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Introduction: Amino acid PET tracers are promising for visualizing gliomas and evaluating radiochemotherapeutic effects. We compared the glioma detection and early response assessment utility between trans-1-amino-3-fluoro-1-(14)C-cyclobutanecarboxylic acid (anti-(14)C-FACBC) and (3)H-methyl-l-methionine ((3)H-Met) by simultaneously analyzing their uptake by rat gliomas treated with and without temozolomide (TMZ) in vitro and in vivo., Methods: C6 rat gliomas were incubated with low-dose TMZ to induce chemoresistance. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay demonstrated a significantly greater surviving fraction in the TMZ-resistant subline (C6R) than in drug-naive cells (C6). The anti-(14)C-FACBC and (3)H-Met uptakes were quantified using a triple-label accumulation assay to examine the relationship between tracer uptake and proliferation ((3)H-thymidine (TdR) accumulation rate) in tumor cells. C6 and C6R cells were inoculated into the right and left basal ganglia, respectively, of rats. Efficacy of TMZ against the orthotopic gliomas was analyzed by MRI, Evans blue extravasation, anti-(14)C-FACBC and (3)H-Met autoradiography, and MIB-5 proliferation index., Results: The (3)H-TdR accumulation rate and amino acid tracer (anti-(14)C-FACBC and (3)H-Met) uptake significantly decreased 48 and 72 h, respectively, after TMZ treatment in C6 but not C6R cells. Anti-(14)C-FACBC uptake correlated significantly with (3)H-Met uptake and the (3)H-TdR accumulation rate. In the intracerebral glioma model, anti-(14)C-FACBC and (3)H-Met autoradiography clearly delineated the tumor extent, which spread well beyond the high-T2-intensity and enhancing lesions visible on MRI and Evans blue extravasation. TMZ significantly decreased anti-(14)C-FACBC and (3)H-Met uptake and the MIB-5 index of C6 but not C6R tumors. TMZ inhibited tracer uptake and tumor proliferation before morphological changes on MRI., Conclusions: Anti-(14)C-FACBC, like (3)H-Met, was more sensitive than post-contrast T1-weighted MRI for detecting tumor extent and early tumor response to TMZ treatment. Anti-(18)F-FACBC should be a sensitive and precise imaging biomarker for tumor extent visualization and response assessment in glioma patients., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The aim of the present study is to understand the therapeutic effects of recombinant human tumor necrosis factor-alpha (rH-TNF) on hemocirculation and metabolism of brain tumors. Using double-label autoradiographic technique, we have monitored changes in regional cerebral blood flow (rCBF) and protein-bound fraction of (3H-methyl)-L-methionine, expressed as acid-insoluble fraction (AIF), in rat brain tumors following treatment with intracarotid rH-TNF. The central portion of tumors showed a significant decrease in rCBF and AIF at 4 hours after the injection (p < 0.01, p < 0.05, respectively, as compared with non-treated control rats), turned microscopically necrotic at 24 hours, and became more extensively necrotic at 72 hours. Tumor cells remained viable only in the peripheral portion of the tumors after the treatment. The peripheral portion also showed a moderate decrease in rCBF, but less change in AIF to 4 to 72 hours after the treatment. Neither ipsilateral nor contralateral non-involved cortex demonstrated appreciable changes in rCBF and AIF during the observed period. Intracarotid rH-TNF selectively reduces tumor rCBF and AIF, resulting in histological modification.

