Biological Markers

The prognostic value of Immunoscore in patients with cancer: A pooled analysis of 10,328 patients The International Journal of Biological Markers, Volume 35, Issue 3, Page 3-13, September 2020. Objectives:Over the past decade, some publications have reported that Immunoscore was associated with the prognosis of several cancers. To better understand this issue, we conducted this pooled analysis.Methods:We systematically searched PubMed, Embase, Web of Science, and the Cochrane Library from their inceptions to 15 May 2019 to identify relevant articles. The pooled hazard ratio (HR) and 95% confidence interval (CI) was estimated for overall survival, disease-free survival, and disease-specific survival.Results:A total of 26 cohort studies with 10,328 patients involving eight cancer specialties were evaluated mainly by the consensus Immunoscore. The pooled analysis indicated that a lower Immunoscore was associated with a poor overall survival (HR 2.23, 95% CI 1.58, 2.70), disease-free survival (HR 2.40, 95% CI 1.96, 2.49), and disease-specific survival (HR 2.81, 95% CI 2.10, 3.77) for all cancers. The same convincing results were found in colorectal cancer, gastric cancer, and non-small cell lung cancer (especially the consensus Immunoscore for colon cancer). In five other types of cancer the results were similar, but the sample sizes were limited.Conclusions:These findings support that Immunoscore is significantly associated with the prognosis of patients with cancer. It provides a reliable estimate of the risk of recurrence in patients with colon cancer. However, more high-quality studies are necessary to assess the prognostic value of Immunoscore in non-colon cancers.

The landscape of gene mutations and clinical significance of tumor mutation burden in patients with soft tissue sarcoma who underwent surgical resection and received conventional adjuvant therapy The International Journal of Biological Markers, Volume 35, Issue 3, Page 14-22, September 2020. BackgroundThe aim of this study was to evaluate the landscape of gene mutations and the clinical significance of tumor mutation burden (TMB) in patients with soft tissue sarcoma who underwent surgical resection and received conventional adjuvant therapy.MethodsA total of 68 patients with soft tissue sarcoma were included. Postoperative tumor tissue specimens from the patients were collected for DNA extraction. Targeted next-generation sequencing of cancer-relevant genes was performed for the detection of gene mutations and the analysis of TMB. Univariate analysis between TMB status and prognosis was carried out using the Kaplan–Meier survival analysis, and multivariate analysis was adjusted by the Cox regression model.ResultsNo specific genetic mutations associated with soft tissue sarcoma were found. The mutation frequency of TP53, PIK3C2G, NCOR1, and KRAS of the 68 patients with soft tissue sarcoma were observed in 19 cases (27.94%), 15 cases (22.06%), 14 cases (20.59%), and 14 cases (20.59%), respectively. With regard to the analysis of TMB, the overall TMB of the 68 patients with soft tissue sarcoma was relatively low (median: 2.05 per Mb (range: 0∼15.5 per Mb)). Subsequently, TMB status was divided into TMB-Low and TMB-Middle according to the median TMB. Patients with TMB-Low and TMB-Middle were 37 cases (54.41%) and 31 cases (45.59%), respectively. Overall survival analysis indicated that the median overall survival of patients with TMB-Low and TMB-Middle was not reached, and 4.5 years, respectively (P=0.015).ConclusionThis study characterizes the genetic background of patients with STS soft tissue sarcoma. The TMB was of clinical significance for patients with soft tissue sarcoma who underwent surgical resection and received conventional adjuvant therapy.

