A surgical technique for safely placing a drug delivery catheter into the pons of primates: preliminary results of carboplatin infusion.
OBJECTIVE
We sought to develop a neurosurgical procedure to access the pons with a drug delivery device for chronic therapy and collect preliminary data on the toxicity of direct infusions of carboplatin in primates.


METHODS
We made midline incisions on five cynomolgus monkeys, identified the inion, made a burr hole 2.5 cm below the inion, and inserted a catheter through the cerebellum into the roof of the pons. Pumps that infused saline for 90 days or carboplatin solutions for 30 to 35 days at 10 microl/d were placed subcutaneously in the low cervical/high thoracic region. Monkeys were assessed by computed tomography and magnetic resonance imaging, laboratory studies, daily neurological observation, postmortem examinations, and histopathology.


RESULTS
Monkeys infused with saline and 82 microg of carboplatin remained neurologically intact throughout the infusion periods. Serial imaging showed that the catheter tip was in the pons and revealed no evidence of hemorrhage, edema, or migration. Two monkeys infused with up to 850 microg of carboplatin showed hyperintense magnetic resonance imaging signals at Days 15 and 18 and neurological deficits at approximately Week 3. Platinum levels greater than 10 ng/mg tissue were detected over a distance of 1 cm in tissue slices. Histopathology demonstrated significant tissue necrosis around the tip of the catheter.


CONCLUSIONS
The pons of monkeys is safely accessed with a catheter for drug delivery by using a posterior midline approach. Clinical observations, radiographic imaging, and laboratory tests of animals infused with saline for 3 months or 0.26 mg/ml of carboplatin for 1 month were unremarkable. Neurotoxicity was seen with dose levels of 2.6 mg/ml of drug for 1 month. This procedure offers opportunities for examining the toxicity of brainstem antitumor therapy in primates.
Storm
Phillip B
PB
Hunterian Brain Tumor Laboratory, Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Clatterbuck
Richard E
RE
Liu
Ya J
YJ
Johnson
Randolph M
RM
Gillis
Edward M
EM
Guarnieri
Michael
M
Carson
Benjamin S
BS
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity*; D020295:Brain Stem Neoplasms / Q000188:drug therapy / Q000473:pathology; D016190:Carboplatin / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity*; D002404:Catheterization / Q000379:methods*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015918:Infusion Pumps, Implantable; D036502:Infusions, Intralesional / Q000379:methods*; D008252:Macaca fascicularis; D008279:Magnetic Resonance Imaging; D008297:Male; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology; D019635:Neurosurgical Procedures / Q000379:methods*; D011149:Pons / Q000473:pathology / Q000601:surgery*
D000970:Antineoplastic Agents; D016190:Carboplatin