MET Uptake Research Articles

Methionine-PET to differentiate between brain lesions appearing similar on conventional CT/MRI scans.

11 C-Methionine (MET)-PET is a useful tool in neuro-oncology. This study aimed to examine whether a combination of diagnostic variables associated with MET uptake could help distinguish between brain lesions that are often difficult to discriminate in conventional CT and MRI. MET-PET was assessed in 129 patients with glioblastoma multiforme, primary central nervous lymphoma, metastatic brain tumor, tumefactive multiple sclerosis, or radiation necrosis. The accuracy of the differential diagnosis was analyzed using five diagnostic characteristics in combination: higher maximum standardized uptake value (SUV) of MET in the lesion/the mean normal cortical SUV of MET ratio, overextension beyond gadolinium, peripheral pattern indicating abundant MET accumulation in the peripheral region, central pattern denoting abundant MET accumulation in the central region, and dynamic-up suggesting increased MET accumulation during dynamic study. The analysis was conducted on sets of two of the five brain lesions. Significant differences in the five diagnostic traits were observed among the five brain lesions, and differential diagnosis could be achieved by combining these diagnostic features. The area under the curve between each set of two of the five brain lesions using MET-PET features ranged from .85 to 1.0. According to the findings, combining the five diagnostic criteria could help with the differential diagnosis of the five brain lesions. MET-PET is an auxiliary diagnostic technique that could help in distinguishing these five brain lesions.

18 F-Fluorodeoxy Glucose and 11 C-Methionine Accumulation in Demyelinating Lesions.

Background Few studies have evaluated the accumulation of 18 F-fluorodeoxyglucose (FDG), 11 C-methionine (MET), and other positron emission tomography (PET) tracers in patients with demyelinating disease. Purpose This study aimed to investigate the accumulation of FDG-PET/computed tomography (CT) and MET-PET/CT in demyelinating lesions. Material and Methods A retrospective search of the patient database in our hospital identified five patients with demyelinating disease in whom PET studies performed in the past 10 years revealed accumulation of FDG or MET. The clinical diagnoses were multiple sclerosis ( n =1), myelitis ( n =1), limbic encephalitis ( n =1), chronic inflammatory demyelinating polyneuropathy (CIDP; n =1), and acute demyelinating encephalomyelitis (ADEM; n =1). Two patients received FDG-PET/CT alone and three patients received both FDG-PET/CT and MET-PET/CT on the same day. Images were visually and conjointly reviewed by two radiologists. In semiquantitative evaluation, the maximum standardized uptake value (SUV max ) of the lesion was measured. The lesion-to-normal brain uptake ratio (L/N ratio) was calculated. Results FDG and/or MET accumulated to a part of the lesions seen on MRI. SUV max on FDG-PET/CT ranged from 3.8 to 10.3, and L/N ratio on MET-PET/CT ranged from 16.6 to 2.4. Conclusion It has been established that neoplastic and demyelinating lesions can be differentiated on the basis of FDG or MET uptake. However, as accumulation of FDG and MET can also occur in demyelinating lesions; knowledge of this possibility is of clinical importance.

Correlation of <sup>11</sup>C-Methionine Combined Positron Emission and Computed Tomography and Ki-67 Proliferation Index in Pretreatment Assessment of Cerebral Gliomas

The purpose of the study was to explore the correlation between 11С-methionine (Met) uptake measured by combined positron emission and computed tomography (PET/CT) in newly diagnosed cerebral gliomas and tumor proliferative activity as measured by Ki-67 labeling index (Ki-67 LI).The results of PET/CT with 11С-methionine (PET-Met) of 236 adult patients with pretreated glial brain tumors were included in retrospective analysis. The final diagnosis of glioma according to WHO classification of CNS tumors (2007) was based on both histology and immunohistochemistry using Ki-67 antibodies. On PET-Met tumor-to normal brain uptake ratio (TBR) was calculated by dividing maximum Met uptake in the tumor (hot spot 10 mm in diameter) to activity concentration in the contralateral cortex. The Spearmen rank correlation test was used to analyze the relationships between TBR and Ki-67 LI.PET-Met analysis showed that TBR increases with an increase in the aggressiveness of the glial tumor. The differences of TBR values between gliomas grade II vs III and grade III vs IV were significant (p < 0,001). Among grades II-III gliomas Met uptake was significantly higher in oligodendroglial and mixed gliomas than in astrocytomas (p < 0,001), but the differences did not depend on Ki-67 LI.Correlation analysis demonstrated significant correlation between Ki-67 LI and TBR values (r = 0,49, p < 0,05, Spearman rank test). With analyzing glioma subgroups TBR values correlated with Ki-67 LI in diffuse astrocytomas (r = 0,52, p < 0,05), oligodendrogliomas (r = 0,40, p < 0,05), oligoastrocytomas (r = 0,47, p < 0,05) and in high-grade gliomas (r = 0,45, p < 0,05) but not in low-grade gliomas. Comparison between TBR value and Ki-67 LI in each glioma showed a lack of coincidence in 22 % of cases (high Met uptake but low Ki-67 LI and vice versa). The main reasons for such discrepancies were tumor molecular biology or incorrect biopsy target.Met uptake in diffuse gliomas correlates with proliferative activity which justifies the use of PET-Met for glioma grading. In case of mismatch between two biomarkers one should rely on the indicator that implies a higher aggressiveness of the glioma.

