European Mistletoe (Viscum album) Extract Is Cytotoxic to Canine High-Grade Astrocytoma Cells In Vitro and Has Additive Effects with Mebendazole

Malignant gliomas are associated with extremely poor clinical outcomes in both humans and dogs, and novel therapies are needed. Glioma-bearing canine patients may serve as promising preclinical models for human therapies, including complementary medicine. The objective of this study was to evaluate the effects of mistletoe extract (Viscum album) alone and in combination with mebendazole in an in vitro model of canine high-grade astrocytoma using the cell line SDT-3G. SDT-3G cells were exposed to a range of concentrations of mistletoe extract alone to obtain an IC50. In separate experiments, cells were exposed to mebendazole at a previously determined IC50 (0.03 µM) alone or in conjunction with varying concentrations of mistletoe extract to determine the additive effects. The IC50 for mistletoe alone was 5.644 ± 0.09 SD μg/mL. The addition of mistletoe at 5 μg/mL to mebendazole at 0.03 µM led to increased cell death compared to what would be expected for each drug separately. The cytotoxicity of mistletoe in vitro and its additive effect with mebendazole support future expanded in vitro and in vivo studies in dogs and supply early evidence that this may be a useful adjunct therapeutic agent for use in glioma-bearing dogs. To the authors’ knowledge, this is the first published report of Viscum album extract in canine glioma.

Laporan Kasus Butterfly gliobasltoma pada Laki-Laki Usia 24 Tahun

Pendahuluan Butterfly Glioma adalah high grade astrocytoma, biasanya glioblastoma (WHO grade IV), yang melintasi garis tengah melalui corpus callosum. Komissura white matter lainnya kadang juga terlibat. Istilah kupu-kupu mengacu pada ekstensi yang melewati garis tengah seperti sayap. Butterfly Glioma paling sering terjadi di lobus frontal, melintasi garis tengah melalui genu corpus callosum, namun butterfly glioma posterior kadang juga ditemui. Laporan kasus Seorang pasien laki-laki usia 24 tahun dengan keluhan utama 9 bulan, yang lalu. Penglihatan kabur, konsentrasi menurun. Kejang(-). Kemudian 3 bulan yang lalu mata tidak bisa melihat. Dan 1 bulan yang lalu tubuh lemas susah digerakkan Pemeriksaan patologi anatomi menunjukkan Pylocytic Astrocytoma. Pemeriksaan CT scan kepala menunjukkan Massa solid inhomogen intraxial ( ukuran ± AP 7,6 x 8,9 x CC 6,2 cm ) disertai kalsifikasi di dalamnya pada corpus callosum yang tampak cross mid line ( sisi kiri lebih dominan ) membentuk gambaran butterfly sign dengan perifocal edema à curiga gambaran glioblastoma multiformis. Pembahasan Hasil pemeriksaan anamnesis dan pemeriksaan fisik pasien ini menunjukkan kecurigaan adanya SOL. Pemeriksaan CT scan kepala menunjukkan Massa solid inhomogen intraxial disertai kalsifikasi di dalamnya pada corpus callosum yang tampak cross mid line ( sisi kiri lebih dominan ) membentuk gambaran butterfly sign dengan perifocal edema à curiga gambaran glioblastoma multiformis. Dari PA didapatkan hasil Pilocytic astrocytoma. Sedangkan gambaran radiologi Pilocytic astrocytoma berupa lesi kistik dengan nodul mural yang enhanced. Kasus ini secara radiologis lebih mengarah ke Butterfly Glioblastoma dengan adanya lesi yang melewati garis tengah, serta ada komponen nekrotik dan perdarahan.. Modalitas imejing pilihan yang dapat dilakukan pada kasus Butterfly Glioblastoma adalah CT scan dan MRI. Kesimpulan Kasus ini secara radiologis lebih mengarah ke Butterfly Glioblastoma dengan adanya lesi yang melewati garis tengah, serta ada komponen nekrotik dan perdarahan. Dan pemeriksaan radiologis yang dapat digunakan pada Butterfly Glioblastoma adalah CT scan dan MRI.

