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Background: The current biomarkers alpha-fetoprotein and human chorionic gonadotropin have limited sensitivity and specificity for diagnosing malignant germ-cell tumours (GCTs). MicroRNAs (miRNAs) from the miR–371–373 and miR–302/367 clusters are overexpressed in all malignant GCTs, and some of these miRNAs show elevated serum levels at diagnosis. Here, we developed a robust technical pipeline to quantify these miRNAs in the serum and cerebrospinal fluid (CSF). The pipeline was used in samples from a cohort of exclusively paediatric patients with gonadal and extragonadal malignant GCTs, compared with appropriate tumour and non-tumour control groups. Methods: We developed a method for miRNA quantification that enabled sample adequacy assessment and reliable data normalisation. We performed qRT–PCR profiling for miR–371–373 and miR–302/367 cluster miRNAs in a total of 45 serum and CSF samples, obtained from 25 paediatric patients. Results: The exogenous non-human spike-in cel–miR–39–3p and the endogenous housekeeper miR–30b–5p were optimal for obtaining robust serum and CSF qRT–PCR quantification. A four-serum miRNA panel (miR–371a–3p, miR–372–3p, miR–373–3p and miR–367–3p): (i) showed high sensitivity/specificity for diagnosing paediatric extracranial malignant GCT; (ii) allowed early detection of relapse of a testicular mixed malignant GCT; and (iii) distinguished intracranial malignant GCT from intracranial non-GCT tumours at diagnosis, using CSF and serum samples. Conclusions: The pipeline we have developed is robust, scalable and transferable. It potentially promises to improve clinical management of paediatric (and adult) malignant GCTs.

Preoperative diagnosis of the nature of PCNSL is crucial for distinguishing it from commonly confused intracranial gliomas, such as glioblastoma multiforme (GBM). The present research aims to sequence peripheral blood exosomal miRNAs from PCNSL and GBM patients, and to identify the discriminative miRNAs with high feasibility. Plasma exosomal RNAs were extracted, and miRNA sequencing was performed. The miRNAs with significant differences were validated by RT-qPCR. A total of 67 miRNAs were significantly different between the PCNSL and GBM groups. Twenty-seven PCNSL and 27 GBM patients were enrolled for the RT-qPCR validation of 10 selected differentially expressed miRNAs. The expression levels of plasma exosomal hsa-miR-148a-3p, hsa-let-7f-5p, hsa-miR-345-5p and hsa-miR-4433b-5p were upregulated in the PCNSL group compared with those in the GBM group ( P  = 0.019, P  = 0.036, P  = 0.009, and P  = 0.001, respectively). The combined panel comprising hsa-miR-148a-3p, hsa-miR-345-5p, and hsa-miR-4433b-5p demonstrated significantly enhanced diagnostic performance, with an area under the ROC curve (AUC) of 0.791. Immunohistochemistry analysis revealed that the expression level of EGFR in PCNSL was significantly lower than that in GBM. Western blot and RT-qPCR analysis of EGFR expression levels in LN229 cells revealed that miR-148a-3p and miR-4433b-5p downregulated EGFR expression. The results of luciferase reporter assay showed that the relative luciferase activity of HEK293T cells transfected with EGFR-WT was notably suppressed by miR-4433b-5p ( P  < 0.001). In conclusion, the plasma exosomal hsa-miR-148a-3p, hsa-miR-345-5p, and hsa-miR-4433b-5p might be identified as novel biomarkers for differentiating PCNSL and GBM. The increased expression level of EGFR in GBM may be achieved by the negative regulatory effects of miR-4433b-5p. The diagnostic performance of the miRNA biomarkers still needs to be further verified in larger sample size cohorts.

