Abstract:
OBJECT:The authors of this study aimed to genetically design a bispecific targeted toxin that would simultaneously target overexpressed markers on glioma as well as the tumor vasculature, to mutate certain amino acids to reduce the immunogenicity of this new drug, and to determine whether the drug was able to effectively reduce aggressive human brain tumors in a rat xenograft model via a novel hollow fiber (HF) catheter delivery system. METHODS:A new bispecific ligand-directed toxin (BLT) was created in which 2 human cytokines-epidermal growth factor ([EGF], targeting overexpressed EGF receptor) and amino acid terminal fragment ([ATF], targeting urokinase plasminogen activator receptor)-were cloned onto the same single-chain molecule with truncated Pseudomonas exotoxin with a terminal lysyl-aspartyl-glutamyl-leucine (KDEL) sequence. Site-specific mutagenesis was used to mutate amino acids in 7 key epitopic toxin regions that dictate the B cell generation of neutralizing antitoxin antibodies to deimmunize the drug, now called "EGFATFKDEL 7mut." Bioassays were used to determine whether mutation reduced the drug's potency, and enzyme-linked immunosorbent assay studies were performed to determine whether antitoxin antibodies were decreased. Aggressive brain tumors were intracranially established in nude rats by using human U87 glioma genetically marked with a firefly luciferase reporter gene (U87-luc), and the rats were stereotactically treated with 2 intracranial injections of deimmunized EGFATFKDEL via convection-enhanced delivery (CED). Drug was administered through a novel HF catheter to reduce drug backflow upon delivery. RESULTS:In vitro, EGFATFKDEL 7mut selectively killed the human glioblastoma cell line U87-luc as well as cultured human endothelial cells in the form of the human umbilical vein endothelial cells. Deimmunization did not reduce drug activity. In vivo, when rats with brain tumors were intracranially treated with drug via CED and a novel HF catheter to reduce backflow, there were significant tumor reductions in 2 experiments (p < 0.01). Some rats survived with a tumor-free status until 130 days post-tumor inoculation. An irrelevant BLT control did not protect establishing specificity. The maximal tolerated dose of EGFATFKDEL 7mut was established at 2 μg/injection or 8.0 μg/kg, and data indicated that this dose was nontoxic. Antitoxin antibodies were reduced by at least 90%. CONCLUSIONS:First, data indicated that the BLT framework is effective for simultaneously targeting glioma and its neovasculature. Second, in the rodent CED studies, newly developed HF catheters that limit backflow are effective for drug delivery. Third, by mutating critical amino acids, the authors reduced the threat of the interference of neutralizing antibodies that are generated against the drug. The authors' experiments addressed some of the most urgent limitations in the targeted toxin field.
journal_name
J Neurosurgjournal_title
Journal of neurosurgeryauthors
Oh S,Tsai AK,Ohlfest JR,Panoskaltsis-Mortari A,Vallera DAdoi
10.3171/2010.11.JNS101214subject
Has Abstractpub_date
2011-06-01 00:00:00pages
1662-71issue
6eissn
0022-3085issn
1933-0693journal_volume
114pub_type
杂志文章abstract:OBJECT:The objective of the present study was to perform a prospective evaluation of the potential efficacy and safety of intraoperative photodynamic therapy (PDT) using talaporfin sodium and irradiation using a 664-nm semiconductor laser in patients with primary malignant parenchymal brain tumors. METHODS:In 27 patie...
journal_title:Journal of neurosurgery
pub_type: 杂志文章,多中心研究
doi:10.3171/2013.7.JNS13415
更新日期:2013-10-01 00:00:00
abstract::Seven patients with spasticity of spinal cord origin have been maintained for up to 2 years with continuous spinal intrathecal infusion of baclofen. Prior to treatment, all of the patients had severe rigidity in their lower limbs and most had frequent and extensive spontaneous spasms, all of which greatly interfered w...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1987.66.2.0181
更新日期:1987-02-01 00:00:00
abstract:OBJECT:At present, the administration of prophylactic antiepileptic medication following aneurysmal subarachnoid hemorrhage (SAH) is controversial, and the practice is heterogeneous. Here, the authors sought to inform clinical decision making by identifying factors associated with the occurrence of seizures following a...