Oncological and functional outcomes of supratotal resection of IDH1 wild-type glioblastoma based on 11C-methionine PET: a retrospective, single-center study

The oncological and functional outcomes in glioblastoma (GBM) patients following supratotal resection (SupTR), involving complete resection of contrast-enhancing enhanced (CE) tumors and areas of methionine (Met) uptake on 11C-met positron emission tomography (Met-PET), are unknown. We conducted a retrospective review in newly diagnosed, IDH1 wild-type GBM patients, comparing SupTR with gross total resection (GTR), in which only CE tumor tissue was resected. All patients underwent standard radiotherapy and temozolomide treatment, and were followed for tumor recurrence and overall survival (OS). Among the 30 patients included in this study, 7 underwent SupTR and 23 underwent GTR. Awake craniotomy with cortical and subcortical mapping was more frequently performed in the SupTR group than in the GTR group. During the follow-up period, significantly different patterns of disease progression were observed between groups. Although more than 80% of recurrences were local in the GTR group, all recurrences in the SupTR group were distant. Median OS in the GTR and SupTR groups was 18.5 months (95% confidence interval [CI] 14.2–35.1) and not reached (95% CI 30.5-not estimable), respectively; this difference was statistically significant (p = 0.03 by log-rank test). No postoperative neurocognitive decline was evident in patients who underwent SupTR. Compared to GTR alone, aggressive resection of both CE tumors and areas with Met uptake (SupTR) under awake craniotomy with functional mapping results in a survival benefit associated with better local control and neurocognitive preservation.

STMO-11 Supratotal resection of Glioblastoma with Methionine PET

Objective: To assess the resection of both of contrast-enhanced (CE) and methionine-uptake (MU) and the oncological outcome in newly diagnosed glioblastoma. Methods: This retrospective study included a glioblastoma cohort from Chiba University who met the two criteria, i) total resection of CE tumor, ii) preoperative evaluation with methionine positron emission tomography (Met-PET). Data regarding the pattern of recurrence and overall survival were collected. Results: Among 247 cases with glioblastoma, total resection of CE was achieved in 112. Preoperative Met-PET was performed in 30 out of 112. The median age at operation, a period of follow-up, and the preoperative tumor volume in 30 patients were 56 year-old, 17.9 months, and 18.8 cc respectively. The promoter region of the O6-methylguanine-DNA methyltransferase was methylated in 37%. Radiological comparison revealed that Met uptake was detected beyond the CE area in 13 out of 30, and the Met uptake was also resected with awake mapping technique in 7 patients (supratotal resection group; STR). The median progression-free survival (PFS) in STR was 23 months, and all the patterns of recurrence were distant recurrence. In contrast, the PFS in total resection group (TRG) was 9 months (p=0.09, Wilcoxon). Furthermore, 14 out of 17 recurrence were local in TRG subgroup. While the median OS in TRG was 18 months, it has not reached in STR (p=0.04, Wilcoxon). Conclusions: The resection of both of CE and MU was associated with better PFS and OS. This finding must be validated in a larger cohort with a multicenter study.

The relationship between cholecystokinin secretion and pancreatic [11C]methionine uptake in patients after partial pancreaticoduodenectomy.

The pancreatic uptake of [11C]methionine ([11C]MET) is associated with beta-cell function and insulin secretion, but [11C]MET uptake and its relationship with exocrine pancreatic performance are less well studied. The postprandial release of cholecystokinin (CCK) depends on gastric emptying velocity and triggers exocrine pancreas secretion. Therefore, we assumed that high postprandial CCK concentrations stimulate the uptake of [11C]MET in the residual pancreas following pancreaticoduodenectomy. Nineteen tumor-free patients after pancreaticoduodenectomy (median age: 64; 25/75 quantile: 56-67years); ten males, nine females and ten healthy controls (median age: 24; 25/75 quantile: 23.8-26years) were given a mixed meal. Plasma CCK, insulin and glucose concentrations were measured before and at 10, 20, 30, 60, 90, 150 and 180min after ingestion. Simultaneously, 800MBq of [11C]MET were administered and the activity [maximum tissue standardized uptake values (SUVmax)] over the pancreas was measured using PET-CT at 15, 30 and 60min after injection. Integrated CCK (AUC30) correlated with SUVmax (AUC60, R2 = 0.45, p value = 0.0013). Multivariate analysis revealed postprandial insulin (AUC60) and CCK concentrations and young age as significant independent predictors of [11C] methionine uptake. The association between CCK concentrations and pancreatic [11C]MET uptake might indicate a causal relationship. Further research should assess whether [11C]MET uptake could serve as a less invasive tool to assess exocrine pancreas activity.

