Hisao Uehara

“Facilitated” Amino Acid Transport Is Upregulated in Brain Tumors

The goal of this study was to determine the magnitude of “facilitated” amino acid transport across tumor and brain capillaries and to evaluate whether amino acid transporter expression is “upregulated” in tumor vessels compared to capillaries in contralateral brain tissue. Aminocyclopentane carboxylic acid (ACPC), a non-metabolized [14C]-labeled amino acid, and a reference molecule for passive vascular permeability, [67Ga]-gallium-diethylenetriaminepentaacetic acid (Ga-DTPA), were used in these studies. Two experimental rat gliomas were studied (C6 and RG2). Brain tissue was rapidly processed for double label quantitative autoradiography 10 minutes after intravenous injection of ACPC and Ga-DTPA. Parametric images of blood-to-brain transport (K1ACPC and K1Ga-DTPA, μL/min/g) produced from the autoradiograms and the histology were obtained from the same tissue section. These three images were registered in an image array processor; regions of interest in tumor and contralateral brain were defined on morphologic criteria (histology) and were transferred to the autoradiographic images to obtain mean values. The facilitated component of ACPC transport (∂KlACPC) was calculated from the K1ACPC and K1Ga-DTPA data, and paired comparisons between tumor and contralateral brain were performed. ACPC flux, K1ACPC, across normal brain capillaries (22.6 ± 8.1 μL/g/min) was >200-fold greater than that of Ga-DTPA (0.09 ± 0.04 μL/g/min), and this difference was largely (~90%) due to facilitated ACPC transport. Substantially higher K1ACPC values compared to corresponding K1DTPA values were also measured in C6 and RG2 gliomas. The ∂K1ACPC values for C6 glioma were more than twice that of contralateral brain cortex. K1ACPC and ∂K1ACPC values for RG2 gliomas was not significantly higher than that of contralateral cortex, although a ~2-fold difference in facilitated transport is obtained after normalization for differences in capillary surface area between RG2 tumors and contralateral cortex. K1ACPC, ∂K1ACPC, and K1DTPA were directly related to tumor cell density, were higher in regions of “impending” necrosis, and the tumor/contralateral brain ACPC radio-activity ratios (0 to 10 minutes) were very similar to that obtained with 0 to 60 minutes experiments. These results indicate that facilitated transport of ACPC is upregulated across C6 and RG2 glioma capillaries, and that tumors can induce upregulation of amino acid transporter expression in their supporting vasculature. They also suggest that early imaging (e.g., 0 to 20 minutes) with radiolabeled amino acids in a clinical setting may be optimal for defining brain tumors.

Imaging Experimental Brain Tumors with 1-Aminocyclopentane Carboxylic Acid and Alpha-Aminoisobutyric Acid Comparison to Fluorodeoxyglucose and Diethylenetriaminepentaacetic Acid in Morphologically Defined Tumor Regions

The goal of this study was to evaluate the differences and define the advantages of imaging experimental brain tumors in rats with two nonmetabolized amino acids, 1-aminocyclopentane carboxylic (ACPC) acid and α-aminoisobutyric (AIB) acid compared with imaging with fluorodeoxyglucose (FDG) or the gallium-diethylenetriaminepentaacetic acid chelate (Ga-DTPA). 1-aminocyclopentane carboxylic acid, AIB, and FDG autoradiograms were obtained 60 minutes after intravenous injection to simulate positron emission tomography (PET) imaging, whereas the Ga-DTPA autoradiograms were obtained 5 or 10 minutes after injection to simulate gadolinium (Gd)-DTPA–enhanced magnetic resonance (MR) images. Three experimental tumors were studied (C6, RG2, and Walker 256) to provide a range of tumor types. Triple-label quantitative autoradiography was performed, and parametric images of the apparent distribution volume (Va, mL/g) for ACPC or AIB, relative glucose metabolism (R, μmol/100 g/min), vascular permeability to Ga-DTPA (K1, μL/min/g), and histology were obtained from the same tissue section. The four images were registered in an image array processor, and regions of interest in tumor and contralateral brain were defined on morphologic criteria (histology) and were transferred to the autoradiographic images. A comparative analysis of all measured values was performed. The location and morphologic characteristics of the tumor had an effect on the images and measurements of Va, R, and K1. Meningeal extensions of all three tumors consistently had the highest amino acid uptake (Va) and vascular permeability (K1) values, and subcortical portions of the tumors usually had the lowest values. Va and R (FDG) values generally were higher in tumor regions with high-cell density and lower in regions with low-cell density. Tumor areas identified as “impending” necrosis on morphologic criteria consistently had high R values, but little or no change in Va or K1. Tumor necrosis was seen consistently only in the larger Walker 256 tumors; low values of R and Va for AIB (less for ACPC) were measured in the necrotic-appearing regions, whereas K1 was not different from the mean tumor value. The highest correlations were observed between vascular permeability (K1 for Ga-DTPA) and Va for AIB in all three tumors; little or no correlation between vascular permeability and R was observed. The advantages of ACPC and AIB imaging were most convincingly demonstrated in C6 gliomas and in Walker 256 tumors. 1-aminocyclopentane was substantially better than FDG or Ga-DTPA for identifying tumor infiltration of adjacent brain tissue beyond the macroscopic border of the tumor; ACPC also may be useful for identifying low-grade tumors with an intact blood–brain barrier. Contrast-enhancing regions of the tumors were visualized more clearly with AIB than with FDG or Ga-DTPA; viable and necrotic-appearing tumor regions could be distinguished more readily with AIB than with FDG. [11C]-labeled ACPC and AIB are likely to have similar advantages for imaging human brain tumors with PET.

