Tetsuhiro Hatakeyama

11C-methionine (MET) and 18F-fluorothymidine (FLT) PET in patients with newly diagnosed glioma

PurposeThe purpose of this prospective study was to clarify the individual and combined role of l-methyl-11C-methionine-positron emission tomography (MET-PET) and 3′-deoxy-3′-[18F]fluorothymidine (FLT)-PET in tumor detection, noninvasive grading, and assessment of the cellular proliferation rate in newly diagnosed histologically verified gliomas of different grades.Materials and methodsForty-one patients with newly diagnosed gliomas were investigated with MET-PET before surgery. Eighteen patients were also examined with FLT-PET. MET and FLT uptakes were assessed by standardized uptake value of the tumor showing the maximum uptake (SUVmax), and the ratio to uptake in the normal brain parenchyma (T/N ratio). All tumors were graded by the WHO grading system using surgical specimens, and the proliferation activity of the tumors were determined by measuring the Ki-67 index obtained by immunohistochemical staining.ResultsOn semiquantitative analysis, MET exhibited a slightly higher sensitivity (87.8%) in tumor detection than FLT (83.3%), and both tracers were 100% sensitive for malignant gliomas. Low-grade gliomas that were false negative on MET-PET also were false negative on FLT-PET. Although the difference of MET SUVmax and T/N ratio between grades II and IV gliomas was statistically significant (P < 0.001), there was a significant overlap of MET uptake in the tumors. The difference of MET SUVmax and T/N ratio between grades II and III gliomas was not statistically significant. Low-grade gliomas with oligodendroglial components had relatively high MET uptake. The difference of FLT SUVmax and T/N ratio between grades III and IV gliomas was statistically significant (P < 0.01). Again, the difference of FLT SUVmax and T/N ratio between grades II and III gliomas was not statistically significant. Grade III gliomas with non-contrast enhancement on MR images had very low FLT uptake. In 18 patients who underwent PET examination with both tracers, a significant but relatively weak correlation was observed between the individual SUVmax of MET and FLT (r = 0.54, P < 0.05) and T/N ratio of MET and FLT (r = 0.56, P < 0.05). Total FLT uptake in the tumor had a higher correlation (r = 0.89, P < 0.001) with Ki-67 proliferation index than MET uptake (r = 0.49, P < 0.01).ConclusionsPET studies using MET and FLT are useful for tumor detection in newly diagnosed gliomas. However, there is no complimentary information in tumor detection with simultaneous measurements of MET- and FLT-PET in low grade gliomas. FLT-PET seems to be superior than MET-PET in noninvasive tumor grading and assessment of proliferation activity in gliomas of different grades.

11C-acetate PET in the evaluation of brain glioma: comparison with 11C-methionine and 18F-FDG-PET.

PurposeThe aim of the study is to retrospectively investigate the usefulness of 11C-acetate (ACE)-positron emission tomography (PET) for evaluation of brain glioma, in comparison with 11C-methionine (MET) and 2-deoxy-2-18F-fluoro-d-glucose (FDG).ProceduresFifteen patients with brain glioma referred to initial diagnosis were examined with ACE, MET, and FDG-PET. Five patients had low-grade gliomas (grade II), three had anaplastic astrocytomas (grade III), and seven had glioblastomas (grade IV). PET results were evaluated by visual and semiquantitative analysis. For semiquantitative analysis, the standardized uptake value (SUV) and tumor to contralateral normal gray matter (T/N) ratio were calculated. The sensitivity for detection of high-grade gliomas was calculated using visual analysis.ResultsSensitivities of ACE, MET, and FDG were 90%, 100%, and 40%, respectively. ACE and MET T/N ratios were significantly higher than that of FDG. ACE and FDG SUV in high-grade gliomas were significantly higher than that in low-grade gliomas. No significant differences were observed using MET.ConclusionsACE PET is a potentially useful radiotracer for detecting brain gliomas and differentiating high-grade gliomas.

