Diagnosis Of Glioblastoma Multiforme Research Articles

Incidence of venous thromboembolism in newly diagnosed glioblastoma multiforme and associated risk factors: A retrospective chart review.

e14040 Background: Patients diagnosed with glioblastoma multiforme (GBM) are recognized as a population at high risk of developing venous thromboembolism (VTE) (1,2). A retrospective chart review of patients diagnosed with GBM at the Juravinski Cancer Centre (JCC) was performed with the primary objective to assess the incidence of the development of VTE in newly diagnosed GBM. The secondary objective was to identify patients who were at higher risk and who could benefit from prophylactic anticoagulation. Methods: This was a single-centre, retrospective cohort study. We reviewed the charts of 528 patients diagnosed with GBM at the JCC from an 8-year period from January 1, 2013 to December 31, 2020. Information on the following factors was collected: Body-mass index (BMI), comorbidities (hypertension, diabetes, dyslipidemia, smoking history), performance status, location and size of tumour, degree of resection, presence of and location of weakness, baseline blood counts, treatments administered, date of diagnosis and time to death or last follow-up. Results: Over the period of review, a total of 528 patients were identified. 111 patients (21%) were diagnosed with VTE. The location of VTE was as follows: 39 patients (35%) unilateral lower extremity deep venous thrombosis (DVT), 8 (7%) unilateral upper extremity DVT, 8 (7%) bilateral lower extremity DVT, 30 (27%) pulmonary embolism (PE), and 25 (23%) DVT and PE. Most VTE (87%) occurred within 12 months of diagnosis of GBM. On univariate and multivariate analysis, no factors were identified that contributed to an increased risk of VTE. Conclusions: Newly diagnosed patients with GBM have been shown to have a significant risk of developing VTE. The AVERT study (3) demonstrated the preventive benefit of administering a direct oral anticoagulant (DOAC) to cancer patients, including those with GBM, at high risk of developing VTE (3). Thus consideration should be given to treating patients with GBM with a DOAC at the time of diagnosis. The benefit of preventive treatment will need to be balanced against the risk of bleeding in these patients.

LncRNA Biomarkers of Glioblastoma Multiforme.

Long noncoding RNAs (lncRNAs) are RNA molecules of 200 nucleotides or more in length that are not translated into proteins. Their expression is tissue-specific, with the vast majority involved in the regulation of cellular processes and functions. Many human diseases, including cancer, have been shown to be associated with deregulated lncRNAs, rendering them potential therapeutic targets and biomarkers for differential diagnosis. The expression of lncRNAs in the nervous system varies in different cell types, implicated in mechanisms of neurons and glia, with effects on the development and functioning of the brain. Reports have also shown a link between changes in lncRNA molecules and the etiopathogenesis of brain neoplasia, including glioblastoma multiforme (GBM). GBM is an aggressive variant of brain cancer with an unfavourable prognosis and a median survival of 14-16 months. It is considered a brain-specific disease with the highly invasive malignant cells spreading throughout the neural tissue, impeding the complete resection, and leading to post-surgery recurrences, which are the prime cause of mortality. The early diagnosis of GBM could improve the treatment and extend survival, with the lncRNA profiling of biological fluids promising the detection of neoplastic changes at their initial stages and more effective therapeutic interventions. This review presents a systematic overview of GBM-associated deregulation of lncRNAs with a focus on lncRNA fingerprints in patients' blood.