Analysis of risk factors for high postoperative D-dimer levels: A single-center nurse-observational study The International Journal of Biological Markers, Volume 35, Issue 3, Page 23-28, September 2020. BackgroundAs an elevated D-dimer level is directly proportional to the degrees of trauma and coagulation, it is often used to assess the severity of the trauma as well as the risk of thrombosis. This study aimed to investigate the risk factors for a high postoperative D-dimer level.MethodsA total of 623 patients undergoing radical mastectomy were included. The association between various clinicopathological factors and D-dimer variation was examined.ResultsAge, neoadjuvant chemotherapy, diabetes, and elevated neutrophil count were significant risk factors for D-dimer variation, after adjusting for other factors.ConclusionsThis study has identified the characteristics of patients who are likely to experience considerable postoperative increases in the D-dimer level. The development of effective nursing interventions for these patients is the focus of future studies.

Over-expression of long non-coding RNA ZEB2-AS1 may predict poor prognosis and promote the migration, invasion, and epithelial-mesenchymal transition of tumor cells in non-small cell lung cancer The International Journal of Biological Markers, Volume 35, Issue 3, Page 29-35, September 2020. Background:Non-small cell lung cancer (NSCLC) remains the most common cause of human cancer-related death worldwide, and the present study aims to explore the roles of long non-coding (lnc)RNA ZEB2-AS1 in NSCLC and the related mechanism.Methods:Quantitative real-time-polymerase chain reaction was performed to compare the expressions of ZEB2-AS1 in NSCLC cancer tissue and the adjacent non-tumorous tissues. The diagnostic and prognostic roles of ZEB2-AS1 in NSCLC were also evaluated by the receiver operating characteristic curve and the Kaplan–Meier survival analysis. NSCLC cell line A549 cells were transfected with ZEB2-AS1 siRNA, and the cell viability, migration, invasion, and epithelial-mesenchymal transition (EMT) of the ZEB2-AS1 siRNA group and control group were compared.Results:ZEB2-AS1 was significantly increased in NSCLC tissues. The knockdown of ZEB2-AS1 markedly inhibited the cell viability, migration, invasion, and EMT of A549 cells in vitro.Conclusion:ZEB2-AS1 was up-regulated in NSCLC, and it may serve as a potential target for the diagnosis, prognosis, and treatment of NSCLC.

Analysis of NTRK mutation and clinicopathologic factors in lung cancer patients in northeast China The International Journal of Biological Markers, Volume 35, Issue 3, Page 36-40, September 2020. Objective:NTRK mutations and clinicopathological factors in patients with lung cancer in northeast China were analyzed by next-generation sequencing (NGS), and references were provided for patients with NTRK mutations undergoing targeted therapy in northeast China.Methods:A total of 224 specimens in 173 patients with lung cancer were collected. This included 51 patients with matched tissue and whole blood samples,133 tissue samples, 84 whole blood samples, and 7 pleural effusion samples. NGS (520 genes) was used to detected NTRK mutations and clinicopathologic factors.Results:NTRK mutation was detected in eight patients (8/173, 4.6%), including four NTRK missense mutations (4/173, 2.3%), two NTRK fusion gene mutations (2/173, 1.2%), and two NTRK copy number deletions (2/173, 1.2%). Among the eight patients with NTRK mutations, four were associated with lung cancer driver gene mutations (3/4 EGFR, 1/4ALK); NTRK in two patients was inconsistent in tissue and paired whole blood testing; NTRK missense mutation was detected in one patient, and NTRK copy number deletion was detected in the other; and NTRK wild type was detected in two patients. There was no correlation between NTRK mutation and clinicopathologic factors (including gender, age, pathological type, smoking status, metastasis site).Conclusion:NTRK mutation was only 4.6%, effective fusion gene mutation was 1.2%, and common driver gene mutation in lung cancer was evident in 50% of patients. The results of NTRK were inconsistent with matched tissues and whole blood. Therefore, patients with NTRK mutation should use a variety of specimen types and large target area sequencing (panel) analysis method to provide individualized treatment.

