ABSTRACT
Leptomeningeal metastasis (LM) is a devastating complication of advanced non-small cell lung cancer (NSCLC). Its diagnosis and monitoring can be challenging. Recently, extracellular vesicle (EV) miRNAs have become a new noninvasive diagnostic biomarker. The purpose of this study was to examine the clinical value and role of EV miRNAs in NSCLC-LM. Next-generation sequencing analysis revealed that miRNAs with differential expression of EVs in sera of patients with NSCLC with LM and non-LM were detected to identify biological markers for the diagnosis of LM. Cellular and in vivo experiments were conducted to explore the pathogenesis of EV miRNA promoting LM in NSCLC. In the present study, we first demonstrated that the serum level of EV-associated miR-374a-5p in patients with LM of lung cancer was much higher than that in patients without LM and was correlated with the survival time of patients with LM. Further studies showed that EV miR-374a-5p efficiently destroys tight junctions and the integrity of the cerebral microvascular endothelial cell barrier, resulting in increased blood-brain barrier permeability. Mechanistically, miR-374a-5p regulates the distribution of ZO1 and occludin in endothelial cells by targeting γ-adducin, increasing vascular permeability and promoting LM. Implications: These results suggest that serum NSCLC-derived EV miR-374a-5p is involved in premetastatic niche formation by regulating the permeability of the blood-brain barrier to promote NSCLC-LM and can be used as a blood biomarker for the diagnosis and prognosis of NSCLC-LM.
Subject(s)
Blood-Brain Barrier , Carcinoma, Non-Small-Cell Lung , Extracellular Vesicles , Lung Neoplasms , MicroRNAs , MicroRNAs/genetics , MicroRNAs/blood , MicroRNAs/metabolism , Humans , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/metabolism , Extracellular Vesicles/metabolism , Extracellular Vesicles/genetics , Blood-Brain Barrier/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/blood , Animals , Mice , Male , Female , Middle Aged , Cell Line, Tumor , Mice, Nude , Meningeal Neoplasms/genetics , Meningeal Neoplasms/secondary , Meningeal Neoplasms/blood , Meningeal Neoplasms/metabolism , PermeabilityABSTRACT
BACKGROUND: Blood transfusion necessity in neurosurgery varies based on surgical type, blood loss, and patient anemia. Leukocytes in red blood cells (RBCs) component release pro-inflammatory cytokines during storage, contributing to transfusion-related immunomodulation (TRIM). Our aim was to examine the impact of the leukocyte content in transfused PRBCs on patients undergoing neurosurgery for meningioma tumours. STUDY DESIGN AND METHODS: This prospective randomized controlled trial conducted from 2018 to 2020 by dividing patients randomly into non-leukoreduced (NLR) (n = 65) and leuko-reduced (LR) (n = 65) groups based on PRBCs received during surgery and hospital stay. Hospital and ICU stays, mechanical ventilation duration, and postoperative bacterial infections were observed. Hematological parameters and cytokine levels (IL-10, INF-gamma, and FAS-L) were assessed at pre-transfusion, 24 h, and 7 days post-transfusion. Data analysis included Mann-Whitney U test, Friedman test, Fisher's chi-square test, with statistical significance at p < 0.05. RESULTS: In our study, ICU and hospital stay duration showed no significant difference (p = 0.06) between groups. However, NLR group had longer mean mechanical ventilation (18 ± 40.1 h) than the LR group (12.8 ± 8.6 h). Both groups showed statistically significant increase in Fas-L level on days 1 and 7 (p < 0.05). The IL-10 levels rose 43% in the NLR group, while and decreased by 7% the LR group on day 1. On day 7, IL-10 increased by 75% in NLR and decreased by 40% in LR, with no significance (p > 0.05). CONCLUSION: In conclusion, leukoreduction appeared to offer some immune response protection in term of reducing mechanical ventilation timings and cytokine level changes.
Subject(s)
Meningioma , Humans , Female , Male , Middle Aged , Meningioma/immunology , Meningioma/therapy , Meningioma/blood , Prospective Studies , Aged , Adult , Immunomodulation , Meningeal Neoplasms/therapy , Meningeal Neoplasms/immunology , Meningeal Neoplasms/bloodABSTRACT
OBJECTIVE: Predicting the aggressiveness of meningiomas may influence the surgical strategy timing. Because of the paucity of robust markers, the systemic immune-inflammation (SII) index is a novel biomarker to be an independent predictor of poor prognosis in various cancers including gliomas. We aimed to investigate the value of SII as well as neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) indices in predicting prognosis. METHODS: Records including demographic, clinical, and laboratory data of patients operated on due to intracranial meningioma in 2017-2023 were retrospectively reviewed. RESULTS: A total of 234 patients were included in this study. All of SII index, NLR, and PLR values at presentation were significantly higher in grade ≥2 meningiomas. A positive correlation was observed between SII index and Ki67 index (r=0.313; P<0.001); between NLR and Ki67 index (r=0.330; P<0.001); and between PLR and Ki67 index (r=0.223; P<0.01). SII index (optimal cutoff level >618), NLR (optimal cutoff level >3.53), and PLR (optimal cutoff level >121.2) showed significant predictive values. CONCLUSIONS: This is the first study to assess the prognostic value of the SII index in patients with intracranial meningiomas. Increased SII index, NLR and PLR were correlated with higher grade and higher Ki-67 index. They also harbor the potential to screen patients that may need more aggressive treatments or more frequent follow-up examinations.
