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Russell R. Lonser, Stuart Walbridge, Alexander O. Vortmeyer, Svetlana D. Pack, Tung T. Nguyen, Nitin Gogate, Jeffery J. Olson, Aytac Akbasak, R. Hunt Bobo, Thomas Goffman, Zhengping Zhuang, and Edward H. Oldfield

Object. To determine the acute and long-term effects of a therapeutic dose of brain radiation in a primate model, the authors studied the clinical, laboratory, neuroimaging, molecular, and histological outcomes in rhesus monkeys that had received fractionated whole-brain radiation therapy (WBRT).

Methods. Twelve 3-year-old male primates (Macaca mulatta) underwent fractionated WBRT (350 cGy for 5 days/week for 2 weeks, total dose 3500 cGy). Animals were followed clinically and with laboratory studies and serial magnetic resonance (MR) imaging. They were killed when they developed medical problems or neurological symptoms, lesions appeared on MR imaging, or at study completion. Gross, histological, and molecular analyses were then performed.

Nine (82%) of 11 animals that underwent long-term follow up (> 2.5 years) developed neurological symptoms and/or enhancing lesions on MR imaging, which were defined as glioblastoma multiforme (GBM), 2.9 to 8.3 years after radiation therapy. The GBMs were categorized as either unifocal (three) or multifocal (six), and were located in the supratentorial (six), infratentorial (two), or both (one) cranial regions. Histological examination revealed distant, noncontiguous tumor invasion within the white matter of all nine animals harboring GBMs. Novel interspecies comparative genomic hybridization (three animals) uniformly showed deletions in the GBMs that corresponded to chromosome 9 in humans.

Conclusions. The high rate of GBM formation (82%) following a therapeutic dose of WBRT in nonhuman primates indicates that radioinduction of these neoplasms as a late complication of this therapy may occur more frequently than is currently recognized in human patients. The development of these tumors while monitoring the monkeys' conditions with clinical and serial MR imaging studies, and access to the tumor and the entire brain for histological and molecular analyses offers an opportunity to gather unique insights into the nature and development of GBMs.

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Russell R. Lonser, Marc-Etienne Corthésy, Paul F. Morrison, Nitin Gogate, and Edward H. Oldfield

Object. Selective treatment of central nervous system (CNS) structures holds therapeutic promise for many neurological disorders, including Parkinson's disease (PD). The ability to inhibit or augment specific neuronal populations within the CNS reliably by using present therapeutic techniques is limited. To overcome this problem, the authors modeled and developed a method in which convection was used to deliver compounds to deep brain nuclei in a reproducible, homogeneous, and targeted manner. To determine the feasibility and clinical efficacy of convective drug delivery for treatment of a neurological disorder, the investigators selectively ablated globus pallidus internus (GPi) neurons with quinolinic acid (QA), an excitotoxin, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)—induced model of primate parkinsonism.

Methods. After the parameters of convective distribution to the GPi were confirmed by infusion of biotinylated albumin into the GPi of a primate (Macaca mulatta), seven adult monkeys of this species were rendered either fully parkinsonian by intravenous injections of MPTP (five animals) or hemiparkinsonian by a right-sided intracarotid injection of this agent (two monkeys). Using convection-enhanced delivery to the GPi, animals were infused with either QA (three fully parkinsonian, two hemiparkinsonian) or saline (two fully parkinsonian).

The three fully parkinsonian animals that underwent GPi lesioning with QA had substantial improvement of PD symptoms, manifested by a marked increase in activity (34 ± 2.5%; mean ± standard deviation) and dramatic improvement of parkinsonian clinical scores. In contrast, the control animals did not improve (activity monitor change = −1.5 × 0.5%). The two hemiparkinsonian animals that underwent QA lesioning of the GPi had dramatic recovery of extremity use. Histological examination revealed selective neural ablation of GPi neurons (mean loss 87%) with sparing of surrounding gray and white matter structures. No animal developed worsening signs of PD or neurological deficits after infusion.

Conclusions. Convection-enhanced delivery of QA permits selective, region-specific (GPi), and safe lesioning of neuronal subpopulations, resulting in dramatic improvement in parkinsonian symptomatology. The properties of convection-enhanced delivery indicate that this method could be used for chemical neurosurgery for medically refractory PD and that it may be ideal for cell-specific therapeutic ablation or trophic treatment of other targeted structures associated with CNS disorders.