Molecular diagnostics helps to identify distinct subgroups of spinal astrocytomas

Primary spinal cord astrocytomas are rare, hence few data exist about the prognostic significance of molecular markers. Here we analyze a panel of molecular alterations in association with the clinical course. Histology and genome sequencing was performed in 26 spinal astrocytomas operated upon between 2000 and 2020. Next-generation DNA/RNA sequencing (NGS) and methylome analysis were performed to determine molecular alterations. Histology and NGS allowed the distinction of 5 tumor subgroups: glioblastoma IDH wildtype (GBM); diffuse midline glioma H3 K27M mutated (DMG-H3); high-grade astrocytoma with piloid features (HAP); diffuse astrocytoma IDH mutated (DA), diffuse leptomeningeal glioneural tumors (DGLN) and pilocytic astrocytoma (PA). Within all tumor entities GBM (median OS: 5.5 months), DMG-H3 (median OS: 13 months) and HAP (median OS: 8 months) showed a fatal prognosis. DMG-H3 tend to emerge in adolescence whereas GBM and HAP develop in the elderly. HAP are characterized by CDKN2A/B deletion and ATRX mutation. 50% of PA tumors carried a mutation in the PIK3CA gene which is seemingly associated with better outcome (median OS: PIK3CA mutated 107.5 vs 45.5 months in wildtype PA). This exploratory molecular profiling of spinal cord astrocytomas allows to identify distinct subgroups by combining molecular markers and histomorphology. DMG-H3 tend to develop in adolescence with a similar dismal prognosis like GBM and HAP in the elderly. We here describe spinal HAP with a distinct molecular profile for the first time.

Overcoming the challenges in the treatment of glioblastoma via nanocarrier based drug delivery approach

Background: Glioblastoma multiforme is the most malignant form of high-grade astrocytoma. Clinically it is characterized as 4thgrade of astrocytoma having necrotic tissue and hyperplastic blood vessel. It is observed to be the most frequent adult brain tumor representing an overall 15.4% of all brain tumors and about 60-75% of the entire astrocytoma. There are limited therapies available and the most widely used therapy includes surgical intrusion followed by radiotherapy plus chemotherapy (paclitaxel, temozolomide, docetaxel, etc); with an overall patient survival rate from 6–14 months. Various studies have proved that nanoformulations offer considerable advantages like enhanced drug solubility, targeted activity, and attenuated side effects. Objective: The key objective of this review article is to exemplify numerous studies carried out using nanocarriers for overcoming the challenges associated with the treatment of glioblastoma. It also describes the pathways associated with the induction, initiation, and progression of glioblastoma. Methods: Research articles that focused on the use of nanocarrier-based drug delivery approach for the treatment of various glioblastoma were collected from different search engines, such as Google Scholar, Science Direct, and PubMed using keywords like glioblastoma, nanocarriers, Brain delivery, etc. Results: Nanocarriers have shown enormous potential in overcoming the challenges associated with the treatment of glioblastoma. Conclusion: Broad research is still needed so that these nanocarriers can be used clinically for the welfare of mankind, in the management of glioblastoma, in near future.

High-grade astrocytoma with piloid features (HGAP): the Charité experience with a new central nervous system tumor entity

