scholarly journals Adamantinomatous craniopharyngioma associated with a compromised blood–brain barrier: patient series

2021 ◽  
Vol 1 (19) ◽  
Author(s):  
Eric W. Prince ◽  
Lindsey M. Hoffman ◽  
Trinka Vijmasi ◽  
Kathleen Dorris ◽  
Jennifer A. McWilliams ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Tumor Tissue ◽  
Pediatric Brain Tumor ◽  
Cyst Fluid ◽  
Brain Barrier ◽  
Enzyme Linked Immunosorbent Assay ◽  
Blood Brain ◽  
Humanized Monoclonal Antibody ◽  
Interleukin 6 Receptor ◽  
Adamantinomatous Craniopharyngioma

BACKGROUND Adamantinomatous craniopharyngioma (ACP) is a highly morbid adult and pediatric brain tumor derived from epithelial remnants of the craniopharyngeal canal (Rathke’s pouch), which gives rise to the anterior pituitary gland. Standard therapy includes maximal safe resection with or without radiation therapy. Systemic antitumor therapy remains elusive. Immune-related paracrine signaling involving the interleukin-6 receptor (IL-6R) may contribute to ACP pathogenesis. Tocilizumab, a recombinant humanized monoclonal antibody against IL-6R, is approved by the US Food and Drug Administration but does not cross an intact blood–brain barrier. OBSERVATIONS In a phase 0 trial design, a single dose of tocilizumab was delivered intravenously before clinically indicated surgical intervention in 3 children with ACP. The presence of tocilizumab was assayed in plasma, tumor tissue, tumor cyst fluid, and cerebrospinal fluid (n = 1) using a novel enzyme-linked immunosorbent assay. Tocilizumab reached ACP tumor tissue and/or cyst fluid after one systemic dose in every patient. LESSONS This finding helps explain extant data that indicate tocilizumab may contribute to ACP therapy. It further indicates that ACP does not reside behind an intact blood–brain barrier, dramatically broadening the range of potential antitumor therapies against this tumor. This has substantial implications for the design of future clinical trials for novel therapies against ACP in both children and adults.

scholarly journals RARE-10. ADAMANTINOMATOUS CRANIOPHARYNGIOMA RESIDES OUTSIDE THE BLOOD BRAIN BARRIER

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii443-iii443
Author(s):  
Eric Prince ◽  
Trinka Vijmasi ◽  
Jennifer McWilliams ◽  
Astrid Hengartner ◽  
Susan Staulcup ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Anterior Pituitary ◽  
Tumor Tissue ◽  
Cyst Fluid ◽  
Brain Barrier ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tumor Control ◽  
Skull Base Tumor ◽  
Blood Brain ◽  
Adamantinomatous Craniopharyngioma

Abstract BACKGROUND Adamantinomatous craniopharyngioma (ACP) is a devastating skull-base tumor believed to derive from epithelial remnants of the primordial craniopharyngeal duct (Rathke’s pouch), which gives rise to the anterior pituitary gland. Genetically engineered mouse models of ACP demonstrate that perturbation of the fetal anterior pituitary can generate tumors analogous to ACP. Clinical and preclinical data indicate that IL-6 blockade may contribute to ACP tumor control, with the most common agent being the humanized monoclonal antibody, tocilizumab. This agent demonstrated poor blood-brain barrier (BBB) penetration in primates. We present findings from two children enrolled on a phase 0 clinical trial (NCT03970226) of a single dose of preoperative intravenous tocilizumab prior to resection of newly diagnosed ACP. METHODS Blood samples were obtained at multiple timepoints. Serum was isolated via ficoll separation. Tumor tissue and cyst fluid were obtained 4–6 hours following the single IV dose of tocilizumab. Tissue was snap-frozen. Tumor was homogenized in RIPA buffer. Free tocilizumab in serum, cyst fluid, and tumor tissue was measured using enzyme-linked immunosorbent assay (ELISA) against a standard curve. RESULTS Both patients in this trial demonstrated clinically relevant levels of tocilizumab (≥ 4µg/mL) in serum, cyst fluid, and tumor tissue, compared to undetectable levels in control samples. CONCLUSION ACP resides outside BBB protection. In addition to demonstrating the feasibility of systemic delivery of tocilizumab, these findings indicate that other large molecules, including those known to have poor BBB penetration, may be systemically delivered as part of an antitumor regimen in the treatment of ACP.

scholarly journals Overcoming the blood–brain barrier for glioma-targeted therapy based on an interleukin-6 receptor-mediated micelle system