Retrospective Review of the Factors Limiting Optune Initiation in GBM patients

Tumor Treating Fields (TTFields) are a proven treatment that prolongs survival in Glioblastoma Multiforme (GBM) patients. The duration of usage of TTFields correlates with its effectiveness. This study aims to identify socioeconomic and clinical factors that prevent GBM patients at a single institution from starting and remaining on TTFields treatment. This is a retrospective review from a single institution. Data were analyzed for each patient with a diagnosis of GBM that was seen in new patient consultation with a radiation oncologist. Data from 2015 to present were available. 178 patients were included in the study. Insurance status (private vs Medicare/Medicaid vs uninsured), zip code, expected income status, race, ethnicity, preferred primary language, work status, performance status (KPS) at time of diagnosis, and family support at home (Spouse vs Other) were analyzed. For those that initiated TTFields, we examined the duration of treatment, usage rates, patient reported tolerability, and reasons for discontinuation. Early termination of treatment was defined as treatment with TTFields for less than 3 months. Of the 178 diagnosed GBM patients, 96 (54%) were offered TTFields and 48 (27%) agreed to treatment, with 46 actually starting. Of 89 Non-Hispanic patients, 53 were offered TTFields (60%) whereas of 73 Hispanic patients, 35 were offered TTFields (48%) (no statistically significant difference). The number one reason for refusing TTFields treatment was rapid deterioration (14/48 patients). The next most common reason was the patient feeling overwhelmed by managing or wearing the device (10/48) as well as the patient's decision to participate in any other clinical trial (10/48). The 3-month dropout rate for patients who received TTFields was 35% (17/48). 5 of the 17 stopped early due to skin rash or annoyance with the device. Patient's median income and insurance status did not predict whether they would start TTFields. 33 out of 109 (31%) patients with spousal support at home started treatment with TTFields compared to 13 of 69 (19%) of those without spousal support (p = .0895, Chi-Square test). TTFields were offered to more patients each successive year, but many patients had no documented discussion offering TTFields, which may indicate room for improvement at our institution. Median income and insurance status did not play a role in patient access to TTFields, most likely due to Novocure sponsorship of un- or under-insured patients. Among those who declined treatment, 21% did so because of perceived difficulty managing the device. The strongest single trend predictive of successful initiation of TTFields is spousal support at home. Further interventions may focus on improving patient support at home, such as home health nursing visits or community support.

The Recent Research Progress of NF-κB Signaling on the Proliferation, Migration, Invasion, Immune Escape and Drug Resistance of Glioblastoma.

Glioblastoma multiforme (GBM) is the most common and invasive primary central nervous system tumor in humans, accounting for approximately 45-50% of all primary brain tumors. How to conduct early diagnosis, targeted intervention, and prognostic evaluation of GBM, in order to improve the survival rate of glioblastoma patients, has always been an urgent clinical problem to be solved. Therefore, a deeper understanding of the molecular mechanisms underlying the occurrence and development of GBM is also needed. Like many other cancers, NF-κB signaling plays a crucial role in tumor growth and therapeutic resistance in GBM. However, the molecular mechanism underlying the high activity of NF-κB in GBM remains to be elucidated. This review aims to identify and summarize the NF-κB signaling involved in the recent pathogenesis of GBM, as well as basic therapy for GBM via NF-κB signaling.

Deep Penetrating and Sensitive Targeted Magnetic Particle Imaging and Photothermal Therapy of Early-Stage Glioblastoma Based on a Biomimetic Nanoplatform.

Early diagnosis can effectively improve the survival of glioblastoma multiforme (GBM). A specific imaging technique that is simultaneously deep penetrating and sensitive to small tissue changes is desired to identify GBM. Due to its excellent features in signal contrast, detection sensitivity, and none or little attenuation in tissue, magnetic particle imaging (MPI) possesses great potential in cancer diagnosis, especially when the imaging modality is equipped with specifically targeted nanoprobes. However, when gliomas are small, the blood-brain barrier (BBB) is complete and prevents nanoprobes from entering the brain, which negates the theranostic effect. This study proposes a biomimetic nanoplatform that assist the MPI tracers in breaking through the BBB and then demonstrate a targeted and sensitive diagnosis of GBM. Afterward, the photothermal therapy and immune regulationshow an excellent therapeutic effect on the GBM. It is experimentally confirmed that the MPI signal does not decay with tissue depthand shows excellent sensitivity for thousands-cells. Only small animals are conducted in this study due to the limitations of the current commercial MPI scanner, however, this research theoretically enables large animal and human studies, which encourages a promising pathway toward the noninvasive diagnosis of early-stage GBM in clinics.

Advanced Bioinformatics Analysis and Genetic Technologies for Targeting Autophagy in Glioblastoma Multiforme.