Comparison of 13N-NH3, 11C-MET and 18F-FDG PET/CT imaging in the diagnosis and evaluation of cerebral glioma

Objective To compare the application of 13N-NH3, 11C-methionine (MET) and 18F-fluorodeoxyglucose (FDG) PET/CT imaging in the diagnosis and evaluation of suspected cerebral glioma. Methods From September 2010 to December 2017, ninety patients (54 males, 36 females; age: (40.0±14.0) years) in the First Affiliated Hospital of Sun Yat-sen University with suspected glioma based on clinical diagnosis, who underwent 13N-NH3, 11C-MET and 18F-FDG PET/CT imaging, were prospectively enrolled in the study. All patients were confirmed by histology or clinical and radiological follow-up. Images were interpreted by visual evaluation (higher radioactive uptake in lesions than that in the contralateral normal brain parenchyma was considered as positive (+ ), equal/lower were considered as negative (-)) and semi-quantitative analysis (the maximum standardized uptake value (SUV) of lesion (L) to the mean SUV of normal white matter (WM) (L/WM ratio)). Receiver operating characteristic (ROC) curve analysis was used and the area under curves (AUCs) were calculated and compared. The diagnostic efficacies of 3 imaging methods and the combination for diagnosing gliomas and the abilities to differentiating high-grade gliomas (HGG) and low-grade gliomas (LGG) were compared. Results In 90 patients, 30 HGG, 27 LGG, 10 non-glioma brain tumors and 23 non-neoplastic lesions (NNL) were diagnosed. On visual evaluation, the sensitivities for differentiating tumors from NNL were 62.7%(42/67), 94.0%(63/67) and 35.8% (24/67) for 13N-NH3, 11C-MET and 18F-FDG PET/CT respectively, while the specificities were 95.7%(22/23), 56.5% (13/23) and 65.2% (15/23), and the accuracies were 71.1%(64/90), 84.4%(76/90) and 43.3% (39/90). Taking the metabolic patterns of + /+ /+ , + /+ /- and + /-/- (11C-MET/13N-NH3/18F-FDG) as the diagnosis standard of tumor lesions, the specificity and accuracy of the combined method increased to 73.9%(17/23) and 88.9%(80/90) with the sensitivity remaining the same (94.0%, 63/67). ROC curve analysis (L/WM) showed that the sensitivity, specificity and AUC were 64.2%(43/67), 100%(23/23) and 0.819 for 13N-NH3 PET/CT, and 89.6%(60/67), 69.6%(16/23) and 0.840 for 11C-MET PET/CT (z=-0.316, P>0.05). The accuracy for differentiating high and low grade glioma were 86.0% (49/57), 87.7%(50/57) and 93.0%(53/57) for 13N-NH3, 11C-MET and 18F-FDG PET/CT, with the AUC of 0.896, 0.928 and 0.964, respectively (z values: -0.554 to 1.334, all P>0.05). Conclusions 13N-NH3 PET/CT imaging has remarkably high specificity but low sensitivity for the differentiation of brain tumors from NNL. 11C-MET PET/CT imaging was found to be highly useful for detection of brain tumors. However, like 18F-FDG, high MET uptake is frequently observed in some NNL. 13N-NH3, 11C-MET and 18F-FDG PET/CT imaging all appear to be valuable for evaluating the histological grade of gliomas, and the combination of them is more useful for the accurate diagnosis of glioma. Key words: Glioma; Positron-emission tomography; Tomography, X-ray computed; NH3; Methionine; Deoxyglucose

Diagnostic accuracy of 13N-ammonia PET, 11C-methionine PET and 18F-fluorodeoxyglucose PET: a comparative study in patients with suspected cerebral glioma

