Regression of a metastatic lung mass after receiving whole brain irradiation: Can the abscopal effect cross the blood-brain barrier?

2018 ◽  
Vol 14 (5) ◽  
pp. e548-e550 ◽  
Author(s):  
Cheng-Hao Chuang ◽  
Jui-Feng Hsu ◽  
Yu-Ting Shen ◽  
Chih-Jen Yang
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Abscopal Effect ◽  
Lung Mass ◽  
Whole Brain Irradiation ◽  
Whole Brain ◽  
Brain Irradiation ◽  
Blood Brain ◽  
Metastatic Lung

scholarly journals Approaching Complete Inhibition of P-Glycoprotein at the Human Blood–Brain Barrier: An (R)-[11C]Verapamil PET Study

2015 ◽  
Vol 35 (5) ◽  
pp. 743-746 ◽  
Author(s):  
Martin Bauer ◽  
Rudolf Karch ◽  
Markus Zeitlinger ◽  
Cécile Philippe ◽  
Kerstin Römermann ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Blood Brain Barrier ◽  
Distribution Volume ◽  
Emission Tomography ◽  
Brain Barrier ◽  
Whole Brain ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Positron Emission ◽  
Pet Scans

As P-glycoprotein (Pgp) inhibition at the blood–brain barrier (BBB) after administration of a single dose of tariquidar is transient, we performed positron emission tomography (PET) scans with the Pgp substrate ( R)-[11C]verapamil in five healthy volunteers during continuous intravenous tariquidar infusion. Total distribution volume ( VT) of ( R)-[11C]verapamil in whole-brain gray matter increased by 273 ± 78% relative to baseline scans without tariquidar, which was higher than previously reported VT increases. During tariquidar infusion whole-brain VT was comparable to VT in the pituitary gland, a region not protected by the BBB, which suggested that we were approaching complete Pgp inhibition at the human BBB.

scholarly journals Ultrasound-Mediated Blood-Brain Barrier Opening Improves Whole Brain Gene Delivery in Mice

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1245
Author(s):  
Marie-Solenne Felix ◽  
Emilie Borloz ◽  
Khaled Metwally ◽  
Ambre Dauba ◽  
Benoit Larrat ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Fold Increase ◽  
Brain Barrier ◽  
Whole Brain ◽  
External Threats ◽  
Blood Brain ◽  
The Brain

Gene therapy represents a powerful therapeutic tool to treat diseased tissues and provide a durable and effective correction. The central nervous system (CNS) is the target of many gene therapy protocols, but its high complexity makes it one of the most difficult organs to reach, in part due to the blood-brain barrier that protects it from external threats. Focused ultrasound (FUS) coupled with microbubbles appears as a technological breakthrough to deliver therapeutic agents into the CNS. While most studies focus on a specific targeted area of the brain, the present work proposes to permeabilize the entire brain for gene therapy in several pathologies. Our results show that, after i.v. administration and FUS sonication in a raster scan manner, a self-complementary AAV9-CMV-GFP vector strongly and safely infected the whole brain of mice. An increase in vector DNA (19.8 times), GFP mRNA (16.4 times), and GFP protein levels (17.4 times) was measured in whole brain extracts of FUS-treated GFP injected mice compared to non-FUS GFP injected mice. In addition to this increase in GFP levels, on average, a 7.3-fold increase of infected cells in the cortex, hippocampus, and striatum was observed. No side effects were detected in the brain of treated mice. The combining of FUS and AAV-based gene delivery represents a significant improvement in the treatment of neurological genetic diseases.

scholarly journals Reproducible abscopal effect in a patient with lung cancer who underwent whole‐brain irradiation and atezolizumab administration

2021 ◽  
Vol 12 (6) ◽  
pp. 985-988
Author(s):  
Takamasa Hotta ◽  
Takae Okuno ◽  
Mika Nakao ◽  
Yoshihiro Amano ◽  
Takeshi Isobe ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Abscopal Effect ◽  
Whole Brain Irradiation ◽  
Whole Brain ◽  
Brain Irradiation

scholarly journals A host-gut microbial co-metabolite of aromatic amino acids, p-cresol glucuronide, promotes blood-brain barrier integrity in vivo