journal_title:Journal of neurosurgery
pub_type: 杂志文章,随机对照试验
doi:10.3171/2013.3.JNS122097
更新日期:2013-08-01 00:00:00
abstract::The known cytoprotective properties of MgSO4 led the authors to study its effects on infarct size in rats when administered intraarterially before reversible focal ischemia. Following an intracarotid infusion of MgSO4 in the amount of 30 mg/kg (24 animals), 90 mg/kg (18 animals), or an equal volume of vehicle (23 anim...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1996.85.1.0117
更新日期:1996-07-01 00:00:00
abstract:OBJECT:Occipital encephaloceles are relatively frequently encountered. Many investigators have addressed the embryogenesis of these formations, but the dural system has never before been studied. In this retrospective analysis the authors sought to gain a better understanding of the origins of these defects. METHODS:T...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1998.89.5.0738
更新日期:1998-11-01 00:00:00
abstract:OBJECT:The aim of this study was to investigate the effects of moderate hyperventilation on intracranial pressure (ICP), jugular venous oxygen saturation ([SjvO2], an index of global cerebral perfusion), and brain tissue PO2 (an index of local cerebral perfusion). METHODS:Ninety-four tests consisting of 20-minute peri...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.2002.96.1.0097
更新日期:2002-01-01 00:00:00
abstract::Metrizamide computerized tomographic cisternography (MCTC) has proved 100% successful in documenting the precise anatomic location of the dural osseous defect in three patients with sphenoethmoidal rhinorrhea. In each patient, direct surgical approach to the site indicated by MCTC terminated the leakage in a single pr...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1980.53.2.0222
更新日期:1980-08-01 00:00:00
abstract:OBJECTIVE:The use of subdural drains after surgical evacuation of chronic subdural hematoma (CSH) decreases the risk of recurrence and has become the standard of care. Halfway through the controlled, randomized TOSCAN (Randomized Trial of Follow-up CT after Evacuation of Chronic Subdural Hematoma) trial, the authors' i...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/2019.5.JNS19858
更新日期:2019-08-30 00:00:00
abstract:OBJECT:The most frequent genetic abnormality in human malignant gliomas is loss of heterozygosity (LOH) on chromosome 10. Candidate genes on chromosome 10 that are associated with the prognosis of patients with anaplastic astrocytoma (AA) and glioblastoma (GBM) were evaluated. METHODS:The authors used 12 fluorescent m...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.2001.95.4.0651
更新日期:2001-10-01 00:00:00
abstract:OBJECT:Brainstem hemangioblastomas are frequently encountered in patients with von Hippel-Lindau (VHL) disease. These tumors can cause significant morbidity, and their optimal management has not been defined. To better define the outcome and management of these tumors, the authors analyzed the long-term results in pati...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/2010.9.JNS10839
更新日期:2011-05-01 00:00:00
abstract:OBJECTIVE:Surgery for low-grade gliomas (LGGs) aims to achieve maximal tumor removal and maintenance of patients' functional integrity. Because extent of resection is one of the factors affecting the natural history of LGGs, surgery could be extended further than total resection toward a supratotal resection, beyond tu...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/2019.2.JNS183408
更新日期:2019-05-17 00:00:00
abstract::Photodynamic therapy is a promising treatment for human brain tumors because of the selective retention of certain compounds by tumor cells. Certain lipophilic cationic compounds, such as tetraphenylphosphonium (TPP), are selectively taken up by a variety of carcinomas. Although preferential retention of TPP has been ...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1991.74.1.0116
更新日期:1991-01-01 00:00:00
abstract::Computerized tomography (CT) scans of 54 patients with an arteriovenous malformation (AVM) of the brain were reviewed. The 31 males and 23 females (mean age: 33 years) were classified according to clinical presentation: 1) intracranial hemorrhage (30 patients); 2) seizure disorder (19 patients); and 3) other neurologi...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1979.51.6.0765
更新日期:1979-12-01 00:00:00
abstract::Artifacts are occasionally encountered on magnetic resonance imaging after operation. These may be due to minute metallic particles from neurosurgical instruments. Particles not detectable on plain x-ray films or computerized tomography scans may cause local change of magnetic resonance activity, resulting in a decept...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1987.67.5.0776
更新日期:1987-11-01 00:00:00
abstract:OBJECT:Application of sensitive infrared imaging is ideally suited to observe blood vessels and blood flow in exposed organs, including the brain. Temporary vascular occlusion is an important part of neurosurgery, but the capacity to monitor the effects of these occlusions in real time is limited. In surgical procedure...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.2002.96.5.0918
更新日期:2002-05-01 00:00:00
abstract::OBJECTIVE Blunt traumatic cerebrovascular injury (TCVI) represents structural injury to a vessel due to high-energy trauma. The Biffl Scale is a widely accepted grading scheme for these injuries that was developed using digital subtraction angiography. In recent years, screening CT angiography (CTA) has been used to i...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/2016.7.JNS16849
更新日期:2017-07-01 00:00:00
abstract::The ability of a single large intravenous dose of the sodium succinate esters of the glucocorticoids methylprednisolone, prednisolone, or hydrocortisone to enhance early neurological recovery after moderate to severe blunt head injury was examined in male CF-1 mice. Unanesthetized mice were restrained and subjected to...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1985.62.6.0882
更新日期:1985-06-01 00:00:00
abstract::The neurological and neuroradiological manifestations of pediatric achondroplasia are analyzed on the basis of 10 cases. In addition to the classical symptomatology of an enlarging head, with or without increased intracranial pressure, several patients presented symptoms related to a small foramen magnum. Respiratory ...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1981.54.1.0049
更新日期:1981-01-01 00:00:00
abstract:OBJECT:Atlantoaxial rotatory fixation (AARF) is an uncommon disorder of childhood in which resolution usually occurs spontaneously or after traction therapy. In a minority of children irreducible or chronic fixation develop, and the natural history then usually involves restriction of head on neck movement, abnormal he...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/spi.2004.100.3.0235
更新日期:2004-03-01 00:00:00
abstract::The search for the origin of the commonly held principle in current neurosurgery regarding the resectability of the anterior one third of the superior sagittal sinus unravels the many fascinating developments that occurred in neurosurgery during the early 20th century. All these occurrences can be traced back to, and ...
