Analysis of Factors Affecting 5-ALA Fluorescence Intensity in Visualizing Glial Tumor Cells—Literature Review

Glial tumors are one of the most common lesions of the central nervous system. Despite the implementation of appropriate treatment, the prognosis is not successful. As shown in the literature, maximal tumor resection is a key element in improving therapeutic outcome. One of the methods to achieve it is the use of fluorescent intraoperative navigation with 5-aminolevulinic acid. Unfortunately, often the level of fluorescence emitted is not satisfactory, resulting in difficulties in the course of surgery. This article summarizes currently available knowledge regarding differences in the level of emitted fluorescence. It may depend on both the histological type and the genetic profile of the tumor, which is reflected in the activity and expression of enzymes involved in the intracellular metabolism of fluorescent dyes, such as PBGD, FECH, UROS, and ALAS. The transport of 5-aminolevulinic acid and its metabolites across the blood–brain barrier and cell membranes mediated by transporters, such as ABCB6 and ABCG2, is also important. Accompanying therapies, such as antiepileptic drugs or steroids, also have an impact on light emission by tumor cells. Accurate determination of the factors influencing the fluorescence of 5-aminolevulinic acid-treated cells may contribute to the improvement of fluorescence navigation in patients with highly malignant gliomas.

Expression of glutamate carboxypeptidase II in the glial tumor recurrence evaluated in vivo using radionuclide imaging

Glutamate carboxypeptidase II (GCP), also known as prostate specific membrane antigen (PSMA) has been found to be expressed in glioma vasculature in in-vitro studies. GCP expression can be traced with the use of [68Ga]Ga-PSMA-11 PET/CT used routinely for prostate cancer imaging. The aim of this paper was to analyze GCP expression in the recurrent glial tumors in vivo. 34 patients (pts.) aged 44.5 ± 10.3 years with suspicion of recurrence of histologically confirmed glioma grade III (6 pts.) and grade IV (28 pts.) were included in the study. All patients underwent contrast-enhanced MR and [68Ga]Ga-PSMA-11 PET/CT. No radiopharmaceutical-related adverse events were noted. PET/CT was positive in all the areas suspected for recurrence at MR in all the patients. The recurrence was confirmed by histopathological examinations or follow-up imaging in all cases. The images showed a very low background activity of the normal brain. Median maximal standard uptake value (SUVmax) of the tumors was 6.5 (range 0.9–15.6) and mean standard uptake value (SUVmean) was 3.5 (range 0.9–7.5). Target-to-background (TBR) ratios varied between 15 and 1400 with a median of 152. Target-to-liver background ratios (TLR) ranged from 0.2 to 2.6, the median TLR was 1.3. No significant difference of the measured parameters was found between the subgroups according to the glioma grade. High GCP expression in the recurrent glioma was demonstrated in-vivo with the use of [68Ga]Ga-PSMA-11 PET/CT. As the treatment options in recurrent glioma are limited, this observation may open new therapeutic perspectives with the use of radiolabeled agents targeting the GCP.

Experience in treatment of glial tumors using the CyberKnife device

The study objective is to determine the effectiveness of stereotactic radiotherapy in treatment of glial cerebral tumors.Materials and methods. Results of using stereotactic radiotherapy in treatment of recurrent cerebral gliomas in 30 patients and primary glial tumor in 1 patient who couldn’t receive traditional radiotherapy were analyzed. Treatment was administered both to adults (n = 22) and children (n = 9). Prior to treatment all patients underwent pre-radiotherapy preparation in the form of contrast-enhanced magnetic resonance topometry of the brain, computed tomography with topometry, as well as positron emission tomography/computed tomography with amino acids (n = 21).Results. During treatment 2 patient developed grade II toxic reactions requiring emergency medical help. In 29 patients, treatment did not cause any complications. At the time of article preparation, 7 patients were alive; maximal follow-up period was 55 months, median follow-up duration was 8 months.Conclusion. Stereotactic radiotherapy can be used for disease stabilization. The results show effectiveness and safety of stereotactic radiotherapy as a salvage method of local treatment in patients with recurrent glial tumors of the brain.