BackgroundThe treatment of patients with glioma depended on the nature of the lesion and on histological grade of the tumor. Positron emission tomography (PET) using 13N-ammonia (NH3), 11C-methionine (MET) and 18F-fluorodeoxyglucose (FDG) have been used to assess brain tumors. Our aim was to compare their diagnostic accuracies in patients with suspected cerebral glioma.MethodsNinety patients with suspicion of glioma based on previous CT/MRI, who underwent NH3 PET, MET PET and FDG PET, were prospectively enrolled in the study. The reference standard was established by histology or clinical and radiological follow-up. Images were interpreted by visual evaluation and semi-quantitative analysis using the lesion-to-normal white matter uptake ratio (L/WM ratio).ResultsFinally, 30 high-grade gliomas (HGG), 27 low-grade gliomas (LGG), 10 non-glioma tumors and 23 non-neoplastic lesions (NNL) were diagnosed. On visual evaluation, sensitivity and specificity for differentiating tumors from NNL were 62.7% (42/67) and 95.7% (22/23) for NH3 PET, 94.0% (63/67) and 56.5% (13/23) for MET PET, and 35.8% (24/67) and 65.2% (15/23) for FDG PET. On semi-quantitative analysis, brain tumors showed significantly higher L/WM ratios than NNL both in NH3 and MET PET (both P < 0.001). The sensitivity, specificity and the area under the curve (AUC) by receiver operating characteristic (ROC) analysis, respectively, were 64.2, 100% and 0.819 for NH3; and 89.6, 69.6% and 0.840 for MET. Besides, the L/WM ratios of NH3, MET and FDG PET in HGG all significantly higher than that in LGG (all P < 0.001). The predicted (by ROC) accuracy of the tracers (AUC shown in parentheses) were 86.0% (0.896) for NH3, 87.7% (0.928) for MET and 93.0% (0.964) for FDG. While no significant differences in the AUC were seen between them.ConclusionNH3 PET has remarkably high specificity for the differentiation of brain tumors from NNL, but low sensitivity for the detection of LGG. MET PET was found to be highly useful for detection of brain tumors. However, like FDG, high MET uptake is frequently observed in some NNL. NH3, MET and FDG PET all appears to be valuable for evaluating the histological grade of gliomas.

Quantitative volumetric analysis of primary glioblastoma multiforme on MRI and 11C-methionine PET: initial study on five patients.

To investigate the discrepancy between 11C-methionine (MET) positron emission tomography (PET) and MRI results in primary glioblastoma multiforme (GBM) through three-dimensional (3D) volumetric analysis, we retrospectively analysed patients with primary GBM who underwent preoperative 3D MRI and MET PET and were operated between June 2016 and January 2017. Tumour delineation and volumetric analysis were conducted using MRIcron software. Tumour volumes defined by MRI (VMRI) were manually drawn slice by slice in axial and sagittal or coronal images of enhanced T1 sequence, while metabolic tumour volumes were automatically segmented in MET PET (VMET) based on three (frontal, occipital and temporal) 3D reference volumes of interest (VOI). Discrepancies were evaluated in terms of both absolute volume and percentage on the combined images. MET PET contours contained and extended beyond MRI contours in all five patients; in a subset of cases, MET PET contours extended to the contralateral hemisphere. The discrepancy between MET uptake and MRI results was 27.67 cm3 (4.20-51.20 cm3), i.e. approximately 39.0% (17.4-64.3%) of the metabolic tumour volume was located outside the volumes of the Gd-enhanced area. Metabolic tumour volume is substantially underestimated by Gd-enhanced area in patients with primary GBM. Quantitative volumetric information derived from MET uptake is useful in defining tumour targets and designing individualised therapy strategies in primary GBM.

Region-by-region analysis of PET, MRI, and histology in en bloc-resected oligodendrogliomas reveals intra-tumoral heterogeneity

PurposeOligodendrogliomas are heterogeneous tumors in terms of imaging appearance, and a deeper understanding of the histopathological tumor characteristics in correlation to imaging parameters is needed. We used PET-to-MRI-to-histology co-registration with the aim of studying intra-tumoral 11C-methionine (MET) uptake in relation to tumor perfusion and the protein expression of histological cell markers in corresponding areas.MethodsConsecutive histological sections of four tumors covering the entire en bloc-removed tumor were immunostained with antibodies against IDH1-mutated protein (tumor cells), Ki67 (proliferating cells), and CD34 (blood vessels). Software was developed for anatomical landmarks-based co-registration of subsequent histological images, which were overlaid on corresponding MET PET scans and MRI perfusion maps. Regions of interest (ROIs) on PET were selected throughout the entire tumor volume, covering hot spot areas, areas adjacent to hot spots, and tumor borders with infiltrating zone. Tumor-to-normal tissue (T/N) ratios of MET uptake and mean relative cerebral blood volume (rCBV) were measured in the ROIs and protein expression of histological cell markers was quantified in corresponding regions. Statistical correlations were calculated between MET uptake, rCBV, and quantified protein expression.ResultsA total of 84 ROIs were selected in four oligodendrogliomas. A significant correlation (p < 0.05) between MET uptake and tumor cell density was demonstrated in all tumors separately. In two tumors, MET correlated with the density of proliferating cells and vessel cell density. There were no significant correlations between MET uptake and rCBV, and between rCBV and histological cell markers.ConclusionsThe MET uptake in hot spots, outside hotspots, and in infiltrating tumor edges unanimously reflects tumor cell density. The correlation between MET uptake and vessel density and density of proliferating cells is less stringent in infiltrating tumor edges and is probably more susceptible to artifacts caused by larger blood vessels surrounding the tumor. Although based on a limited number of samples, this study provides histological proof for MET as an indicator of tumor cell density and for the lack of statistically significant correlations between rCBV and histological cell markers in oligodendrogliomas.