As the most malignant primary brain tumor in adults, a diagnosis of glioblastoma multiforme (GBM) continues to carry a poor prognosis. GBM is characterized by cytoprotective homeostatic processes such as the activation of autophagy, capability to confer therapeutic resistance, evasion of apoptosis, and survival strategy even in the hypoxic and nutrient-deprived tumor microenvironment. The current gold standard of therapy, which involves radiotherapy and concomitant and adjuvant chemotherapy with temozolomide (TMZ), has been a game-changer for patients with GBM, relatively improving both overall survival (OS) and progression-free survival (PFS); however, TMZ is now well-known to upregulate undesirable cytoprotective autophagy, limiting its therapeutic efficacy for induction of apoptosis in GBM cells. The identification of targets utilizing bioinformatics-driven approaches, advancement of modern molecular biology technologies such as clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas9) or CRISPR-Cas9 genome editing, and usage of microRNA (miRNA)-mediated regulation of gene expression led to the selection of many novel targets for new therapeutic development and the creation of promising combination therapies. This review explores the current state of advanced bioinformatics analysis and genetic technologies and their utilization for synergistic combination with TMZ in the context of inhibition of autophagy for controlling the growth of GBM.

Design and Computational Analysis of an MMP9 Inhibitor in Hypoxia-Induced Glioblastoma Multiforme.

The main therapeutic difficulties in treating hypoxia-induced glioblastoma multiforme (GBM) are toxicity of current treatments and the resistance brought on by the microenvironment. More effective therapeutic alternatives are urgently needed to reduce tumor lethality. Hence, we screened plant-based natural product panels intending to identify novel drugs without elevating drug resistance. We explored GEO for the hypoxia GBM model and compared hypoxic genes to non-neoplastic brain cells. A total of 2429 differentially expressed genes expressed exclusively in hypoxia were identified. The functional enrichment analysis demonstrated genes associated with GBM, further PPI network was constructed, and biological pathways associated with them were explored. Seven webtools, including GEPIA2.0, TIMER2.0, TCGA-GBM, and GlioVis, were used to validate 32 hub genes discovered using Cytoscape tool in GBM patient samples. Four GBM-specific hypoxic hub genes, LYN, MMP9, PSMB9, and TIMP1, were connected to the tumor microenvironment using TIMER analysis. 11 promising hits demonstrated positive drug-likeness with nontoxic characteristics and successfully crossed blood-brain barrier and ADMET analyses. Top-ranking hits have stable intermolecular interactions with the MMP9 protein according to molecular docking, MD simulation, MM-PBSA, PCA, and DCCM analyses. Herein, we have reported flavonoids, 7,4'-dihydroxyflavan, (3R)-3-(4-hydroxybenzyl)-6-hydroxy-8-methoxy-3,4-dihydro-2H-1-benzopyran, and 4'-hydroxy-7-methoxyflavan, to inhibit MMP9, a novel hypoxia gene signature that could serve as a promising predictor in various clinical applications, including GBM diagnosis, prognosis, and targeted therapy.

Role of the Ca2+ channel α2δ-1 auxiliary subunit in proliferation and migration of human glioblastoma cells.

The overexpression of α2δ-1 is related to the development and degree of malignancy of diverse types of cancer. This protein is an auxiliary subunit of voltage-gated Ca2+ (CaV) channels, whose expression favors the trafficking of the main pore-forming subunit of the channel complex (α1) to the plasma membrane, thereby generating an increase in Ca2+ entry. Interestingly, TLR-4, a protein belonging to the family of toll-like receptors that participate in the inflammatory response and the transcription factor Sp1, have been linked to the progression of glioblastoma multiforme (GBM). Therefore, this report aimed to evaluate the role of the α2δ-1 subunit in the progression of GBM and investigate whether Sp1 regulates its expression after the activation of TLR-4. To this end, the expression of α2δ-1, TLR-4, and Sp1 was assessed in the U87 human glioblastoma cell line, and proliferation and migration assays were conducted using different agonists and antagonists. The actions of α2δ-1 were also investigated using overexpression and knockdown strategies. Initial luciferase assays and Western blot analyses showed that the activation of TLR-4 favors the transcription and expression of α2δ-1, which promoted the proliferation and migration of the U87 cells. Consistent with this, overexpression of α2δ-1, Sp1, and TLR-4 increased cell proliferation and migration, while their knockdown with specific siRNAs abrogated these actions. Our data also suggest that TLR-4-mediated regulation of α2δ-1 expression occurs through the NF-kB signaling pathway. Together, these findings strongly suggest that the activation of TLR-4 increases the expression of α2δ-1 in U87 cells, favoring their proliferative and migratory potential, which might eventually provide a theoretical basis to examine novel biomarkers and molecular targets for the diagnosis and treatment of GBM.