Primal-dual for classification with rejection (PD-CR): a novel method for classification and feature selection—an application in metabolomics studies

Background Supervised classification methods have been used for many years for feature selection in metabolomics and other omics studies. We developed a novel primal-dual based classification method (PD-CR) that can perform classification with rejection and feature selection on high dimensional datasets. PD-CR projects data onto a low dimension space and performs classification by minimizing an appropriate quadratic cost. It simultaneously optimizes the selected features and the prediction accuracy with a new tailored, constrained primal-dual method. The primal-dual framework is general enough to encompass various robust losses and to allow for convergence analysis. Here, we compare PD-CR to three commonly used methods: partial least squares discriminant analysis (PLS-DA), random forests and support vector machines (SVM). We analyzed two metabolomics datasets: one urinary metabolomics dataset concerning lung cancer patients and healthy controls; and a metabolomics dataset obtained from frozen glial tumor samples with mutated isocitrate dehydrogenase (IDH) or wild-type IDH. Results PD-CR was more accurate than PLS-DA, Random Forests and SVM for classification using the 2 metabolomics datasets. It also selected biologically relevant metabolites. PD-CR has the advantage of providing a confidence score for each prediction, which can be used to perform classification with rejection. This substantially reduces the False Discovery Rate. Conclusion PD-CR is an accurate method for classification of metabolomics datasets which can outperform PLS-DA, Random Forests and SVM while selecting biologically relevant features. Furthermore the confidence score provided with PD-CR can be used to perform classification with rejection and reduce the false discovery rate.

The Inhibitory Effects of Terminalia catappa L. Extract on the Migration and Invasion of Human Glioblastoma Multiforme Cells

Glioblastoma multiforme (GBM) is one of the most aggressive and common types of brain tumor. Due to its high proliferation ability, a high lethality rate has been observed with this malignant glial tumor. Terminalia catappa L. (T. catappa) is currently known to have anti-inflammatory and anti-carcinogenesis effects. However, few studies have examined the mechanisms of the leaf extracts of T. catappa (TCE) on GBM cells. In the current study, we demonstrated that TCE can significantly inhibit the migration and invasion capabilities of GBM cell lines without showing biotoxic effects. Matrix metalloproteinases-2 (MMP-2) activity and protein expression were attenuated by reducing the p38 phosphorylation involved in the mitogen-activated protein kinase (MAPK) pathway. By treating with TCE and/or p38 inhibitor (SB203580), we confirmed that p38 MAPK is involved in the inhibition of cell migration. In conclusion, our results demonstrated that TCE inhibits human GBM cell migration and MMP-2 expression by regulating the p38 pathway. These results reveal that TCE contains potent therapeutic compounds which could be applied for treating GBM brain tumors.