Diagnosis of Brain Tumors Using Amino Acid Transport PET Imaging with 18F-fluciclovine: A Comparative Study with L-methyl-11C-methionine PET Imaging.

Objective(s):18F-fluciclovine (trans-1-amino-3-[18F] fluorocyclobutanecarboxylic acid, [FACBC]) is an artificial amino acid radiotracer used for positron emission tomography (PET) studies, which is metabolically stable in vivo and has a long half-life. It has already been shown that FACBC-PET is useful for glioma imaging. However, there have been no reports evaluating the efficiency of FACBC-PET in the diagnosis of brain tumors in comparison with other PET tracers in clinical studies. The purpose of this study was to investigate the efficacy of FACBC-PET imaging in glioma diagnosis, compared to L-methyl-11C-methionine (MET)-PET.Methods:Six consecutive patients (four male, two female), who were clinically suspected of having high- or low-grade glioma, received both FACBC-PET and MET-PET within a two-week interval. T1-weighted, contrast-enhanced, T1-weighted, and fluid-attenuated inversion recovery magnetic resonance imaging was performed to assist with subsequent tissue resection. Visual findings and semi-quantitative analyses of FACBC and MET uptake, using standardized uptake values (SUVs) and lesion-to-contralateral normal brain tissue (LN) ratios, were evaluated to compare PET images.Results:SUVs for FACBC were lower than those for MET in the non-lesion cerebral cortex, brain stem, and cerebellar hemisphere. There was a weak positive correlation between FACBC and MET uptake in glioma tissue, although L/N ratios for FACBC were higher than those for MET in all the cases.Conclusion:FACBC-PET showed higher contrast than MET-PET by both visual and semi-quantitative analyses and may therefore provide better assessment for the detection of glioma. This study was registered as clinical trial (No. JapicCTI-132289).

**-Postprandial pancreatic [11C]methionine uptake after pancreaticoduodenectomy mirrors basal beta cell function and insulin release

Purpose[S-methyl-11C]-L-methionine ([11C]MET) uptake in the pancreas might be a central indicator of beta cell function. Since gastric emptying was recently shown to influence glycemic control in subjects after pancreaticoduodenectomy (PD, the surgical treatment of neoplasms of the pancreas head), we looked for imaginable relationships between gastric emptying, pre- and postprandial insulin concentrations, and [11C]MET uptake.MethodsNineteen tumor-free survivors after PD (age mean ± SD: 61 ± 8.7 yrs.; 10 male, 9 female) and 10 healthy controls (age: 27 ± 8.7 yrs.; 7 male, 3 female) were given a mixed test meal. One gram of paracetamol was ingested with the meal to evaluate the speed of gastric emptying. Insulin, glucose, and paracetamol plasma concentrations were measured before and over 180 minutes after ingestion. Beta cell function was calculated from fasting glucose and insulin plasma concentrations. Simultaneously, 800 MBq of [11C]MET were administered and the activity (maximum tissue standardized uptake values [SUVmax]) over the pancreas was measured at 15, 30, and 60 minutes after injection. Total integrated SUVmax (area under the curve [AUC]) and incremental SUVmax were calculated.ResultsThe uptake of [11C]MET in the pancreas was significantly higher (p < 0.0001) in controls compared to the PD group. Gastric emptying was significantly slower in controls compared to pancreatectomy subjects (p < 0.0001). Paracetamol AUC30 correlated with the SUVmax increment between 15 and 30 minutes (R2 = 0.27, p = 0.0263), suggesting a relationship between gastric emptying and the uptake of [11C]MET. Total integrated SUVmax correlated with insulin AUC60 (R2 = 0.66,p < 0.0001) in patients after PD. Multivariate regression analysis revealed insulin AUC60 and beta cell function, calculated from the fasting insulin to glucose ratio, as independent predictors of 11C-methionine uptake, i.e. total integrated SUVmax, in patients after PD (R2 = 0.78, p < 0.0001).ConclusionPostprandial [11C]MET uptake may represent basal and postprandial beta cell function. The findings suggest a possible usefulness of this imaging procedure for further studying beta cell function.