Significance of "de novo" appearance of thyroglobulin antibodies in patients with differentiated thyroid cancer The International Journal of Biological Markers, Volume 35, Issue 3, Page 41-49, September 2020. ObjectiveClinical and laboratory guidelines recommend thyroglobulin antibodies (TgAbs) measurement with every thyroglobulin (Tg) measurement for the follow-up of differentiated thyroid cancer (DTC) patients. However, no evidence exists on the need for perpetual TgAbs testing in patients who are TgAb-negative at baseline. Our study was carried out to evaluate the prevalence, the dynamic changes, and the clinical significance of TgAbs that appeared de novo during the follow-up of DTC patients who were TgAb-negative at baseline.MethodsThe data of DTC patients with negative pre-ablation TgAbs were reviewed retrospectively. The main characteristics of patients with both transient and sustained de novo TgAbs appearance were analyzed. DTC patients with persistently negative TgAbs served as controls.ResultsAmong 119 patients with pre-ablation negative TgAbs, 14 cases (11.7%) with de novo TgAbs appearance (10 and 4 patients with a transient and sustained de novo TgAbs appearance, respectively) were detected. No differences in disease-free survival were observed in patients with de novo TgAbs appearance compared to controls. The TgAbs peak value was higher in patients with sustained de novo appearance compared to patients with transient de novo. Two of 14 patients with de novo TgAbs developed structural disease with concurrently detectable Tg in both cases.ConclusionsTransient de novo TgAbs appearance is not infrequent during DTC patients' follow-up, and it has no apparent clinical impact. Sustained de novo TgAbs appearance is rare and may predict structural recurrences; however, similar disease-free survival was observed in patients with sustained de novo TgAbs and TgAb-negative DTC patients.

PD-1 expression on uveal melanoma induces tumor proliferation and predicts poor patient survival The International Journal of Biological Markers, Volume 35, Issue 3, Page 50-58, September 2020. Introduction:Uveal melanoma is one of the most common primary intraocular malignant tumors with poor prognosis and limited treatments. Programmed cell death receptor-1 (PD-1) blockade represents the primary treatment strategy of immune checkpoint inhibition; however, there is a lack of studies on whether PD-1 expression in primary (ocular) uveal melanoma affects tumor progression.Methods:PD-1 expression in 82 cases of primary (ocular) uveal melanoma was detected by immunohistochemistry. The clinical significance of PD-1 expression was evaluated using univariate and multivariate analysis. PD-1 overexpression and knockdown studies were conducted in C918 and Mum-2B cell lines to analyze the effect of PD-1 expression on tumor cell proliferation and intracellular cell signaling transduction. real-time qPCR (RT-qPCR) and western blot analysis were performed to investigate the gene expression level. CCK8 assays were performed to examine the cell proliferation ability.Results:High expression of primary (ocular) intratumor PD-1 was associated with poor patient survival. Moreover, PD-1 expression was correlated with the largest tumor diameter. PD-1 expression and optic nerve invasion were independent prognostic risk factors. PD-1 overexpression in uveal melanoma cell lines promoted tumor cell proliferation, while knockdown of PD-1 inhibited cell proliferation capacity.Conclusion:Our study established the role of PD-1 in the progression of uveal melanoma and provided a new potential treatment selection for uveal melanoma.

