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PubMed1999

Radiosurgery for brain metastases: is whole brain radiotherapy necessary?

PURPOSE: Because whole brain radiotherapy (WBRT) may cause dementia in long-term survivors, selected patients with brain metastases may benefit from initial treatment with radiosurgery (RS) alone reserving WBRT for salvage as needed. We reviewed results of RS +/- WBRT in patients with newly diagnosed brain metastasis to provide background for a prospective trial. METHODS AND MATERIALS: Patients with single or multiple brain metastases managed initially with RS alone vs. RS + WBRT (62 vs. 43 patients) from 1991 through February 1997 were retrospectively reviewed. The use of upfront WBRT depended on physician preference and referral patterns. Survival, freedom from progression (FFP) endpoints, and brain control allowing for successful salvage therapy were measured from the date of diagnosis of brain metastases. Actuarial curves were estimated using the Kaplan-Meier method. Analyses to adjust for known prognostic factors were performed using the Cox proportional hazards model (CPHM) stratified by primary site. RESULTS: Survival and local FFP were the same for RS alone vs. RS + WBRT (median survival 11.3 vs. 11.1 months and 1-year local FFP by patient 71% vs. 79%, respectively). Brain FFP (scoring new metastases and/or local failure) was significantly worse for RS alone vs. RS + WBRT (28% vs. 69% at 1 year; CPHM adjustedp = 0.03 and hazard ratio = 0.476). However, brain control allowing for successful salvage of a first failure was not significantly different for RS alone vs. RS + WBRT (62% vs. 73% at 1 year; CPHM adjusted p = 0.56). CONCLUSIONS: The omission of WBRT in the initial management of patients treated with RS for up to 4 brain metastases does not appear to compromise survival or intracranial control allowing for salvage therapy as indicated. A randomized trial of RS vs. RS + WBRT is needed to assess survival, quality of life, and cost in good-prognosis patients with newly diagnosed brain metastases.

Adult↗

PubMed1998

Radiosurgery without whole brain radiotherapy in melanoma brain metastases. Club de Cancérologie Cutanée.

To evaluate the effectiveness of radiosurgery without whole brain radiotherapy in the palliative treatment of melanoma brain metastases, we retrospectively assessed the results in 35 patients: 4 with a solitary brain metastasis, 13 with a single brain metastasis and metastases elsewhere and 18 with multiple brain metastases. The local control rate was 98.2% (55/56 metastases) at 3 months. Median survival was 22 months in patients with a solitary brain metastasis, 7.5 months in patients with a single brain metastasis and metastases elsewhere, and 4 months in patients with multiple brain metastases. Complications were unusual and surgery was required in 2 of 35 patients. These results show for the first time that melanoma patients with a unique brain metastasis with or without metastases elsewhere clearly benefit from tumour control easily obtained by radiosurgery. Although the comparison of radiosurgery with surgery and/or whole brain radiotherapy cannot be adequately addressed, radiosurgery alone seems to provide similar results with lower morbidity and impact on quality of life.

Adult↗

PubMed1995

Specific activity of brain palmitoyl-CoA pool provides rates of incorporation of palmitate in brain phospholipids in awake rats.

In vivo rates of palmitate incorporation into brain phospholipids were measured in awake rats following programmed intravenous infusion of unesterified [9,10-3H]palmitate to maintain constant plasma specific activity. Animals were killed after 2-10 min of infusion by microwave irradiation and analyzed for tracer distribution in brain phospholipid and phospholipid precursor, i.e., brain unesterified palmitate and palmitoyl-CoA, pools. [9,10-3H]Palmitate incorporation into brain phospholipids was linear with time and rapid, with > 50% of brain tracer in choline-containing glycerophospholipids at 2 min of infusion. However, tracer specific activity in brain phospholipid precursor pools was low and averaged only 1.6-1.8% of plasma unesterified palmitate specific activity. Correction for brain palmitoyl-CoA specific activity increased the calculated rate of palmitate incorporation into brain phospholipids (0.52 nmol/s/g) by approximately 60-fold. The results suggest that palmitate incorporation and turnover in brain phospholipids are far more rapid than generally assumed and that this rapid turnover dilutes tracer specific activity in brain palmitoyl-CoA pool owing to release and recycling of unlabeled fatty acid from phospholipid breakdown.

