Successful and safe perfusion of the primate brainstem: in vivo magnetic resonance imaging of macromolecular distribution during infusion

Lonser, Russell R.; Walbridge, Stuart; Garmestani, Kayhan; Butman, John A.; Walters, Hugh A.; Vortmeyer, Alexander O.; Morrison, Paul F.; Brechbiel, Martin W.; Oldfield, Edward H.

doi:10.3171/jns.2002.97.4.0905

Cited by 173 publications

(138 citation statements)

References 13 publications

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“…1 Therefore, novel therapeutic strategies for the treatment of this tumor, including the use of small-molecule inhibitors and novel drug delivery methods, continue to be investigated. Although innovative methods of drug delivery have been tested successfully in animals only, 26 several pediatric trials are already testing the efficacy or activity of novel biologic agents in children with newly diagnosed or progressive diffuse brainstem glioma. To identify additional molecules and cellular pathways that can be targeted by these novel strategies, it will be important to better understand the mechanisms that are associated with the genesis of this neoplasm.…”

Section: Discussionmentioning

confidence: 99%

Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children

Broniscer

Iacono

Chintagumpala

et al. 2004

Cancer

100

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BACKGROUNDThe role of chemotherapy in the treatment of children with newly diagnosed diffuse brainstem glioma is uncertain. In the current study, the authors tested the efficacy of temozolomide treatment after radiotherapy (RT) in this setting.METHODSPatients ages 3–21 years were eligible for the current multiinstitutional study. An optional window therapy regimen consisting of 2 cycles of intravenous irinotecan (10 doses of 20 mg/m2 per day separated by 2 days of rest per cycle) was delivered over 6 weeks and was followed by conventionally fractionated RT. The 5‐day schedule of temozolomide (200 mg/m2 per day) was initiated 4 weeks after RT and was continued for a total of 6 cycles. The pharmacokinetics of temozolomide and its active metabolite, 5‐(3‐methyltriazen‐1‐yl)imidazole‐4‐carboxamide (MTIC), were analyzed during Cycles 1 and 3.RESULTSThirty‐three patients (median age at diagnosis, 6.4 years) were enrolled. Of the 16 patients who received window therapy, 6 had irinotecan treatment discontinued due to clinical progression (n = 5) or toxicity (n = 1); the remaining 10 experienced disease stabilization after 2 cycles. All patients completed RT (median dose, 55.8 gray). Twenty‐nine patients received a combined total of 125 cycles of temozolomide. Grade 3/4 neutropenia and thrombocytopenia occurred in 33% and 29% of all temozolomide cycles, respectively. In approximately one‐third of the cycles, dose reduction was required due to myelosuppression. No correlation was demonstrated between temozolomide/MTIC exposure and myelosuppression at the conclusion of Cycle 1. All patients died of disease progression (median survival, 12 months). The estimated 1‐year survival rate was 48% (standard error, 8%).CONCLUSIONSThe administration of temozolomide after RT did not alter the poor prognosis associated with newly diagnosed diffuse brainstem glioma in children. Cancer 2005. © 2004 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children

Broniscer

Iacono

Chintagumpala

et al. 2004

Cancer

100

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“…The larger the catheter diameter, the more easily reflux can be induced. We, 40 along with others, 27,41,42 have documented that CED infusion flow rates less than 0.5 L/min may be necessary to prevent reflux in catheters up to 0.6 mm (outer diameter [OD]). However, in a recent phase III trial of transferrin-CRM107 (Xenova Biomedix Ltd, Guilford, Surrey, UK) in glioblastoma, investigators used a ventriculo-peritoneal shunt catheter (2.5 mm OD) at a flow rate of 3.3 L/min (unpublished data).…”

Section: Introductionmentioning

confidence: 99%

Image-Guided Convection-Enhanced Delivery Platform in the Treatment of Neurological Diseases