Subject(s)
Meningeal Neoplasms , Meningioma , Neoplasm Grading , Neutrophils , Humans , Meningioma/blood , Meningioma/pathology , Meningioma/surgery , Female , Male , Middle Aged , Meningeal Neoplasms/blood , Meningeal Neoplasms/pathology , Meningeal Neoplasms/surgery , Retrospective Studies , Adult , Aged , Neutrophils/pathology , Prognosis , Ki-67 Antigen/analysis , Ki-67 Antigen/metabolism , Lymphocytes/pathology , Platelet Count , Blood Platelets/pathology , Young Adult , Predictive Value of Tests , Lymphocyte Count , Aged, 80 and overABSTRACT
PURPOSE: Up to 30% of patients with glioblastoma (GBM) develop venous thromboembolism (VTE) over the course of the disease. Although not as high, the risk for VTE is also increased in patients with meningioma. Direct measurement of peak thrombin generation (TG) allows quantitative assessment of systemic coagulation activation in patients with GBM and meningioma. Our aim was to determine the extent of systemic coagulation activation induced by brain tumors, to measure the shift between pre- and post-operative peak TG in patients with GBM, and to assess the relationship between pre-surgical peak TG and pre-operative brain tumor volume on imaging. METHODS: Pre- and post-surgical plasma samples were obtained from successive patients with GBM and once from patients with meningioma and healthy age- and sex-matched blood donor controls. TG was measured using the calibrated automated thrombogram (CAT) assay, and tumor volumes were measured in pre-surgical MRI scans. RESULTS: Pre-surgical peak TG was higher in patients with GBM than in controls (288.6 ± 54.1 nM vs 187.1 ± 41.7 nM, respectively, P < 0.001), and, in the nine patients with GBM and paired data available, peak TG was significantly reduced after surgery (323 ± 38 nM vs 265 ± 52 nM, respectively, P = 0.007). Similarly, subjects with meningioma demonstrated higher peak TG compared to controls (242.2 ± 54.9 nM vs 177.7 ± 57.0 nM, respectively, P < 0.001). There was no association between peak TG and pre-operative tumor volume or overall survival. CONCLUSION: Our results indicate that systemic coagulation activation occurs with both meningioma and GBM, but to a greater degree in the latter. Preoperative peak TG did not correlate with tumor volume, but removal of GBM caused a significant decrease in coagulation activation.
Subject(s)
Blood Coagulation , Brain Neoplasms , Glioblastoma , Meningeal Neoplasms , Meningioma , Blood Coagulation/physiology , Brain Neoplasms/blood , Glioblastoma/blood , Humans , Meningeal Neoplasms/blood , Meningioma/bloodABSTRACT
BACKGROUND: Tumor markers (TM) in cerebrospinal fluid (CSF) are useful for diagnosing leptomeningeal metastasis (LM). It has not been fully exploited the diagnostic possibilities of the CSF levels since the basic fact that the TM concentration of CSF depends strongly upon the serum levels as well as upon the condition of the blood brain barrier (BBB). To analyze the intrathecal TM synthesis and evaluate the integrity of BBB can be helpful for the definitive diagnosis of LM. Therefore, the aim of this study was to further explore the clinical value of intrathecal TM synthesis and BBB in the diagnosis for the lung cancer patients with LM. METHODS: Twenty-five lung cancer patients with LM and 57 patients with nonmalignant neurological diseases (NMNDs) admitted to Nanjing Drum Tower Hospital from December 2016 to March 2020 were included. We compared the integrity of BBB and intrathecal TM synthesis between two groups, analyzed the correlation of CSF TM between the detection and intrathecal synthesis, and evaluated serial CSF cytology, the integrity of BBB and intrathecal TM synthesis when intrathecal chemotherapy for one patient. RESULTS: Ninety-four percent LM patients showed the dysfunction of BBB, and all LM patients showed at least one intrathecal synthesized TM in CSF. In one patient, the CSF cytology was negative for the first time, but LM was eventually diagnosed based on the the intrathecal TM synthesis and positive CSF cytology of repeated lumbar puncture. In LM group, no correlation was observed between the detection and intrathecal synthesized TM in CSF. In the control group, only 3.5% (2/57) NMNDs patients had the dysfunction of BBB and no patients had intrathecal TM synthesis, both the differences of which were statistically significant (P<0.05). Finally, evaluating the CSF cytology, integrity of BBB and intrathecal TM synthesis can be used to assess the intracranial treatment effect. Moreover, intrathecal TM synthesis changes earlier than cytology. CONCLUSIONS: The evaluation of intrathecal TM synthesis and integrity of BBB are novel clinical diagnostic tools. In addition, serial measurement of intrathecal synthesized TM may play an important role in monitoring efficacy of lung cancer patients with LM, which is worthy of further promotion and clinical application.
