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Review
. 2018 Jan 22;20(2):184-191.
doi: 10.1093/neuonc/nox175.

Is the blood-brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data

Jann N Sarkaria  1 , Leland S Hu  2 , Ian F Parney  1 , Deanna H Pafundi  1 , Debra H Brinkmann  1 , Nadia N Laack  1 , Caterina Giannini  1 , Terence C Burns  1 , Sani H Kizilbash  1 , Janice K Laramy  3 , Kristin R Swanson  2 , Timothy J Kaufmann  1 , Paul D Brown  1 , Nathalie Y R Agar  4 , Evanthia Galanis  1 , Jan C Buckner  1 , William F Elmquist  1
Affiliations
Review

Is the blood-brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data

Jann N Sarkaria et al. Neuro Oncol. .

Abstract

The blood-brain barrier (BBB) excludes the vast majority of cancer therapeutics from normal brain. However, the importance of the BBB in limiting drug delivery and efficacy is controversial in high-grade brain tumors, such as glioblastoma (GBM). The accumulation of normally brain impenetrant radiographic contrast material in essentially all GBM has popularized a belief that the BBB is uniformly disrupted in all GBM patients so that consideration of drug distribution across the BBB is not relevant in designing therapies for GBM. However, contrary to this view, overwhelming clinical evidence demonstrates that there is also a clinically significant tumor burden with an intact BBB in all GBM, and there is little doubt that drugs with poor BBB permeability do not provide therapeutically effective drug exposures to this fraction of tumor cells. This review provides an overview of the clinical literature to support a central hypothesis: that all GBM patients have tumor regions with an intact BBB, and cure for GBM will only be possible if these regions of tumor are adequately treated.

Keywords: blood brain barrier; drug therapy; glioblastoma; magnetic resonance imaging.

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Figures

Fig. 1
Fig. 1
Illustration of key components of the BBB that provide physical (tight and adherens junctions) and biochemical (transporter-mediated efflux) barriers to brain penetration of antiglioma agents.
Fig. 2
Fig. 2
Illustrative case for a patient with significant tumor burden beyond contrast-enhancing regions. Sequential imaging with (A) T1W+contrast, (B) T2W FLAIR, (C) FDOPA PET (cyan contour), and (D) PET/CT fusion demonstrate significant regions of an FDOPA-positive GBM without contrast enhancement on MRI. Location of a stereotactic biopsy is marked with a magenta contour. Samples were processed for photomicroscopy of hematoxylin and eosin at (E) 100x magnification and (F) 400x magnification showing hypercellularity. (G) Ki-67 staining of the same sample, imaged at 100x magnification shows a high proliferative index (>20%).
Fig. 3
Fig. 3
Patient-specific simulations of tumor cell distribution and density for both a diffuse and a nodular newly diagnosed GBM. T1W + gadolinium (Gd) contrast and T2W MRIs for a diffuse (A, C) or nodular (B, D) tumor. A simulation estimating glioma cell extent is overlaid on the T1Gd MRI with red and blue indicating high and low (but nonzero) glioma cell density, respectively (E, F).
See this image and copyright information in PMC

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