RSC Advances ◽  
2017 ◽  
Vol 7 (44) ◽  
pp. 27162-27169 ◽  
Author(s):  
Wei Shi ◽  
Xuexue Cui ◽  
Jinlong Shi ◽  
Jian Chen ◽  
Yi Wang
Keyword(s):  
Targeted Therapy ◽  
Blood Brain Barrier ◽  
Interleukin 6 ◽  
Brain Barrier ◽  
Blood Brain ◽  
System P ◽  
Interleukin 6 Receptor ◽  
Micelle System

An interleukin-6 receptor-mediated micelle-drug system was prepared for cascade-targeting chemotherapy of glioma, which exhibited high BBB-crossing and glioma-targeted efficiency.

scholarly journals Plasma and Cerebrospinal Fluid Inflammation and the Blood Brain Barrier in Older Surgical Patients: The Role of Inflammation after Surgery for Elders Study

2020 ◽  
Author(s):  
Sarinnapha Vasunilashorn ◽  
Long H. Ngo ◽  
Simon T. Dillon ◽  
Tamara G Fong ◽  
Becky C Carlyle ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Blood Brain Barrier ◽  
Inflammatory Markers ◽  
Brain Barrier ◽  
Enzyme Linked Immunosorbent Assay ◽  
Markers Of Inflammation ◽  
Blood Brain ◽  
Csf Levels ◽  
The Relationship

Abstract Background Our understanding of the relationship between plasma and cerebrospinal fluid (CSF) remains limited, which poses an obstacle to the identification of blood-based markers of neuroinflammatory disorders. To better understand the relationship between peripheral and central nervous system (CNS) markers of inflammation before and after surgery, we aimed to: examine whether surgery compromises the blood-brain barrier (BBB), evaluate postoperative changes in inflammatory markers, and assess the correlations between plasma and CSF levels of inflammation. Methods We examined the Role of Inflammation after Surgery for Elders (RISE) study of adults aged ≥ 65 who underwent elective hip or knee surgery under spinal anesthesia who had plasma and CSF samples collected at baseline and postoperative 1 month (PO1MO) (n = 29). Plasma and CSF levels of three inflammatory markers previously identified as increasing after surgery were measured using enzyme-linked immunosorbent assay: interleukin-6 (IL-6), C-reactive protein (CRP), and chitinase 3-like protein (also known as YKL-40). Integrity of the BBB was computed as the ratio of CSF/plasma albumin levels (Qalb). Mean Qalb and levels of inflammation were compared between baseline and PO1MO. Spearman correlation coefficients were used to determine correlation between biofluids. For the plasma-CSF biofluids with significant correlations, we determined whether the markers were associated by using linear regression models. Results Mean Qalb did not change between baseline and PO1MO. Plasma and CSF levels of IL-6, CRP, and YKL-40 were higher on PO1MO relative to baseline, with a disproportionally higher increase in CSF levels relative to plasma levels (IL-6 doubled and CRP tripled in CSF). Significant plasma-CSF correlations for CRP (baseline r = 0.70 and PO1MO r = 0.89, p < .01 for both) and IL-6 (PO1MO r = 0.48, p < .01) were observed, with higher correlations on PO1MO compared with baseline. Conclusions In this elective surgical sample of older adults, BBB integrity was similar between baseline and PO1MO, inflammation levels were higher PO1MO than baseline, and plasma-CSF correlations were observed for CRP and IL-6. Our identification of potential promising plasma markers of inflammation in the CNS may facilitate the early identification of patients at greatest risk for neuroinflammation and its associated adverse cognitive outcomes.

scholarly journals NOD2 Expression in Streptococcus pneumoniae Meningitis and Its Influence on the Blood-Brain Barrier

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Ying Wang ◽  
Xinjie Liu ◽  
Qi Liu
Keyword(s):  
Streptococcus Pneumoniae ◽  
Rat Brain ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Inflammatory Factors ◽  
Enzyme Linked Immunosorbent Assay ◽  
Expression Change ◽  
Blood Brain ◽  
Bbb Permeability ◽  
Brain Tissues