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J. David Wood, Russell R. Lonser, Nitin Gogate, Paul F. Morrison, and Edward H. Oldfield

Object. Many macromolecules have the potential to enhance recovery after injury and other lesions of the spinal cord, but because of the limited penetration of these compounds across the blood—spinal cord barrier, they cannot be used effectively. To determine if convective delivery could be used in a common animal model to investigate potential therapeutic macromolecules and to examine the effects of trauma on convective delivery in that model, the authors examined the distribution of a macromolecule in naive and traumatized rat spinal cords.

Methods. Using convection, various infusion volumes ([Vi]; 1, 2, and 4 µl) of 14C-albumin were infused into the dorsal columns of 13 naive and five traumatized rat spinal cords. Volume of distribution (Vd), homogeneity, percentage of recovery, and anatomical location were determined using quantitative autoradiography, scintillation analysis, calculation of kurtosis (K) value, and histological analysis. In the nontraumatized group, Vd was linearly proportional (R2 = 0.98) to Vi (Vd/Vi, 4.3 ± 0.6; mean ± standard deviation), with increases in Vd resulting from linear expansion (R2 = 0.94) primarily in the craniocaudal dimension. In the traumatized spinal cords, the Vd/Vi ratio (3.7 ± 0.5) was smaller (p < 0.02) and distributions were less confined to the craniocaudal dimension, with significantly larger cross-sectional distributions in the region of injury (p < 0.02) compared to the noninjured spinal cords. Histological analysis revealed that after infusion into the dorsal columns, albumin distribution in naive cords was limited to the dorsal white matter, but in the traumatized cords there was penetration into the central gray matter. The distribution of the infusate was homogeneous in the nontraumatized (K = −1.1) and traumatized (K = −1.1) spinal cords. Recovery of radioactivity was not significantly different (p > 0.05) between the nontraumatized (84.8 ± 6.8%) and traumatized (79.7 ± 12.1%) groups.

Conclusions. Direct convective delivery of infusate can be used to distribute macromolecules in a predictable, homogeneous manner over significant volumes of naive and traumatized rat spinal cord. These characteristics make it a valuable tool to investigate the therapeutic potential of various compounds for the treatment of injury and spinal cord disease.

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Russell R. Lonser, Nitin Gogate, Paul F. Morrison, J. David Wood, and Edward H. Oldfield

Object. Because of the limited penetration of macromolecules across the blood—spinal cord barrier, numerous therapeutic compounds with potential for treating spinal cord disorders cannot be used effectively. The authors have developed a technique to deliver and distribute macromolecules regionally in the spinal cord by using convection in the interstitial space.

Methods. The authors designed a delivery system connected to a “floating” silica cannula (inner diameter 100 µm, outer diameter 170 µm) that provides for constant volumetric inflow to the spinal cord. A solution containing albumin that was either unlabeled or labeled with carbon-14 or gadolinium was infused at various volumes (3, 6, 10, 20, 40, or 50 µl) at a rate of 0.1 µl/minute into the spinal cord dorsal columns of nine swine and into the lateral columns of three primates (Macaca mulatta). Volume of distribution (Vd), concentration homogeneity, and percentage of recovery were determined using scintillation analysis, kurtosis calculation (K), and quantitative autoradiography (six swine), magnetic resonance imaging (one swine and three primates), and histological analysis (all animals). Neurological function was observed for up to 3 days in four of the swine and up to 16 weeks in the three primates.

The Vd of 14C-albumin was linearly proportional (R2 = 0.97) to the volume of infusion (Vi) (Vd/Vi = 4.4 ± 0.5; [mean ± standard deviation]). The increases in Vd resulting from increases in Vi were primarily in the longitudinal dimension (R2 = 0.83 in swine; R2 = 0.98 in primates), allowing large segments of spinal cord (up to 4.3 cm; Vi 50 µl) to be perfused with the macromolecule. The concentration across the area of distribution was homogeneous (K = −1.1). The mean recovery of infused albumin from the spinal cord was 85.5 ± 5.6%. Magnetic resonance imaging and histological analysis combined with quantitative autoradiography revealed the albumin infusate to be preferentially distributed along the white matter tracts. No animal exhibited a neurological deficit as a result of the infusion.

Conclusions. Regional convective delivery provides reproducible, safe, region-specific, and homogeneous distribution of macromolecules over large longitudinal segments of the spinal cord. This delivery method overcomes many of the obstacles associated with current delivery techniques and provides for research into new treatments of various conditions of the spinal cord.