Osteoma of the frontal sinus complicated by intracranial mucocele.

We present a rare case of intracranial mucocele associated with frontal sinus osteoma in a patient suffering from generalized convulsion. The intracranial mucocele occurs as a complication of obstruction of sinus drainage caused by osteoma, but it is often diagnosed preoperatively as an intracranial or intracerebral cyst because of the rarity of these combined lesions in neurosurgical practice. However, once the mucocele extends intracranially, several other complications, including infections and/or a convulsion, can occur, indicating the necessity for surgical treatment. Moreover, the differentiation of the mucocele from the intracranial endodermal cyst predominantly depends upon its continuity with the intracranial osteoma portion or the sinus. Thus, knowledge of this rare lesion is important for accurate diagnosis and clinical management.

Unusual Clinical Presentation of a Presumed Pineal Germinoma with Two Disseminated Lesions

We report a case of a presumed pineal germinoma in a 28-year-old man. Although the pineal body, the presumed primary lesion, was small, there were two disseminated tumors, one in the posterior fossa and the other in the left parietal region. The initial symptom was cerebellar ataxia. These two disseminated tumors had attachments to the inferior surface of the cerebellar tentorium and the dura mater of the parietal convexity, respectively, and they were fed by external carotid artery branches, like meningiomas. Neither angiography nor magnetic resonance imaging could provide the differential diagnosis between germinoma and meningioma. Computed tomographic scanning revealed slight enlargement of the pineal body suggestive of a germinoma.

Mutational analysis of human p53 gene in human gliomas by Cleavase® fragment length polymorphism

Cleavase® fragment length polymorphism (CFLP) is a newly developed method used for the detection of gene mutation. This study evaluates the usefulness of this method. Thirty‐three human glioma specimens obtained at surgery were analyzed for human p53 gene mutation using radiolabeled polymerase chain reaction (PCR)‐based CFLP analysis and the results were compared with results of direct sequencing. Three (one of five anaplastic astrocytomas and two of 24 glioblastomas) and five (one of four low‐grade gliomas, one of five anaplastic astrocytomas and three of 24 glioblastomas) samples were suspected as being mutations in exon 5–6 and 7–8 of the p53 gene, respectively. Further, two of three (one anaplastic astrocytoma and one glioblastoma) and two of five (both glioblastoma) samples were confirmed as having mutations in direct sequence (their positive rates were 66.7 and 40%, respectively). However, the false‐negative rate of CFLP analysis was very low (0%, 0/60). Therefore, it was concluded that although PCR‐CFLP using a radioisotope might be too sensitive given its superior false‐negative rate, it offers an alternative protocol for the screening of the mutation of human p53 gene.

Characteristic patterns of Tl-201 chloride and Tc-99m MIBI uptake in a pineocytoma.

Tl-201 SPECT in a 33-year-old man with a pineocytoma showed increased uptake with rapid washout. Tc-99m MIBI SPECT showed diffuse, Increased uptake with marked retention. Histologically, this, tumor was negative for P-glycoprotein. It is thought that MIBI is effluxed by P-glycoprotein. Findings on Tc-99m MIBI imaging might be a result of defects of P-glycoprotein.