Transmembrane Protein TMEM230, a Target of Glioblastoma Therapy

Glioblastomas (GBM) are the most aggressive tumors originating in the brain. Histopathologic features include circuitous, disorganized, and highly permeable blood vessels with intermittent blood flow. These features contribute to the inability to direct therapeutic agents to tumor cells. Known targets for anti-angiogenic therapies provide minimal or no effect in overall survival of 12–15 months following diagnosis. Identification of novel targets therefore remains an important goal for effective treatment of highly vascularized tumors such as GBM. We previously demonstrated in zebrafish that a balanced level of expression of the transmembrane protein TMEM230/C20ORF30 was required to maintain normal blood vessel structural integrity and promote proper vessel network formation. To investigate whether TMEM230 has a role in the pathogenesis of GBM, we analyzed its prognostic value in patient tumor gene expression datasets and performed cell functional analysis. TMEM230 was found necessary for growth of U87-MG cells, a model of human GBM. Downregulation of TMEM230 resulted in loss of U87 migration, substratum adhesion, and re-passaging capacity. Conditioned media from U87 expressing endogenous TMEM230 induced sprouting and tubule-like structure formation of HUVECs. Moreover, TMEM230 promoted vascular mimicry-like behavior of U87 cells. Gene expression analysis of 702 patients identified that TMEM230 expression levels distinguished high from low grade gliomas. Transcriptomic analysis of patients with gliomas revealed molecular pathways consistent with properties observed in U87 cell assays. Within low grade gliomas, elevated TMEM230 expression levels correlated with reduced overall survival independent from tumor subtype. Highest level of TMEM230 correlated with glioblastoma and ATP-dependent microtubule kinesin motor activity, providing a direction for future therapeutic intervention. Our studies support that TMEM230 has both glial tumor and endothelial cell intracellular and extracellular functions. Elevated levels of TMEM230 promote glial tumor cell migration, extracellular scaffold remodeling, and hypervascularization and abnormal formation of blood vessels. Downregulation of TMEM230 expression may inhibit both low grade glioma and glioblastoma tumor progression and promote normalization of abnormally formed blood vessels. TMEM230 therefore is both a promising anticancer and antiangiogenic therapeutic target for inhibiting GBM tumor cells and tumor-driven angiogenesis.

The High-Grade Glial Component Of Pediatric Primary Anaplastic Ganglioglioma Characterized Astroblastoma-Like Pseudorosettes With BRAFV600E Mutation And Deletion Of CDKN2A/B, PTEN, And BMPR1A: A Case Report

Background: Ganglioglioma (GG) is a low-grade mixed neuronal-glial tumor which is the most common type of long-term epilepsy-associated tumors (LEATs). However, primary anaplastic ganglioglioma (AGG) which composes of malignant changes is rare. Here, we report a case of pediatric primary AGG which is consisted of low-grade/begnin GG and high-grade glioma that was characterized by astroblastoma-like pseudorosettes. Case presentation: We describe a case of 4-year-old female who presented with medically refractory seizure for 14 months by a temporal mass. The patient underwent a gross total mass resection at the first surgery, and was only treated with antiepileptic therapy and followed by observation. After nine months, tumor recurrence was found. Followed by second operation, the patient was treated with chemotherapy (oral temozolomide and antiepileptic drugs) and local radiotherapy. At 58-month follow-up after the second operation, no epileptic seizures and tumor recurrence were found again. In the first sample, the tumor contained two different components. The major component presented the low-grade GG’s features of neoplastic glial cells and dysplastic ganglion cells. The minor component was a heterogeneous high-grade glioma characterized astroblastic-like pseudorosettes clusters with increased mitotic figure (about 4-6 per 10 high-power fields). CD34 staining was negative. BRAFV600E was positive in both components. In the recurrent sample, the heterogeneous high-grade glioma became the major component. The fuorescence in situ hybridization (FISH) of MN1 break-apart probe and MYB–QKI fusions probe were negative. BRAFV600E mutation, and deletion of CDKN2A/B, PTEN and BMPR1A were detected by targeted DNA sequencing. Conclusion: This case extends the histomorphologic spectrum and enriched genetic features of primary AGG in childhood. The high-grade glioma charactered astroblastoma-like pseudorosettes may be an important cause of tumor recurrence in a short period of time. Tumor gross total surgical resection and adjuvant chemoradiotherapy were important to achive an event-free survival.