NIMG-86. REVEALING THE BIOLOGY BEHIND MRI SIGNATURES IN GLIOBLASTOMA

Abstract The brain is notoriously difficult to access because of its location and protective mechanisms, both internal and external. Imaging-based approaches, such as multiparametric magnetic resonance imaging (mpMRI), provide a method to bypass these obstacles. mpMRI can capture a wide range of data from tumors embedded in brain tissue through various imaging features. However, the biological function captured by each imaging feature remains largely unknown, particularly within the aggressive disease glioblastoma multiforme (GBM). We integrated our GBM SYstems Genetics Network AnaLysis (gbmSYGNAL) gene regulatory network (Plaisier, et al. 2016), based on the multi-omic patient data from The Cancer Genome Atlas (TCGA), with mpMRI-localized patient tumor biopsies. The gbmSYGNAL network was reconstructed within the new image-localized biopsies, and associations revealed a strong connection between the spoiled gradient recalled echo + contrast (SPGR+C) feature and the immune hallmarks of cancer. The SPGR+C method generates an image by employing a contrast agent that bypasses the blood brain barrier (BBB) through leaky blood vessels that have weakened from the force of the rapidly growing GBM tumor. Furthermore, a significant association between SPGR+C signal and the presence of both infiltrating macrophages and T cells indicated that peripheral immune cells may also cross the BBB at these leaky sites. Separately, the mean diffusivity (MD) & T2 features were linked to the sustained angiogenesis hallmark. These features displayed high association with angiogenic genes, such as FLT1, KDR, and PDGFRB, and correlated with the presence of histologically identified vessels. Detection of these disease-relevant functions via mpMRI features has powerful clinical applications, providing a non-invasive approach to GBM diagnosis, prognosis, and treatment direction.

MicroRNA and mRNA Expression Changes in Glioblastoma Cells Cultivated under Conditions of Neurosphere Formation.

Glioblastoma multiforme (GBM) is one of the most highly metastatic cancers. The study of the pathogenesis of GBM, as well as the development of targeted oncolytic drugs, require the use of actual cell models, in particular, the use of 3D cultures or neurospheres (NS). During the formation of NS, the adaptive molecular landscape of the transcriptome, which includes various regulatory RNAs, changes. The aim of this study was to reveal changes in the expression of microRNAs (miRNAs) and their target mRNAs in GBM cells under conditions of NS formation. Neurospheres were obtained from both immortalized U87 MG and patient-derived BR3 GBM cell cultures. Next generation sequencing analysis of small and long RNAs of adherent and NS cultures of GBM cells was carried out. It was found that the formation of NS proceeds with an increase in the level of seven and a decrease in the level of 11 miRNAs common to U87 MG and BR3, as well as an increase in the level of 38 and a decrease in the level of 12 mRNA/lncRNA. Upregulation of miRNAs hsa-miR: -139-5p; -148a-3p; -192-5p; -218-5p; -34a-5p; and -381-3p are accompanied by decreased levels of their target mRNAs: RTN4, FLNA, SH3BP4, DNPEP, ETS2, MICALL1, and GREM1. Downregulation of hsa-miR: -130b-5p, -25-5p, -335-3p and -339-5p occurs with increased levels of mRNA-targets BDKRB2, SPRY4, ERRFI1 and TGM2. The involvement of SPRY4, ERRFI1, and MICALL1 mRNAs in the regulation of EGFR/FGFR signaling highlights the role of hsa-miR: -130b-5p, -25-5p, -335-3p, and -34a-5p not only in the formation of NS, but also in the regulation of malignant growth and invasion of GBM. Our data provide the basis for the development of new approaches to the diagnosis and treatment of GBM.