A 56-yr-old housewife with cerebral astrocytoma was reported with positron emission tomography findigns using 11C-methyl-L-methionine (11C-Met) and 18F-fluorophenylalanine (18F-Phe) tracers. 11C-Met and 18F-Phe accumulated intensely in tumor lesions, although CT scans showed only a foggy low-density area. Five years and one month after, an enhancing mass appeared on CT scans. Thus, amino acid tracers may play a important role in the early diagnosis of gliomas.

cis-diamminedichloroplatinum (II) (CDDP) has been used both alone and in combination with other chemotherapeutics for cancer chemotherapy. Although CDDP acts primarily on DNA, it can also act at the tumor-cell membrane to inhibit methionine transport. The latter mechanism of CDDP is reported to have an important role as a chemical modulator in enhancing chemotherapeutic effects of 5-fluorouracil in tumor cells. We report here the effects of CDDP on methionine uptake in an in vivo brain-tumor model. C6 brain-tumor cells were stereotactically inoculated in the right basal ganglia of 6-week-old male Sprague-Dawley rats. Ten days after the inoculation, autoradiographic images were obtained using (14C-methyl)-L-methionine. The tracer uptake, represented as differential absorption ratio (DAR) and an acid-insoluble fraction (AIF), was measured in both brain tumors and normal brain with or without an intravenous injection of CDDP. The tumor/non-tumor DAR and AIF decreased significantly (P < 0.01, as determined by the Mann-Whitney U-test) after CDDP treatment, whereas the non-tumor DAR and AIF remained almost unchanged. These findings indicate that CDDP inhibits methionine uptake selectively in brain-tumor tissue and may therefore be a potent chemical modulator in the chemotherapy of brain tumors.

A case of frontal hypertrophic cranial pachymeningitis was presented with positron emission tomography (PET) using (11C-methyl)-L-methionine (11C-Met). A 55-year-old male developed right hemiparesis after generalized tonic convulsion one month prior to admission. MR images revealed patchy enhancement extending from the dura mater to the cerebral parenchyma surrounding high T2-weighted signal in the left frontal region. Left carotid angiogram showed atresia of the rostral superior sagittal sinus and obliteration of the cortical veins associated with compensatory venous channels coursing in the frontal deep white matter. PET demonstrated high 11C-Met uptake in the area corresponding to the enhancing lesion on the MR images. The ratio of lesion/normal cortex was 1.58 as an indicator of selective uptake in the lesion. The contralateral temporal gray matter was representative of a normal cortex. In contrast, 11C-Met did not accumulate in the frontal white matter where T2-weighted MR images showed abnormal high intensity lesion. This suggested that the frontal white matter lesion was derived from vasogenic edema due to venous infarction. The patient underwent an uneventful exploratory biopsy. The dura mater had proliferated to a thickness of 3.5mm and was tightly adherent to the left middle frontal gyrus. Microscopically, the thickened dura mater where the tracers had accumulated was composed of abundant collagenous fibers together with diffuse infiltration of inflammatory cells, including predominantly lymphocytes, plasma cells, and neutrocytes. The lymphocytes, which proved positive in both UCHL-1 and L26 staining, had no atypism. Histological findings corresponded to hypertrophic pachymeningitis. Met-PET clearly represented viable and infiltrative zones of inflammatory cells. The patient's neurological symptoms and signs gradually improved. Follow-up MR images three months after the surgery showed the enhancing lesion to be diminished and a marked regression of the vasogenic edema. Spatial determination of viable lesions permitting differentiation from biological inactive or vasogenic edema is an important guideline in selecting an appropriate surgical procedure in the diagnosis and treatment of hypertrophic cranial pachymeningitis. Met-PET would appear useful in delineating inflammatory lesions such as hypertrophic cranial pachymeningitis.

An intramedullary spinal cord ependymoma was studied by positron emission tomography (PET) using (11C-methyl)-L-methionine (11C-Met). MRI showed a homogeneously enhancing tumour at C6-T2 with cysts at its rostral and caudal ends. Sagittal PET images demonstrated high 11C-Met uptake in the solid portion of the tumour, particularly ventrally at C7-T2, where viable tumour cells proliferated in association with abundant perforating vessels. Met-PET would appear useful for delineating the viable portion of intramedullary ependymomas.