Multiprong control of glioblastoma multiforme invasiveness: blockade of pro-inflammatory signaling, anti-angiogenesis, and homeostasis restoration

Glioblastoma multiforme (GBM) is the most invasive type of glial tumor with poor overall survival, despite advances in surgical resection, chemotherapy, and radiation. One of the main challenges in treating GBM is related to the tumor’s location, complex and heterogeneous biology, and high invasiveness. To meet the demand for oxygen and nutrients, growing tumors induce new blood vessels growth. Antibodies directed against vascular endothelial growth factor (VEGF), which promotes angiogenesis, have been developed to limit tumor growth. Bevacizumab (Avastin), an anti-VEGF monoclonal antibody, is the first approved angiogenesis inhibitor with therapeutic promise. However, it has limited efficacy, likely due to adaptive mutations in GBM, leading to overall survival compared to the standard of care in GBM patients. Molecular connections between angiogenesis, inflammation, oxidative stress pathways, and the development of gliomas have been recognized. Improvement in treatment outcomes for patients with GBM requires a multifaceted approach due to the converging dysregulation of signaling pathways. While most GBM clinical trials focus on “anti-angiogenic” modalities, stimulating inflammation resolution is a novel host-centric therapeutic avenue. The selective therapeutic possibilities for targeting the tumor microenvironment, specifically angiogenic and inflammatory pathways expand. So, a combination of agents aiming to interfere with several mechanisms might be beneficial to improve outcomes. Our approach might also be combined with other therapies to enhance sustained effectiveness. Here, we discuss Suramab (anti-angiogenic), LAU-0901 (a platelet-activating factor receptor antagonist), Elovanoid (ELV; a novel lipid mediator), and their combination as potential alternatives to contain GBM growth and invasiveness.

RARE PRESENTATION OF LHERMITTE-DUCLOS DISEASE

Lhermitte-Duclos disease (LDD) arises from an uncommon benign lesion which alters the normal cerebellar laminar pattern. This case report shows the imaging ndings of this condition in 39 year-old male, presented with history of headache and dizziness for duration of ten days. Intial assessment included a non-contrast CT which showed a mass in left cerebellar hemisphere with surrounding mass effect. MRI multiplanar sequences showed a well dened T2 hyperintense lesion with a tigroid appearance.The lesion showed a mild bright signal on diffusion-weighted images, whereas MR Spectroscopy shows reduced choline levels. Differential diagnosis in terms of imaging include subacute infarct, cerebellitis, glial tumor,encephalitis but these do not give the classical tigroid appearance on MRI. Lack of contrast enhancement , signicant diffusion and cellularity of the lesions can help in differentiating among them.

Imaging of glial tumor recurrence using [68Ga]Ga-PSMA-11 PET/CT

Background and PurposeLimited data is available on the possible use of [68Ga]Ga-PSMA-11 PET/CT for the diagnosis of glioma recurrence. The aim of this paper was to assess the use of [68Ga]Ga-PSMA-11 PET/CT for the detection of recurrence in different glial tumors.Materials and Methods34 patients (pts.) aged 44.5±10.3 years with suspicion of recurrence of histologically confirmed glioma grade III (6 pts.) and grade IV (28 pts.) were included in the study. All patients underwent contrast-enhanced MR and [68Ga]Ga-PSMA-11 PET/CT.ResultsNo radiopharmaceutical-related adverse events were noted. PET/CT was positive in all the areas suspected for recurrence at MR in all the patients. The recurrence was confirmed by histopathological examinations or follow-up imaging in all cases. The images showed a very low background activity of the normal brain. Median maximal standard uptake value (SUVmax) of the tumors was 6.5 (range: 0.9–15.6) and mean standard uptake value (SUVmean) was 3.5 (range: 0.9–7.5). Target-to-background (TBR) ratios varied between 15 and 1400 with a median of 152. Target-to-liver background ratios (TLR) ranged from 0.2 to 2.6, the median TLR was 1.3. No significant difference of the measured parameters was found between the subgroups according to the glioma grade.Conclusion[68Ga]Ga-PSMA-11 PET/CT shows excellent results in the diagnosis of glioma recurrence of various grades. Due to the very low background activity, this method provides high-quality images and allows for the detection of well-defined recurrence lesions.