Novel serum peptide model revealed by MALDI-TOF-MS and its diagnostic value in early bladder cancer The International Journal of Biological Markers, Volume 35, Issue 3, Page 59-66, September 2020. Background:Bladder cancer is the ninth most common cancer worldwide and has high morbidity and mortality. We aimed to search for potential serum peptide biomarkers and establish a diagnostic model for early bladder cancer.Methods:A total of 67 bladder cancer patients and 64 healthy volunteers were randomly divided into a training set and testing set 1. There were 30 hematuria patients used as testing set 2. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry based on weak cation exchange magnetic beads was used to obtain and analyze the serum peptide profiles between bladder cancer patients and healthy volunteers in the training set. Serum peptide diagnostic model through a k-nearest neighbor algorithm, was established and validated, and significantly differentially expressed protein biomarkers were ultimately identified.Results:We constructed a diagnostic model containing five peptides (m/z 1954.9, m/z 2081.0, m/z 3938.3, m/z 3946.5, and m/z 4268.8). In the training set, the area under the curve (AUC) value of the five-peptide model was 0.923, and the sensitivity and specificity was 93.75% and 96.77%, respectively. In testing set 1, the sensitivity and specificity was 91.43% and 90.91%, respectively, and the specificity of testing set 2 was 73.33%. For early-stage bladder cancer, the sensitivity and specificity was 92.31% and 93.75%, respectively; the sensitivity of early low-grade bladder cancer was 90.00%; and the AUC value was 0.944.Conclusion:The five-peptide diagnostic model established in this study had high sensitivity and specificity, especially in the diagnosis of early bladder cancer, and could differentiate between healthy volunteers and hematuria patients.

PIM-1 may function as an oncogene in cervical cancer via activating the EGFR signaling The International Journal of Biological Markers, Volume 35, Issue 3, Page 67-73, September 2020. Background:This work was designed to explore the roles of PIM-1 in the development of cervical cancer.Methods:There were 90 paired cervical tumor samples and the non-tumor adjacent tissue. The levels of PIM-1 in different samples were examined using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) methods. The potential diagnostic value of PIM-1 was analyzed by the receiver operating characteristic (ROC) curve; furthermore, the expression of EGFR in tumor samples was detected, and Pearson's correlation analysis was performed to analyze the relationship between the expression of PIM-1 and EGFR. Finally, cervical cancer cell line Hela cells were cultured and treated by PIM-1 siRNA, and MTT assay and Pi/Annexin V assay were performed to explore the effects of PIM-1 siRNA on the growth and apoptosis ability of the Hela cells.Results:PIM-1 was significantly up-regulated in cervical cancer tissue compared to adjacent tissue, and the expression of PIM-1 in patients with cervical cancer is positively associated with the size and metastasis of the tumor. ROC analysis showed PIM-1 is a sensitive biomarker for the diagnosis of cervical cancer. Furthermore, EGFR was over-expressed in cervical cancer tumor tissues, and the levels of PIM-1 and EGFR in cervical cancer tissue were positively correlated. Finally, PIM-1 siRNA dramatically inhibited the viability and promoted the apoptosis of the Hela cells.Conclusion:Our findings prove that PIM-1 may function as an oncogene in cervical cancer and can regulate the EGFR signaling in cervical cancer.

A three-miRNA panel in serum as a noninvasive biomarker for colorectal cancer detection The International Journal of Biological Markers, Volume 35, Issue 3, Page 74-82, September 2020. Background:Circulating miRNAs have been proved to be promising biomarkers for disease detection in recent years. The present study aimed at exploring available serum miRNA biomarkers for the detection of colorectal cancer.Methods:A three-phase study was performed to select and validate candidate miRNAs with significant dysregulation in colorectal cancer using quantitative reverse transcription-polymerase chain reaction. This study recruited 137 colorectal cancer patients and 145 healthy controls. The diagnostic values of miRNAs were evaluated by receiver operating characteristic analysis. Bioinformatics analyses were utilized to predict target genes of miRNAs, and to conduct functional annotation and enrichment.Results:miR-30e-3p, miR-31-5p, miR-34b-3p and miR-146a-5p, miR-148a-3p and miR-192-5p were significantly dysregulated in colorectal cancer serum when compared with healthy controls. The panel composed of miR-30e-3p, miR-146a-5p, and miR-148a-3p exhibited strong diagnostic ability. The area under the receiver operating characteristic curve of the three-miRNA panel was 0.883, with a sensitivity of 0.800 and specificity of 0.787.Conclusion:The present study identified a three-miRNA panel in serum with a strong diagnostic ability of colorectal cancer, which may be able to serve as a novel noninvasive biomarker for colorectal cancer detection.

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

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