Animals↗

PubMed1990

Effect of atrial natriuretic peptide on ischemic brain edema: changes in brain water and electrolytes.

The effects of intraventricularly administered atrial natriuretic peptide (ANP) on the brain water, sodium, and potassium contents in ischemic brain edema were investigated. By use of a three-vessel occlusion model, ischemic brain edema was produced in the rat brain by 15 minutes of global ischemia followed by recirculation. Water content was measured by means of a drying/weighing method; sodium and potassium contents were measured by means of flame photometry. The effects of intraventricular administration of ANP were evaluated by a comparison between the groups given 2 and 5 micrograms of atriopeptin II (treated) and those given 0.9% NaCl (sham-treated). The treated groups showed significant decreases in brain water (P less than 0.02) and sodium (P less than 0.01) contents at 15 and 30 minutes after recirculation, whereas the brain potassium contents remained unaltered. Before ischemia and immediately after 15 minutes of ischemia, intraventricularly administered ANP did not significantly change the brain water, sodium, or potassium contents. There was no significant difference in the effect on the amount of brain water and sodium between the two doses (2 and 5 micrograms). These effects of ANP were thought not to be mediated by primary changes in serum osmolality and sodium and potassium concentrations, because intraventricular administration of ANP did not change them significantly. The present results reveal that, in ischemic brain edema, ANP may act directly on the central nervous system to inhibit brain water and sodium accumulation.

Animals↗

PubMed2006

Randomized study of paclitaxel and tamoxifen deposition into human brain tumors: implications for the treatment of metastatic brain tumors.

PURPOSE: Drug resistance in brain tumors is partially mediated by the blood-brain barrier of which a key component is P-glycoprotein, which is highly expressed in cerebral capillaries. Tamoxifen is a nontoxic inhibitor of P-glycoprotein. This trial assessed, in primary and metastatic brain tumors, the differential deposition of paclitaxel and whether tamoxifen could increase paclitaxel deposition. EXPERIMENTAL DESIGN: Patients for surgical resection of their primary or metastatic brain tumors were prospectively randomized to prior paclitaxel alone (175 mg/m(2)/i.v.) or tamoxifen for 5 days followed by paclitaxel. Central and peripheral tumor, surrounding normal brain and plasma, were analyzed for paclitaxel and tamoxifen. RESULTS: Twenty-seven patients completed the study. Based on a multivariate linear regression model, no significant differences in paclitaxel concentrations between the two study arms were found after adjusting for treatment group (tamoxifen versus control). However, in analysis for tumor type, metastatic brain tumors had higher paclitaxel concentrations in the tumor center (1.93-fold, P = 0.10) and in the tumor periphery (2.46-fold, P = 0.039) compared with primary brain tumors. Pharmacokinetic analyses showed comparable paclitaxel areas under the serum concentration between treatment arms. CONCLUSIONS: Paclitaxel deposition was not increased with this tamoxifen schedule as the low plasma concentrations were likely secondary to concurrent use of P-450-inducing medications. However, the statistically higher paclitaxel deposition in the periphery of metastatic brain tumors provides functional evidence corroborating reports of decreased P-glycoprotein expression in metastatic versus primary brain tumors. This suggests that metastatic brain tumors may respond to paclitaxel if it has proven clinical efficacy for the primary tumor's histopathology.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Rat brain osmolality during barbiturate anesthesia and global brain ischemia.