Background: MicroRNA-210 (miR-210) is an oncogenic miRNA previously associated with prognosis in human gliomas, an incurable tumour type of the central nervous system. Here miR-210 was investigated as a potential serum biomarker in the diagnosis and prognosis of glioma. Methods: Serum was immediately prepared from blood samples collected from patients with glioma grades I–IV at primary diagnosis ( n =136) and healthy controls ( n =50) from February 2007 to March 2014 in the Department of Neurosurgery of the First Affiliated Hospital of Wannan Medical College (Wuhu, China). Total RNA was isolated from serum. cDNA was synthesised with primers specific for miR-210 and miR-16-1 (internal control), and quantitative real-time RT-PCR was performed. Results were statistically analysed to determine the role of miR-210 in the diagnosis and prognosis of human glioma patients. Results: An approximately seven-fold increase in miR-210 expression was detected in serum samples from glioblastoma patients relative to healthy controls. A threshold expression value (2.259) was chosen from receiver operator characteristic curves (ROC), and the low and high miR-210 expression groups were analysed by multivariate Cox proportional hazard regression and Kaplan–Meier analyses. Results revealed an association of high serum miR-210 expression with tumour grade and poor patient outcome ( P -values <0.001). Conclusions: Serum miR-210 is a promising diagnostic and prognostic biomarker that can be detected in the peripheral blood of patients with glioma.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and carries a poor prognosis when it involves the central nervous system (CNS), a condition known as secondary CNS lymphoma (SCNSL). Although the CNS International Prognostic Index (CNS-IPI) is used to estimate SCNSL risk, its limited sensitivity highlights the need for more reliable biomarkers to improve risk stratification and enable earlier intervention. We evaluated pretreatment levels of interleukin-10 (IL-10) and interleukin-6 (IL-6) in both peripheral blood (PB) and cerebrospinal fluid (CSF), and compared clinical characteristics between DLBCL patients with and without SCNSL. Fifty-six newly diagnosed DLBCL patients who received at least two treatment cycles were included. Compared to patients without CNS relapse, those with SCNSL exhibited distinct clinical features: more frequent B symptoms, increased bone marrow involvement, and lower B-cell lymphoma 6 (BCL6) immunohistochemical positivity. Biochemically, SCNSL patients showed elevated serum IL-10 levels, higher serum IL-10/IL-6 ratios, increased CSF IL-10 concentrations, and markedly elevated CSF IL-10/IL-6 ratios. On multivariate analysis, a serum IL-10/IL-6 ratio ≥2.30 independently predicted both progression-free survival (PFS) (HR = 7.300, = 0.010) and SCNSL development (OR = 43.200, = 0.001). Notably, time to CNS relapse did not significantly differ between high- and non-high-risk groups defined by CNS-IPI (χ² = 1.654, = 0.198). However, incorporating the serum IL-10/IL-6 ratio into the CNS-IPI yielded a refined scoring model-CNS-IPI-ratio-where the high-risk group had a significantly shorter median time to CNS relapse compared to the non-high-risk group (22.32 vs. 40.35 months; χ² = 5.680, = 0.017). Although survival outcomes were similar between high- and non-high-risk groups based on the NCCN-IPI alone ( > 0.05), adding the serum IL-10/IL-6 ratio identified significantly poorer outcomes in high-risk patients (PFS: = 0.046; OS: = 0.023). Furthermore, SCNSL patients demonstrated significantly higher CSF IL-10/IL-6 ratios compared to non-SCNSL patients and controls (67.88 vs. 0.74-0.79, < 0.05), with this ratio strongly correlating with CSF lactate dehydrogenase (LDH) levels (r = 0.625, = 0.006). In DLBCL, an elevated serum IL-10/IL-6 ratio at diagnosis independently predicts disease progression and SCNSL risk. Incorporating this biomarker enhances the prognostic utility of both CNS-IPI and NCCN-IPI models. Additionally, the markedly elevated CSF IL-10/IL-6 ratio in SCNSL patients suggests potential diagnostic value for CNS involvement, warranting further investigation.