2022 ◽  
Author(s):  
Andrew V Stachulski ◽  
Tobias B-A Knausenberger ◽  
Sita N Shah ◽  
Lesley Hoyles ◽  
Simon McArthur
Keyword(s):  
Amino Acids ◽  
Blood Brain Barrier ◽  
Aromatic Amino Acids ◽  
Biologically Active ◽  
Brain Barrier ◽  
Whole Brain ◽  
Blood Brain ◽  
Bbb Permeability

Purpose: The sequential activity of gut microbial and host processes can exert a powerful modulatory influence on dietary components, as exemplified by the metabolism of the amino acids tyrosine and phenylalanine to p-cresol by gut microbes, and then to p-cresol glucuronide (pCG) by host enzymes. Although such glucuronide conjugates are classically thought to be biologically inert, there is accumulating evidence that this may not always be the case. We investigated the activity of pCG, studying its interactions with the cerebral vasculature and the brain in vitro and in vivo. Methods: Male C57Bl/6J mice were used to assess blood-brain barrier (BBB) permeability and whole brain transcriptomic changes in response to pCG treatment. Effects were then further explored using the human cerebromicrovascular endothelial cell line hCMEC/D3, assessing paracellular permeability, transendothelial electrical resistance and barrier protein expression. Results: Mice exposed to pCG showed reduced BBB permeability and significant changes in whole brain transcriptome expression. Surprisingly, treatment of hCMEC/D3 cells with pCG had no notable effects until co-administered with bacterial lipopolysaccharide, at which point it was able to prevent the permeabilising effects of endotoxin. Further analysis suggested that pCG acts as an antagonist at the principal lipopolysaccharide receptor TLR4. Conclusion: The amino acid phase II metabolic product pCG is biologically active at the BBB, highlighting the complexity of gut microbe to host communication and the gut-brain axis.

Abstract P71: Global Blood-Brain Barrier Disruption After Acute Stroke

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Richard Leigh ◽  
Kyle Kern ◽  
Clinton B Wright
Keyword(s):  
White Matter ◽  
Blood Brain Barrier ◽  
Multivariable Analysis ◽  
Brain Barrier ◽  
Acute Ischemia ◽  
Periventricular White Matter ◽  
Stroke Patients ◽  
Whole Brain ◽  
Deep White Matter ◽  
Blood Brain

Background: Acute ischemia is known to cause local disruption of the blood-brain barrier (BBB), but studies have also shown that BBB disruption can be detected remote from the acute lesion. We sought to test a whole brain measurement of BBB disruption. Methods: This is a retrospective analysis of a deidentified dataset of stroke patients who did not undergo thrombolysis or thrombectomy and had an MRI performed with perfusion weighted imaging (PWI) 4-24 hours after symptom onset. We used PWI source images to identify voxels that demonstrated gadolinium leakage during the acquisition. BBB disruption was defined as a >1% change in signal due to leakage compared with normal tissue. Voxels that did not demonstrate adequate bolus tracking where excluded as noise. This yielded a whole brain average of voxels demonstrating BBB disruption that was not due to noise (wbBBB). We examined age, sex, NIHSS, Fazekas score, and time from onset as predictors of wbBBB using linear regression (continuous variables) and logistic regression (binary variables). Results: The 432 patients included in the analysis had a median age of 72 and 50% were women (mean NIHSS=6). wbBBB was highly correlated with age (p<0.001); figure 1A shows the 95% confidence intervals for the linear fit between age and wbBBB. There was no significant association with sex (p=0.143), NIHSS (p=0.097), or time from onset (p=0.149). wbBBB was associated with Fazekas score of the deep white matter (p<0.001) and the periventricular white matter (p<0.001). In multivariable analysis, age (p=0.011) and deep WMH (p=0.027), but not periventricular WMH (p=0.725), were independently associated with wbBBB. Figure 1B shows a boxplot of how wbBBB increases with increasing Fazekas score in the deep white matter. Conclusions: Global BBB disruption measured in stroke patients increased with increasing age and cerebral small vessel disease. It remains to be determined if these findings represent an acute exacerbation of a chronic process.

scholarly journals Contribution of Tissue Inflammation and Blood-Brain Barrier Disruption to Brain Softening in a Mouse Model of Multiple Sclerosis

