Permeability In Brain Tumors Research Articles

On the Use of DSC-MRI for Measuring Vascular Permeability.

Contrast agent extravasation has been shown to confound brain tumor perfusion measurements with DSC-MR imaging, necessitating the use of correction techniques (eg, Weisskoff, Bjornerud). Leakage parameters (K2 and K(a)) postulated to reflect vessel permeability can be extracted from these correction methods; however, the biophysical interpretation of these parameters and their relationship to commonly used MR imaging measures of vascular permeability (eg, contrast agent volume transfer constant, [K(trans)]) remain unclear. Given that vascular density, as assessed by blood volume, and vascular permeability, as reflected by K(trans) (and potentially K2 or K(a)), report on unique and clinically informative vascular characteristics, there is a compelling interest to simultaneously assess these features. We acquired multiecho DSC-MR imaging data, allowing the simultaneous computation and voxelwise comparison of single- and dual-echo derived measures of K2, K(a) and K(trans) in patients with glioma. This acquisition enabled the investigation of competing T1 and T2* leakage effects and TE dependency on these parameters. K2 and K(a) displayed nonsignificant (P = .150 and P = .060, respectively) voxelwise linear correlations with K(trans), while a significant (P < .001) inverse relationship was observed between K2 and Ka (coefficient of determination [r(2)] = 0.466-0.984). Significantly different (P < .005) mean estimates were found between voxels exhibiting predominately T1 and T2* effects for K2 and K(a). K(trans), however, was observed to be similar between these voxels (0.109 versus 0.092 minutes(-1)). Significant differences (P < .001) in extracellular-extravascular volume fraction (v(e)) (0.285 versus 0.167) were also observed between cohorts. Additionally, K2 and K(a) were found to have a significant quadratic relationship (P = .031 and P = .005, respectively) with v(e). Estimates of vascular permeability in brain tumors may be simultaneously acquired from multiple-echo DSC-MR imaging via K(trans); however, caution should be used in assuming a similar relationship for K2 and K(a).

Evaluation of IAUGC indices and two DCE-MRI pharmacokinetic parameters assessed by two different theoretical algorithms in patients with brain tumors

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) quantifies blood–brain barrier (BBB) microvascular permeability in brain tumors where it is structurally and functionally abnormal. Twenty-five patients with glioblastomas (105 regions of interest) were compared using DCE-MRI metrics obtained with Tofts–Kety (TK) and extended TK (ETK) models using different arterial input function assessments and different initial area under the gadolinium curve (IAUGC) indices.Strong correlations between ve and IAUGC90 were found (EKT model: R=0.75 and R=0.69), while correlations of Ktrans with both IAUGC80/90 indices were weak. Differences in the permeability parameters, calculated by these two models, were found.While the IAUGC method can be implemented more easily than pharmacokinetic models, at this time, the IAUGC approach alone does not substitute pharmacokinetic models in BBB permeability characterization.

Abstract 3930: Analysis of longitudinal relaxation time mapping for monitoring vascular permeability in brain tumors.