Discrepancies of 11C-MET Uptake and MRI Contrast Enhancement in a Glioblastoma: A PET/MRI Case Report

A 58-year-old female patient suffered from convulsion in the left upper limb and weakness in the left lower extremity for one month. In MR contrast-enhancing (CE) images, obvious rim-enhancement was only found in the frontal nodule, while fused 11C-MET PET/MRI images showed increased MET uptake not only in the right frontal lesion but also in the body of corpus callosum. We postulated the discrepancy between MRI CE and MET uptake for the corpus callosum lesion maybe due to the following two reasons: firstly, a relative low malignant potential where absent of BBB disruption; secondly, the special affinity of MET to the oligodendroglioma. In addition, the 1H-MRS, TDI and ASL data acquired simultaneously with PET scan indicated the frontal lesion had the features of typical malignant intracranial tumor. Finally, the pathological results confirmed the frontal lesion a WHO-IV grade glioblastoma with partial anaplasia oligodendroglioma. The imaging follow-up showed a newly abnormal CE in the body of corpus callosum, which was consistent with the previous increased MET uptake on PET/MRI examination. Our case indicates that one-stop multiparametric MET-PET/MRI has advantages for the management of intracranial tumor lesions by providing complementary information.

Demonstration of high coincidence of pituitary adenoma in patients with ruptured Rathke's cleft cyst: Results of a prospective study

ObjectiveRepeated chronic inflammation, such as under circumstances of ruptured Rathke's cleft cyst (RCC), is known as the fundamental basis of various pathological changes including neoplastic change, therefore to examine accurate incidence of pituitary adenomas is important for the preventive medicine. Materials and methodsAs a prospective study, patients were initially screened by the symptoms such as periodic headache and dizziness together with the abnormal findings such as seller floor bone defect on 3D-CT. Those screened patients who showed abnormal basal pituitary hormone values were additionally examined by several loading test and 3T magnetic resonance imaging (MRI) by three-dimensional reconstructions of Flair cube images. The presence of pituitary adenomas was evaluated by composite 3T MRI and 11C methionine MET positron-emission tomography imaging. Immunohistochemical studies were employed for surgical biopsy specimens to demonstrate hormone production. Results308 cases of RCC were diagnosed by both radiologic and intraoperative findings. Pathological examination confirmed 111 pituitary adenomas in 106 patients with ruptured RCC, therefore the rate of coincidence was revealed 34%. In 78 patients with abnormalities of pituitary hormone secretion, MET uptake was observed in the pituitary gland and verified pituitary adenoma pathologically. In addition, 28 adenomas were verified without MET-PET study on pathological examination only, for a total of 106 cases. ConclusionsHigh coincidence (34%) of ruptured RCC and pituitary adenomas was demonstrated, which is a proof that ruptured RCC is contributed to a risk factor of pituitary adenoma.

¹⁸F-fluorodeoxyglucose and ¹¹C-methionine positron emission tomography in relation to methyl-guanine methyltransferase promoter methylation in high-grade gliomas.

Methylation status of the methyl-guanine methyltransferase (MGMT) promoter is associated with a favorable response to a DNA alkylating agent in high-grade gliomas. We analyzed PET scans of patients with high-grade gliomas to determine whether the MGMT methylation status affects the tumor metabolic characteristics. Twenty-three patients with high-grade glioma, who were initially examined with 11C-methionine (MET) and 18F-fluorodeoxyglucose (FDG) PET, were retrospectively enrolled. MET and FDG PET images were coregistered to each other and quantitative uptake of MET or FDG was assessed using tumor-to-normal uptake ratio of the cortex (TNR). TNRs for MET and FDG PET were compared between the two groups classified by MGMT promoter methylation status. Maximum TNR(FDG) of the MGMT methylated group was significantly higher than that of the MGMT unmethylated group (1.80±0.90 vs. 1.29±0.19; P=0.02). The MGMT methylated group also showed a trend for increased mean TNRFDG compared with the unmethylated group (0.85±0.21 vs. 0.72±0.11; P=0.10). There was no significant difference in TNR(MET) between the groups. In subgroup analyses with WHO grade 3 and 4, a trend for higher maximum TNR(FDG) was found in the MGMT methylated group compared with the unmethylated group. The MGMT methylated group showed higher glucose metabolism compared with the unmethylated group, whereas MET uptake did not show a significant difference. This suggests that MGMT methylation in high-grade gliomas could affect the tumor glucose metabolism. Thus, MGMT methylation status can cause a discrepancy in the prognostic prediction of high-grade gliomas by FDG PET, especially in patients scheduled for DNA alkylating chemotherapeutics.

