title: Convection enhanced delivery of carmustine to the murine brainstem: a feasibility study.
abstract: BACKGROUND
  Systemic delivery of therapeutic agents remains ineffective against diffuse intrinsic pontine glioma (DIPG), possibly due to an intact blood-brain-barrier (BBB) and to dose-limiting toxicity of systemic chemotherapeutic agents. Convection-enhanced delivery (CED) into the brainstem may provide an effective local delivery alternative for DIPG patients.
  
  
  METHODS
  The aim of this study is to develop a method to perform CED into the murine brainstem and to test this method using the chemotherapeutic agent carmustine (BiCNU). To this end, a newly designed murine CED catheter was tested in vitro and in vivo. After determination of safety and distribution, mice bearing VUMC-DIPG-3 and E98FM-DIPG brainstem tumors were treated with carmustine dissolved in DW 5% or carmustine dissolved in 10% ethanol.
  
  
  RESULTS
  Our results show that CED into the murine brainstem is feasible and well tolerated by mice with and without brainstem tumors. CED of carmustine dissolved in 5% DW increased median survival of mice with VUMC-DIPG-3 and E98FM-DIPG tumors with 35% and 25% respectively. Dissolving carmustine in 10% ethanol further improved survival to 45% in mice with E98FM-DIPG tumors.
  
  
  METHODS
  Since genetically engineered and primary DIPG models are currently only available in mice, murine CED studies have clear advantages over CED studies in other animals.
  
  
  CONCLUSIONS
  CED in the murine brainstem can be performed safely, is well tolerated and can be used to study efficacy of chemotherapeutic agents orthotopically. These results set the foundation for more CED studies in murine DIPG models.
authors.affiliation: Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands; Neuro-oncology Research Group, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: A Charlotte P
authors.initials: AC
authors.lastname: Sewing
authors.affiliation: Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands; Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands; Neuro-oncology Research Group, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Viola
authors.initials: V
authors.lastname: Caretti
authors.affiliation: Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands; Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands; Neuro-oncology Research Group, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Tonny
authors.initials: T
authors.lastname: Lagerweij
authors.affiliation: Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands; Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands; Neuro-oncology Research Group, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Pepijn
authors.initials: P
authors.lastname: Schellen
authors.affiliation: Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands; Neuro-oncology Research Group, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Marc H A
authors.initials: MH
authors.lastname: Jansen
authors.affiliation: Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands; Neuro-oncology Research Group, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Dannis G
authors.initials: DG
authors.lastname: van Vuurden
authors.affiliation: Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands; Neuro-oncology Research Group, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Idema
authors.affiliation: Nuclear Medicine & PET Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Carla F M
authors.initials: CF
authors.lastname: Molthoff
authors.affiliation: Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: W Peter
authors.initials: WP
authors.lastname: Vandertop
authors.affiliation: Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
authors.affiliation: Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands; Neuro-oncology Research Group, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: David P
authors.initials: DP
authors.lastname: Noske
authors.affiliation: Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands; Neuro-oncology Research Group, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: e.hulleman@vumc.nl.
authors.forename: Esther
authors.initials: E
authors.lastname: Hulleman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001933:Brain Stem / Q000187:drug effects* / Q000473:pathology; D020295:Brain Stem Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D002330:Carmustine / Q000008:administration & dosage*; D057785:Catheters; D018481:Convection; D016503:Drug Delivery Systems / Q000379:methods*; D004867:Equipment Design; D000431:Ethanol / Q000737:chemistry; D005240:Feasibility Studies; D005910:Glioma / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D005947:Glucose / Q000737:chemistry; D006801:Humans; D053208:Kaplan-Meier Estimate; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D012997:Solvents / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D012997:Solvents; D000431:Ethanol; D005947:Glucose; D002330:Carmustine
keywords: Brainstem; Carmustine; Convection-enhanced delivery; DIPG; Mouse model; Pontine glioma