP-1 and MMP-7 were significantly higher in patients with colorectal cancer compared to healthy controls (both, P < 0.001). TIMP-1 and MMP-7 correlate with the presence of colon involvement (P = 0.001; P = 0.012) and the presence of liver metastases (P = 0.002; P = 0.037), and negatively correlate with pulmonary metastases (P = 0.014; P = 0.005). MMP-7 had similar sensitivity and the same specificity as carcinoembryonic antigen. TIMP-1 and MMP-7 had better sensitivity than CA19-9. TIMP-1 and MMP-7 level correlate with worse outcome (P = 0.002).

The results indicate that TIMP-1 and MMP-7 are effective biomarkers in patients with metastatic colorectal cancer with good sensitivity. TIMP-1 and MMP-7 levels strongly correlate with the extent of liver disease and have prognostic value.

miR-142-3p has proved to be involved in tumorigenesis and the development of renal cell carcinoma. The present study aimed to explore the prognostic value of miR-142-3p.

Total RNA was extracted from renal cell carcinoma specimens and the expression level of miR-142-3p was measured. Pearson Chi-square test, Kaplan–Meier analysis, as well as univariate and multivariate regression analysis were performed to determine the correlation between miR-142-3p and the prognosis of renal cell carcinoma patients. Receiver operating characteristic curves were constructed to evaluate the predictive efficiency of miR-142-3p for the prognosis of renal cell carcinoma patients. Data from The Cancer Genome Atlas (TCGA) were utilized to validate our findings.

Our results demonstrated that upregulation of miR-142-3p was correlated with shorter overall survival (P=0.002) and was, in the meantime, an independent prognostic factor for renal cell carcinoma patients (P=0.002). The receiver operating characteristic curve combining miR-142-3p expression with tumor stage showed an area under the curve of 0.633 (95% confidence interval 0.563, 0.702). The result of TCGA data was consistent with our findings.

Our results suggest miR-142-3p expression is correlated with poor prognosis of renal cell carcinoma patients and may serve as a prognostic biomarker in the future.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant tumors. The purpose of this study was to establish and validate a gene-expression-based prognostic signature in non-metastatic patients with HNSCC.

All the patients were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We randomly divided the GSE65858 samples into 70% (training cohort, n = 190) and 30% (internal validation cohort, n = 72). A total of 36 samples collected from the TCGA HNSCC databases were selected as an independent external validation cohort. The oligo package in R was used to normalize the raw data before analysis. Data characteristics were extracted, and a gene signature was built via the least absolute shrinkage and selection operator regression model. The predictive model was developed by multivariable Cox regression analysis. T stage, N stage, human papilloma virus status, and the gene signature were incorporated in this predictive model, which was shown as a nomogram. Calibration and discrimination were performed to assess the performance of the nomogram. The clinical utility of this nomogram was assessed by the decision curve analysis.

Overall, 2001 significant messenger RNAs in HNSCC samples were identified compared with normal samples. The gene signature contained seven genes and significantly correlated with overall survival. The gene signature was also significant in subgroup analysis of the primary cohort. The calibration was plotted in the external cohort (C-index 0.90, 95% CI 0.85, 0.95) compared with the training (C-index 0.76, 95% CI 0.73, 0.79) and internal (C-index 0.71, 95% CI 0.66, 0.77) cohorts. In clinic, a decision curve analysis demonstrated that the model including the prognostic gene signature score status was better than that without it.

This study developed and validated a predictive model, which can promote the individualized prediction of overall survival in non-metastatic patients with HNSCC.

The aim of this study is to investigate the effect of colchicine and other medications for gout treatment on serum CA72-4 and other tumor markers including alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), CA19-9, CYFRA21-1, neuron specific enolase (NSE), prostate-specific antigen (PSA).

A total of 143 gout patients and 40 healthy individuals were randomly recruited. Of these patients, 38 did not receive any treatment; 42 received colchicines; 62 received other medications for gout treatment (Etoricoxib, glucocorticoid, Benzbromarone, allopurinol, Febuxostat, nonsteroidal antiinflammatory drugs or their combinations). Of 42 gout patients receiving colchicines, 23 were followed up. All tumor markers were detected by electrochemiluminescence immunoassays. Statistical analysis was performed by SPSS 17.0 software.

The serum CA72-4 level was significantly higher in gout patients receiving colchicine than that in healthy control and gout patients without any treatment or who were receiving other treatments (P<0.001). There was no significant difference regarding other tumor markers among the various groups. All patients receiving colchicine, but no healthy individuals, patients with no treatment, or those receiving other medications had increased serum CA72-4 levels. Additionally, none or only a few of the subjects had increased AFP, CA19-9, CYFRA21-1, NSE, CEA, or PSA, while the proportion was not significantly different among various groups.

Colchicine can cause abnormal elevation of serum CA72-4, but other medications have no effect on serum CA72-4. Furthermore, serum CA72-4 gradually increased and decreased after the initiation and cessation of colchicine therapy, respectively. Other tumor markers are not influenced by colchicine and other medications.