Correlation of 11C-methionine PET and diffusion-weighted MRI

11C-Methionine (MET) PET and diffusion-weighted (DW) MRI are commonly used for evaluation of gliomas. We assessed the correlation between MET uptake and diffusion restriction measured on DW MRI in glioma. Thirty-one patients with gliomas, who were initially examined with MET PET and DW MRI, were enrolled retrospectively. MET PET and apparent diffusion coefficient (ADC) images were coregistered to each other, using rigid-body transformation. Tumor-to-normal count density ratio of the cortex (TNR) and normalized apparent diffusion coefficient (nADC) value were measured for each voxel on the MET PET and ADC map. The maximum TNR (TNRmax) and minimum nADC (nADCmin) were obtained for each tumor. Correlations between those parameters were evaluated. The TNRmax and nADCmin values of a glioma were significantly correlated (r=-0.42). TNRmax and nADCmin were significantly correlated with glioma grades. Furthermore, TNRmax and nADCmin showed a trend for correlation with the Ki-67 index. We analyzed the correlation between voxel-based TNR and ADC within a tumor and observed no correlation between them. Regions with high MET uptake did not correspond with regions with low nADC. We found a negative correlation between TNRmax and nADCmin for each glioma; however, MET uptake and ADC within a tumor were independent of each other and were heterogeneous. The two parameters represent different biological features; thus, as a comprehensive approach, MET PET and DW MRI might have a complementary role in the characterization of gliomas.

Characterization of Glioblastoma Multiforme Non-Distant Failures After Intensity Modulated Radiation Therapy in Relation to Pre-irradiation Carbon 11-Methionine Positron Emission Tomography

To determine the patterns of non-distant failure of glioblastoma multiforme (GBM) after treatment based on magnetic resonance imaging (MRI) volumes with simultaneous integrated boost intensity modulated radiation therapy (IMRTSIB), in relation to pre-irradiation C11-methionine positron emission tomography (mPET) imaging. On the third week after gross total resection, 94 GBM patients were prospectively imaged with mPET and MRI. Radiation was delivered to MRI based target volumes- TVGd (enhancing region on gadolinium contrast T1 MRI, +1.5 cm margin) and TVT2F (T2-FLAIR +1.5 cm margin) by the use of IMRTSIB over 30 fractions, with TVGd and TVT2F receiving 60 Gy (2 Gy/fraction) and 51 Gy (1.7 Gy/fraction) respectively. Volumes were also drawn on pre-RT mPET, with PV2, PV1.8 and PV1.4 representing regions with MET uptake ≥2, 1.8, and 1.4 times that of the normal cerebellar uptake, without margins. Comparisons between various volumes in cubic centimeters (cc) were performed using the two tailed paired t-test. At the instance of first failure, the post-failure MRI was co-registered with pre-RT mPET so as to facilitate correlations. Failures were assigned to be within a said volume if it contained >50% of the lesion bulk. All patients received concurrent and adjuvant temozolomide. After a median post-RT span of 18 months, 54 failures were noted. After excluding 5 distant failures, 49 cases of non-distant failure (NDF) were analyzed. Ratio of volume means of TVT2F:PV1.4 was 3.3 (47.5 cc vs 14.3 cc; 95% CI of difference 31.39 → 35.01, p < 0.0001). The ratios TVGd:PV1.8 and TVGd:PV2 were 0.9 (4.8 cc vs 5.3 cc; 95% CI of difference -1.03 → 0.03, p = 0.0489) and 1.6 (4.8 cc vs 1.9 cc; 95% CI of difference 2.63 → 3.16, p < 0.0001), respectively. Volumes PV1.4 and TVT2F both contained 100% of subsequent NDFs. Other pre-RT volumes TVGd, PV1.8 and PV2 contained 75.5%, 79.6%, and 71.4% of NDFs, respectively. The mPET volume PV1.4 was able to predict 100% of NDFs despite being significantly smaller than the MRI volume TVT2F. The mPET volumes PV1.8 and PV2 were comparable to contrast enhanced MRI volume TVGd.

Comparative evaluation of transport mechanisms of trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid and l-[methyl-11C]methionine in human glioma cell lines

Positron emission tomography (PET) with amino acid tracers is useful for the visualization and assessment of therapeutic effects on gliomas. Our purpose is to elucidate the transport mechanisms of trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid (anti-[18F]FACBC) and l-[methyl-11C]methionine ([11C]Met) in normal human astrocytes (NHA), low-grade (Hs683, SW1088), and high-grade (U87MG, T98G) human glioma cell lines. Because the short half-lives of fluorine-18 and carbon-11 are inconvenient for in vitro experiments, trans-1-amino-3-fluoro[1-14C]cyclobutanecarboxylic acid (anti-[14C]FACBC) and l-[methyl-14C]methionine ([14C]Met) were used instead of the PET tracers. Time-course uptake experiments showed that uptake of anti-[14C]FACBC was 1.4–2.6 times higher than that of [14C]Met in NHA and low-grade glioma cells, and was almost equal to that of [14C]Met in high-grade glioma cells. To identify the amino acid transporters (AATs) involved in the transport of anti-[14C]FACBC and [14C]Met, we carried out competitive inhibition experiments using synthetic/naturally-occurring amino acids as inhibitors. We found that anti-[14C]FACBC uptake in the presence of Na+ was strongly inhibited by l-glutamine and l-serine (the substrates for ASC system AATs), whereas l-phenylalanine and 2-amino-bicyclo[2,2,1]heptane-2-carboxylic acid (BCH, the substrates for L system AATs) robustly inhibited Na+-independent anti-[14C]FACBC uptake. Regardless of Na+, [14C]Met uptake was inhibited strongly by l-phenylalanine and BCH. Moreover, the exchange transport activity of l-glutamine for anti-[14C]FACBC was stronger than that of BCH in the presence of Na+, whereas that for [14C]Met was almost equal to BCH. These results demonstrate that ASC and L are important transport systems for anti-[18F]FACBC uptake, while system L is predominantly involved in [11C]Met transport in human astrocytes and glioma cells.