et al. 2008

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Summary: Convection-enhanced delivery (CED) of substances within the human brain is becoming a more frequent experimental treatment option in the management of brain tumors, and more recently in phase 1 trials for gene therapy in Parkinson's disease (PD). Benefits of this intracranial drugtransfer technology include a more efficient delivery of large volumes of therapeutic agent to the target region when compared with more standard delivery approaches (i.e., biopolymers, local infusion). In this article, we describe specific technical modifications we have made to the CED process to make it more effective. For example, we developed a reflux-resistant infusion cannula that allows increased infusion rates to be used. We also describe our efforts to visualize the CED process in vivo, using liposomal nanotechnology and real-time intraoperative MRI. In addition to carrying the MRI contrast agent, nanoliposomes also provide a standardized delivery vehicle for the convection of drugs to a specific brain-tissue volume. This technology provides an added level of assurance via visual confirmation of CED, allowing intraoperative alterations to the infusion if there is reflux or aberrant delivery. We propose that these specific modifications to the CED technology will improve efficacy by documenting and standardizing the treatment-volume delivery. Furthermore, we believe that this image-guided CED platform can be used in other translational neuroscience efforts, with eventual clinical application beyond neuro-oncology and PD.

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“…Previous work has been published with regards to the intracranial distribution of ITs. [44][45][46][47][48] Since intracranial injection of ITs relies on concentration-based diffusion, the distance of penetration decreases exponentially as the IT concentration declines. Thus, recent studies show that convection-enhanced delivery (CED) of IT is superior to bolus injection of IT.…”

Section: Discussionmentioning

confidence: 99%

Intracranial therapy of glioblastoma with the fusion protein DTIL13 in immunodeficient mice

Rustamzadeh

Hall

Todhunter

et al. 2006

Intl Journal of Cancer

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A fusion protein consisting of human interleukin-13 and the first 389 amino acids of diphtheria toxin was assembled in order to target human glioblastoma cell lines in a murine intracranial model. In vitro studies to determine specificity indicated that the protein called DTIL13 was highly selective for human glioblastoma. In vivo, the maximum tolerated dose of DTIL13 was 1 lg/injection given every other day and repeated for 3 days. Doses that exceeded this amount resulted in weight loss and liver damage as determined by histology and enzyme assay. Experiments in IL-4 receptor knockout mice revealed that liver toxicity was receptorrelated. This same dose given to nude mice with established U373 MG brain tumors resulted in significant reductions in tumor volume and significantly prolonged survival (p < 0.0001). Magnetic resonance imaging (MRI) proved to be extremely useful in (i) determining the ability of DTIL13 to reduce tumor size and (ii) for studying toxicity since diffusion-weighted and gradient echoweighted MRI revealed that vascular leak syndrome was not a limiting toxicity at this dose. These results suggest that DTIL13 is as effective in an intracranial rodent model as it was in a flank model in previous studies and that DTIL13 might be an effective treatment for glioblastoma multiforme. ' 2005 Wiley-Liss, Inc.Key words: diphtheria toxin; glioblastoma; interleukin-13; brain tumor; immunotoxin Glioblastoma multiforme (GBM) is an incurable, heterogeneous, high-grade astrocytic glioma, thought to originate from glial nonneuronal cells. 1 More recent studies have identified a subpopulation of cancer stem-cells within GBM that retain the capacity for self-renewal and the ability to differentiate into a phenotypically diverse population of cells. 2-4 With a 2-year-patient survival rate of <30%, 5 effective treatment has been hindered by the lack of tumor-specific markers in the majority of patients. Recently, the IL-13 receptor (IL-13R) has been found to be overexpressed on cultured human GBM cell lines and surgical GBM specimens, but is not detectable in normal brain tissue. [6][7][8] Targeting the IL-13 receptor with an immunotoxin (IT) has already proven to have potential for treating brain tumors. [8][9][10][11][12] ITs are not mainstream pharmaceuticals, and treatment of systemic tumors with ITs has been limited by their failure to localize in tumor. The promise of these drugs is considerably greater for brain-cancer therapy, since IT can be directly administered intracranially. In an earlier study, we assembled an IL-13 IT made by fusing gene fragments encoding for human IL-13 and the first 389 amino acids of diphtheria toxin. 13 In vivo studies with this agent showed that it had a potent antitumor effect against IL-13R-positive GBM cells grown in the flanks of nude mice without significant toxicity.Although encouraging, the flank model has limitations as a model for intracranial therapy. First, intratumoral pressure within the flank model does not reach the pressures that occur in intracranial tumors ...

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Successful and safe perfusion of the primate brainstem: in vivo magnetic resonance imaging of macromolecular distribution during infusion

Cited by 173 publications

References 13 publications

Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children

Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children

Image-Guided Convection-Enhanced Delivery Platform in the Treatment of Neurological Diseases

Intracranial therapy of glioblastoma with the fusion protein DTIL13 in immunodeficient mice

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