Abstract Introduction: Vessel permeability measurement in tumors, as assessed by Ktrans exchange coefficient, may have diagnostic value for determining treatment effectiveness and are an emerging parameter for drug transport modeling. Transvascular exchange models have been the standard for deriving Ktrans in an imaging voxel based on the pharmacokinetic analysis of the longitudinal relaxation time (T1) measurements following systemic delivery of T1-shortening contrast reagent (CR) in tissue using dynamic contrast-enhanced (DCE)-MRI. Analysis requires a pre-contrast longitudinal relaxation time (T10) as a model input. This study investigates the effect of using T10 maps versus an average value for analyzing changes in Ktrans measurements in intracerebral lung carcinoma, glioma, and melanoma xenograft models before and after treatment with agents targeting tumor edema. Materials and Methods: Rats were inoculated in the right basal ganglia with LX-1 human lung carcinoma (n = 10), UW28 human glioma (n = 11), or A2058 human melanoma cells (n = 15). After baseline MRI scans, animals received glyburide (∼24 μg/kg oral), dexamethasone (∼1.8 mg/kg IV) or vehicle control. MRI study was performed using a horizontal bore 11.75 T magnet system. T10 in tumor tissue was measured using a spin-echo inversion recovery sequence. DCE-MRI was done with a fast-gradient-echo sequence. Ktrans was calculated by non-linear squared fitting to the T1 measurements; animal-specific arterial input functions were used. A Student's two-tailed, paired t-test was used to test statistical significance of change in Ktrans between using T10 maps versus ROI-based T10 value. Results and Discussion: On pre-treatment MRI, 50% of lung and melanoma metastases showed standard deviation ≥10% the average T10 value. For UW28 tumors, standard deviation was &amp;lt;10% of the average T10 for all animals. LX-1 metastases became more heterogeneous based on σ increase. Ktrans was assessed using an ROI-based average T10 value and T10 maps before and after treatment. T10 mapping reduced average Ktrans in over 88% of cases (including pre- and post- treatment). Change in Ktrans from T10 mapping did not change with treatment (p ≥ 0.07) and change in Ktrans resulting from treatment was not significantly affected by T10 mapping (p ≥ 0.09) the treatment groups. There was a trend towards significance observed with larger animal numbers. Conclusions: LX-1 and A2058 metastases were more heterogeneous than the UW28 model based on standard deviation of T10 values within tumor. Using an ROI-based average T10 value was likely to overpredict average Ktrans values, but not likely to significantly affect treatment outcomes of study for these tumors and therapies despite tumor heterogeneity. Overpredicted Ktrans hot spots could have more consequences on hot spot analysis to monitor treatment outcome rather than average Ktrans. Citation Format: Gregory L. Pishko, Eric M. Thompson, Edward A. Neuwelt. Analysis of longitudinal relaxation time mapping for monitoring vascular permeability in brain tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3930. doi:10.1158/1538-7445.AM2013-3930

Abstract 2678: First demonstration of in vivo PET imaging for ALK inhibitor using [11C]ASP3026, a novel brain-permeable type of ALK inhibitor.

Abstract The recent breakthrough identifying the onco-driver fusion mutant of ALK kinase and its inhibitor crizotinib commercially termed as Xalkori has brought significant benefit to a portion of non-small cell lung cancer (NSCLC) patients. However, a number of clinical issues in ALK-positive lung cancer remain, involving resistance to crizotinib caused by secondary mutation, amplification of the ALK gene, activation of alternative pathways, and metastatic resistance, etc. Among these mechanisms, brain metastasis is a critical issue because of its poor prognosis. We have recently identified ASP3026 as a novel type of ALK inhibitor under development, and have reported that ASP3026 shows antitumor activities in several crizotinib-refractory models including gate keeper mutants. Here, we report the first PET imaging of an ALK inhibitor using [11C]ASP3026. The study has revealed that ASP3026 shows a brain tumor permeability in an intracranial xenograft model of H2228-luc ALK fusion positive cells. In this model, significant growth inhibition of H2228 intracranial tumor was observed by treatment with ASP3026 (10 mg/kg, q.d.), but not with crizotinib (10 mg/kg, q.d.) as determined by a bioluminescent imaging technique. Pharmacokinetic measurements of ASP3026 and crizotinib indicated that ASP3026 showed a four-fold better brain penetration than crizotinib on AUC0-24 base analysis, with a brain/plasma ratio=0.72 and 0.18 for ASP3026 and crizotinib, respectively. Further, we synthesized positron-labeled [11C]ASP3026 and performed PET imaging to clarify penetration of ASP3026 into cranial tumors. Quantitative analysis of [11C]ASP3026-PET data indicated that ASP3026 showed higher uptake into cranial tumors (SUV=3.0) than brain parenchyma (SUV=0.8). Moreover, comparison of pharmacokinetic profiles in several tumor models showed that tumor uptake of ASP3026 was higher than that of surrounding tissue, suggesting that tumor accumulation of ASP3026 was dependent on the microenvironment of tumor. Taken together, these results suggest that ASP3026 has favorable properties that may be useful for the treatment of brain metastases in ALK-positive NSCLC patients. Thus, PET imaging using 11C-labeled ASP3026 may allow the tumor penetration of ASP3026 to be clarified in any primary or metastatic tumor site. Citation Format: Hiroshi Fushiki, Rika Saito, Makoto Jitsuoka, Itsuro Shimada, Yutaka Kondoh, Hideki Sakagami, Yukiko Funatsu, Akihiro Noda, Yoshihiro Murakami, Sousuke Miyoshi, Yoko Ueno, Satoshi Konagai, Takatoshi Soga, Shintaro Nishimura, Masamichi Mori, Sadao Kuromitsu. First demonstration of in vivo PET imaging for ALK inhibitor using [11C]ASP3026, a novel brain-permeable type of ALK inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2678. doi:10.1158/1538-7445.AM2013-2678