Autoradiographic study of (14C-methyl)-L-methionine with brain tumor bearing rats aimed at an elucidation of the mechanism of tracer accumulation in the protein synthesis of tumor. Twice as much tracer accumulated in the tumors compared as in the contralateral gray matter (nontumor region) at 90 min post intravenous injection. The protein-bound fraction of the tumors, expressed as acid-insoluble fraction (AIF), was 1.7 +/- 0.6 (mean +/- standard deviation, n = 6), significantly higher than that (0.8 +/- 0.2) of the nontumor region (p < 0.05 by the Mann-Whitney test). The tumor AIF comprised 82.3 +/- 9.2% of the total amount of the tracers accumulated in the tumors. The protein synthesis inhibitor cycloheximide reduced the tracer uptake and the AIF of the tumors to an almost same level as the nontumor region. These findings indicate that metabolic acceleration of protein synthesis may be a main reason for the high accumulation of (14C-methyl)-L-methionine in tumor.

To elucidate metabolic pathways of methionine in brain tumors, we studied autoradiographic images of (14C-methyl)-L-methionine (14C-Met) in transplanted rat brain tumors. 14C-Met accumulated in the tumor almost twice as much as in the gray matter 90 min after injection. The acid-insoluble fraction, which was bound to macromolecules, comprised 84% the total count of the accumulated tracers in the tumor. Analysis of 14C-Met tracer accumulation is informative for understanding amino acid metabolism in brain tumors.

A case of gliomatosis cerebri was studied with positron emission tomography (PET). Carbon-11-L-methionine (11C-Met) accumulated in the diffusely infiltrative tumorous area more widely and accurately than the lesion detected by conventional x-ray computerized tomography (CT) or magnetic resonance (MR) imaging. Autopsy findings three months after the time of the PET study showed good anatomical correspondence between the extent of densely aggregated tumor cells and the region with high uptake of 11C-Met. PET may offer an innovative approach in the delineation of gliomatosis cerebri, which has not been clearly recognized by CT or MR.

Sixteen patients with gliomas (7 low grade, 9 high grade) were examined using positron emission tomography (PET) with intravenous administration of 22.2 MBq/kg (0.6 mCi/kg) of (11C-methyl)-L-methionine (C-11 Met). The tracer uptake in regions of interest was calculated on PET images taken 45 minutes after injection; the uptake index was represented as a percentage of the total count in the arterial blood summed over 45 minutes. C-11 Met uptake indices in the tumors ranged from 0.020 to 0.041% with a mean of 0.032% for the low-grade gliomas and from 0.013 to 0.044% with a mean of 0.036% for the high-grade gliomas. These indices significantly increased as compared with those in the contralateral gray matter (0.008-0.032% with a mean of 0.023%; p less than 0.01 vs. low-grade gliomas, p less than 0.001 vs. high-grade gliomas). In the low-grade gliomas, C-11 Met PET images clearly depicted the existence and even the extent of the tumors, although x-ray computed tomography (CT) did not always distinguish tumoral lesions. In the high-grade gliomas, the areas of tracer accumulation regionally extended to peritumoral low density on CT scans, where malignant tumor cell infiltration was proved by operative and follow-up CT findings. C-11 Met may be a useful radiopharmaceutical for differential diagnosis of gliomas, and the accuracy of tumor localization will give us a better rationale in therapeutic strategies for surgery and radiation therapy of gliomas.

We have studied changes in the (11C-methyl)-L-methionine (C-11 Met) uptake index in six glioma cases subsequent to radiotherapy, using positron emission tomography (PET) to evaluate the effects of radiotherapy on the amino acid metabolism of the tumor. The uptake index of the tumor represented as a percentage of the total count in the atrial blood recorded during a period of 45 min, showed an average of 0.037% and 0.039% prior to and within two months after the therapy, respectively. Out of three cases where a fall in the index was seen, two cases showed tumor regression in the size of the contrast enhanced lesion measured by CT; all three cases had a relatively long period of clinical and neurological amelioration. However, following a short period of clinical improvement, the other three patients with a rise in the index showed no change or tumor progression on CT. These findings indicate that changes in the C-11 Met uptake index can be a sensitive and precise indicator for evaluating the effect of radiotherapy on gliomas.