Ischemic brain damage can be partially ameliorated by barbiturate therapy applied postinsult. Catabolism-induced brain hyperosmolality during ischemia may contribute to the development of brain edema after restoration of circulation. To determine changes in brain osmolality during ischemia and the effect of barbiturate anesthetics in altering its course, we measured whole and regional (cerebral cortex, diencephalon-midbrain, and cerebellum) brain osmolality for up to 2 hours after decapitation ischemia in unanesthetized and pentobarbital anesthetized rats. Normal (nonischemic) brain osmolality in pentobarbital anesthetized rats was 319 +/- 2 mOsm/1 (mean +/- SEM) and higher than in unanesthetized rats (307 +/- 6 mOsm/1). The rate of increase in whole brain osmolality was 60% slower in pentobarbital anesthetized rats in the first 60 minutes of ischemia and regional brain osmolality increased by a maximum of 32 mOsm/1 compared to 45 mOsm/1 in unanesthetized rats. The potential for edema based on percent change in brain osmolality as well as the rapidity of the change was greater in unanesthetized rats. The significance of the increase in brain osmolality with barbiturate anesthesia and its attenuation of the rate and magnitude of increase during ischemia is discussed.

Animals↗

PubMed2002

Brain size and grey matter volume in the healthy human brain.

Magnetic resonance imaging was used to evaluate the influence of sex and brain size on compartmental brain volumes (grey matter, white matter, CSF) in a large and well-matched sample of neurologically normal women (n = 50) and men (n = 50). As expected, we found a significant sex difference for the absolute volumes of total brain, grey matter, white matter and CSF, with greater volumes for men. Relating these compartmental volume measures to brain volume resulting in proportional volume measures revealed a higher proportion of grey matter in women. No significant sex differences were found for white matter and CSF proportions. However, when the influence of sex was partialized out by regression analyses, brain volume explained 40-81% of the variance of the absolute grey matter, white matter and CSF volumes. Performing these regression analyses for the proportional volume measures revealed that brain volume explained approximately 16% of the variance in grey matter proportion. Sex or the interaction between sex and brain volume revealed no additional predicitve values. Interestingly, the correlation between brain volume and grey matter proportion was negative, with larger brains exhibiting relatively smaller proportions of grey matter. Thus, sex is not the main variable explaining the variability in grey matter volume. Rather, we suggest that brain size is the main variable determining the proportion of grey matter.

Adult↗

PubMed1977

Detection and molecular characterization of the thymus-brain antigen in human brain.

Anti-human brain sera were found to contain antibodies reacting with determinants present on murine thymocyte plasma membranes. This determinant is borne by the thymocyte-brain antigen of mouse thymocytes. The non species-specific determinant of the thymocyte-brain system is detectable on the thymocyte-brain antigen of human and mouse brain in comparable amounts. In contrast to these findings, the allogenic Thy-1 and the species-specific determinant of this system were only found on the thymocyte-brain antigen of mouse brain but not on the corresponding antigen of human brain. The molecular weight, Stokes radius and diffusion coefficient of the thymocyte-brain antigen of human and mouse brain are in good accordance with the data estimated for the corresponding antigen of murine thymocytes.

Animals↗

PubMed2005

S100beta as a predictor of brain metastases: brain versus cerebrovascular damage.

BACKGROUND: The identification of brain metastases in patients with malignant disease has important implications for determining their treatment and prognosis. Asymptomatic metastatic brain tumors may be detected by surveillance imaging techniques, but longitudinal follow-up of patients who are at risk is sporadic primarily due to cost. Because the development of brain metastases is accompanied and detected by extravasation of contrast agents across the blood-brain barrier (BBB), the authors hypothesized that peripheral analysis of the BBB indicator S100beta may be useful as a screening tool for brain metastases in patients who have no neurologic symptoms. METHODS: Thirty-eight patients were enrolled for the current study. All patients had newly diagnosed lung carcinoma and had no neurologic symptoms or known history of brain metastasis. Patients underwent an initial magnetic resonance imaging (MRI) scans and S100beta blood tests. S100beta tests were repeated in a subset of patients at the time of routine follow-up MRI scans. RESULTS: Based on imaging studies and on serum S100beta analyses, the patients were divided in 3 categories: 1) patients with normal S100beta levels (0.08 +/- 0.02 microg/L; n = 22 patients) and normal MRI scans; 2) patients with elevated S100beta levels (0.5 +/- 0.28 microg/L; n = 8 patients) and pronounced microvascular changes on MRI scans but with no metastases; and 3) patients with elevated S100beta levels (0.28 +/- 0.19 microg/L; n = 7 patients) and metastatic brain tumor(s) on MRI scans. CONCLUSIONS: Because of the significant overlap in S100beta levels between patients with cerebral microvascular diseases and patients with brain metastases, the authors concluded that the serum S100beta level may be used as a surveillance tool to predict or detect brain metastases if appropriate prescreening radiologic tests are obtained and if patients who are candidates for false-positive results are identified and excluded.