Subject(s)
Biomarkers, Tumor , Lung Neoplasms , Meningeal Neoplasms , Adult , Aged , Biomarkers, Tumor/blood , Biomarkers, Tumor/cerebrospinal fluid , Blood-Brain Barrier/physiopathology , Female , Humans , Lung Neoplasms/blood , Lung Neoplasms/cerebrospinal fluid , Lung Neoplasms/diagnosis , Lung Neoplasms/physiopathology , Male , Meningeal Carcinomatosis/blood , Meningeal Carcinomatosis/cerebrospinal fluid , Meningeal Carcinomatosis/physiopathology , Meningeal Carcinomatosis/secondary , Meningeal Neoplasms/blood , Meningeal Neoplasms/cerebrospinal fluid , Meningeal Neoplasms/physiopathology , Meningeal Neoplasms/secondary , Middle AgedABSTRACT
AIM: To measure serum levels of thrombospondin-1 (TSP-1) and thrombospondin-2 (TSP-2) in patients with common brain tumors, namely high-grade glioma (HGG), low-grade glioma (LGG), and meningioma. MATERIAL AND METHODS: For this prospective study, a total of 56 patients were operated on for supratentorial gliomas and meningiomas, and 18 healthy subjects were evaluated. Serum levels of angiostatic molecules were measured with enzyme-linked immunosorbent assay. The results of patients were compared with those of healthy subjects. RESULTS: High serum levels of TSP-1 were seen in HGG, followed by LGG, meningioma groups, and controls. The only significant difference was found between HGGs and controls (p=0.004). There was a trend to decrease from HGG to controls. High serum levels of TSP-2 were seen in controls, followed by meningioma, LGG, and HGG. None of the patient groups showed significant differences compared with controls. Among the patient groups, TSP-2 was significantly higher in the meningioma group than the HGG group (p=0.01). No correlation was found with any of the molecules and the clinical parameters, including the presence of peritumoral edema or seizure, the anterior-posterior diameter of the tumor, and, more importantly, the grade of glioma. CONCLUSION: Our results indicate that TSP-2 might be more important than TSP-1 in preventing angiogenesis and a major angiostatic factor in glioma cells.
Subject(s)
Brain Neoplasms/blood , Glioma/blood , Meningeal Neoplasms/blood , Meningioma/blood , Thrombospondin 1/blood , Thrombospondins/blood , Adult , Aged , Brain Neoplasms/pathology , Female , Glioma/pathology , Humans , Male , Meningeal Neoplasms/pathology , Meningioma/pathology , Middle Aged , Prospective StudiesABSTRACT
There is an unmet need for the identification of biomarkers to aid in the diagnosis, clinical management, prognosis and follow-up of meningiomas. There is currently no consensus on the optimum management of WHO grade II meningiomas. In this study, we identified the calcium binding extracellular matrix glycoprotein, Fibulin-2, via mass-spectrometry-based proteomics, assessed its expression in grade I and II meningiomas and explored its potential as a grade II biomarker. A total of 87 grade I and 91 grade II different meningioma cells, tissue and plasma samples were used for the various experimental techniques employed to assess Fibulin-2 expression. The tumours were reviewed and classified according to the 2016 edition of the Classification of the Tumours of the central nervous system (CNS). Mass spectrometry proteomic analysis identified Fibulin-2 as a differentially expressed protein between grade I and II meningioma cell cultures. Fibulin-2 levels were further evaluated in meningioma cells using Western blotting and Real-time Quantitative Polymerase Chain Reaction (RT-qPCR); in meningioma tissues via immunohistochemistry and RT-qPCR; and in plasma via Enzyme-Linked Immunosorbent Assay (ELISA). Proteomic analyses (p < 0.05), Western blotting (p < 0.05) and RT-qPCR (p < 0.01) confirmed significantly higher Fibulin-2 (FBLN2) expression levels in grade II meningiomas compared to grade I. Fibulin-2 blood plasma levels were also significantly higher in grade II meningioma patients compared to grade I patients. This study suggests that elevated Fibulin-2 might be a novel grade II meningioma biomarker, when differentiating them from the grade I tumours. The trend of Fibulin-2 expression observed in plasma may serve as a useful non-invasive biomarker.