Usefulness of FDG, MET and FLT-PET Studies for the Management of Human Gliomas

The use of positron imaging agents such as FDG, MET, and FLT is expected to lead the way for novel applications toward efficient malignancy grading and treatment of gliomas. In this study, the usefulness of FDG, MET and FLT-PET images was retrospectively reviewed by comparing their histopathological findings. FDG, MET, and FLT-PET were performed in 27 patients with WHO grade IV, 15 patients with WHO grade III, and 12 patients with WHO grade II during 5.5 years. The resulting PET images were compared by measuring SUVs and T/N ratios (tumor to normal tissue ratios). Although there were no significant differences in FDG-PET, there were significant differences in the T/N ratios in the MET-PET between WHO grades II and IV and in the FLT-PET between the WHO grades III and IV. In glioblastoma patients, the SUVs of the areas depicted by MRI in the MET-PET were different from those SUVs in the FLT-PET. Importantly, the areas with high SUVs in both MET-PET and FLT-PET were also high in Ki-67 index and were histologically highly malignant. PET imaging is a noninvasive modality that is useful in determining a tumor area for removal as well as improving preoperative diagnosis for gliomas.

Diagnostic value of kinetic analysis using dynamic 18F-FDG-PET in patients with malignant primary brain tumor.

ObjectiveThe purpose of this study was to evaluate the efficacy of quantitative imaging of glucose metabolism with positron emission tomography (PET) using kinetic analysis for differentiating between high-grade glioma and central nervous system (CNS) lymphoma. MethodsDynamic fluorine-18-fluorodeoxyglucose (18F-FDG)-PET scans obtained in 20 patients with high-grade glioma (World Health Organization grade III, five lesions; grade IV, 15 lesions) and in 12 patients with CNS lymphoma (16 lesions) were retrospectively reviewed. Applying a three-compartment model, parametric images of K1, k2, k3, and k4 and cerebral metabolic rate of glucose (CMRGlc) were obtained. ResultsOn visual analysis, one grade III glioma lesion showed an increase of K1, k2, and k3 values as observed on their respective images. Four grade IV glioma lesions showed an increase of K1 and k2, 11 of k3, and six of CMRGlc on their respective images. Fourteen CNS lymphoma lesions showed an increase of K1, 16 of k3, two of k4, and 14 of CMRGlc. Both k3 and CMRGlc values (mean±SD) of CNS lymphoma (0.096±0.046 and 77.4±37.7, respectively) were significantly higher than those of the normal gray matter (0.059±0.015 and 41.3±9.3, respectively; P<0.007 and P<0.002, respectively). The k3 value of CNS lymphoma was significantly higher than that of grade III (0.058±0.022) and grade IV (0.065±0.024) gliomas (P<0.03 and P<0.04, respectively). The CMRGlc value of CNS lymphoma was significantly higher than that of grade III (33.8±7.8) and grade IV (41.5±23.1) gliomas (P<0.001 and P<0.004, respectively). The value of k2 of CNS lymphoma was significantly lower than that of grade IV glioma (P<0.05). ConclusionThe direct measurement of the regional rate constants by kinetic analysis might be useful for the delineation of CNS lymphoma and for differential diagnosis of high-grade glioma and CNS lymphoma.

Comparison of 4′-[methyl- 11 C]thiothymidine ( 11 C-4DST) and 3′-deoxy-3′-[ 18 F]fluorothymidine ( 18 F-FLT) PET/CT in human brain glioma imaging