Adult↗

PubMed1998

Effects of systemic hypothermia and selective brain cooling on ischemic brain damage and swelling.

The present study investigates the neuroprotective effects of temporary mild systemic hypothermia and selective brain cooling against focal cerebral infarction in the rat and the changes of cortical blood flow, and compares these two treatment modalities. In permanent middle cerebral artery (MCA) model, the treatments were induced 15 min following the artery occlusion. The animals were kept at the desired rectal or brain temperature (about 32 degrees C) for 30 min; (each, n = 6) and for 1 hr (each, n = 6), and then allowed to rewarm spontaneously, whereas control animals were kept at normothermia throughout the experiment. The volumes of brain infarction and edema were assessed 24 hr post-occlusion. The blood flow of the dorsolateral cortex was monitored by Laser-Doppler flowmetry (LDF) in the other experiments. Hemispheric infarct volume was attenuated only in the animals treated for 1 hr with systemic hypothermia (49.2%, P < 0.001) and selective brain cooling (26.7%, P < 0.01). The volume of brain swelling was diminished only in the animals treated with systemic hypothermia for 1 hr (23.6%, P < 0.05). LDF examination revealed a sharp drop in blood flow upon MCA occlusion and maintaining in low blood flow throughout the experiment in the control and systemic hypothermia. However, in the selective brain cooling, the reduced blood flow increased from 40% to 70% of baseline value while the brain was rewarmed. The present study indicates that mild systemic hypothermia has much stronger protective effects against focal cerebral infarction and edema than selective brain cooling. The lack of protective effects of selective brain cooling may be caused by post-cooling cerebral hyperemia in the ischemia area.

Animals↗

PubMed2002

Acute exposure to sarin increases blood brain barrier permeability and induces neuropathological changes in the rat brain: dose-response relationships.

We hypothesize that a single exposure to an LD(50) dose of sarin induces widespread early neuropathological changes in the adult brain. In this study, we evaluated the early changes in the adult brain after a single exposure to different doses of sarin. Adult male rats were exposed to sarin by a single intramuscular injection at doses of 1, 0.5, 0.1 and 0.01 x LD(50). Twenty-four hours after the treatment, both sarin-treated and vehicle-treated (controls) animals were analyzed for: (i) plasma butyrylcholinesterase (BChE) activity; (ii) brain acetylcholinesterase (AChE) activity, (iii) m2 muscarinic acetylcholine receptor (m2 mAChR) ligand binding; (iv) blood brain barrier (BBB) permeability using [H(3)]hexamethonium iodide uptake assay and immunostaining for endothelial barrier antigen (EBA); and (v) histopathological changes in the brain using H&E staining, and microtubule-associated protein (MAP-2) and glial fibrillary acidic protein immunostaining. In animals treated with 1 x LD(50) sarin, the significant changes include a decreased plasma BChE, a decreased AChE in the cerebrum, brainstem, midbrain and the cerebellum, a decreased m2 mAChR ligand binding in the cerebrum, an increased BBB permeability in the cerebrum, brainstem, midbrain and the cerebellum associated with a decreased EBA expression, a diffuse neuronal cell death and a decreased MAP-2 expression in the cerebral cortex and the hippocampus, and degeneration of Purkinje neurons in the cerebellum. Animals treated with 0.5 x LD(50) sarin however exhibited only a few alterations, which include decreased plasma BChE, an increased BBB permeability in the midbrain and the brain stem but without a decrease in EBA expression, and degeneration of Purkinje neurons in the cerebellum. In contrast, animals treated with 0.1 and 0.01 x LD(50) did not exhibit any of the above changes. However, m2 mAChR ligand binding in the brainstem was increased after exposure to all doses of the sarin.Collectively, the above results indicate that, the early brain damage after acute exposure to sarin is clearly dose-dependent, and that exposure to 1 x LD(50) sarin induces detrimental changes in many regions of the adult rat brain as early as 24 hours after the exposure. The early neuropathological changes observed after a single dose of 1 x LD(50) sarin could lead to a profound long-term neurodegenerative changes in many regions of the brain, and resulting behavioral abnormalities.

