Selective Uptake of Hematoporphyrin Derivative into Human Cerebral Glioma

Neurosurgery ◽  
1990 ◽  
Vol 26 (2) ◽  
pp. 248-254 ◽  
Author(s):  
John S. Hill ◽  
Andrew H. Kaye ◽  
William H. Sawyer ◽  
George Morstyn ◽  
Phillip D. Megison ◽  
...  
Keyword(s):  
Low Grade ◽  
Normal Brain ◽  
Hematoporphyrin Derivative ◽  
Cerebral Glioma ◽  
Normal Brain Tissue ◽  
Selective Uptake ◽  
Tumor Region ◽  
Wet Weight ◽  
The Brain ◽  
Adjacent Brain

Abstract The uptake of hematoporphyrin derivative (HpD) into human cerebral glioma was measured using a porphyrin extraction technique. Patients with cerebral glioma were injected with HpD at a dose of 5 mg/kg body weight 24 hours before surgery and photoradiation therapy (PRT). Biopsies of tumor, and where possible, adjacent brain and normal brain were taken for analysis of HpD uptake. HpD was selectively localized into all grades of glioma, and there was a direct correlation between the grade of glioma and HpD level in the tumor. The levels were highest in glioblastoma multiforme (mean uptake of 5.9 mg of HpD/g of tumor wet weight) and lower in the intermediate-grade anaplastic astrocytoma (mean uptake of 2.4 mg/g of tumor) and the low-grade astrocytoma (1.6 mg/g of tumor), Uptake into normal brain tissue taken from HpD-sensitized patients was 0.2 mg/g. HpD was also localized into the “brain adjacent to tumor” region. The selective uptake into the low-grade glioma suggests that PRT may be of use as an adjuvant therapy in these tumors and the detection of HpD in this region indicates that PRT may control the spread of tumor infiltrating into the adjacent normal brain.

scholarly journals P11.57 A 3D brain organoid coculture system delineates the invasive cell components in glioblastoma

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii56-iii57
Author(s):  
W Zhou ◽  
B Klink ◽  
G Dittmar ◽  
P Nazarov ◽  
E M Garcia ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Cell Invasion ◽  
Ex Vivo ◽  
Normal Brain ◽  
Rna Seq ◽  
Normal Brain Tissue ◽  
Coculture System ◽  
Mature Brain ◽  
Brain Organoid ◽  
The Brain

Abstract BACKGROUND Glioblastoma (GBM) cell infiltration into the surrounding normal brain tissue where the blood brain barrier is intact, represents a major problem for clinical management and therapy. There is a vital need to understand the molecular mechanism that drives tumor cell invasion into the surrounding brain. We have previously developed a 3D coculture model where mature brain organoids are confronted with patient-derived glioblastoma stem-like cells (GSCs). In such a coculture system, single cell invasion into the normal brain tissue can be studied in detail. Here, we first describe in detail, by RNA-seq and proteomics, the differentiation of various neural cell lineages into mature brain organoids as well as their cellular organization. By real-time confocal microscopy and imaging analyses we also determine the speed of tumor cell invasion into the brain. Finally, we used this coculture system to delineate in detail the cellular heterogeneity within the invasive compartment and their gene expression. MATERIAL AND METHODS Immunohistochemistry and immunofluorescence were used to determine the expression and distribution of mature neurons, astrocytes, oligodendrocytes, and microglia within the brain organoids. Proteomics and RNA-seq were used to determine brain development ex-vivo. To assess the clonal composition of the GBM-invasive compartment, we used cellular (RGB) barcoding technology. By advanced imaging, we tracked in real time the invasion of barcoded cells into the brain organoids. Finally, we isolated invasive cells and non-invasive cells from our coculture system and used single cell sequencing to analyze their gene expression profiles and molecular phenotypes. RESULTS Immunohistochemistry and immunofluorescence showed that brain organoids, after 21 days of differentiation, display a highly cellular and structural organization. RNA-seq and proteomics, performed at different time points of organoid differentiation, revealed that the brain organoids develop into mature brain structures after 21 days as verified by a comparative analysis to normal rat brain development in vivo. Imaging analyses showed that multiple clones within the GBMs have the capacity to invade into the brain tissue with an average speed of ~ 20 μm/h. RNA-sec analysis of the invasive compartment revealed a strong up-regulation of genes and pathways associated with anaerobic respiration (glycolysis). CONCLUSION We describe a highly standardized brain organoid coculture system that can be used to delineate GBM invasion ex-vivo. We demonstrate that this platform can be used to unravel the mechanisms that drive GBM invasion into the normal brain.