Metabolism of Radiolabeled Methionine in Hepatocellular Carcinoma

Radiolabeled methionine (Met) promises to be useful in the positron emission tomography (PET) imaging of hepatocellular carcinoma (HCC). However, its metabolic routes in HCC have not yet been fully understood. In this study, the metabolic pathway(s) of radiolabeled Met in HCC were investigated. To simulate the rapid blood clearance of radiolabeled Met, pulse-chase experiments were conducted. L-[methyl-(3)H]-Met or L-[1-(14)C]-Met was pulsed over control or cycloheximide-treated WCH17 cells and rat hepatocytes for 5min and chased with cold media. The water-soluble, lipid-soluble, DNA, RNA, and protein phases were subsequently extracted and measured from the acid-precipitable and acid-soluble fractions of whole cells. The radioactive metabolites Met, S-adenosylmethionine (SAM), S-adenosylhomocysteine, Met sulfoxide, and Met sulfone were further separated by radio thin layer chromatography. (1) The uptake of L-[methyl-(3)H]-Met in both cell types was higher than that of L-[1-(14)C]-Met. In rat hepatocytes, the uptake of L-[methyl-(3)H]-Met was significantly higher than that of L-[1-(14)C]-Met, which may contribute to its physiologic accumulation in surrounding hepatic tissues seen in PET imaging of HCC using L-[methyl-(11)C]-Met. Compared to rat hepatocytes, WCH17 cells had significantly higher uptake of both radiotracers. (2) For L-[methyl-(3)H]-Met, the major intracellular uptake was found mostly in the protein phase and, to a lesser degree, in the phosphatidylethanolamine (PE) methylation pathway, which is fairly stabilized within the 55-min chase period (the main metabolites were SAM, Met, Met sulfoxide, and Met sulfone). In contrast, the uptake of Met in rat hepatocytes mainly points to phosphatidylcholine (PC) synthesis through the PE methylation pathway (the main metabolite was PC). (3) Both cell types incorporated L-[1-(14)C]-Met predominantly into protein synthesis. (4) Finally, when the protein synthesis pathway was inhibited, the incorporation of SAM derived from L-[methyl-(3)H]-Met to lipid class (PC was the main metabolite) occurred at a reduced rate in WCH17 cells, suggesting that the route may be impaired in HCC. This study demonstrated that different metabolic pathways of radiolabeled Met exist between HCC and surrounding hepatic tissue and contribute to the patterns of increased uptake of radiolabeled Met in HCC.

Simultaneous PET/MR body imaging in rats: initial experiences with an integrated PET/MRI scanner

We recently developed an integrated positron emission tomography (PET)/magnetic resonance imaging (MRI) (iPET/MRI) scanner for small animals, which had relatively large field-of-view (FOV) covering up to the size of a rat body. The purpose of this study was to report results of simultaneous PET/MRI of a rat body using this scanner with some radiotracers. C-11-methionine (MET), F-18-fluorodeoxyglucose (FDG), or F-18-sodium fluoride (NaF) was injected as a radiotracer for PET portion in addition to gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid, a hepatobiliary contrast agent, for MRI portion. Simultaneous PET/MRI was performed in normal rats. PET, MRI, and co-registered fusion images were evaluated regarding image quality and feasibility for rat imaging studies. MET uptake was clearly shown in the liver and pancreas, which was confirmed with magnetic resonance (MR) and fused PET/MR images. PET/MR images depicted intense FDG uptake in the brain, Harderian glands, and myocardium. NaF uptake was observed in all bones and joints within FOV, except in ribs, which was well recognized with the help of MR and fused PET/MR images. This study demonstrated that simultaneous PET/MRI with an integrated dual-modality molecular imaging scanner was a feasible technique for imaging studies targeting on a rat body. However, further developments including attenuation correction methods are required to use this technique routinely in rat imaging studies.