Acetylcholinesterase↗

PubMed1990

Model for drug uptake by brain tumors: effects of osmotic treatment and of diffusion in brain.

A mathematical model describing drug uptake into brain tumors, directly from blood and indirectly from neighboring tissue, is presented. The model quantitatively describes uptake into tumor, brain surrounding tumor (BST), and normal brain and uptake following reversible osmotic blood-brain barrier (BBB) and blood-tumor barrier disruption. It employs published data on the time course for reclosure of the BBB following osmotic treatment and on the brain and tumor uptake of [14C]alpha-aminoisobutyric acid by Walker 256 carcinomas and C6 gliomas implanted into the rat brain. Constant infusion and bolus injection infusion schedules are considered. In untreated brain, the BST acts as a sink, reducing the integrated exposure of the adjacent tumor to the drug, whereas following osmotic treatment, tumor exposure to drug is enhanced, not only by increased delivery from blood but also by diffusion (and bulk flow) from neighboring brain. The model provides a quantitative framework for examining the efficacy of osmotic treatment to enhance chemotherapy of brain tumors.

Aminoisobutyric Acids↗

PubMed2005

Release of bradykinin and expression of kinin B2 receptors in the brain: role for cell death and brain edema formation after focal cerebral ischemia in mice.

Pharmacological studies using bradykinin B2 receptor antagonists suggest that bradykinin, an early mediator of inflammation and the main metabolite of the kallikrein-kinin system, is involved in secondary brain damage after cerebral ischemia. However, the time-course of bradykinin production and kinin receptor expression as well as the conclusive role of bradykinin B2 receptors for brain damage after experimental stroke have not been elucidated so far. C57/Bl6 mice were subjected to 45 mins of middle cerebral artery occlusion (MCAO) and 2, 4, 8, 24, and 48 h later brains were removed for the analysis of tissue bradykinin concentration and kinin B2 receptor mRNA and protein expression. Brain edema, infarct volume, functional outcome, and long-term survival were assessed in WT and B2-/- mice 24 h or 7 days after MCAO. Tissue bradykinin was maximally increased 12 h after ischemia (three-fold), while kinin B2 receptor mRNA upregulation peaked 24 to 48 h after MCAO (10- to 12-fold versus naïve brain tissue). Immunohistochemistry revealed that kinin B2 receptors were constitutively and widely expressed in mouse brain, were upregulated 2 h after ischemia in cells showing signs of ischemic damage, and remained upregulated in the penumbra up to 24 h after ischemia. B2-/- mice had improved motor function (P<0.05), smaller infarct volumes (-38%; P<0.01), developed less brain edema (-87%; P<0.05), and survived longer (P<0.01) as compared with wild-type controls. The current results show that bradykinin is produced in the brain, kinin B2 receptors are upregulated on dying cells, and B2 receptors are involved in cell death and brain edema formation after experimental stroke.

Animals↗

PubMed1994

Alterations in regional brain catecholamine concentrations after experimental brain injury in the rat.