scholarly journals The Emerging Role of the Interplay Among Astrocytes, Microglia, and Neurons in the Hippocampus in Health and Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Daniele Lana ◽  
Filippo Ugolini ◽  
Daniele Nosi ◽  
Gary L. Wenk ◽  
Maria Grazia Giovannini
Keyword(s):  
Acute Inflammation ◽  
Brain Aging ◽  
Morphological Changes ◽  
Brain Regions ◽  
Stratum Radiatum ◽  
Low Grade ◽  
Normal Brain ◽  
Chronic Inflammatory Response ◽  
Health And Disease ◽  
The Brain

For over a century, neurons have been considered the basic functional units of the brain while glia only elements of support. Activation of glia has been long regarded detrimental for survival of neurons but more it appears that this is not the case in all circumstances. In this review, we report and discuss the recent literature on the alterations of astrocytes and microglia during inflammaging, the low-grade, slow, chronic inflammatory response that characterizes normal brain aging, and in acute inflammation. Becoming reactive, astrocytes and microglia undergo transcriptional, functional, and morphological changes that transform them into cells with different properties and functions, such as A1 and A2 astrocytes, and M1 and M2 microglia. This classification of microglia and astrocytes in two different, all-or-none states seems too simplistic, and does not correspond to the diverse variety of phenotypes so far found in the brain. Different interactions occur among the many cell populations of the central nervous system in health and disease conditions. Such interactions give rise to networks of morphological and functional reciprocal reliance and dependency. Alterations affecting one cell population reverberate to the others, favoring or dysregulating their activities. In the last part of this review, we present the modifications of the interplay between neurons and glia in rat models of brain aging and acute inflammation, focusing on the differences between CA1 and CA3 areas of the hippocampus, one of the brain regions most susceptible to different insults. With triple labeling fluorescent immunohistochemistry and confocal microscopy (TIC), it is possible to evaluate and compare quantitatively the morphological and functional alterations of the components of the neuron-astrocyte-microglia triad. In the contiguous and interconnected regions of rat hippocampus, CA1 and CA3 Stratum Radiatum, astrocytes and microglia show a different, finely regulated, and region-specific reactivity, demonstrating that glia responses vary in a significant manner from area to area. It will be of great interest to verify whether these differential reactivities of glia explain the diverse vulnerability of the hippocampal areas to aging or to different damaging insults, and particularly the higher sensitivity of CA1 pyramidal neurons to inflammatory stimuli.

scholarly journals Isavuconazole Diffusion in Infected Human Brain

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Claire Rouzaud ◽  
Vincent Jullien ◽  
Anne Herbrecht ◽  
Bruno Palmier ◽  
Simona Lapusan ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Plasma Concentration ◽  
Brain Tissue ◽  
Radical Surgery ◽  
Neurological Complication ◽  
Lymphocytic Leukemia ◽  
Normal Brain ◽  
Granulomatous Disease ◽  
Normal Brain Tissue ◽  
The Brain

ABSTRACT We report the cases of a 39-year-old woman with chronic lymphocytic leukemia and a 21-year-old man with chronic granulomatous disease treated for cerebral aspergillosis. The patients required radical surgery for infection progression despite adequate isavuconazole plasma concentration or neurological complication. We thus decided to measure the brain isavuconazole concentration. These results suggest that the concentrations of isavuconazole obtained in the infected brain tissue clearly differ from those obtained in the normal brain tissue and the cerebrospinal fluid.