Streptococcus pneumoniae meningitis is one of the most common disorders seen in clinical practice. It is believed that the brain tissue immune injury is caused by the expression of pattern-recognition receptors (PRR) which can further induce the release of other cytokines and inflammatory cascades. The aim of this study is to investigate the expression of nucleotide-binding oligomerization domain 2 (NOD2) and inflammatory factors in rat brain tissues infected with Streptococcus pneumoniae and its influence on the blood-brain barrier (BBB) permeability. Rats were given an intracranial injection of Streptococcus pneumoniae to construct the Streptococcus pneumoniae meningitis rat models. The expression change curves of NOD2 and inflammatory factors at different time points (0 h, 12 h, 24 h, 48 h, and 7 d) after Streptococcus pneumoniae were evaluated by enzyme-linked immunosorbent assay (ELISA). Western blotting analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were engaged to examine the expression of NOD2. Furthermore, the changing processes of pathological characteristics, nervous system score, cerebral oedema, and BBB permeability were observed. Our results showed that NOD2 expression began to increase in the 12 h after Streptococcus pneumoniae infection group, while the remaining inflammatory factors were not obviously increased. Meanwhile, the levels of NOD2, as well as inflammatory factors IL-1β, TNF-α, and IL-6 were markedly elevated in 24 h and 48 h infection groups, which were consistent with the increases in BBB permeability and BWC, and the positive expression of NOD2 in the infected rat brain tissues was observed using immunohistochemistry (IHC). This study suggests that NOD2 might be related to the activation of inflammation pathways and the damage to the blood-brain barrier. NOD2 and inflammatory factors have played vital roles in the pathogenesis of Streptococcus pneumoniae meningitis.

scholarly journals The Role of Circulating Tight Junction Proteins in Evaluating Blood Brain Barrier Disruption following Intracranial Hemorrhage

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Xiaoyang Jiao ◽  
Ping He ◽  
Yazhen Li ◽  
Zhicheng Fan ◽  
Mengya Si ◽  
...  
Keyword(s):  
Brain Injury ◽  
Tight Junction ◽  
Blood Brain Barrier ◽  
Intracranial Hemorrhage ◽  
Brain Barrier ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tight Junction Proteins ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Junction Proteins

Brain injury after intracranial hemorrhage (ICH) results in significant morbidity and mortality. Blood brain barrier (BBB) disruption is a hallmark of ICH-induced brain injury; however, data mirroring BBB disruption in human ICH are scarce. The aim of this study was to assess the significance of circulating biomarkers in evaluating BBB disruption after ICH. Twenty-two patients with ICH were recruited in this study. Concentrations of the tight junction proteins (TJs) Claudin-5 (CLDN5), Occludin (OCLN), and zonula occludens 1 (ZO-1) and vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) were measured by using enzyme-linked immunosorbent assay in serum and cerebrospinal fluid (CSF) samples obtained from patients with ICH. The white blood cell (WBC) count in blood and CSF, albumin (ALB) levels in the CSF (ALBCSF), and the BBB ratio were significantly higher in the ICH than in controls (p<0.05). Significantly higher levels of CLDN5, OCLN, ZO-1, MMP-9, and VEGF in CSF were observed in the ICH group; these biomarkers were also positively associated with BBB ratio (p<0.05). Our data revealed that circulating TJs could be considered the potential biomarkers reflecting the integrity of the BBB in ICH.

scholarly journals Targeting intracranial patient-derived glioblastoma (GBM) with a NIR-I fluorescent immunoconjugate for facilitating its image-guided resection

RSC Advances ◽  
2020 ◽  
Vol 10 (69) ◽  
pp. 42413-42422
Author(s):  
Kenneth S. Hettie ◽  
Nutte Tarn Teraphongphom ◽  
Robert D. Ertsey ◽  
Eben L. Rosenthal ◽  
Frederick T. Chin
Keyword(s):  
Brain Tumor ◽  
Blood Brain Barrier ◽  
Tumor Tissue ◽  
Brain Barrier ◽  
Image Guided ◽  
Blood Brain

Fluorescent immunoconjugate cetuximab-IRDye800 bypasses the blood-brain-barrier to afford visualization of patient-derived GBM39 brain tumor tissue for facilitating its fluorescence-guided resection.

scholarly journals Brain Bioavailability of Human Intravenous Immunoglobulin and its Transport through the Murine Blood–Brain Barrier

2013 ◽  
Vol 33 (12) ◽  
pp. 1983-1992 ◽  
Author(s):  
Isabelle St-Amour ◽  
Isabelle Paré ◽  
Wael Alata ◽  
Katherine Coulombe ◽  
Cassandra Ringuette-Goulet ◽  
...  
Keyword(s):  
Intravenous Immunoglobulin ◽  
Blood Brain Barrier ◽  
Elimination Rate ◽  
Therapeutic Targets ◽  
Brain Barrier ◽  
Enzyme Linked Immunosorbent Assay ◽  
Brain Uptake ◽  
Blood Brain ◽  
Qualitative Methodologies ◽  
The Brain

