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David I. Sandberg, Mark A. Edgar and Mark M. Souweidane

, 1986 Albright AL, Guthkelch AN, Packer RJ, et al: Prognostic factors in pediatric brain-stem gliomas. J Neurosurg 65: 751–755, 1986 3. Allen JC , Siffert J : Contemporary chemotherapy issues for children with brainstem gliomas. Pediatr Neurosurg 24 : 98 – 102 , 1996 Allen JC, Siffert J: Contemporary chemotherapy issues for children with brainstem gliomas. Pediatr Neurosurg 24: 98–102, 1996 4. Bobo RH , Laske DW , Akbasak A , et al : Convection-enhanced delivery to macromolecules in the

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Russell R. Lonser, Malisa Sarntinoranont, Paul F. Morrison and Edward H. Oldfield

effective treatments is the inability to deliver these agents past the CNS blood-brain barrier (BBB) in a reliable, targeted, and homogeneous way using currently available approaches for drug delivery, including systemic delivery, intrathecal and/or intraventricular distribution, and polymer implantation. 6 , 15 , 47 , 67 , 80 To surmount the limitations of available CNS drug delivery techniques, targeted direct perfusion of regions of the nervous system using the convection-enhanced delivery (CED) of infusate is increasingly used in research models of neurological

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Xiaotong Fan, Brian D. Nelson, Yi Ai, David K. Stiles, Don M. Gash, Peter A. Hardy and Zhiming Zhang

. Such an approach would minimize side effects and would reduce the amount of drug needed to treat a condition. Continuous convection-enhanced delivery (CED) into targeted brain areas has been tested in nonhuman primates (NHPs) for the treatment of various neurological diseases. 10 , 12 , 17 , 22 , 26 , 30 , 31 , 38 Translational studies using CED have also gone into early clinical trials. 4 , 9 , 16 , 18 , 27 , 35 However, few CED studies have explored the challenges of designing hardware, along with the surgical procedures necessary for conducting chronic CED

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Alexander Ksendzovsky, Stuart Walbridge, Richard C. Saunders, Ashok R. Asthagiri, John D. Heiss and Russell R. Lonser

– 473 , 2011 3 Bankiewicz KS , Eberling JL , Kohutnicka M , Jagust W , Pivirotto P , Bringas J , : Convection-enhanced delivery of AAV vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach . Exp Neurol 164 : 2 – 14 , 2000 4 Bobo RH , Laske DW , Akbasak A , Morrison PF , Dedrick RL , Oldfield EH : Convection-enhanced delivery of macromolecules in the brain . Proc Natl Acad Sci U S A 91 : 2076 – 2080 , 1994 5 Chen MY , Hoffer A

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Gregory J. A. Murad, Stuart Walbridge, Paul F. Morrison, Nicholas Szerlip, John A. Butman, Edward H. Oldfield and Russell R. Lonser

/kg) was administered to each primate to induce death at the completion of the observation period. The brain and other tissues were obtained, processed, and analyzed as described previously. Imaging of the Gd-DTPA and Gemcitabine Distribution Convection-Enhanced Delivery and MR imaging Two animals were coinfused with 100 or 125 μl of Gd-DTPA (5 mM) and gemcitabine (0.4 mg/ml) by using CED. Magnetic resonance was performed throughout the infusion. Clinical Observation The animals were observed daily for 28 days following infusion to determine if they had

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Walter A. Hall, Edward Rustamzadeh and Anthony L. Asher

The poor prognosis associated with the current management of malignant gliomas has led investigators to develop alternative treatments such as targeted toxin therapy. The optimal method for administering these agents is under development but appears to be convection-enhanced delivery (CED).

The direct intratumoral infusion of targeted toxins was first performed in nude mouse flank tumor models of human malignant glioma. After the demonstration of in vivo efficacy, these potent cytotoxic compounds were tested in Phase I and Phase II clinical trials.

Using a high-flow microinfusion technique, volumes of up to 180 ml were infused by CED through catheters placed directly into brain tumors. Minor systemic toxicity was seen in the form of hepatic enzyme elevation. Neural toxicity manifested as seizure activity and hemiparesis resulted from peritumoral edema that followed the completion of the infusion. Peritumoral toxicity was believed to be more related to the concentration of the infused immunotoxin than to the infusion volume. In approximately half of patients treated with CED a stable disease course, a partial response, or a complete response was demonstrated in some clinical trials.

Targeted toxin therapy has clinical efficacy in patients with malignant gliomas. Convection-enhanced delivery appears to represent an effective method for administering these agents in patients with malignant brain tumors.

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Ryuta Saito, Yukihiko Sonoda, Toshihiro Kumabe, Ken-ichi Nagamatsu, Mika Watanabe and Teiji Tominaga

. Analysis and interpretation of data: Saito, Sonoda, Kumabe, Nagamatsu. Drafting the article: Saito. Critically revising the article: Sonoda, Kumabe, Watanabe. Reviewed final version of the manuscript and approved it for submission: all authors. Study supervision: Tominaga. References 1 Degen JW , Walbridge S , Vortmeyer AO , Oldfield EH , Lonser RR : Safety and efficacy of convection-enhanced delivery of gemcitabine or carboplatin in a malignant glioma model in rats . J Neurosurg 99 : 893 – 898 , 2003 2 Ding D , Kanaly CW , Bigner DD

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John D. Heiss, Stuart Walbridge, Ashok R. Asthagiri and Russell R. Lonser

Institute of Neurological Disorders and Stroke at the National Institutes of Health. References 1 Baraldi M , Grandison L , Guidotti A : Distribution and metabolism of muscimol in the brain and other tissues of the rat . Neuropharmacology 18 : 57 – 62 , 1979 2 Bobo RH , Laske DW , Akbasak A , Morrison PF , Dedrick RL , Oldfield EH : Convection-enhanced delivery of macromolecules in the brain . Proc Natl Acad Sci U S A 91 : 2076 – 2080 , 1994 3 Cavagna FM , Maggioni F , Castelli PM , Dapra M , Imperatori LG

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Vanja Varenika, Peter Dickinson, John Bringas, Richard LeCouteur, Robert Higgins, John Park, Massimo Fiandaca, Mitchel Berger, John Sampson and Krystof Bankiewicz

infusion catheter to create bulk flow, which “pushes” the drug throughout the extracellular space. 2 This displacement allows the infused material to engage the vasculature, and the rhythmic contractions of blood vessels act as an efficient motive force to move particles along perivascular tracts. 6 As a result, a higher concentration of drug is distributed more evenly and over a larger volume than by diffusion alone. Convection-enhanced delivery requires accurate placement of catheters in the brain for microinfusion of the drug, making the technique a precise system

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Raghu Raghavan, Martin L. Brady, María Inmaculada Rodríguez-Ponce, Andreas Hartlep, Christoph Pedain and John H. Sampson

, 1972 . 579 – 663 5 Broaddus WC , Gillies GT , Kucharczyk J : Minimally invasive procedures. Advances in image-guided delivery of drug and cell therapies into the central nervous system . Neuroimag Clin N Am 11 : 727 – 735 , 2001 6 Chen MY , Lonser RR , Morrison PF , : Variables affecting convection-enhanced delivery to the striatum: a systematic examination of rate of infusion, cannula size, infusate concentration, and tissue-cannula sealing time . J Neurosurg 90 : 315 – 320 , 1999 7 Chen ZJ , Gillies GT , Broaddus WC , : A