scholarly journals Enrichment of Aldolase C Correlates with Low Non-Mutated IDH1 Expression and Predicts a Favorable Prognosis in Glioblastomas

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1238 ◽  
Author(s):  
Chang ◽  
Tsai ◽  
Huang ◽  
Chen ◽  
Hsiao ◽  
...  
Keyword(s):  
Protein Expression ◽  
Mrna Expression ◽  
Brain Tissue ◽  
Low Grade ◽  
Normal Brain ◽  
Normal Brain Tissue ◽  
Expression Levels ◽  
Glioblastoma Patient ◽  
Favorable Prognosis ◽  
Aldolase C

The aldolases family is one of the main enzymes involved in the process of glycolysis. Aldolase C (ALDOC), which belongs to the aldolase family, is found in normal brain tissue and is responsible for the repair of injured tissue. However, the role of ALDOC in glioblastoma remains unclear. In this study, we data-mined in silico databases to evaluate aldolase family members’ mRNA expression in glioblastoma patient cohorts for determining its prognostic values. After that, we also performed immunohistochemical stain (IHC) analysis to evaluate protein expression levels of ALDOC in glioblastoma tissues. From The Cancer Genome Atlas (TCGA) database analyses, higher mRNA expression levels in normal brain tissue compared to glioblastoma was observed. In addition, compared to low-grade glioma, ALDOC expression was significantly downregulated in high-grade glioblastoma. Besides, the expression level of ALDOC was associated with molecular subtypes of glioblastomas and recurrent status in several data sets. In contrast, aldolase A (ALDOA) and aldolase B (ALDOB) revealed no significant prognostic impacts in the glioblastoma cohorts. Furthermore, we also proved that ALDOC mRNA and protein expression inversely correlated with non-mutated IDH1 expressions in glioblastoma patient cohorts. Additionally, the concordance of low ALDOC and high non-mutated IDH1 expressions predicted a stronger poor prognosis in glioblastoma patients compared to each of above tests presented alone. The plausible ALDOC and IDH1 regulatory mechanism was further elucidated. Our results support high ALDOC expression in glioblastomas that might imply the mutated status of IDH1, less possibility of mesenchymal subtype, and predict a favorable prognosis.

scholarly journals Elucidating the kinetics of sodium fluorescein for fluorescence-guided surgery of glioma

2019 ◽  
Vol 131 (3) ◽  
pp. 724-734 ◽  
Author(s):  
Margaret Folaron ◽  
Rendall Strawbridge ◽  
Kimberley S. Samkoe ◽  
Caroline Filan ◽  
David W. Roberts ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Sodium Fluorescein ◽  
Normal Brain ◽  
Normal Brain Tissue ◽  
Guided Surgery ◽  
Fluorescence Guided Surgery ◽  
Kinetics Of ◽  
The Brain ◽  
Pegylated Form ◽  
Tissue Kinetics