Purpose High-grade astrocytoma with piloid features (HGAP) is a recently described brain tumor entity defined by a specific DNA methylation profile. HGAP has been proposed to be integrated in the upcoming World Health Organization classification of central nervous system tumors expected in 2021. In this series, we present the first single-center experience with this new entity. Methods During 2017 and 2020, six HGAP were identified. Clinical course, surgical procedure, histopathology, genome-wide DNA methylation analysis, imaging, and adjuvant therapy were collected. Results Tumors were localized in the brain stem (n = 1), cerebellar peduncle (n = 1), diencephalon (n = 1), mesencephalon (n = 1), cerebrum (n = 1) and the thoracic spinal cord (n = 2). The lesions typically presented as T1w hypo- to isointense and T2w hyperintense with inhomogeneous contrast enhancement on MRI. All patients underwent initial surgical intervention. Three patients received adjuvant radiochemotherapy, and one patient adjuvant radiotherapy alone. Four patients died of disease, with an overall survival of 1.8, 9.1, 14.8 and 18.1 months. One patient was alive at the time of last follow-up, 14.6 months after surgery, and one patient was lost to follow-up. Apart from one tumor, the lesions did not present with high grade histology, however patients showed poor clinical outcomes. Conclusions Here, we provide detailed clinical, neuroradiological, histological, and molecular pathological information which might aid in clinical decision making until larger case series are published. With the exception of one case, the tumors did not present with high-grade histology but patients still showed short intervals between diagnosis and tumor progression or death even after extensive multimodal therapy.

LPA1 Receptor Promotes Progesterone Receptor Phosphorylation through PKCα in Human Glioblastoma Cells

Lysophosphatidic acid (LPA) induces a wide range of cellular processes and its signaling is increased in several cancers including glioblastoma (GBM), a high-grade astrocytoma, which is the most common malignant brain tumor. LPA1 receptor is expressed in GBM cells and its signaling pathways activate protein kinases C (PKCs). A downstream target of PKC, involved in GBM progression, is the intracellular progesterone receptor (PR), which can be phosphorylated by this enzyme, increasing its transcriptional activity. Interestingly, in GBM cells, PKCα isotype translocates to the nucleus after LPA stimulation, resulting in an increase in PR phosphorylation. In this study, we determined that LPA1 receptor activation induces protein-protein interaction between PKCα and PR in human GBM cells; this interaction increased PR phosphorylation in serine400. Moreover, LPA treatment augmented VEGF transcription, a known PR target. This effect was blocked by the PR selective modulator RU486; also, the activation of LPA1/PR signaling promoted migration of GBM cells. Interestingly, using TCGA data base, we found that mRNA expression of LPAR1 increases according to tumor malignancy and correlates with a lower survival in grade III astrocytomas. These results suggest that LPA1/PR pathway regulates GBM progression.

Canine Gliomatosis Cerebri: Morphologic and Immunohistochemical Characterization Is Supportive of Glial Histogenesis

Gliomatosis cerebri (GC) is a glioma subtype with diffuse neuroparenchymal infiltration without architectural distortion. GC was first used in human neuropathology and remained controversial until its elimination from the diagnostic lexicon in 2016. GC is currently defined as a diffuse growth pattern of glioma rather than a distinct entity. In this article, we characterize 24 cases of canine GC and classify these neoplasms as diffuse gliomas. Selected cases of canine GC were reviewed and immunolabeled for oligodendrocyte lineage transcription factor 2 (Olig2), glial fibrillary acidic protein (GFAP), and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase). The mean age of affected dogs was 7 years, and 9 were brachycephalic. Gross lesions (8 cases) consisted mainly of parenchymal swelling. Histologically, of the 24 cases, there was widespread infiltration of neoplastic cells with astrocytic (12 cases), oligodendroglial (8 cases), or mixed morphology (4 cases) in the brain (18 cases), spinal cord (4 cases), or both (2 cases). Secondary structures occurred across different tumor grades and were not restricted to high-grade neoplasms. Astrocytic neoplasms had moderate nuclear immunolabeling for Olig2 and robust cytoplasmic immunolabeling for GFAP. Oligodendroglial neoplasms had robust nuclear immunolabeling for Olig2, moderate or absent cytoplasmic immunolabeling for GFAP, and moderate cytoplasmic immunolabeling for CNPase. Tumors with mixed morphology had robust nuclear immunolabeling for Olig2 and variable cytoplasmic immunolabeling for GFAP and CNPase. Morphologic and immunohistochemical features confirmed a glial histogenesis for all tumors and allowed for their classification as diffuse, low- or high-grade astrocytoma; oligodendroglioma; or undefined glioma. Further research is needed to confirm or refute the hypothesis that canine GC represents an infiltrative growth pattern of canine glioma.