Chemotherapy administration directly into the fourth ventricle in a new piglet model: Laboratory investigation

David I. Sandberg, Kenneth M. Crandall, Carol Petito, Kyle Padgett, John Landrum, Darwin Babino, Danshe He, Juan Solano, Manuel Gonzalez-Brito, John W. Kuluz

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Object. The authors hypothesized that chemotherapy infusions directly into the fourth ventricle may potentially play a role in treating malignant posterior fossa tumors. In this study the safety and pharmacokinetics of etoposide administration into the fourth ventricle was tested using an indwelling catheter in piglets. Methods. A closed-tip silicone lumbar drain catheter was inserted into the fourth ventricle via a posterior fossa craniectomy and 5 daily infusions of etoposide (0.5 mg in 5 animals) or normal saline (in 2 animals) were instilled. Piglets (10-18 kg, 2-3 months of age) underwent daily neurological examinations and 4.7-T magnetic resonance (MR) imaging after the final infusion and were then killed for postmortem examination. Pharmacokinetics were studied using reversed-phase high-performance liquid chromatography on cerebrospinal fluid (CSF) samples at 0.25, 1, 2, 4, 8, 12, and 24 hours after etoposide infusion. Peak and trough CSF etoposide levels were measured for each subsequent infusion. Serum etoposide levels were obtained at 2 and 4 hours after infusion. Results. All piglets remained neurologically intact, and MR images demonstrated catheter placement within the fourth ventricle without signal changes in the brainstem or cerebellum. Serum etoposide was absent at 2 and 4 hours after intraventricular infusions. When adequate samples could be obtained for analysis, CSF etoposide levels peaked 15 minutes after infusion and progressively decreased. Cytotoxic levels (< 0.1 μg/ml) were maintained for 5 consecutive peak and trough measurements with 1 exception. Etoposide-related neuropathology included moderate-to-severe T-lymphocytic meningitis and fourth and lateral ventricular choroid plexitis with associated subependymal inflammation. Conclusions. Etoposide can be infused directly into the fourth ventricle without clinical or imaging evidence of damage. Cytotoxic CSF etoposide levels can be maintained for 24 hours with a single daily infusion into the fourth ventricle using an indwelling catheter. Intraventricular etoposide elicits an inflammatory response, the long-term effects of which are as yet undetermined.

Original languageEnglish
Pages (from-to)373-380
Number of pages8
JournalJournal of Neurosurgery: Pediatrics
Volume1
Issue number5
DOIs
StatePublished - May 1 2008

Fingerprint

Fourth Ventricle
Etoposide
Drug Therapy
Cerebrospinal Fluid
Indwelling Catheters
Catheters
Pharmacokinetics
Infratentorial Neoplasms
Intraventricular Infusions
Choroid
Neurologic Examination
Silicones
Reverse-Phase Chromatography
Serum
Meningitis
Cerebellum
Brain Stem
Autopsy
Magnetic Resonance Spectroscopy
High Pressure Liquid Chromatography

Keywords

  • Animal model
  • Chemotherapy
  • Fourth ventricle
  • Magnetic resonance imaging
  • Piglet
  • Posterior fossa tumor

ASJC Scopus subject areas

  • Clinical Neurology
  • Surgery
  • Pediatrics, Perinatology, and Child Health

Cite this

Chemotherapy administration directly into the fourth ventricle in a new piglet model : Laboratory investigation. / Sandberg, David I.; Crandall, Kenneth M.; Petito, Carol; Padgett, Kyle; Landrum, John; Babino, Darwin; He, Danshe; Solano, Juan; Gonzalez-Brito, Manuel; Kuluz, John W.

In: Journal of Neurosurgery: Pediatrics, Vol. 1, No. 5, 01.05.2008, p. 373-380.

Research output: Contribution to journalArticle

Sandberg, DI, Crandall, KM, Petito, C, Padgett, K, Landrum, J, Babino, D, He, D, Solano, J, Gonzalez-Brito, M & Kuluz, JW 2008, 'Chemotherapy administration directly into the fourth ventricle in a new piglet model: Laboratory investigation', Journal of Neurosurgery: Pediatrics, vol. 1, no. 5, pp. 373-380. https://doi.org/10.3171/PED/2008/1/5/373
Sandberg, David I. ; Crandall, Kenneth M. ; Petito, Carol ; Padgett, Kyle ; Landrum, John ; Babino, Darwin ; He, Danshe ; Solano, Juan ; Gonzalez-Brito, Manuel ; Kuluz, John W. / Chemotherapy administration directly into the fourth ventricle in a new piglet model : Laboratory investigation. In: Journal of Neurosurgery: Pediatrics. 2008 ; Vol. 1, No. 5. pp. 373-380.
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abstract = "Object. The authors hypothesized that chemotherapy infusions directly into the fourth ventricle may potentially play a role in treating malignant posterior fossa tumors. In this study the safety and pharmacokinetics of etoposide administration into the fourth ventricle was tested using an indwelling catheter in piglets. Methods. A closed-tip silicone lumbar drain catheter was inserted into the fourth ventricle via a posterior fossa craniectomy and 5 daily infusions of etoposide (0.5 mg in 5 animals) or normal saline (in 2 animals) were instilled. Piglets (10-18 kg, 2-3 months of age) underwent daily neurological examinations and 4.7-T magnetic resonance (MR) imaging after the final infusion and were then killed for postmortem examination. Pharmacokinetics were studied using reversed-phase high-performance liquid chromatography on cerebrospinal fluid (CSF) samples at 0.25, 1, 2, 4, 8, 12, and 24 hours after etoposide infusion. Peak and trough CSF etoposide levels were measured for each subsequent infusion. Serum etoposide levels were obtained at 2 and 4 hours after infusion. Results. All piglets remained neurologically intact, and MR images demonstrated catheter placement within the fourth ventricle without signal changes in the brainstem or cerebellum. Serum etoposide was absent at 2 and 4 hours after intraventricular infusions. When adequate samples could be obtained for analysis, CSF etoposide levels peaked 15 minutes after infusion and progressively decreased. Cytotoxic levels (< 0.1 μg/ml) were maintained for 5 consecutive peak and trough measurements with 1 exception. Etoposide-related neuropathology included moderate-to-severe T-lymphocytic meningitis and fourth and lateral ventricular choroid plexitis with associated subependymal inflammation. Conclusions. Etoposide can be infused directly into the fourth ventricle without clinical or imaging evidence of damage. Cytotoxic CSF etoposide levels can be maintained for 24 hours with a single daily infusion into the fourth ventricle using an indwelling catheter. Intraventricular etoposide elicits an inflammatory response, the long-term effects of which are as yet undetermined.",
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AU - Sandberg, David I.