2021 ◽  
Vol 15 ◽  
Author(s):  
Rafaela Vieira Silva ◽  
Anna S. Morr ◽  
Susanne Mueller ◽  
Stefan Paul Koch ◽  
Philipp Boehm-Sturm ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Blood Brain Barrier ◽  
Immune Cell ◽  
Brain Barrier ◽  
Brain Atlas ◽  
Similar Degree ◽  
Iron Oxide Particles ◽  
Whole Brain ◽  
Blood Brain ◽  
Inflammatory Processes

Neuroinflammatory processes occurring during multiple sclerosis cause disseminated softening of brain tissue, as quantified by in vivo magnetic resonance elastography (MRE). However, inflammation-mediated tissue alterations underlying the mechanical integrity of the brain remain unclear. We previously showed that blood-brain barrier (BBB) disruption visualized by MRI using gadolinium-based contrast agent (GBCA) does not correlate with tissue softening in active experimental autoimmune encephalomyelitis (EAE). However, it is unknown how confined BBB changes and other inflammatory processes may determine local elasticity changes. Therefore, we aim to elucidate which inflammatory hallmarks are determinant for local viscoelastic changes observed in EAE brains. Hence, novel multifrequency MRE was applied in combination with GBCA-based MRI or very small superparamagnetic iron oxide particles (VSOPs) in female SJL mice with induced adoptive transfer EAE (n = 21). VSOPs were doped with europium (Eu-VSOPs) to facilitate the post-mortem analysis. Accumulation of Eu-VSOPs, which was previously demonstrated to be sensitive to immune cell infiltration and ECM remodeling, was also found to be independent of GBCA enhancement. Following registration to a reference brain atlas, viscoelastic properties of the whole brain and areas visualized by either Gd or VSOP were quantified. MRE revealed marked disseminated softening across the whole brain in mice with established EAE (baseline: 3.1 ± 0.1 m/s vs. EAE: 2.9 ± 0.2 m/s, p &lt; 0.0001). A similar degree of softening was observed in sites of GBCA enhancement i.e., mainly within cerebral cortex and brain stem (baseline: 3.3 ± 0.4 m/s vs. EAE: 3.0 ± 0.5 m/s, p = 0.018). However, locations in which only Eu-VSOP accumulated, mainly in fiber tracts (baseline: 3.0 ± 0.4 m/s vs. EAE: 2.6 ± 0.5 m/s, p = 0.023), softening was more pronounced when compared to non-hypointense areas (percent change of stiffness for Eu-VSOP accumulation: −16.81 ± 16.49% vs. for non-hypointense regions: −5.85 ± 3.81%, p = 0.048). Our findings suggest that multifrequency MRE is sensitive to differentiate between local inflammatory processes with a strong immune cell infiltrate that lead to VSOP accumulation, from disseminated inflammation and BBB leakage visualized by GBCA. These pathological events visualized by Eu-VSOP MRI and MRE may include gliosis, macrophage infiltration, alterations of endothelial matrix components, and/or extracellular matrix remodeling. MRE may therefore represent a promising imaging tool for non-invasive clinical assessment of different pathological aspects of neuroinflammation.

Intracranial response after extracranial radiation in a patient with rapidly progressing metastatic melanoma

2021 ◽  
Vol 14 (6) ◽  
pp. e240921
Author(s):  
Oliver Piercey ◽  
Jonathan Mark Tomaszewski ◽  
Kortnye Smith
Keyword(s):  
Metastatic Melanoma ◽  
Blood Brain Barrier ◽  
Metabolic Response ◽  
Immune Checkpoint Blockade ◽  
Brain Barrier ◽  
Abscopal Effect ◽  
Complete Metabolic Response ◽  
Immunological Responses ◽  
Metastatic Lesions ◽  
Blood Brain

Growing literature supports the synergistic effect of radiation as a primer for renewed enhanced systemic immunological responses in patients receiving immunotherapy for metastatic melanoma. Radiographic regression of extracranial tumours after treatment of intracranial metastatic lesions has been reported and these observations point to an abscopal effect that traverses the blood–brain barrier. We describe a patient with rapidly progressing metastatic melanoma despite combined immune checkpoint blockade, who achieved a complete metabolic response of both his extracranial and intracranial disease after the commencement of palliative radiation to his axilla. This is the first published case, to our knowledge, of a sustained, complete intracranial abscopal response from extracranial radiation. We discuss potential mechanistic relations between radiation, the blood–brain barrier and the abscopal effect.

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