Subject(s)
Biomarkers, Tumor/blood , Calcium-Binding Proteins/blood , Extracellular Matrix Proteins/blood , Meningeal Neoplasms/blood , Meningioma/blood , Adult , Aged , Aged, 80 and over , Female , Gene Expression Regulation, Neoplastic/genetics , Humans , Male , Meningeal Neoplasms/genetics , Meningeal Neoplasms/pathology , Meningioma/genetics , Meningioma/pathology , Middle Aged , Neoplasm Grading , Prognosis , ProteomicsABSTRACT
BACKGROUND AND OBJECTIVE: Meningiomas are among the most common intracranial tumors of the central nervous system. It is widely accepted that the initiation and progression of meningiomas involve the accumulation of nucleus genetic alterations, but little is known about the implication of mitochondrial genomic alterations during development of these tumors. The human mitochondrial DNA (mtDNA) contains a short hypervariable, noncoding displacement loop control region known as the D-Loop. Alterations in the mtDNA D-loop have been reported to occur in most types of human cancers. The purpose of this study was to assess the mtDNA D-loop mutations in Malaysian meningioma patients. MATERIALS AND METHODS: Genomic DNA was extracted from 21 fresh-frozen tumor tissues and blood samples of the same meningioma patients. The entire mtDNA D-loop region (positions 16024-576) was polymerase chain reaction amplified using designed primers, and then amplification products were purified before the direct DNA sequencing proceeds. RESULTS: Overall, 10 (47.6%) patients were detected to harbor a total of 27 somatic mtDNA D-loop mutations. Most of these mtDNA mutations were identified in the hypervariable segment II (40.7%), with 33.3% being located mainly in the conserved sequence block II of the D310 sequence. Furthermore, 58 different germline variations were observed at 21 nucleotide positions. CONCLUSION: Our results suggest that mtDNA alterations in the D-loop region may be an important and early event in developing meningioma. Further studies are needed, including validation in a larger patient cohort, to verify the clinicopathological outcomes of mtDNA mutation biomarkers in meningiomas.
Subject(s)
DNA, Mitochondrial/genetics , Meningeal Neoplasms/genetics , Meningioma/genetics , Adult , Aged , Base Sequence/genetics , Conserved Sequence/genetics , DNA Mutational Analysis , DNA Replication/genetics , Female , Humans , Male , Meningeal Neoplasms/blood , Meningeal Neoplasms/pathology , Meninges/pathology , Meningioma/blood , Meningioma/pathology , Middle Aged , Preliminary Data , Young AdultABSTRACT
BACKGROUND: Leptomeningeal metastasis (LM) are a severe complication of non-small cell lung cancer (NSCLC), and normally accompanied by poor prognosis. For the patients with targetable mutations, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the preferred treatment, but the acquired TKI resistance is inextricable. The aim of this study is to analyze the different gene mutation spectrum and mutation frequency of the cerebrospinal ï¬uid (CSF) and plasma in NSCLC patients with LM, and screen out the drug-resistant mutations so as to guide the choice of treatment accurately. METHODS: The paired CSF and plasma samples were collected from the NSCLC-LM patients with acquired TKI resistance. Next generation sequencing (NGS) was used to detect the gene variations of circulating tumor DNA (ctDNA). RESULTS: A total of 18 NSCLC patients with LM were collected. Of the basic mutations, 11 cases (61.11%) were EGFR, 6 cases (33.33%) were anaplastic lymphoma kinase (ALK), and 1 case (5.56%) was ROS proto-oncogene 1, receptor tyrosine kinase (ROS1). Tumor protein p53 gene (TP53) and mesenchymal-epithelial transition factor (MET) were the two most frequently accompanying mutated genes in CSF ctDNA. The detected mutation rate of CSF samples was higher than that of plasma samples (100.00% vs 66.67%, P=0.006), and the maximum allelic fractions were all higher in CSF than in plasma (P<0.001). Abundant single-nucleotide variations (SNV) and copy number variants (CNV) were detected in CSF, the amount of both of which were more than in blood. In addition, the CSF and plasma samples of patients treated with several TKIs had more SNV mutations than patients who received only a single TKI treatment. CONCLUSIONS: For the patients of NSCLC, ctDNA in CSF could reveal genomic alterations of LM more exactly and overally than it in plasma, thus could be an optimal source of liquid biopsy for guiding therapy, monitoring therapeutic effect, and predicting prognosis.
Subject(s)
Adenocarcinoma of Lung/complications , Adenocarcinoma of Lung/genetics , Carcinoma, Non-Small-Cell Lung/complications , Carcinoma, Non-Small-Cell Lung/genetics , Meningeal Neoplasms/secondary , Mutation/genetics , Adenocarcinoma of Lung/blood , Adenocarcinoma of Lung/cerebrospinal fluid , Adult , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/cerebrospinal fluid , DNA Copy Number Variations/genetics , Female , High-Throughput Nucleotide Sequencing , Humans , Male , Meningeal Neoplasms/blood , Meningeal Neoplasms/cerebrospinal fluid , Middle Aged , Proto-Oncogene MasABSTRACT
Liquid biopsy-based methods to test biomarkers (e.g., serum proteins and extracellular vesicles) may help to monitor brain tumors. In this proteomics-based study, we aimed to identify a characteristic protein fingerprint associated with central nervous system (CNS) tumors. Overall, 96 human serum samples were obtained from four patient groups, namely glioblastoma multiforme (GBM), non-small-cell lung cancer brain metastasis (BM), meningioma (M) and lumbar disc hernia patients (CTRL). After the isolation and characterization of small extracellular vesicles (sEVs) by nanoparticle tracking analysis (NTA) and atomic force microscopy (AFM), liquid chromatography -mass spectrometry (LC-MS) was performed on two different sample types (whole serum and serum sEVs). Statistical analyses (ratio, Cohen's d, receiver operating characteristic; ROC) were carried out to compare patient groups. To recognize differences between the two sample types, pairwise comparisons (Welch's test) and ingenuity pathway analysis (IPA) were performed. According to our knowledge, this is the first study that compares the proteome of whole serum and serum-derived sEVs. From the 311 proteins identified, 10 whole serum proteins and 17 sEV proteins showed the highest intergroup differences. Sixty-five proteins were significantly enriched in sEV samples, while 129 proteins were significantly depleted compared to whole serum. Based on principal component analysis (PCA) analyses, sEVs are more suitable to discriminate between the patient groups. Our results support that sEVs have greater potential to monitor CNS tumors, than whole serum.