PH-Responsive chitosan-modified gadolinium oxide nanoparticles delivering 5-aminolevulinic acid: A dual cellular and metabolic T1-T2* contrast agent for glioblastoma brain tumors detection

Diagnosis of glioblastoma multiforme (GBM) with high sensitivity and specificity requires cellular and metabolic imaging. In this study, we aimed to endow gadolinium oxide nanoparticles (Gd2O3 NPs) as an interesting T1 contrast agent with T2* contrast ability through intracellular iron assistance induced by 5-aminolevulinic acid (5-ALA) with ferric ammonium citrate (FAC). Chitosan (CS)-loaded Gd2O3 NPs were loaded with 5-aminolevulinic acid (Gd2O3/CS-TPP@5-ALA NPs), and then evaluated as a pH-responsive dual cellular and metabolic T1 and T2* contrast agent for GBM diagnosis. The target NPs with an average size of 138 nm revealed concentration-dependent toxicity against glioblastoma C6 cells. The relaxation rate (R1) of the C6 cells treated with Gd2O3/CS-TPP@5-ALA NPs plus FAC was remarkably higher than the controls including Gd2O3/CS-TPP NPs, Gd2O3/CS-TPP@5-ALA NPs, and FAC (17.2 ± 2.4 vs. 8 ± 1.5, 8.4 ± 1.2, and 2.3 ± 0.5, respectively). Interestingly, the transverse relaxation rate (R2*) of the C6 cells treated with Gd2O3/CS-TPP@5-ALA NPs + FAC was significantly higher than the controls including Gd2O3/CS-TPP NPs, Gd2O3/CS-TPP@5-ALA NPs, and FAC (96 ± 8 vs. 25 ± 4, 27 ± 5, and 19 ± 2.6, respectively). We believe that Gd2O3/CS-TPP@5-ALA NPs + FAC could be introduced as promising dual cellular and metabolic T1-T2* contrast agents for GBM diagnosis in MRI.

Diagnostic Accuracy and Imaging Appearance Glioblastoma Multiforme on MRI and MRS

Objective: To determine the diagnostic accuracy of contrast-enhanced MRI with conventional sequences and MR Spectroscopy in the diagnosis of Glioblastoma Multiforme, taking histopathology as the gold standard. We also determined the MR imaging appearance of GBM on conventional sequences.
 Methodology: This descriptive cross-sectional study was conducted at a tertiary care hospital from 19th August 2019 to 18th August 2020 on 165 adult patients suspected of having an intracranial space-occupying lesion. Informed consent was sought and a questionnaire was filled out for patient data, MRI imaging findings, and MRS results.
 Histopathology results were subsequently followed and recorded. The diagnostic accuracy of contrast enhanced MRI brain as well as MRS was determined in terms of sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy, taking histopathology as gold standard.
 Results: In a total of 165 patients selected for the study, the mean age was 56.34±10.04 years with a male to female ratio of 1:1 and the frontal lobe being the most common location (34.5%). In histopathological positive GBM cases, margins of the mass were ill-defined in 55.1%, intralesional low ADC values were observed in 63.3%, signal drop out on susceptibility imaging in 42.8%, and MRS with raised choline and reduced NAA in 75.5%. MRI had a sensitivity of 81.6% and specificity of 94.8%, and MRS has a sensitivity of 75.5% and a specificity of 100%.
 Conclusion: Ill-defined margins, necrosis, and hemorrhage are important MRI features suggesting GBM. MRS combined with conventional MR sequences has high sensitivity and specificity in its diagnosis.