BackgroundThe presence of specific mutations in the EGFR gene informs the clinical pathway of therapy for patients with lung adenocarcinoma (LAC), including those with central nervous system (CNS) metastases. Plasma circulating cell-free DNA (cfDNA) has been demonstrated to carry the mutational information of LACs, which serves as a biomarker to guide treatment. However, whether the cerebrospinal fluid (CSF) enriches circulating tumor DNA (ctDNA) released from CNS metastatic lesions of LAC, and whether the CSF ctDNA can be used to characterize these lesions remains unknown.ObjectiveTo explore the EGFR status in CNS metastases of LAC patients, and to guide the treatment of intra- and extracranial tumors in these patients.Patients and methodsThe EGFR mutational status in the cfDNA from paired CSF and plasma samples from LAC patients with CNS metastases, including 20 brain metastases (BM) and 15 leptomeningeal metastases (LM), was assessed by droplet digital polymerase chain reaction (ddPCR). The clinical outcomes of the EGFR status-based intervention were investigated.ResultsEGFR mutations were detected in 23/35 LAC patients (65.7%). EGFR mutations in the plasma or CSF were detected in 6/11 (54.5%) and 5/10 (50%) BM patients, and in 4/11 (36.4%) and 9/12(75%) LM patients, respectively. The prevalence of the T790M mutation was significantly higher in plasma (9/23) than in CSF (3/23) samples. The sensitivity and specificity of the ddPCR-based EGFR mutation test in CSF or plasma samples versus the primary tumor samples were 56% and 89% versus 46% and 100%, respectively. Twelve patients received a first-generation EGFR TKI (tyrosine kinase inhibitor) after the detection of sensitive EGFR mutations in their CSF or plasma, and five patients were switched from a first-generation EGFR TKI to osimertinib after the detection of the T790M mutation.ConclusionsThe EGFR T790M mutation in plasma cfDNA is a sensitive marker for EGFR TKI resistance when CNS metastases progressed. CSF ctDNA increases the diagnostic validity for EGFR genotyping of lung cancer brain metastasis. ddPCR in CSF and plasma samples could provide less invasive and close monitoring of the EGFR status of LAC patients with CNS metastases.

[This corrects the article DOI: 10.3389/fimmu.2025.1658015.].

The immune system plays a significant role in cancer prevention and outcome. In high grade astrocytomas (HGA), severe lymphopenia is associated with shortened survival due to tumor progression. This study was performed to quantify serial changes in lymphocyte subsets in HGA following standard radiation (RT) and temozolomide (TMZ). Adults (KPS >60, HIV negative) with newly diagnosed HGA scheduled to receive concurrent RT and TMZ and adjuvant TMZ were eligible. Blood was collected before beginning concurrent RT/TMZ and at weeks 6, 10, 18, and 26, and 3 months after completing adjuvant TMZ. Lymphocyte subsets were analyzed by flow cytometry. Twenty patients (70% glioblastoma, median age 53, 50% male, 80% Caucasian) who enrolled from January 2014 to August 2014 were followed until April 2016. Baseline dexamethasone dose was 0.5 mg/day and 15% had absolute lymphocyte counts (ALC) <1000 cells/mm 3 before starting RT/TMZ. However, 75% developed lymphopenia with ALC <1000 cells/mm 3 after completion of RT/TMZ. NK cells, B cells and all T lymphocytes subsets dropped significantly after concurrent RT/TMZ and remained depressed for the 48 weeks of observation. The CD4+/CD8+ ratio was not affected significantly during follow-up. Severe lymphopenia involving all subsets occurred early in treatment and remained present for nearly 1 year. To our knowledge, this is the first report of serial trends in lymphocyte subsets following standard RT and TMZ for HGA.