OBJECTIVEThe use of the optical contrast agent sodium fluorescein (NaFl) to guide resection of gliomas has been under investigation for decades. Although this imaging strategy assumes the agent remains confined to the vasculature except in regions of blood-brain barrier (BBB) disruption, clinical studies have reported significant NaFl signal in normal brain tissue, limiting tumor-to-normal contrast. A possible explanation arises from earlier studies, which reported that NaFl exists in both pure and protein-bound forms in the blood, the former being small enough to cross the BBB. This study aims to elucidate the kinetic binding behavior of NaFl in circulating blood and its effect on NaFl accumulation in brain tissue and tumor contrast. Additionally, the authors examined the blood and tissue kinetics, as well as tumor uptake, of a pegylated form of fluorescein selected as a potential optical analog of gadolinium-based MRI contrast agents.METHODSCohorts of mice were administered one of the following doses/forms of NaFl: 1) high human equivalent dose (HED) of NaFl, 2) low HED of NaFl, or 3) pegylated form of fluorescein. In each cohort, groups of animals were euthanized 15, 30, 60, and 120 minutes after administration for ex vivo analysis of fluorescein fluorescence. Using gel electrophoresis and fluorescence imaging of blood and brain specimens, the authors quantified the temporal kinetics of bound NaFl, unbound NaFl, and pegylated fluorescein in the blood and normal brain tissue. Finally, they compared tumor-to-normal contrast for NaFl and pegylated-fluorescein in U251 glioma xenografts.RESULTSAdministration of NaFl resulted in the presence of unbound and protein-bound NaFl in the circulation, with unbound NaFl constituting up to 70% of the signal. While protein-bound NaFl was undetectable in brain tissue, unbound NaFl was observed throughout the brain. The observed behavior was time and dose dependent. The pegylated form of fluorescein showed minimal uptake in brain tissue and improved tumor-to-normal contrast by 38%.CONCLUSIONSUnbound NaFl in the blood crosses the BBB, limiting the achievable tumor-to-normal contrast and undermining the inherent advantage of tumor imaging in the brain. Dosing and incubation time should be considered carefully for NaFl-based fluorescence-guided surgery (FGS) of glioma. A pegylated form of fluorescein showed more favorable normal tissue kinetics that translated to higher tumor-to-normal contrast. These results warrant further development of pegylated-fluorescein for FGS of glioma.

Chemotherapy of brain tumors

1972 ◽  
Vol 37 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Charles H. Tator
Keyword(s):  
Brain Tumors ◽  
Chemotherapeutic Agent ◽  
Normal Brain ◽  
Neoplastic Cells ◽  
Central Mass ◽  
Content Type ◽  
Intracerebral Tumor ◽  
Almost All ◽  
The Brain ◽  
Adjacent Brain

✓ The uptake and distribution in brain tumors of a parenterally administered chemotherapeutic agent were studied in mice bearing intracerebral implants of a transplantable ependymoblastoma. Tritiated methotrexate (3H-MTX) was injected intravenously, and autoradiographs of the tumors and adjacent brain were prepared at 2, 10, and 60 min after injection using a technique suitable for soluble compounds. In the tumors at 2 min the drug was mainly intravascular and interstitial while at 60 min the drug was mainly intracellular. This is the first demonstration of cellular uptake of a chemotherapeutic agent by neoplastic cells within the brain. At 60 min, almost all the cells in the central mass of the intracerebral tumors were heavily labeled. However, cells at the periphery of the mass and those infiltrating into adjacent brain showed scanty labeling. Uptake in normal brain was very low, while uptake in edematous brain adjacent to the tumors was much higher although not as high as in the tumors. The study shows that this chemotherapeutic agent is capable of penetrating into the neoplastic cells of an intracerebral tumor following parenteral administration, but that the degree of penetration varies considerably depending on the location of the cells within the brain.

Distribution of hematoporphyrin derivative in the rat 9L gliosarcoma brain tumor analyzed by digital video fluorescence microscopy

1984 ◽  
Vol 61 (6) ◽  
pp. 1113-1119 ◽  
Author(s):  
James E. Boggan ◽  
Robert Walter ◽  
Michael S. B. Edwards ◽  
Janis K. Borcich ◽  
Richard L. Davis ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Model ◽  
Normal Brain ◽  
Hematoporphyrin Derivative ◽  
Content Type ◽  
9L Gliosarcoma ◽  
Video Fluorescence Microscopy ◽  
Brain Tumor Model ◽  
The Brain ◽  
Fine Print