P11.76.A Retrospective evaluation of Overall Survival and Progression Free Survival in patients with glioblastoma comparing 6 vs 12 cycles of Adjuvant Temozolomide

Abstract Background The standard of care for glioblastoma multiforme (GBM) is surgery followed by adjuvant concomitant chemo-radiotherapy and adjuvant temolomide (TMZ) for 6 cycles. Extending the duration of adjuvant TMZ did not demonstrate an overall survival (OS) benefit in a meta-analysis including 2214 GBM patients. A phase II randomized clinical trial including 166 GBM patients compared 6 vs 12 cycles of TMZ, showing no differences in progression-free-survival (PFS), although MGMT methylated patients showed better outcomes. The objective of this study is to analyze PFS and OS of GMB patients receiving 6 vs 12 cycles of adjuvant TMZ. Material and Methods Patients with a pathological diagnosis of GBM between 1 December 2016 and 31 December 2020 in a single center (Hospital Universitario La Paz) were retrospectively reviewed. Inclusion criteria were confirmed pathological diagnosis and patients receiving multimodality treatment (surgery, radiation and chemotherapy). Two cohorts were analyzed, cohort A patients receiving 6 cycles of adjuvant TMZ and cohort B patients receiving 12 cycles of adjuvant TMZ. Statistical analysis was performed via SPSS v.21 (differences between both cohorts were calculated using χ² and T Student and survival outcomes with Kaplan Meier curves, comparing its differences using log-rank test). Results Sixty-eight patients were included in the final analysis, with a median age of 58 years at diagnosis. Fourty-two patients (62%) received 6 cycles of adjuvant TMZ (cohort A), whereas 26 patients (38%) received 12 cycles (cohort B). Median OS was 10 months for cohort A and 20 months for cohort B (p<0,001), median PFS was 8 months for cohort A and 19 months for cohort B (p=0,001). No significant differences were shown between both cohorts regarding age at diagnosis, being 60 years in cohort A and 54 years in cohort B (p = 0,06), and positive-margins after surgery (p=0,796), being 9,5% and 7,7% respectively in each cohort. Significant differences were found regarding MGMT methylation (30% in cohort A and 68% in cohort B). Conclusion In our study, patients receiving 12 cycles of adjuvant TMZ had better median OS and median PFS, compared to patients receiving 6 cycles, although the latter group had significantly less MGMT methylated patients, which is a known prognostic and predictive factor of response to TMZ.

Advances in nano-based materials for glioblastoma multiforme diagnosis: A mini-review

The development of nano-based materials for diagnosis enables a more precise prognosis and results. Inorganic, organic, or hybrid nanoparticles using nanomaterials, such as quantum dots, extracellular vesicle systems, and others, with different molecular compositions, have been extensively explored as a better strategy to overcome the blood-brain barrier and target brain tissue and tumors. Glioblastoma multiforme (GBM) is the most common and aggressive primary tumor of the central nervous system, with a short, established prognosis. The delay in early detection is considered a key challenge in designing a precise and efficient treatment with the most encouraging prognosis. Therefore, the present mini-review focuses on discussing distinct strategies presented recently in the literature regarding nanostructures’ use, design, and application for GBM diagnosis.

NIR-II absorptive dithienopyrrole-thiadiazolobenzotriazole conjugated polymer for photoacoustic imaging-guided glioblastoma multiforme photothermal therapy