A Simulation Tool for Dynamic Contrast Enhanced MRI

The quantification of bolus-tracking MRI techniques remains challenging. The acquisition usually relies on one contrast and the analysis on a simplified model of the various phenomena that arise within a voxel, leading to inaccurate perfusion estimates. To evaluate how simplifications in the interstitial model impact perfusion estimates, we propose a numerical tool to simulate the MR signal provided by a dynamic contrast enhanced (DCE) MRI experiment. Our model encompasses the intrinsic and relaxations, the magnetic field perturbations induced by susceptibility interfaces (vessels and cells), the diffusion of the water protons, the blood flow, the permeability of the vessel wall to the the contrast agent (CA) and the constrained diffusion of the CA within the voxel. The blood compartment is modeled as a uniform compartment. The different blocks of the simulation are validated and compared to classical models. The impact of the CA diffusivity on the permeability and blood volume estimates is evaluated. Simulations demonstrate that the CA diffusivity slightly impacts the permeability estimates ( for classical blood flow and CA diffusion). The effect of long echo times is investigated. Simulations show that DCE-MRI performed with an echo time may already lead to significant underestimation of the blood volume (up to 30% lower for brain tumor permeability values). The potential and the versatility of the proposed implementation are evaluated by running the simulation with realistic vascular geometry obtained from two photons microscopy and with impermeable cells in the extravascular environment. In conclusion, the proposed simulation tool describes DCE-MRI experiments and may be used to evaluate and optimize acquisition and processing strategies.

Quantification of cerebral tumour blood flow and permeability with T1-weighted dynamic contrast enhanced MRI: A feasibility study

Recently, T1-weighted DCE-MRI was proposed as an alternative to T2*-weighted DSC-MRI for the quantification of perfusion and permeability in brain tumors. The aim of the present feasibility study was to explore the clinical potential of the technique in different tumor types using a case-based review of initial results. The method for data analysis was adapted from cerebral perfusion CT and applied in this study to a small group of patients with grade IV glioma and other brain tumors. The possible use of the proposed methodology was also explored for characterizing, following-up and planning the therapy of brain tumors. Parametric maps clearly differentiated tumor from the surrounding brain tissue, and also distinguished areas within the tumor presenting with different characteristics, thereby allowing identification of significant target areas for biopsy and/or treatment. Differences in cerebral blood flow (CBF) and lower extraction fractions (E) were observed in various tumors. Progression from a grade II to grade IV glioma over the course of a year was characterized by an increase in CBF and a decrease in E. DCE-MRI-based quantitative perfusion and permeability may be helpful for tumor-grade characterization, biopsy guidance, radiotherapy planning, radiotherapy monitoring and clinical follow-up, thereby improving the non-invasive characterization of brain tumors.

Abstract 1447: PDE5 inhibitors increase trastuzumab transport for treatment of HER2-positive metastatic brain tumors