Intravenous immunoglobulin (IVIg) is currently evaluated in clinical trials for the treatment of various disorders of the central nervous system. To assess its capacity to reach central therapeutic targets, the brain bioavailability of IVIg must be determined. We thus quantified the passage of IVIg through the blood–brain barrier (BBB) of C57Bl/6 mice using complementary quantitative and qualitative methodologies. As determined by enzyme-linked immunosorbent assay, a small proportion of systemically injected IVIg was detected in the brain of mice (0.009±0.001% of injected dose in the cortex) whereas immunostaining revealed localization mainly within microvessels and less frequently in neurons. Pharmacokinetic analyses evidenced a low elimination rate constant (0.0053  per hour) in the cortex, consistent with accumulation within cerebral tissue. In situ cerebral perfusion experiments revealed that a fraction of IVIg crossed the BBB without causing leakage. A dose-dependent decrease of brain uptake was consistent with a saturable blood-to-brain transport mechanism. Finally, brain uptake of IVIg after a subchronic treatment was similar in the 3xTg-AD mouse model of Alzheimer disease compared with nontransgenic controls. In summary, our results provide evidence of BBB passage and bioavailability of IVIg into the brain in the absence of BBB leakage and in sufficient concentration to interact with the therapeutic targets.

scholarly journals Hyperbaric Oxygen Intervention Modulates Early Brain Injury after Experimental Subarachnoid Hemorrhage in Rats: Possible Involvement of TLR4/NF-κ B-Mediated Signaling Pathway

2016 ◽  
Vol 38 (6) ◽  
pp. 2323-2336 ◽  
Author(s):  
Hao Liu ◽  
Ming Yang ◽  
Li Pan ◽  
Peng Liu ◽  
Lianting Ma
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Signaling Pathway ◽  
Brain Edema ◽  
Blood Brain Barrier ◽  
Hyperbaric Oxygen ◽  
Early Brain Injury ◽  
Brain Barrier ◽  
Enzyme Linked Immunosorbent Assay ◽  
Blood Brain

Background/Aims: Previous studies have proved that the activation of TLR4/NF-κ B signaling pathway is involved in inflammatory processes in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Hyperbaric oxygen (HBO) intervention has successfully been used to treat several animal models of tissue injury via its anti-inflammation property. This study was undertaken to investigate the influence of HBO administration on the TLR4/NF-κ B signaling pathway in rats at the early stage of SAH. Methods: Male Sprague-Dawley rats (n = 150) were randomly divided into 5 groups: the sham, the sham + 2.8 atmospheres absolute (ATA) HBO group, the SAH group, the SAH + 2.0ATA HBO group, the SAH + 2.8ATA HBO group. Each group (n = 30) was randomly subdivided into three subgroups that were examined at the following time points: 24 h, 48 h and 72 h post-injury. HBO (100% O2, 2.0ATA or 2.8ATA for 90mins) was initiated 12 h after injury. Neurological deficit, brain edema and blood-brain barrier (BBB) permeability were assessed to evaluate the development of EBI. The expressions of TLR4, NF-κ B and pro-inflammatory cytokines in the cortical were determined by real time polymerase chain reaction (RT-PCR), western blot, immunohistochemistry, or enzyme-linked immunosorbent assay (ELISA). Results: Our study showed that treatment with HBO significantly decreased the expressions of TLR4, NF-κ B and the downstream inflammatory agents, such as TNF-α, IL-6, IL-1β and ICAM-1, and also improved brain edema, blood-brain barrier permeability and neurologic function. Conclusions: These findings indicate that HBO treatment may result in abatement of the development of EBI after SAH, possibly through suppression of TLR4/NF-κ B signaling pathway.