The development of new diagnostic imaging and precise treatment methods for glioblastoma multiforme (GBM) is significant to improve patients' quality of life and prolong their survival time. Herein, we proposed a photoacoustic imaging (PAI)-guided GBM high-efficient photothermal therapy (PTT) based on a second near-infrared (NIR-II) absorptive polymer (PDTP-TBZ) conjugated with intense electron donor dithienopyrrole (DTP) and strong electron acceptor thiadiazolobenzotriazole (TBZ). By nanoprecipitation, PDTP-TBZ can form into nanoparticles (PT NPs), and c(RGDfK) cyclic peptide with integrin-specific targeting was then modified on the surface of PT NPs to obtain the ability of active targeting GBM multifunctional nano-reagent (cRGD@PT NPs). Both in vitro and in vivo experiments demonstrated that cRGD@PT NPs as NIR-II GBM phototheranostic reagents can greatly improve the enrichment rate at tumor sites under PAI monitoring, and carry out precise NIR-II PTT with high effective tumor cell phototoxicity and high biological safety. Thus, cRGD@PT NPs have great potential for the future GBM phototheranostic application in clinic. Statement of significanceIn this work, we successfully constructed an intense electron donor dithienopyrrole (DTP) with a strong electron acceptor thiadiazolobenzotriazole (TBZ) into a novel NIR-II optical absorptive conjugated polymer (PDTP-TBZ). Then, the c(RGDfK) cyclic peptide was modified on the surface of PT NPs to obtain multifunctional nanodiagnostic reagents (cRGD@PT NPs) that can effectively target GBM neovascularization and tumor cells. Both in vitro and in vivo experiments demonstrate that cRGD@PT NPs possess high photothermal conversion efficiency and practical photoacoustic imaging capability under 1064 nm laser irradiation. The results of this work suggested that cRGD@PT NPs have great potential in efficient NIR-II PTT guided by accurate PAI, which provide a good perspective for the treatment and diagnosis of GBM.

TfR Aptamer Enhanced Blood-Brain Barrier Penetration of Biomimetic Nanocomplexes for Intracellular Transglutaminase 2 Imaging and Silencing in Glioma.

Engineering a versatile nanocomplex integrating effective penetration of the blood-brain barrier (BBB), accurate diagnosis, and boosting therapy has always been an intractable challenge in glioblastoma multiforme (GBM). Herein, biomimetic nanocomplexes (TMPsM) for single intracellular transglutaminase 2 (TG2)-triggered self-assembly imaging and RNAi therapy for GBM are subtly developed. To prove the concept, transferrin receptor (TfR) aptamer-modified brain metastatic tumor cell membrane is prepared as the shell for dual BBB targeting capability and prolonged blood retention time. Upon targeting entering into GBM, hollow MnO2 is decomposed to release KKGKGQQ-tetraphenylethene (Pep-TPE) and siRNA. Owing to TG2 dependence, the non-emissive Pep-TPE would be self-aggregated to induce the emission turn-on in GBM that contain overexpressed TG2. The resulting aggregation-induced emission fluorescence imaging with a high signal-to-noise ratio can achieve the precise localization of the tumor and dynamic detection of TG2 activity, thereby allowing the GBM accurate diagnosis. Notably, the TG2 can be silenced by the released siRNA to cause cell apoptosis and increase chemotherapeutic sensitivity, ultimately realizing excellent antitumor efficacy. In vitro and in vivo results demonstrate that the as-prepared TMPsM indeed possess superior BBB penetration, precise diagnosis, and effective therapy of GBM. The proposed strategy may pioneer a new path for the theranostics of brain tumors.

Construction of an immune-related gene signature for the prognosis and diagnosis of glioblastoma multiforme.

BackgroundIncreasing evidence has suggested that inflammation is related to tumorigenesis and tumor progression. However, the roles of immune-related genes in the occurrence, development, and prognosis of glioblastoma multiforme (GBM) remain to be studied.MethodsThe GBM-related RNA sequencing (RNA-seq), survival, and clinical data were acquired from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) databases. Immune-related genes were obtained from the Molecular Signatures Database (MSigDB). Differently expressed immune-related genes (DE-IRGs) between GBM and normal samples were identified. Prognostic genes associated with GBM were selected by Kaplan–Meier survival analysis, Least Absolute Shrinkage and Selection Operator (LASSO)-penalized Cox regression analysis, and multivariate Cox analysis. An immune-related gene signature was developed and validated in TCGA and CGGA databases separately. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to explore biological functions of the signature. The correlation between immune cell infiltration and the signature was analyzed by single-sample gene set enrichment analysis (ssGSEA), and the diagnostic value was investigated. The gene set enrichment analysis (GSEA) was performed to explore the potential function of the signature genes in GBM, and the protein–protein interaction (PPI) network was constructed.ResultsThree DE-IRGs [Pentraxin 3 (PTX3), TNFSF9, and bone morphogenetic protein 2 (BMP2)] were used to construct an immune-related gene signature. Receiver operating characteristic (ROC) curves and Cox analyses confirmed that the 3-gene-based prognostic signature was a good independent prognostic factor for GBM patients. We found that the signature was mainly involved in immune-related biological processes and pathways, and multiple immune cells were disordered between the high- and low-risk groups. GSEA suggested that PTX3 and TNFSF9 were mainly correlated with interleukin (IL)-17 signaling pathway, nuclear factor kappa B (NF-κB) signaling pathway, tumor necrosis factor (TNF) signaling pathway, and Toll-like receptor signaling pathway, and the PPI network indicated that they could interact directly or indirectly with inflammatory pathway proteins. Quantitative real-time PCR (qRT-PCR) indicated that the three genes were significantly different between target tissues.ConclusionThe signature with three immune-related genes might be an independent prognostic factor for GBM patients and could be associated with the immune cell infiltration of GBM patients.