Subject(s)
Biomarkers, Tumor/blood , Carcinoma, Non-Small-Cell Lung/blood , Extracellular Vesicles/metabolism , Lung Neoplasms/blood , Meningeal Neoplasms , Neoplasm Proteins/blood , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Meningeal Neoplasms/blood , Meningeal Neoplasms/secondary , Middle AgedABSTRACT
BACKGROUND: Meningiomas are the most common primary intracranial tumors in adults. They are initially detected with neuroimaging techniques, but definite histological diagnosis requires tumor surgery to collect tumor tissue. Gross total resection is an optimal and final treatment for the majority of patients, followed by radiotherapy in malignant or refractory cases. However, there are a lot of uncertainties about i.a. the need for intervention in incidental cases, estimation of growth kinetics, risk of malignant transformation, or response to radiotherapy. Therefore a new diagnostic approach is needed. It has already been shown that epigenetics plays a crucial role in cancer biology, development, and progression. DNA methylation, the presence of 5-methylcytosine in DNA, is one of the main elements of a broad epigenetic program in a eukaryotic cell, with superior regulatory significance. Therefore, we decided to look at meningioma through changes of 5-methylcytosine. METHODS: We performed an analysis of the total amount of 5-methylcytosine in DNA isolated from intracranial meningioma tissues and peripheral blood samples of the same patients. The separation and identification of radioactively labeled nucleotides were performed using thin-layer chromatography. RESULTS: We found that the 5-methylcytosine level in DNA from intracranial meningiomas is inversely proportional to the malignancy grade. The higher the tumor WHO grade is, the lower the total DNA methylation. The amount of 5-methylcytosine in tumor tissue and peripheral blood is almost identical. CONCLUSIONS: We conclude that the total DNA methylation can be a useful marker for brain meningioma detection, differentiation, and monitoring. It correlates with tumor WHO grade, and the 5-methylcytosine level in peripheral blood reflects that in tumor tissue. Therefore it's applicable for liquid biopsy. Our study creates a scope for further research on epigenetic mechanisms in neurooncology and can lead to the development of new diagnostic methods in clinical practice.
Subject(s)
5-Methylcytosine/metabolism , Biomarkers, Tumor/metabolism , DNA Methylation , Meningeal Neoplasms/diagnosis , Meningioma/diagnosis , 5-Methylcytosine/blood , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/blood , DNA/blood , DNA/metabolism , DNA Damage , Diagnosis, Differential , Epigenesis, Genetic , Female , Humans , Liquid Biopsy/methods , Male , Meningeal Neoplasms/blood , Meningeal Neoplasms/genetics , Meningeal Neoplasms/surgery , Meninges/pathology , Meninges/surgery , Meningioma/blood , Meningioma/genetics , Meningioma/surgery , Middle Aged , Young AdultABSTRACT
BACKGROUND: Meningioma and glioma are common central nervous system tumors. Hypoxic tumor cells secrete angiogenic cytokines, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) that stimulate neovascular formation and inflammatory cytokine, such as TNF-α and IL-1ß. We measured these serum levels in patients with glial cell tumors and meningioma. MATERIALS AND METHODS: This was a case-control study in 2014-2015 on patients diagnosed with meningioma/glioma. All demographic and clinical data were registered. The tumor volume and intraoperative bleeding were recorded. Serum levels of VEGF, PDGF, FGF, TNF-α and IL-1ß were measured by ELISA methods. RESULTS: Ninety-six patients were enrolled in this study, 32 in each group. Patients VEGF level with cranial tumor, glioma/meningioma had increased. VEGF level was highest among grade IV tumors, larger tumors, and in glioblastoma multiform. There was an upsurge in VEGF serum level as glioma grade increased. The highest VEGF levels were seen in parasagittal meningioma. In contrast to VEGF, PDGF was slightly elevated in glial cell tumors, which was significantly elevated in meningioma. Higher PDGF correlated with increased intraoperative bleeding, especially in meningioma cases. Oligodendroglial tumors expressed higher PDGF levels in contrast to other glial tumors. FGF level was not statistically significant. TNF-α and IL-1ß expressions were significantly higher in the meningioma and glioma group in comparison to control group. CONCLUSION: We found increased VEGF and PDGF serum levels in CNS patient's tumor. A different role for PDGF was found in the pathogenesis of neovascularization of meningioma, as well as oligodendroglioma. No significant result was found for FGF. TNF-α and IL-1ß can serve as key prognostic biomarker in high-grade glioma and meningioma patients.