Abstract Objective: Chemotherapeutic drugs and newly developed therapeutic antibodies can be adequately delivered to most solid and systemic tumors. However, drug delivery into primary brain tumors and metastases is impeded by the blood-brain tumor barrier (BTB), significantly limiting drug use in brain cancer treatment. Our previous publication showed that phosphodiesterase type (PDE) 5 inhibitors enhance brain tumor permeability and efficacy of chemotherapy in a rat brain tumor model. Here, we further examined the effect of PDE 5 inhibitors on drug delivery to intracranial human lung and breast tumors in nude mice as a model of brain metastasis, and the underlying mechanisms of drug transport. Methods: In the in vitro setting, a Corning transwell system seeded with mouse brain endothelial cells (MBEC) was used for cellular [14C]dextran transport study as a model of blood brain barrier (BBB). For in vitro uptake of a therapeutic monoclonal antibody to HER2/neu, trastuzumab (Herceptin®), MBEC were treated with labeled drug with or without pre-incubation with vardenafil. To study the underlying mechanisms of transport, inhibitors of caveolae and macropinocytosis endocytic pathways were used to block the effect of PDE5 inhibitors. In the in vivo study, vardenafil was given at an oral dose of 10 mg/kg for transport of [14C]dextran and labeled trastuzumab to mice with human lung tumor growing in the brain. For the survival experiments, HER2/neu-positive human lung or breast intracranial tumor-bearing mice were randomly divided into four groups treated as follows: (1) control saline; (2) vardenafil (10 mg/kg, po); (3) trastuzumab (10 mg/kg, iv); and (4) vardenafil (10 mg/kg, P.O.) + trastuzumab (10 mg/kg, I.V.). Results: In vitro assay demonstrated that PDE5 inhibitors enhanced the uptake of [14C]dextran and trastuzumab by cultured MBECs. Inhibitor analysis strongly implicated caveolae and macropinocytosis endocytic pathways involvement in the PDE5 inhibitor-enhanced trastuzumab uptake. Oral administration of PDE5 inhibitor vardenafil to mice with intracranial lung tumors led to an increased tumor permeability to high molecular weight [14C]dextran (2.6-fold increase) and to trastuzumab (2-fold increase). Survival of intracranial lung cancer-bearing mice treated with trastuzumab in combination with vardenafil significantly increased as compared to the untreated, vardenafil alone- or trastuzumab alone-treated mice (p&amp;lt;0.01). In mice bearing intracranial breast tumors, log-rank analysis of survival curves also showed a significant survival increase (p&amp;lt;0.02) in the group treated with trastuzumab plus vardenafil as compared to other groups. Conclusion: These findings suggest that PDE5 inhibitors may effectively modulate BTB permeability and enhance drug delivery, and may increase the efficacy of therapeutic monoclonal antibodies in hard-to-treat brain metastases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1447.

Different effects of K Ca and K ATP agonists on brain tumor permeability between syngeneic and allogeneic rat models

The blood–brain tumor barrier (BTB) significantly limits delivery of effective concentrations of chemotherapeutic drugs to brain tumors. Previous studies suggest that BTB permeability may be modulated via alteration in the activity of potassium channels. In this study, we studied the relationship of BTB permeability increase mediated by potassium channel agonists to channel expression in two rat brain tumor models. Intravenous infusion of KCO912 (K ATP agonist), minoxidil sulfate (K ATP agonist) or NS1619 (K Ca agonist) increased tumor permeability more in the 9L allogeneic brain tumor model than in the syngeneic brain tumor model. Consistently, expression of both K ATP and K Ca channels in 9L tumors was increased to a significantly greater extent in Wistar rats (allogeneic) as compared to Fischer rats (syngeneic). Furthermore, as a preliminary effort to understand clinical implication of potassium channels in brain tumor treatment, we determined the expression of K ATP in surgical specimens. K ATP mRNA was detected in glioblastoma multiforme (GBM) from nineteen patients examined, with a wide range of expression levels. Interestingly, in paired GBM tissues from seven patients before and after vaccination therapy, increased levels of K ATP were detected in five patients after vaccination that had positive response to chemotherapy after vaccination. The present study indicates that the effects of potassium channel agonists on BTB permeability are different between syngeneic and allogeneic models which have different expression levels of potassium channels. The expression of potassium channels in brain tumors is variable, which may be associated with different tumor permeability to therapeutic agents among patients.

Increase in Brain Tumor Permeability in Glioma-Bearing Rats with Nitric Oxide Donors

The blood-brain tumor barrier (BTB) significantly limits the delivery of chemotherapeutics to brain tumors. Nitric oxide (NO) is involved in the regulation of cerebral vascular permeability. We investigated the effects of NO donors, L-arginine and hydroxyurea, on BTB permeability in 9L gliosarcoma-bearing Fischer rats. The rats implanted with 9L gliosarcoma were dosed orally with hydroxyurea and L-arginine. BTB permeability, defined by the unidirectional transport constant, Ki, for [14C]sucrose was measured. The expression of neural and endothelial NO synthase (NOS) in tumors and normal brain tissue was examined. Further, the levels of NO, L-citrulline, and cGMP in the tumor and normal brain tissue were measured. Oral administration of l-arginine or hydroxyurea significantly increased BTB permeability when compared with the nontreated control. The selective effects were abolished by iberiotoxin, an antagonist of calcium-dependent potassium (KCa) channel that is a cGMP pathway effector. The expression of endothelial NOS, but not neural NOS, was higher in tumor vessels than in those of normal brain. Moreover, the levels of NO, L-citrulline, a byproduct of NO formation from L-arginine, and cGMP were enhanced in the tumor tissue by oral administration of L-arginine and/or hydroxyurea. Oral administration of L-arginine or hydroxyurea selectively increased tumor permeability, which is likely mediated by alteration in cGMP levels. The findings suggest that use of oral NO donors may be a strategy to enhance the delivery of chemotherapeutics to malignant brain tumors.