Glioblastoma multiforme in patients with human immunodeficiency virus: an integrated review and analysis.

As lifespans for persons living with HIV (PLWH) have improved over the last decade, there has been a simultaneous increase in non-AIDS-related cancer in that group. However, there is a paucity of data regarding the incidence of glioblastoma multiforme (GBM) in PLWH. Better understanding of the oncogenesis, natural history, and treatment outcomes of GBM in PLWH should lead to improved treatment strategies. We performed a comprehensive literature search of six electronic databases to identify eligible cases of GBM among PLWH. Kaplan-Meier estimates, Fisher's exact test, and logistic regression were used to interrogate the data. Epidemiologic data on global HIV prevalence was obtained from the 2016 UNAIDS incidence report, and CNS cancer incidence was obtained from the GDB 2016 Brain and Other CNS Cancer Collaborators. There is an inverse relationship between the incidence of HIV and CNS cancer globally. Median overall survival (OS) from GBM diagnosis was 8months. Estimates for survival at 1 and 2years were 28 and 5%, respectively. There were no statistically significant predictors of OS in this setting. There was a significant difference (p < 0.01) in OS in PLWH and GBM when compared to TCGA age matched cohorts. The diagnosis of GBM in PLWH is severely underreported in the literature. Despite maximal treatment, OS in this patient population is significantly less than in HIV-negative people. There was a poor prognosis of GBM in PLWH, which is inconsistent with previous reports. Further investigation is required for PLWH and concomitant GBM. Analyses must consider if HAART is maintained in PLWH during GBM treatment.

Ribosomes and Ribosomal Proteins Promote Plasticity and Stemness Induction in Glioma Cells via Reprogramming.

Glioblastoma multiforme (GBM) is a lethal tumor that develops in the adult brain. Despite advances in therapeutic strategies related to surgical resection and chemo-radiotherapy, the overall survival of patients with GBM remains unsatisfactory. Genetic research on mutation, amplification, and deletion in GBM cells is important for understanding the biological aggressiveness, diagnosis, and prognosis of GBM. However, the efficacy of drugs targeting the genetic abnormalities in GBM cells is limited. Investigating special microenvironments that induce chemo-radioresistance in GBM cells is critical to improving the survival and quality of life of patients with GBM. GBM cells acquire and maintain stem-cell-like characteristics via their intrinsic potential and extrinsic factors from their special microenvironments. The acquisition of stem-cell-like phenotypes and aggressiveness may be referred to as a reprogramming of GBM cells. In addition to protein synthesis, deregulation of ribosome biogenesis is linked to several diseases including cancer. Ribosomal proteins possess both tumor-promotive and -suppressive functions as extra-ribosomal functions. Incorporation of ribosomes and overexpression of ribosomal protein S6 reprogram and induce stem-cell-like phenotypes in GBM cells. Herein, we review recent literature and our published data on the acquisition of aggressiveness by GBM and discuss therapeutic options through reprogramming.

64-Year-Old Woman With Aphasia and Troponin Elevation

64-Year-Old Woman With Aphasia and Troponin Elevation