Background3′-deoxy-3′-[18F]fluorothymidine (18F-FLT) has been used to evaluate tumor malignancy and cell proliferation in human brain gliomas. However, 18F-FLT has several limitations in clinical use. Recently, 11C-labeled thymidine analogue, 4′-[methyl-11C]thiothymidine (11C-4DST), became available as an in vivo cell proliferation positron emission tomography (PET) tracer. The present study was conducted to evaluate the usefulness of 11C-4DST PET in the diagnosis of human brain gliomas by comparing with the images of 18F-FLT PET.MethodsTwenty patients with primary and recurrent brain gliomas underwent 18F-FLT and 11C-4DST PET scans. The uptake values in the tumors were evaluated using the maximum standardized uptake value (SUVmax), the tumor-to-normal tissue uptake (T/N) ratio, and the tumor-to-blood uptake (T/B) ratio. These values were compared among different glioma grades. Correlation between the Ki-67 labeling index and the uptake values of 11C-4DST and 18F-FLT in the tumor was evaluated using linear regression analysis. The relationship between the individual 18F-FLT and 11C-4DST uptake values in the tumors was also examined.Results11C-4DST uptake was significantly higher than that of 18F-FLT in the normal brain. The uptake values of 11C-4DST in the tumor were similar to those of 18F-FLT resulting in better visualization with 18F-FLT. No significant differences in the uptake values of 18F-FLT and 11C-4DST were noted among different glioma grades. Linear regression analysis showed a significant correlation between the Ki-67 labeling index and the T/N ratio of 11C-4DST (r = 0.50, P < 0.05) and 18F-FLT (r = 0.50, P < 0.05). Significant correlations were also found between the Ki-67 labeling index and the T/B ratio of 11C-4DST (r = 0.52, P < 0.05) and 18F-FLT (r = 0.55, P < 0.05). A highly significant correlation was observed between the individual T/N ratio of 11C-4DST and 18F-FLT in the tumor (r = 0.79, P = 0.0001).ConclusionsThe present study demonstrates that 11C-4DST is useful for the imaging of human brain gliomas with PET. A relatively higher background uptake of 11C-4DST in the normal brain compared to 18F-FLT limits the detection of low-tracer-uptake tumors. Moreover, no superiority was found in 11C-4DST over 18F-FLT in the evaluation of cell proliferation.

Usefulness of positron emission tomographic studies for gliomas

Non-invasive positron emission tomography (PET) enables the measurement of metabolic and molecular processes with high sensitivity. PET plays a significant role in the diagnosis, prognosis, and treatment of brain tumors and predominantly detects brain tumors by detecting their metabolic alterations, including energy metabolism, amino acids, nucleic acids, and hypoxia. Glucose metabolic tracers are related to tumor cell energy and exhibit good sensitivity but poor specificity for malignant tumors. Amino acid metabolic tracers provide a better delineation of tumors and cellular proliferation. Nucleic acid metabolic tracers have a high sensitivity for malignant tumors and cellular proliferation. Hypoxic metabolism tracers are useful for detecting resistance to radiotherapy and chemotherapy. Therefore, PET imaging techniques are useful for detecting biopsy-targeting points, deciding on tumor resection, radiotherapy planning, monitoring therapy, and distinguishing brain tumor recurrence or progression from post-radiotherapy effects. However, it is not possible to use only one PET tracer to make all clinical decisions because each tracer has both advantages and disadvantages. This study focuses on the different kinds of PET tracers and summarizes their recent applications in patients with gliomas. Combinational uses of PET tracers are expected to contribute to differential diagnosis, prognosis, treatment targeting, and monitoring therapy.

Correlation of 4′-[methyl-11C]-thiothymidine uptake with human equilibrative nucleoside transporter-1 and thymidine kinase-1 expressions in patients with newly diagnosed gliomas

ObjectiveWe examined expressions of human equilibrative nucleoside transporter-1 (hENT1) and thymidine kinase-1 (TK1), the key enzyme in 4′-[methyl-11C]-thiothymidine (4DST) phosphorylation, to elucidate the mechanism of 4DST uptake in patients with newly diagnosed gliomas.MethodsA total of 19 patients with newly diagnosed gliomas were examined with 4DST PET. Tumor lesions were identified as areas of focally increased uptake, exceeding that of normal brain background. For semi-quantitative analysis, tumor-to-contralateral normal brain tissue (T/N) ratio was determined by dividing the maximal standardized uptake value (SUV) for tumor by that of the mean SUV for reference tissue. The expressions of hENT1, TK1 and Ki-67 in tumor specimens were examined by immunohistochemistry and compared with 4DST T/N ratio.ResultsAll but two gliomas showed focally increased 4DST uptake. All gliomas showed hENT1 staining, except one grade II glioma, which was also not visualized on 4DST PET. A significant correlation was observed between T/N ratio and hENT1 score (ρ = 0.90, p < 0.001). All gliomas showed TK1 staining, except two gliomas which were also not visualized on 4DST PET. There was a significant correlation between T/N ratio and TK1 score (ρ = 0.92, p < 0.001). There was a significant correlation between T/N ratio and Ki-67 index (ρ = 0.50, p < 0.03).ConclusionResults of this preliminary study indicate that expressions of hENT1 and TK1 appear to be important determinants of 4DST uptake in newly diagnosed gliomas.