AU - Crandall, Kenneth M.

AU - Petito, Carol

AU - Padgett, Kyle

AU - Landrum, John

AU - Babino, Darwin

AU - He, Danshe

AU - Solano, Juan

AU - Gonzalez-Brito, Manuel

AU - Kuluz, John W.

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N2 - Object. The authors hypothesized that chemotherapy infusions directly into the fourth ventricle may potentially play a role in treating malignant posterior fossa tumors. In this study the safety and pharmacokinetics of etoposide administration into the fourth ventricle was tested using an indwelling catheter in piglets. Methods. A closed-tip silicone lumbar drain catheter was inserted into the fourth ventricle via a posterior fossa craniectomy and 5 daily infusions of etoposide (0.5 mg in 5 animals) or normal saline (in 2 animals) were instilled. Piglets (10-18 kg, 2-3 months of age) underwent daily neurological examinations and 4.7-T magnetic resonance (MR) imaging after the final infusion and were then killed for postmortem examination. Pharmacokinetics were studied using reversed-phase high-performance liquid chromatography on cerebrospinal fluid (CSF) samples at 0.25, 1, 2, 4, 8, 12, and 24 hours after etoposide infusion. Peak and trough CSF etoposide levels were measured for each subsequent infusion. Serum etoposide levels were obtained at 2 and 4 hours after infusion. Results. All piglets remained neurologically intact, and MR images demonstrated catheter placement within the fourth ventricle without signal changes in the brainstem or cerebellum. Serum etoposide was absent at 2 and 4 hours after intraventricular infusions. When adequate samples could be obtained for analysis, CSF etoposide levels peaked 15 minutes after infusion and progressively decreased. Cytotoxic levels (< 0.1 μg/ml) were maintained for 5 consecutive peak and trough measurements with 1 exception. Etoposide-related neuropathology included moderate-to-severe T-lymphocytic meningitis and fourth and lateral ventricular choroid plexitis with associated subependymal inflammation. Conclusions. Etoposide can be infused directly into the fourth ventricle without clinical or imaging evidence of damage. Cytotoxic CSF etoposide levels can be maintained for 24 hours with a single daily infusion into the fourth ventricle using an indwelling catheter. Intraventricular etoposide elicits an inflammatory response, the long-term effects of which are as yet undetermined.

AB - Object. The authors hypothesized that chemotherapy infusions directly into the fourth ventricle may potentially play a role in treating malignant posterior fossa tumors. In this study the safety and pharmacokinetics of etoposide administration into the fourth ventricle was tested using an indwelling catheter in piglets. Methods. A closed-tip silicone lumbar drain catheter was inserted into the fourth ventricle via a posterior fossa craniectomy and 5 daily infusions of etoposide (0.5 mg in 5 animals) or normal saline (in 2 animals) were instilled. Piglets (10-18 kg, 2-3 months of age) underwent daily neurological examinations and 4.7-T magnetic resonance (MR) imaging after the final infusion and were then killed for postmortem examination. Pharmacokinetics were studied using reversed-phase high-performance liquid chromatography on cerebrospinal fluid (CSF) samples at 0.25, 1, 2, 4, 8, 12, and 24 hours after etoposide infusion. Peak and trough CSF etoposide levels were measured for each subsequent infusion. Serum etoposide levels were obtained at 2 and 4 hours after infusion. Results. All piglets remained neurologically intact, and MR images demonstrated catheter placement within the fourth ventricle without signal changes in the brainstem or cerebellum. Serum etoposide was absent at 2 and 4 hours after intraventricular infusions. When adequate samples could be obtained for analysis, CSF etoposide levels peaked 15 minutes after infusion and progressively decreased. Cytotoxic levels (< 0.1 μg/ml) were maintained for 5 consecutive peak and trough measurements with 1 exception. Etoposide-related neuropathology included moderate-to-severe T-lymphocytic meningitis and fourth and lateral ventricular choroid plexitis with associated subependymal inflammation. Conclusions. Etoposide can be infused directly into the fourth ventricle without clinical or imaging evidence of damage. Cytotoxic CSF etoposide levels can be maintained for 24 hours with a single daily infusion into the fourth ventricle using an indwelling catheter. Intraventricular etoposide elicits an inflammatory response, the long-term effects of which are as yet undetermined.

KW - Animal model

KW - Chemotherapy

KW - Fourth ventricle

KW - Magnetic resonance imaging

KW - Piglet

KW - Posterior fossa tumor

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