Subject(s)
Fibroblast Growth Factors/blood , Glioma/blood , Interleukin-1beta/blood , Meningioma/blood , Platelet-Derived Growth Factor/analysis , Tumor Necrosis Factor-alpha/blood , Vascular Endothelial Growth Factor A/blood , Adult , Biomarkers, Tumor/blood , Case-Control Studies , Female , Follow-Up Studies , Glioma/epidemiology , Glioma/pathology , Humans , Iran/epidemiology , Male , Meningeal Neoplasms/blood , Meningeal Neoplasms/epidemiology , Meningeal Neoplasms/pathology , Meningioma/epidemiology , Meningioma/pathology , Middle Aged , PrognosisABSTRACT
BACKGROUND: Thyroid hormone (TH) metabolism can have prognostic significance in brain tumors. We studied the association of common variations in three deiodinase gene single-nucleotide polymorphisms (SNPs) with circulating TH concentrations and prognosis of brain tumor patients. METHODS: Patients admitted for glioma and meningioma surgery between January, 2010 and September, 2011 were evaluated for functional status (Barthel Index or BI) and circulating free tri-iodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) concentrations. Ten common SNPs in the DIO1 gene; five SNPs in the DIO2 gene; and one SNP in the DIO3 gene were genotyped. Follow-up continued until November, 2017. RESULTS: In glioblastoma patients, the DIO1 SNP rs2235544 CC genotype was associated with significantly lower risk of death at 2 years when compared to AA + CA genotypes after adjusting for patient gender, age, pre-operative functional status, adjuvant therapy, and extent of resection (HR = 0.34, 95% CI: 0.13-0.84, p = 0.019). The TT genotype vs. CC + TC genotypes of the DI02 SNP rs12885300 was associated with increased mortality risk after adjusting for patient gender, age, pre-operative functional status, adjuvant therapy, extent of resection, and FT3/FT4 (HR = 3.13, 95% CI: 1.20-8.16, p < 0.019). The C-allele of the DI01 SNP rs2235544 was related to increased circulating free T3/ free T4 ratio in glioma and meningioma patients, indicating greater T4 to T3 conversion. CONCLUSIONS: SNPs of DIO1 gene (rs2235544) and DIO2 gene (rs12885300) have independent prognostic significance in glioblastoma patients. The C-allele of the DIO1 (rs2235544) is associated with greater T4 to T3 conversion.
Subject(s)
Brain Neoplasms/genetics , Glioblastoma/genetics , Iodide Peroxidase/genetics , Meningeal Neoplasms/genetics , Meningioma/genetics , Thyroid Hormones/blood , Adult , Aged , Aged, 80 and over , Brain Neoplasms/blood , Brain Neoplasms/diagnosis , Brain Neoplasms/mortality , Female , Glioblastoma/blood , Glioblastoma/diagnosis , Glioblastoma/mortality , Humans , Lithuania/epidemiology , Male , Meningeal Neoplasms/blood , Meningeal Neoplasms/diagnosis , Meningeal Neoplasms/mortality , Meningioma/blood , Meningioma/diagnosis , Meningioma/mortality , Middle Aged , Polymorphism, Single Nucleotide , Prognosis , Prospective StudiesABSTRACT
PURPOSE: To compare the effectiveness of octreotide/everolimus vs. sunitinib for the systemic treatment of recurrent aggressive meningiomas. METHODS: 31 patients with recurrent or refractory WHO II or WHO III meningiomas were examined in two reference centers in Colombia. Patients who had systemic treatment (sunitinib, everolimus/octreotide) and a complete follow-up were included. Overall survival (OS), progression-free survival (PFS) and toxicities were evaluated. Additionally, tissue samples were examined for PDGFRß and VEGFR2, their expression was correlated with outcomes. RESULTS: Twenty-two patients (72%) were female with a median age of 55 years (SD±15.3). The most prevalent histology was anaplastic meningioma in 20 patients (65%) with 48% of patients suffering from three previous relapses before the start of systemic treatment. A total of 14 patients received combination therapy with octreotide/everolimus, 11 received sunitinib and the remaining 6 received other second-line agents. Median OS was 37.3 months (95%CI 28.5-42.1) and the PFS during the treatment with everolimus/octreotide (EO) and sunitinib (Su) was 12.1 months (95%CI 9.2-21.1) and 9.1 months (95%CI 6.8-16.8); p = 0.43), respectively. The OS of the group treated with the EOâSuâBev sequence (1st/2nd/3rd line) was 6.5 months longer than the SuâEOâBev sequence (36.0 vs. 29.5 months) (p = 0.0001). When analyzing molecular markers, the positive PDGFRß and negative VEGFR2 expression were associated with longer survival both in OS and PFS. CONCLUSION: Sunitinib and octreotide/everolimus have similar efficacy and safety in the systemic management of refractory meningioma. VEGFR2 and PDGFRß expression are associated with better outcomes.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Biomarkers, Tumor/blood , Gene Expression Regulation, Neoplastic/drug effects , Meningeal Neoplasms , Meningioma , Neoplasm Proteins/blood , Receptor, Platelet-Derived Growth Factor beta/blood , Vascular Endothelial Growth Factor Receptor-2/blood , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Everolimus/administration & dosage , Female , Follow-Up Studies , Humans , Male , Meningeal Neoplasms/blood , Meningeal Neoplasms/drug therapy , Meningeal Neoplasms/mortality , Meningioma/blood , Meningioma/drug therapy , Meningioma/mortality , Middle Aged , Octreotide/administration & dosage , Retrospective Studies , Sunitinib/administration & dosage , Survival RateABSTRACT