journal_title:Journal of neurosurgery
pub_type: 传,历史文章,杂志文章
doi:10.3171/jns.2003.99.4.0787
更新日期:2003-10-01 00:00:00
abstract:OBJECT:This study was conducted to determine if there is a change in intracranial arterial diameters after papaverine infusion for vasospasm and to determine whether the change occurs in proximal, intermediate, and distal arteries. METHODS:The authors measured arterial diameters retrospectively in all patients who rec...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1998.88.1.0038
更新日期:1998-01-01 00:00:00
abstract::The author, who was editor of the Journal of Neurosurgery from 1975 to 1985, recalls the history of the journal during the 15 hears beginning in 1965, when Dr. Louise Eisenhardt resigned as its first editor. In an addendum, he presents some thoughts on the future of neurosurgery and the role the journal should play in...
journal_title:Journal of neurosurgery
pub_type: 历史文章,杂志文章
doi:10.3171/jns.1994.80.5.0939
更新日期:1994-05-01 00:00:00
abstract:OBJECT:Expression of matrix metalloproteinases (MMPs) has been postulated to play a central role in brain tumor invasion; however, its underlying mechanism is not yet fully understood. In the present study, by assessing the effect of a specific p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, on the sec...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.2002.97.1.0112
更新日期:2002-07-01 00:00:00
abstract:OBJECT:To provide greater accuracy in determining the epileptogenic zone during preoperative evaluation, the authors retrospectively examined 123I-iomazenil single-photon emission computed tomography (IMZ SPECT) studies obtained in patients with temporal lobe epilepsy (TLE) in whom there was no evidence of an abnormali...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/JNS-07/08/0352
更新日期:2007-08-01 00:00:00
abstract::Calcified cervical intervertebral discs in children are manifestations of an uncommon, distinct disease of unknown cause. Acute symptoms are usually followed by a benign course of spontaneous recovery, frequently culminating in resorption of the calcium. Rarely herniation of the disc may cause neurological complicatio...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1977.46.2.0233
更新日期:1977-02-01 00:00:00
abstract::The fibrinolytic activity in cerebrospinal fluid has been monitored by determination of levels of fibrin split products (FSP) in 23 patients with ruptured intracranial aneurysms. In 20 of these 23, FSP was found in the cerebrospinal fluid (CSF), with levels ranging from 10 to 80 micrograms/ml. Eleven of the 23 patient...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1980.52.4.0453
更新日期:1980-04-01 00:00:00
abstract::OBJECTIVE Treatment with a BRAF mutation inhibitor might shrink otherwise refractory craniopharyngiomas and is a promising preoperative treatment to facilitate tumor resection. The aim of this study was to investigate the noninvasive diagnosis of BRAF-mutated craniopharyngiomas based on MRI characteristics. METHODS Fi...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/2017.4.JNS163113
更新日期:2018-07-01 00:00:00
abstract::A study of computerized tomography (CT) scans was performed in a consecutive series of 100 patients with ruptured saccular cerebral aneurysms who were admitted, diagnosed, and operated on within 72 hours after subarachnoid hemorrhage (SAH) and treated with calcium antagonists. The aneurysms were in the anterior portio...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1986.65.2.0217
更新日期:1986-08-01 00:00:00
abstract::The authors present the case of a 78-year-old woman who developed right lower-extremity paralysis after a focal seizure. Neuroradiological studies revealed a small parasagittal meningioma, which at the time of resection was found to contain a bacterial intratumoral abscess secondary to Proteus mirabilis. This is only ...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1998.88.5.0895
更新日期:1998-05-01 00:00:00
abstract::Rupture of an intracranial dissecting aneurysm is a rare but dangerous event. The authors' experience with 14 cases of these lesions on the vertebrobasilar circulation suggests that these aneurysms have typical angiographic silhouettes and that, at least in the vertebral artery, they are treatable by proximal arterial...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1984.60.2.0325
更新日期:1984-02-01 00:00:00