Correlation of 18F-FDG and 11C-methionine uptake on PET/CT with Ki-67 immunohistochemistry in newly diagnosed intracranial meningiomas

ObjectiveWe evaluated the uptake of 2-deoxy-2-18F-fluoro-d-glucose (FDG) and l-[methyl-11C]-methionine (MET) in patients with newly diagnosed intracranial meningiomas and correlated the results with tumor proliferation.MethodsData from 22 patients with newly diagnosed intracranial meningioma (12 grade I and 10 grade II) who underwent both FDG and MET brain PET/CT studies were retrospectively analyzed. The PET images were evaluated by a qualitative method and semiquantitative analysis using standardized uptake value (SUV) (SUVmax and SUVpeak) and tumor-to-reference tissue ratio (Tmax/N ratio and Tpeak/N ratio). Proliferative activity as indicated by the Ki-67 index was estimated in tissue specimens.ResultsMET PET/CT showed a higher detection rate of meningioma than did FDG PET/CT (100 vs. 46%, respectively). The Tmax/N ratio and Tpeak/N ratio on MET PET/CT were significantly higher than those on FDG PET/CT (p < 0.001 and p < 0.001, respectively). There was a significant difference between grades I and II with respect to FDG SUVmax (p = 0.003), FDG SUVpeak (p = 0.003), FDG Tmax/N ratio (p = 0.02), FDG Tpeak/N ratio (p = 0.006), MET SUVmax (p = 0.002), MET SUVpeak (p = 0.002), MET Tmax/N ratio (p = 0.002), and MET Tpeak/N ratio (p = 0.002). There was a significant correlation between Ki-67 index and FDG PET/CT for SUVmax (p = 0.02), SUVpeak (p = 0.005), and Tpeak/N ratio (p = 0.05) and between Ki-67 index and MET PET/CT for SUVmax (p = 0.004), SUVpeak (p = 0.007), Tmax/N ratio (p = 0.002), and Tpeak/N ratio (p = 0.004).ConclusionMET PET/CT showed a high sensitivity compared with FDG PET/CT for detection of newly diagnosed WHO grades I and II intracranial meningiomas. Both FDG and MET uptake were found to be useful for evaluating tumor proliferation in meningiomas.

Reconstruction of input functions from a dynamic PET image with sequential administration of 15O2 and H215O for noninvasive and ultra-rapid measurement of CBF, OEF, and CMRO2

CBF, OEF, and CMRO2 images can be quantitatively assessed using PET. Their image calculation requires arterial input functions, which require invasive procedure. The aim of the present study was to develop a non-invasive approach with image-derived input functions (IDIFs) using an image from an ultra-rapid O2 and C15O2 protocol. Our technique consists of using a formula to express the input using tissue curve with rate constants. For multiple tissue curves, the rate constants were estimated so as to minimize the differences of the inputs using the multiple tissue curves. The estimated rates were used to express the inputs and the mean of the estimated inputs was used as an IDIF. The method was tested in human subjects (n = 24). The estimated IDIFs were well-reproduced against the measured ones. The difference in the calculated CBF, OEF, and CMRO2 values by the two methods was small (<10%) against the invasive method, and the values showed tight correlations (r = 0.97). The simulation showed errors associated with the assumed parameters were less than ∼10%. Our results demonstrate that IDIFs can be reconstructed from tissue curves, suggesting the possibility of using a non-invasive technique to assess CBF, OEF, and CMRO2.