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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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Evan D. Bander, Karima Tizi, Eva Wembacher-Schroeder, Rowena Thomson, Maria Donzelli, Elizabeth Vasconcellos and Mark M. Souweidane

revising the article: Souweidane, Bander, Wembacher-Schroder, Thomson. Reviewed submitted version of manuscript: Souweidane, Bander, Wembacher-Schroder, Thomson. Approved the final version of the manuscript on behalf of all authors: Souweidane. Statistical analysis: Souweidane, Bander. Administrative/technical/material support: Souweidane, Donzelli. Study supervision: Souweidane. References 1 Anderson RCE , Kennedy B , Yanes CL , Garvin J , Needle M , Canoll P , : Convection-enhanced delivery of topotecan into diffuse intrinsic brainstem tumors in

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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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Davis P. Argersinger, Stuart Walbridge, Nicholas M. Wetjen, Alexander O. Vortmeyer, Tianxia Wu, John A. Butman and John D. Heiss

-resistant form of the disease. 39 Although ablative surgery for epilepsy treatment is successful in eliminating seizures in 2 of 3 patients, 42 recent experimental approaches for DRE have investigated less invasive, safer, more selective, and more effective treatment options. 13 , 37 Convection-enhanced delivery (CED) is one such modality. CED, a drug delivery method that uses stereotactic infusion cannula placement and hydrostatic pressure gradients to transport therapeutic compounds directly across the blood-brain and blood-nervous system barriers, 5 , 20 , 30 , 32 , 34

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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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Toshio Kikuchi, Ryuta Saito, Shin-ichirou Sugiyama, Yoji Yamashita, Toshihiro Kumabe, Michal Krauze, Krystof Bankiewicz and Teiji Tominaga

-dose delivery occurs only within mm of the implant. 3 Therefore, a drug delivery method that achieves extensive distribution of the therapeutic agent together with slow-release capability may further improve the therapeutic efficacy. 12 , 13 Convection-enhanced delivery is a relatively new drug delivery method that might overcome the problems of local drug delivery. This technique uses a pressure gradient established at the tip of an infusion catheter to create the bulk flow that pushes the drug through the interstitial space. 1 We previously reported the efficacy of PLD