High-dose methotrexate (HD-MTX)-based polychemotherapy is widely used for patients with central nervous system (CNS) lymphoma. The pharmacokinetic (PK) variability and unpredictable occurrence of toxicity remain major concerns in HD-MTX treatment. This study aimed to characterize the population PK of HD-MTX in patients with CNS lymphoma and to identify baseline predictors and exposure thresholds that predict a high risk of nephro- and hepatotoxicity. Routinely monitored serum MTX concentrations after intravenous infusion of HD-MTX and MTX dosing information were collected retrospectively. Acute event of toxicity (≥ grade 1) was defined according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 on the basis of serum creatinine and alanine aminotransferase. A population PK model was developed in NONMEM. Toxicity data were analyzed using a logistic regression model, and potential baseline and exposure-related predictors were investigated. In total, 1584 MTX concentrations from 110 patients were available for analysis. A two-compartment population PK model adequately described the data. Estimated glomerular filtration rate (eGFR), treatment regimen, albumin, alkaline phosphatase, and body weight were identified as significant covariates that explain the PK variability of HD-MTX. Baseline eGFR and sex were identified as significant predictors for renal toxicity, and MTX dose (mg/m ) was the strongest predictor for hepatotoxicity. The MTX area under the concentration-time curve (AUC ) and concentration at 24 h (C ) were shown to correlate with renal toxicity only, and 49,800 μg/L × h (109.6 μmol/L × h) and C > 3930 μg/L (8.65 μmol/L) were potential exposure thresholds predicting high risk (proportion > 60%). A population PK model was developed for HD-MTX in patients with CNS lymphoma. The toxicity analysis showed that lower baseline eGFR and male sex, and higher MTX dose are associated with increased risk of acute nephro- and hepatotoxicity, respectively. The proposed exposure thresholds that predict high risk of renal toxicity and the developed models hold the potential to guide HD-MTX dosage individualization and better prevent acute toxicity.

Cerebral blood volume (CBV) measurement complements conventional magnetic resonance imaging (MRI) to indicate pathologies in the central nervous system (CNS). Dynamic susceptibility contrast (DSC) perfusion imaging is limited by low resolution and distortion. Steady-state (SS) imaging may provide higher resolution CBV maps but was not previously possible in patients. We tested the feasibility of clinical SS-CBV measurement using ferumoxytol, a nanoparticle blood pool contrast agent. SS-CBV measurement was analyzed at various ferumoxytol doses and compared with DSC-CBV using gadoteridol. Ninety nine two-day MRI studies were acquired in 65 patients with CNS pathologies. The SS-CBV maps showed improved contrast to noise ratios, decreased motion artifacts at increasing ferumoxytol doses. Relative CBV (rCBV) values obtained in the thalamus and tumor regions indicated good consistency between the DSC and SS techniques when the higher dose (510 mg) ferumoxytol was used. The SS-CBV maps are feasible using ferumoxytol in a clinical dose of 510 mg, providing higher resolution images with comparable rCBV values to the DSC technique. Physiologic imaging using nanoparticles will be beneficial in visualizing CNS pathologies with high vascularity that may or may not correspond with blood–brain barrier abnormalities.

Glioma, the most common type of primary central nervous system cancers, was progressive with poor survival. MicroRNA, as a novel biomarker, was suspected to be novel biomarkers for glioma diagnosis and prognosis. The study aimed at investigating the diagnostic and predictive value of miR-221/222 family for glioma. In the first phase, we compared plasma miR-221/222 family levels between 50 glioma patients and 51 healthy controls by real-time qRT-PCR amplification. Meanwhile, a meta-analysis based on published studies and presents study was performed to explore the diagnostic performance of miR-221/222 family in human cancers. In the second phase, we correlated the miR-221/222 family expression level with prognosis of glioma using Kaplan-Meier survival curves. The plasma miR-221/222 family levels were found to be significantly upregulated in glioma patients ( P  = 0.001). The ROC curve analysis yielded an AUC values of 0.84 (95 % confidence interval (CI): 0.74–0.93) for miR-221 and 0.92 (95 % CI 0.87–0.94) for miR-222. In the meta-analysis, the summary receiver operating characteristic (sROC) was plotted with an AUC of 0.82 (95 % CI 0.78–0.85) for miR-221/222 family. It was also demonstrated that high positive plasma miR-221 and miR-222 were both correlated with poor survival rate (miR-221: HR = 2.13; 95 % CI, 1.05–4.31; miR-222: HR = 2.09; 95 % CI, 1.00–4.37). This study demonstrated that the detection of the miRNA-221/222 family should be considered as a new additional tool to better characterize glioma.