✓ A digital video fluorescence microscopy technique was used to evaluate the distribution of hematoporphyrin derivative (HPD) in the rat intracerebral 9L gliosarcoma brain-tumor model at 4, 24, 48, and 72 hours after intravenous administration of 10 mg/kg of the drug. Compared to surrounding normal brain, there was significant preferential uptake of HPD into the tumor. In sections surveyed, fluorescence reached a maximum value by 24 hours; however, only 33% to 44% of the tumor was fluorescent. In contrast, fluorescence within the surrounding normal brain was maximum at 4 hours, but was present in less than 1% of the brain tissue evaluated. The effect of HPD sensitization to a laser light dose (633 nm) of 30 joules/sq cm delivered through the intact skull was evaluated histologically in 10 rats. A patchy coagulation necrosis, possibly corresponding to the distribution of HPD fluorescence seen within the tumor, was observed. There was evidence that photoradiation therapy (PRT) affects defective tumor vasculature and that a direct tumor cell toxicity spared normal brain tissue. Despite these findings, limited uptake of HPD in tumor and the brain adjacent to tumor may decrease the effectiveness of PRT in the 9L gliosarcoma brain-tumor model. Because of the similarity between the capillary system of the 9L tumor and human brain tumors, PRT may have a limited therapeutic effect in patients with malignant brain tumors.

scholarly journals The Relationship between Intra-Operative Ultrasonography and Pathological Grade in Cerebral Glioma

2008 ◽  
Vol 36 (6) ◽  
pp. 1426-1434 ◽  
Author(s):  
J Wang ◽  
X Liu ◽  
WH Hou ◽  
G Dong ◽  
Z Wei ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Low Grade ◽  
Normal Brain ◽  
Residual Tumour ◽  
Cerebral Glioma ◽  
Pathological Grade ◽  
Early Evaluation ◽  
Cerebral Gliomas ◽  
Operative Ultrasound ◽  
The Relationship

The value of intra-operative ultrasound as a tool in guiding resection of cerebral gliomas and the relationship between the appearance of brain tissue on intra-operative ultrasonography and pathological grade of cerebral glioma were investigated in 98 patients who underwent neurosurgical tumour removal. Lesions were classified according to pathological grade. Intra-operative ultrasonography orientated all the cerebral gliomas accurately and helped the neurosurgeon in assessing the tumour prior to removal. All lesions were hyperechoic compared with normal brain tissue, and the majority of lesions displayed irregular shapes and indistinct margins. Different pathological grades of glioma presented different ultrasonographic appearances. The majority of low-grade (I and II) cerebral gliomas were homogeneous, with distinct margins and clear surrounding oedema compared with adjacent brain tissue. High-grade (III and IV) cerebral gliomas mostly exhibited poorly defined borders and central necrosis, and the surrounding oedema was difficult to distinguish from the lesions. Residual tumour or haematoma were identified. In conclusion, intra-operative ultrasonography is of great value in locating and assessing the grade of cerebral glioma, and is conducive to enabling early evaluation and total removal of the lesion.

Radiosurgery for Gliomas

US Neurology ◽  
2009 ◽  
Vol 05 (01) ◽  
pp. 45 ◽  
Author(s):  
Jay Jagannathan ◽  
Nader Pouratian ◽  
Jason P Sheehan ◽  
◽  
◽  
...  
Keyword(s):  
Stereotactic Radiosurgery ◽  
Malignant Gliomas ◽  
Biological Properties ◽  
Low Grade ◽  
Normal Brain ◽  
Normal Brain Tissue ◽  
Randomized Controlled ◽  
Randomized Controlled Studies ◽  
Operative Planning

Stereotactic radiosurgery is a neurosurgical modality that involves delivering a large dose of focused radiation to a lesion while sparing the surrounding normal brain tissue. The biological properties of some gliomas, specifically relating to their oxygenation and invasiveness, can make them good targets for stereotactic radiosurgery. Although randomized controlled studies are lacking, preliminary data suggest that radiosurgery may be a viable alternative for low-grade gliomas, with improved survival and a low rate of complications. Although the prognosis for malignant gliomas is poor even after radiosurgery, it is possible the radiosurgical treatment can allow the surgeon more flexibility in terms of operative planning and subsequently result in better quality of life for patients post-operatively.

Sign in / Sign up

Export Citation Format

Share Document