BACKGROUND: We sought to determine whether systemic inflammatory markers (SIMs) can be used to predict the pathological grade of meningioma before surgery. METHODS: Patients with histopathologically proven intracranial meningiomas who had undergone surgery from January 2014 to April 2018 were identified. The 14 most recent SIM levels measured before surgery were retrieved. The Mann-Whitney U test was used to determine the statistically significant differences between groups. Receiver operating characteristic curves were constructed, and the areas under the curve (AUC) were calculated to assess the diagnostic value of each biomarker. Predictive models built with biomarker pairs using logistic regression or support vector machine classifiers were used to assess their combined performance. RESULTS: A total of 672 patients with 575 and 97 low-grade and high-grade meningiomas, respectively, were investigated. Of the 14 SIMS, 7 differed significantly between the 2 meningioma groups. However, receiver operating characteristic analysis showed that none of these 7 SIMs alone could predict for the meningioma grade; the highest AUC was 0.61. Two biomarkers (erythrocyte and neutrophil/lymphocyte ratio) were incorporated into the logistic regression model; the corresponding AUC was 0.64. Moreover, 21 biomarker pairs were used to train the support vector machine classifiers; the AUCs of 6 pairs were >0.55; the maximum AUC was 0.60. CONCLUSIONS: SIMs obtained from routine preoperative laboratory testing had a limited ability to differentiate low- and high-grade meningioma in our cohort of 672 patients. Further prospective, multicenter studies with larger sample sizes are warranted to confirm this finding.
Subject(s)
Biomarkers, Tumor/blood , Inflammation Mediators/blood , Meningeal Neoplasms/blood , Meningioma/blood , Preoperative Care/methods , Adult , Female , Humans , Male , Meningeal Neoplasms/diagnosis , Meningeal Neoplasms/surgery , Meningioma/diagnosis , Meningioma/surgery , Middle Aged , Neoplasm Grading/methods , Predictive Value of Tests , Retrospective StudiesABSTRACT
Objective: Brain tumors are of high mortality and morbidity for which there is still no cure. The TNF family cytokine, A Proliferation Inducing Ligand (APRIL), is shown to help proliferation and development of tumor cells. We assessed serum levels of APRIL in patients with glioma, meningioma and schwannoma in comparison to healthy individuals. Methods: Peripheral blood samples of 68 patients with brain tumors, divided into three groups of gliomas (n=25), meningiomas (n=30) and schwannomas (n=13), as well as 45 healthy individuals were obtained. Serum samples were prepared and stored in -40°C until usage. Using a commercial ELISA method, APRIL concentration was measured in each serum sample. The obtained data were then analyzed using SPSS software. Results: APRIL serum levels were higher in all patients compared to the controls (P<0.001). Moreover, APRIL serum levels were higher in each of the tumor bearing groups (gliomas, meningiomas and schwannomas) in comparison to the controls (P<0.001, <0.001 and =0.001, respectively). Comparing APRIL between the patients groups showed no significant difference. Age and gender showed no significant correlation with serum APRIL levels, although the age of patients in glioma group was significantly lower than controls (P=0.017). The serum APRIL levels in gliomas with histological grade showed no difference, but in meningiomas, it was lower in tumors with higher grades (P= 0.011). Conclusion: Increased serum levels of APRIL in patients with meningioma and schwannoma as well as glioma may indicate a common role of this cytokine in brain tumors.
Subject(s)
Biomarkers, Tumor/blood , Brain Neoplasms/blood , Glioma/blood , Meningeal Neoplasms/blood , Meningioma/blood , Neurilemmoma/blood , Tumor Necrosis Factor Ligand Superfamily Member 13/blood , Adult , Brain Neoplasms/pathology , Case-Control Studies , Female , Follow-Up Studies , Glioma/pathology , Humans , Male , Meningeal Neoplasms/pathology , Meningioma/pathology , Middle Aged , Neurilemmoma/pathology , PrognosisABSTRACT
BACKGROUND: Post-operative pneumonia (Pop) following meningioma surgery is the dominant systemic complication which could cause serious threats to patients. It is unclear whether hematological biochemical markers are independently associated with the Pop. This study attempted to perform a more comprehensive study of taking both clinical factors and hematological biomarkers into account to promote the management of patients after meningioma surgery. METHODS: We collected clinical and hematological parameters of 1156 patients undergoing meningioma resection from January 2009 to January 2013. According to whether the symptoms of pneumonia had manifested,patients were divided into the Pop group and the Non-Pop group. We analyzed the distinctions of clinical factors between the two groups. We successively performed univariate and multivariate regression analysis to identify risk factors independently associated with the Pop. RESULTS: 4.4% patients infected with the Pop (51 of 1156). The median age at diagnosis of the Pop patients was significantly older than the Non-Pop group (p = 0.002). There were strike distinctions of post-operative hospital stays between two groups, with 21 days and 7 days each (p < 0.001). On multivariate analysis, tumor relapse (p < 0.001), skull base lesions (p = 0.001), intra-operative blood transfusion (p = 0.018) and cardiovascular diseases (p = 0.001) were linked with increased risk of the Pop following meningioma resection. For hematological biochemical markers, it was the factor of Red blood cell distribution width-standard deviation (RDW-SD) (OR 5.267, 95%CI 1.316, 21.078; p = 0.019) and Neutrophils lymphocytes ratio (NLR) (OR 2.081, 95%CI 1.063, 4.067; p = 0.033) that could appreciably predict the Pop. CONCLUSIONS: Apart from tumor recurrence, localizations, intra-operative blood transfusion and cardiovascular diseases are independent risk factors for the Pop. We initially found hematological RDW-SD and NLR are also important predictors.