Calcium-activated potassium channels mediated blood-brain tumor barrier opening in a rat metastatic brain tumor model

BackgroundThe blood-brain tumor barrier (BTB) impedes the delivery of therapeutic agents to brain tumors. While adequate delivery of drugs occurs in systemic tumors, the BTB limits delivery of anti-tumor agents into brain metastases.ResultsIn this study, we examined the function and regulation of calcium-activated potassium (KCa) channels in a rat metastatic brain tumor model. We showed that intravenous infusion of NS1619, a KCa channel agonist, and bradykinin selectively enhanced BTB permeability in brain tumors, but not in normal brain. Iberiotoxin, a KCa channel antagonist, significantly attenuated NS1619-induced BTB permeability increase. We found KCa channels and bradykinin type 2 receptors (B2R) expressed in cultured human metastatic brain tumor cells (CRL-5904, non-small cell lung cancer, metastasized to brain), human brain microvessel endothelial cells (HBMEC) and human lung cancer brain metastasis tissues. Potentiometric assays demonstrated the activity of KCa channels in metastatic brain tumor cells and HBMEC. Furthermore, we detected higher expression of KCa channels in the metastatic brain tumor tissue and tumor capillary endothelia as compared to normal brain tissue. Co-culture of metastatic brain tumor cells and brain microvessel endothelial cells showed an upregulation of KCa channels, which may contribute to the overexpression of KCa channels in tumor microvessels and selectivity of BTB opening.ConclusionThese findings suggest that KCa channels in metastatic brain tumors may serve as an effective target for biochemical modulation of BTB permeability to enhance selective delivery of chemotherapeutic drugs to metastatic brain tumors.

609 KCa channel-mediated regulation of metastatic brain tumor permeability and proliferation

609 KCa channel-mediated regulation of metastatic brain tumor permeability and proliferation

Intracarotid RMP-7 enhanced indocyanine green staining of tumors in a rat glioma model.

The extent of resection in patients with primary brain tumors may affect the quality of life, time to tumor progression, and survival. Currently, the extent of resection during surgery is guided by the visual appearance and consistency of tumor, frozen sections of the margins, intraoperative ultrasound, and frameless navigational systems and intraoperative imaging modalities. A new method that enhances the visualization of an infiltrating tumor and its margins may further aid in obtaining a more complete resection. A study was thus undertaken to assess the staining of brain tumors using Indocyanine green (ICG), a water-soluble emerald green tricarbocynanine dye concomitantly with RMP-7, a bradykinin analog, that selectively increases vascular permeability in brain tumors. A syngeneic ethyl-nitrosourea-induced F-344 rat cell line (36B-10) was stereotactically implanted into 25 rats, and allowed to mature for 15-18 days. Intracarotid administration of 0.75 ml of RMP-7 at a standard dose of 0.4 microg/ml over 15 min was then infused. Varying doses of ICG (range, 0-60 mg/kg) were then injected 15 min after the RMP-7 infusion ended. The animals were sacrificed 15 min after the ICG infusion was completed, and the brains examined macroscopically and microscopically for evidence of tumor staining. This study demonstrated consistent staining of the tumor at only slightly lower ICG doses than previously described, however uptake at the tumor margins was evident at much lower doses. Thus the combination of ICG and RMP-7 administered preoperatively may provide visual enhancement of an infiltrating tumor and its margins to help facilitate a radical tumor removal.