A phase 0 first-in-human study using NU-0129: A gold base spherical nucleic acid (SNA) nanoconjugate targeting BCL2L12 in recurrent glioblastoma patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3012-3012 ◽  
Author(s):  
Priya Kumthekar ◽  
Alfred Rademaker ◽  
Caroline Ko ◽  
Karan Dixit ◽  
Margaret A. Schwartz ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Tumor Tissue ◽  
Human Study ◽  
Tumor Resection ◽  
Brain Barrier ◽  
Open Label ◽  
Apoptotic Markers ◽  
Blood Brain ◽  
Phase 0 ◽  
Grade 3

3012 Background: Glioblastoma is a difficult to treat tumor with therapeutics limited by their ability to cross the blood brain barrier. SNAs, i.e., gold nanoparticle cores covalently conjugated with a corona of densely packed, highly oriented siRNA oligonucleotides targeted to the GBM oncogene BCL2L12, represent a novel class of blood-brain and blood-tumor barrier-permeable nanomedicinal conjugates, for suppressing gene expression in the tumors of GBM patients. Methods: This is a single-arm, open-label, “window of opportunity” phase 0 first-in-human trial to determine the safety and bioavailability of a novel nanotherapeutic compound, NU-0129. Enrolled patients were treated with intravenous NU-0129 at the dose of 0.04mg/kg. This treatment dosing was considered microdosing defined as 1/50ththe NOAEL (no observed adverse event level) from non-human primate studies. Treatment was followed by tumor resection 8-48 hours later. Primary outcome patient safety and toxicity was monitored weekly for 3 weeks post-infusion. Secondary objectives included biodistribution of NU0129 in tissue, evaluation of pharmacokinetics of NU0129 and the feasibility of NU0129 administration. Exploratory objectives included Bcl2L12 expression and post treatment apoptotic markers as well as progression free survival and overall survival rates. Results: 8 patients were enrolled, treated and subsequently underwent surgical resection. No significant treatment related toxicities were seen. Severe ( > grade 3) adverse events were observed in two patients: hypophosphatemia (one grade 3, one grade 4) and one patient with grade 3 lymphopenia, all were considered as “possibly related” by treating oncologists. In 6 of the 8 patients sufficient tumor tissue was available for analysis of gold accumulation by ICP-MS (inductively coupled plasma-mass spectrometry), and gold accumulation was seen in the tumor tissue of all 6 of these patients. Conclusions: Macrodosing of the nanotherapeutic NU-0129 was well tolerated in glioblastoma patients with no unexpected adverse effects and showed initial evidence of crossing blood brain barrier. Immunohistochemistry for Bcl2L12 expression, apoptotic markers, and PK studies are pending. The demonstration of gold nanoparticles in the tumor tissue validates this approach for drug delivery. Clinical trial information: NCT03020017.

scholarly journals Traversal of Candida albicans across Human Blood-Brain Barrier In Vitro

2001 ◽  
Vol 69 (7) ◽  
pp. 4536-4544 ◽  
Author(s):  
Ambrose Y. Jong ◽  
Monique F. Stins ◽  
Sheng-He Huang ◽  
Steven H. M. Chen ◽  
Kwang Sik Kim
Keyword(s):  
Candida Albicans ◽  
Blood Brain Barrier ◽  
Human Blood ◽  
Morphological Changes ◽  
Host Cells ◽  
Brain Barrier ◽  
Enzyme Linked Immunosorbent Assay ◽  
Morphological Studies ◽  
Blood Brain

ABSTRACT Candida albicans is an opportunistic pathogen, which primarily affects neonates and immunocompromised individuals. The pathogen can invade the central nervous system, resulting in meningitis. At present, the pathogenesis of C. albicansmeningitis is unclear. We used an in vitro model of the human blood-brain barrier to investigate the interaction(s) of C. albicans with human brain microvascular endothelial cells (BMEC). Binding of C. albicans to human BMEC was time and inoculum dependent. Invasion of C. albicans into human BMEC was demonstrated by using an enzyme-linked immunosorbent assay based on fluorescent staining of C. albicans with calcoflour. In contrast, avirulent Candida mutant strains and nonpathogenic yeast Saccharomyces cerevisiae were not able to bind and invade human BMEC. Morphological studies revealed that on association with human BMEC, C. albicans formed germ tubes and was able to bud intracellularly. Transmission electron microscopy showed various stages of C. albicans interactions with human BMEC, e.g., pseudopod-like structures on human BMEC membrane and intracellular vacuole-like structures retaining C. albicans. Of interest, C. albicans was able to bud and develop pseudohyphae inside human BMEC without apparent morphological changes of the host cells. In addition, C. albicans penetrates through human BMEC monolayers without a detectable change in transendothelial electrical resistance and inulin permeability. This is the first demonstration that C. albicans is able to adhere, invade, and transcytose across human BMEC without affecting monolayer integrity. A complete understanding of the interaction(s) of C. albicans with human BMEC should contribute to the understanding of the pathogenic mechanism(s) ofC. albicans meningitis.

Sign in / Sign up

Export Citation Format

Share Document