Subject(s)
Meningeal Neoplasms/blood , Meningioma/blood , Pneumonia/epidemiology , Postoperative Complications/epidemiology , Adult , Aged , Biomarkers/blood , China/epidemiology , Erythrocyte Indices , Female , Humans , Leukocyte Count , Lymphocytes/cytology , Male , Meningeal Neoplasms/surgery , Meningioma/surgery , Middle Aged , Neutrophils/cytology , Preoperative Period , Regression Analysis , Retrospective Studies , Risk FactorsABSTRACT
The purpose of this study was to analyse the characteristics of 6 patients managed in a university hospital between 1996 and 2016 for non-islet cell tumor hypoglycemia (NICTH), a form of hypoglycaemia due to the paraneoplastic secretion of IGF-2 or its related substances. RESULTS: Three of these 6 patients (50%), aged over 69 years, including 2 with acromegaloid phenotype, presented with a pleural solitary fibrous tumor (SFT), with median diameter 20 cm (interquartile range, 12.5-20.5) with a low median SUV (3.3 g/mL (QR, 2-7.5)) on 18F-FDG PET. The other 3 patients presented respectively neuroendocrine carcinoma (NEC) of the palate (70-year-old woman), retroperitoneal myxofibrosarcoma (66-year-old man) and meningeal hemangiopericytoma (36-year-old woman). All 3 were inoperable and did not respond to any therapy other than glucose solution. Corticosteroid therapy was effective in the 3 SFTs and the NEC. One of the SFTs recurred 10 years later with asymptomatic hypoglycemia, which resolved after reintervention. Median (IQR) blood glucose levels of the 6 patients was 0.4g/L (QR, 0.31-0.41), with hypoinsulinemia at 0.7mIU/L (QR 0.7-2.0), undetectable GH, low IGF-1, normal IGF-2 level in 5/6 cases, a high IGF-2:IGF-1 ratio at 26.9 (QR, 20.8-37.8), hypokalemia and hypomagnesemia. CONCLUSION: NICTH is a rare syndrome, which should be considered in the presence of hypoinsulinemic hypoglycemia with low GH and IGF-1, and a IGF-2:IGF-1 ratio>10. Corticosteroid therapy was effective in elderly subjects, particularly with solitary fibrous tumor, which was generally operable. Hemangiopericytoma and myxofibrosarcoma had poor prognosis in younger patients.
Subject(s)
Hypoglycemia/etiology , Neuroendocrine Tumors/complications , Solitary Fibrous Tumor, Pleural/complications , Adult , Aged , Blood Glucose/analysis , Female , Fibroma , Fibrosarcoma/blood , Fibrosarcoma/complications , Hemangiopericytoma/blood , Hemangiopericytoma/complications , Hospitals, University , Human Growth Hormone/blood , Humans , Hypoglycemia/blood , Hypoglycemia/drug therapy , Insulin-Like Growth Factor I/analysis , Insulin-Like Growth Factor II/analysis , Magnesium/blood , Male , Meningeal Neoplasms/blood , Meningeal Neoplasms/complications , Neuroendocrine Tumors/blood , Potassium/blood , Prognosis , Retroperitoneal Neoplasms/blood , Retroperitoneal Neoplasms/complications , Solitary Fibrous Tumor, Pleural/bloodABSTRACT
AIM: Bearing in mind the association of breast cancer and meningioma, the present study aimed to investigate the levels of the soluble extracellular domain of HER2 protein in meningioma cases and control group. Besides, in the present research, its associations with pathological features and prognostic indicators of meningioma were examined. MATERIAL AND METHODS: A total of 68 meningioma patients along with 20 healthy age-sex matched individuals, as controls, were selected. Levels of HER2 in the sera were measured by a quantitative enzyme-linked immunosorbent assay (ELISA). RESULTS: The observations showed that Serum HER2 levels in meningioma patients were significantly lower than normal controls. However, outlier quantities were mostly observed in the cases. Furthermore, in meningiomas with higher histological grade (grade II, III), statistically significant elevated serum levels of HER2 were observed compared to patients with low-grade meningiomas (grade I). CONCLUSION: Serum HER2 levels were a poor biomarker for determination of pathological and prognostic characteristics of meningiomas and coupling serum HER2 levels with immunohistochemistry examination of HER2 in meningioma tissue samples would be helpful in future studies.