Improved 3D quantitative mapping of blood volume and endothelial permeability in brain tumors

We describe a new method to allow simultaneous mapping of endothelial permeability and blood volume in intracranial lesions. The technique is based on a tumor leakage profile during the first pass (fp) of contrast bolus calculated from the time-dependent plasma-contrast concentration function (PCCF) in three-dimensional (3D) T1-weighted dynamic studies. The performance of the method has been evaluated by comparing results with those obtained from more conventional methods in patients with primary brain neoplasms. The new permeability maps (kfp) are visually compatible with those calculated using a conventional multicompartment model (ktran). Quantitatively, the new maps are free from overestimation of ktran due to first-pass effects. The new blood volume maps, which segment out the contamination of contrast leakage, agree closely with maps derived from susceptibility studies. The new method is fast, robust, and easy to perform. The method is suitable for use in clinical environments and is likely to be of benefit where longitudinal assessment of treatment response is required. J. Magn. Reson. Imaging 2000;12:347–357. © 2000 Wiley-Liss, Inc.

Improved 3D quantitative mapping of blood volume and endothelial permeability in brain tumors.

We describe a new method to allow simultaneous mapping of endothelial permeability and blood volume in intracranial lesions. The technique is based on a tumor leakage profile during the first pass (fp) of contrast bolus calculated from the time-dependent plasma-contrast concentration function (PCCF) in three-dimensional (3D) T1-weighted dynamic studies. The performance of the method has been evaluated by comparing results with those obtained from more conventional methods in patients with primary brain neoplasms. The new permeability maps (k(fp)) are visually compatible with those calculated using a conventional multicompartment model (k(tran)). Quantitatively, the new maps are free from overestimation of k(tran) due to first-pass effects. The new blood volume maps, which segment out the contamination of contrast leakage, agree closely with maps derived from susceptibility studies. The new method is fast, robust, and easy to perform. The method is suitable for use in clinical environments and is likely to be of benefit where longitudinal assessment of treatment response is required.

The effect of 5-lipoxygenase inhibition on blood-brain barrier permeability in experimental brain tumors.

To determine if leukotrienes are important mediators of vascular permeability in brain tumors, the effect of 5-lipoxygenase inhibitors on blood-tumor barrier permeability in rats harboring HK Walker 256 brain tumors was examined using quantitative autoradiography with alpha-14C-aminoisobutyric acid. The 5-lipoxygenase enzyme converts arachidonic acid to leukotrienes. Three 5-lipoxygenase inhibitors were utilized: BW755C, nordihydroguaiaretic acid, and AA-861. All three 5-lipoxygenase inhibitors significantly decreased vascular permeability both within the tumors and in brain adjacent to tumor. This suggests that capillary permeability in and adjacent to tumors is influenced by endogenous leukotrienes and that leukotrienes play an important role in brain tumor edema.

Temporal effects of dexamethasone on blood-to-brain and blood-to-tumor transport of 14C-alpha-aminoisobutyric acid in rat C6 glioma

We used quantitative autoradiography (QAR) to evaluate the effect of systemically administered dexamethasone on capillary permeability in brain tumors and surrounding brain. Rats bearing unilateral right hemispheric C6 gliomas were studied at one and twelve hours after 10 mg/kg of intraperitoneal dexamethasone. Capillary permeability was determined by measuring unidirectional blood-to-brain and blood-to-tumor transport of 14C-alpha aminoisobutyric acid (14C-AIB) over fifteen minutes. 14C-AIB entry into tumor, brain adjacent-to-tumor (BAT), and ipsilateral and contralateral cortices was determined and expressed as a unidirectional transfer constant, K. Nontreated tumor K was more than two-fold greater than K for BAT and ten-fold greater than ipsilateral cortical K, confirming substantial barrier disruption in tumor. In addition, the K for BAT was also significantly greater than K for cortex, indicating that the barrier in the peritumoral region was also disrupted. One hour after dexamethasone treatment, tumor K fell to 63% of its pretreatment value (p less than 0.025). By twelve hours post-treatment, tumor K fell to 25% of the untreated value (p less than 0.001) and to 47% of the one-hour value (p less than 0.005). BAT K fell to 29% of its untreated value (p less than 0.02) and to 46% of its one-hour value (p less than 0.02). By 12 hours, ipsilateral cortical K fell to 67% of the untreated cortical value (p less than 0.05). Compared to untreated values, there was no significant difference between contralateral cortical K at either one or twelve hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Permeability in brain tumors.

Permeability in brain tumors.