Although activation of brain catecholaminergic systems has been implicated in the cerebrovascular and metabolic changes during subarachnoid hemorrhage, cerebral ischemia, cortical ablation, and cortical freeze lesions, little is known of the response of regional brain catecholamine systems to traumatic brain injury. The present study was designed to characterize the temporal changes in concentrations of norepinephrine (NE), dopamine (DA), and epinephrine (E) in discrete brain regions following experimental fluid-percussion traumatic brain injury in rats. Anesthetized rats were subjected to fluid-percussion brain injury of moderate severity (2.2-2.3 atm) and killed at 1 h, 6 h, 24 h, 1 week, and 2 weeks postinjury (n = 6 per timepoint). Control animals (surgery and anesthesia without injury) were killed at identical timepoints (n = 6 per timepoint). Tissue concentrations of NE, DA, and E were evaluated using HPLC. Following brain injury, an acute decrease was observed in DA concentrations in the injured cortex (p < 0.05) at 1 h postinjury, which persisted up to 2 weeks postinjury. Striatal concentrations of DA were significantly increased (p < 0.05) only at 6 h postinjury. Hypothalamic concentrations of DA and NE increased significantly beginning at 1 h postinjury (p < 0.05 and p < 0.05, respectively) and persisted up to 24 h for DA (p < 0.05) and 1 week (p < 0.05) for NE. These data suggest that acute alterations occur in regional concentrations of brain catecholamines following brain trauma, which may persist for prolonged periods postinjury.

Animals↗

PubMed2000

Application of 2,3,5-triphenyltetrazolium chloride staining to evaluate injury volume after controlled cortical impact brain injury: role of brain edema in evolution of injury volume.

A reliable method for measuring injury volume after traumatic brain injury (TBI) is of great importance when studying pharmacological protective agents in the field of head trauma research. Utilization of 2,3,5-triphenyltetrazolium chloride (TTC) has gained extensive acceptance in stroke research and has recently been applied to injury volume measurement in the lateral fluid percussion model. The present study was undertaken to apply this method to the controlled cortical impact (CCI) model and to study the role of brain edema. Male Sprague-Dawley rats were subjected to CCI brain injury at a velocity of 3 m/sec and 1 mm (mild), 2 mm (moderate), and 3 mm (severe injury) deformation, while rats in the control group were subjected to the same surgical procedure but received no injury. Absolute and corrected injury volumes with TTC staining and brain edema measurements with the wet-dry method were evaluated at 1, 2, 3, 4, and 7 days after TBI. The most prominent injury volume in the moderate injury group (2 mm deformation) was seen at postinjury day 1 and 2 (day 1, absolute: 49.1+/-5.6, corrected: 40.5+/-7.9; day 2, absolute: 46+/-6.9, corrected: 40.2+/-10.5), whereas the smallest injury volume was found at postinjury day 7 (absolute: 24.9+/-7, corrected: 27.4+/-7.4). The time course of brain edema studies demonstrates that brain edema formation peaks at postinjury day 1. A statistically significant reduction of injury volume was observed after postinjury day 4. We also observed that due to the presence of brain edema absolute injury volume is more than corrected injury volume in the first 3 days after injury as opposed to injury volume at postinjury day 7. These results suggest that the measurement of injury volume with TTC staining should be corrected for brain edema in the CCI brain injury model.

Animals↗

PubMed1981

Plasma proteins in fetal sheep brain: blood-brain barrier and intracerebral distribution.

1. Plasma proteins have been demonstrated to be present in early fetal sheep brain in amounts which cannot be accounted for by blood contamination. 2. The distribution of alpha-fetoprotein, albumin, fetuin, alpha 1-antitrypsin and transferrin has been studied by immunoassay of extracts from brain homogenates and by immunoperoxidase histochemistry of fetal brains between 37 and 125 days gestation (term is 150 days). 3. At 35 days gestation fetuin and albumin were quantitatively the most important proteins in fetal brain, both as estimated by extraction and by immunohistochemistry. Both of these proteins, and also alpha-fetoprotein and alpha 1-antitrypsin, declined considerably in amount by 60 days gestation. After 60 days the concentrations of albumin and alpha-fetoprotein were not significantly different from that due to blood contamination and only occasional cells could be demonstrated by immunohistochemistry. Fetuin and alpha 1-antitrypsin were present in reduced but significant amounts at least up to 125 days gestation. 4. The immunohistochemical results showed that considerable numbers of immature neurones were stained for some plasma proteins. Fetuin positive cells predominated both in terms of the larger number of cells which stained at 35-40 days gestation and in the persistence of positive cells up to 125 days gestation. Numerous cells in the neuroependymal layer and in several layers of the developing cortical plate were positive, especially early in gestation. Only a few transferrin or alpha 1-antitrypsin positive cells were observed. 5. Permeability of the blood-brain barrier to sheep or human serum albumin (labelled with 125I) was tested in 60 day fetal sheep by intravenous injection and estimation of brain radioactivity at 3 or 6 hr with allowance for blood contamination. Only a very small (but significant) penetration of protein was detected. Unlike penetration of protein into c.s.f. at the same age, it did not reach its natural steady state in brain. 6. It is concluded that the blood-brain barrier to protein is well developed in the immature fetal sheep but that developing neurones probably acquire certain plasma proteins directly from the c.s.f. when they are differentiating in the neuroependyma. The subsequent distribution of plasma protein positive cells in different brain regions is suggested to be due to the migration of developing neurones for the neuroependyma although the possibility of local synthesis of plasma proteins has not been excluded.

