A Charlotte P Sewing1, Viola Caretti2, Tonny Lagerweij2, Pepijn Schellen2, Marc H A Jansen1, Dannis G van Vuurden1, Sander Idema3, Carla F M Molthoff4, W Peter Vandertop5, Gertjan J L Kaspers6, David P Noske3, Esther Hulleman7. 1. Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands; Neuro-oncology Research Group, VU University Medical Center, Amsterdam, The Netherlands. 2. 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. 3. Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands; Neuro-oncology Research Group, VU University Medical Center, Amsterdam, The Netherlands. 4. Nuclear Medicine & PET Research, VU University Medical Center, Amsterdam, The Netherlands. 5. Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands. 6. Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands. 7. 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.
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. NEW METHOD: 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. COMPARISON WITH EXISTING 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. CONCLUSION: 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.
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 DIPGpatients. NEW METHOD: 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-DIPGbrainstem 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. COMPARISON WITH EXISTING 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. CONCLUSION: 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 murineDIPG models.
Authors: Vanessa Bellat; Yago Alcaina; Ching-Hsuan Tung; Richard Ting; Adam O Michel; Mark Souweidane; Benedict Law Journal: Neuro Oncol Date: 2020-10-14 Impact factor: 12.300
Authors: Julian S Rechberger; Erica A Power; Victor M Lu; Liang Zhang; Jann N Sarkaria; David J Daniels Journal: Neurosurg Focus Date: 2020-01-01 Impact factor: 4.047
Authors: David S Hersh; Aniket S Wadajkar; Nathan Roberts; Jimena G Perez; Nina P Connolly; Victor Frenkel; Jeffrey A Winkles; Graeme F Woodworth; Anthony J Kim Journal: Curr Pharm Des Date: 2016 Impact factor: 3.116
Authors: Catherine S Grasso; Yujie Tang; Nathalene Truffaux; Noah E Berlow; Lining Liu; Marie-Anne Debily; Michael J Quist; Lara E Davis; Elaine C Huang; Pamelyn J Woo; Anitha Ponnuswami; Spenser Chen; Tessa B Johung; Wenchao Sun; Mari Kogiso; Yuchen Du; Lin Qi; Yulun Huang; Marianne Hütt-Cabezas; Katherine E Warren; Ludivine Le Dret; Paul S Meltzer; Hua Mao; Martha Quezado; Dannis G van Vuurden; Jinu Abraham; Maryam Fouladi; Matthew N Svalina; Nicholas Wang; Cynthia Hawkins; Javad Nazarian; Marta M Alonso; Eric H Raabe; Esther Hulleman; Paul T Spellman; Xiao-Nan Li; Charles Keller; Ranadip Pal; Jacques Grill; Michelle Monje Journal: Nat Med Date: 2015-05-04 Impact factor: 53.440
Authors: Melvin F Lorenzo; Sean C Thomas; Yukitaka Kani; Jonathan Hinckley; Matthew Lee; Joy Adler; Scott S Verbridge; Fang-Chi Hsu; John L Robertson; Rafael V Davalos; John H Rossmeisl Journal: Cancers (Basel) Date: 2019-11-23 Impact factor: 6.639