Albumins↗

PubMed2006

The fibrinolytic system facilitates tumor cell migration across the blood-brain barrier in experimental melanoma brain metastasis.

BACKGROUND: Patients with metastatic tumors to the brain have a very poor prognosis. Increased metastatic potential has been associated with the fibrinolytic system. We investigated the role of the fibrinolytic enzyme plasmin in tumor cell migration across brain endothelial cells and growth of brain metastases in an experimental metastatic melanoma model. METHODS: Metastatic tumors to the brain were established by direct injection into the striatum or by intracarotid injection of B16F10 mouse melanoma cells in C57Bl mice. The role of plasminogen in the ability of human melanoma cells to cross a human blood-brain barrier model was studied on a transwell system. RESULTS: Wild type mice treated with the plasmin inhibitor epsilon-aminocaproic acid (EACA) and plg-/- mice developed smaller tumors and survived longer than untreated wild type mice. Tumors metastasized to the brain of wild type mice treated with EACA and plg-/- less efficiently than in untreated wild type mice. No difference was observed in the tumor growth in any of the three groups of mice. Human melanoma cells were able to cross the human blood-brain barrier model in a plasmin dependent manner. CONCLUSION: Plasmin facilitates the development of tumor metastasis to the brain. Inhibition of the fibrinolytic system could be considered as means to prevent tumor metastasis to the brain.

Aminocaproic Acid↗

PubMed1990

Effect of hyperosmotic blood-brain barrier disruption on transcapillary transport in canine brain tumors.

Whether hyperosmotic blood-brain barrier (BBB) disruption is a technique that can be used to increase permeability of brain-tumor capillaries and thereby transiently increase drug delivery to the brain tumor is controversial. Nine virally induced brain tumors were studied in seven dogs, before and after hyperosmotic BBB disruption with 1.4 osmolar mannitol. Each dog was studied with computerized tomography (CT) after administration of the water-soluble tracer meglumine iothalamate. Each study lasted 30 minutes. A baseline CT scan and 35 to 40 additional CT scans were obtained to provide a time-related measurement of the amount of meglumine iothalamate in tissue (Am(t], and 30 plasma samples were collected to provide the time-related measurement of meglumine iothalamate in plasma (Cp(t]. The data were analyzed by three different methods: 1) a two-compartment model and nonlinear curve fitting were used to calculate K1 (blood-to-tissue or influx constant), k2 (tissue-to-blood or efflux constant), and Vp (plasma vascular space); 2) K1 values were calculated with a two-compartment model, assuming no efflux, at the time point for each CT scan; and 3) a "tissue advantage ratio" was calculated that expressed the ratio of tissue uptake of meglumine iothalamate at each time point, comparing values before and after BBB disruption. Regardless of which method of data analysis was used, there was a marked and significant increase in transcapillary transport of meglumine iothalamate to tumor-free brain regions, while there was only a small, transient, and insignificant increase to the brain tumors. Although there were often marked increases in delivery to cortex in the same hemisphere as the tumors, there was no significant increase to brain immediately surrounding the tumors, perhaps due to altered circulatory dynamics in this region. These data raise serious questions as to the wisdom of using this technique to increase drug delivery to brain tumors in patients and strongly support the continued study of this technique in experimental brain tumors before it is used in patients.

Animals↗