Toshimitsu Fukumura

FDG-PET in infectious lesions: The detection and assessment of lesion activity

The usefulness of FDG-PET in the detection of infectious foci and the assessment of lesion activity was evaluated. The study covered 24 patients with 25 FDG-PET studies, including lesions of bacterial, tuberculous and fungal origins. The FDG uptake was determined by the lesion to muscle ratio (LMR) on the static images. The time activity curves (TACs) were classified into four patterns based on both the existence of an initial peak and a slope thereafter. A high FDG uptake was observed in 23 of 25 lesions (92%). Two lesions, in which no abnormal uptake was noted, included one in the healing stage and the other consisting of a cavity with a thin wall. The acute active lesions showed higher LMRs than the chronic active or healing lesions (mean ± SD: 9.8 ± 3.6, 3.6 ±1.8 and 4.3 ± 1.7, respectively, p < 0.05), and they could be approximately distinguished by an LMR of 6. The patterns of the TACs in acute or chronic active lesions were either an increase without an initial peak or a plateau, while those in the healing lesions demonstrated predominantly an increase with an initial sharp peak. Our results indicated that FDG-PET is clinically useful in the detection of the infection of miscellaneous microorganisms as well as in the assessment of lesion activity.

The usefulness of FDG positron emission tomography for the detection of mediastinal lymph node metastases in patients with non-small cell lung cancer : a comparative study with X-ray computed tomography

We evaluated the usefulness of fluorine-18-fluoro-2-deoxy-d-glucose positron emission tomography (FDG PET) in the detection of mediastinal lymph node metastases in patients with non-small cell lung cancer and then compared the findings with the results of X-ray CT by region based on the histological diagnoses. We examined 29 patients with non-small cell lung cancer. One hundred and thirty-two mediastinal lymph nodes were surgically removed and the histological diagnoses were confirmed. FDG PET images, including 146 mediastinal regions, were visually analysed and the mediastinal lymph nodes were scored as positive when the FDG uptake was higher than that in the other mediastinal structures. On the X-ray CT scans, any mediastinal lymph nodes with a diameter of 10 mm or larger were scored as positive. All three examinations were successfully performed on 71 regions. For FDG PET, we found a sensitivity of 76%, a specificity of 98% and an accuracy of 93%. On the other hand, for X-ray CT a sensitivity of 65%, a specificity of 87% and an accuracy of 82% were observed. A significant difference was observed in respect of both specificity and accuracy (P<0.05). Based on the above findings, FDG PET is suggested to be superior to X-ray CT when used for the detection of mediastinal lymph node metastases in patients with non-small cell lung cancer.

A comparative study of thallium-201 SPET, carbon-11 methionine PET and fluorine-18 fluorodeoxyglucose PET for the differentiation of astrocytic tumours

Abstract. Thallium-201, carbon-11 methionine (MET) and fluorine-18 fluorodeoxyglucose (FDG) have all been used to assess brain tumours. The aim of this study was to determine which of these tracers are of use for evaluating the histological grade and the extent of astrocytoma. 201Tl single-photon emission tomography (SPET), MET positron emission tomography (PET) and FDG PET were all performed in 23 patients (13 men, 10 women) with newly diagnosed astrocytic tumours [seven with astrocytoma (grade II), ten with anaplastic astrocytoma (grade III) and six with glioblastoma (grade IV)]. The 201Tl uptake of the tumours was evaluated by a lesion-to-normal region count ratio. Both MET and FDG uptake of the tumours was evaluated by a semiquantitative analysis using the standardized uptake value. 201Tl uptake was found to increase in rank order with histological grade and was significantly different among the three groups (grade II: 1.51±0.36; grade III: 2.58±1.50; grade IV: 7.65±3.84). MET uptake in grade II (1.49±0.44) was also significantly lower than that in both grade III (3.29±1.44) and grade IV (3.20±0.92). FDG uptake was not significantly different among the three groups (grade II: 2.90±0.45; grade III: 3.86±1.56; grade IV: 3.57±0.83). No significant correlation was observed between 201Tl uptake and either MET uptake or FDG uptake. In most patients, the extent of the increased MET uptake was the largest while that of the increased FDG uptake was the smallest. In patients with positive 201Tl uptake, the extent of the 201Tl uptake was equal to or smaller than that of gadolinium enhancement. For evaluation of histological grade of astrocytic tumours. 201Tl is therefore considered to be useful though the 201Tl uptake in some grade III astrocytomas was not different from that in grade II astrocytomas. MET was found to be highly useful for detecting astrocytomas, for differentiating between benign and malignant astrocytomas, and for evaluating the extent of astrocytomas; however, it was not sufficiently useful permit evaluation of the histological grade. FDG was not found to be useful either for evaluating the histological grade or for differentiating between benign and malignant astrocytomas.

In vivo positron emission tomographic imaging of glial responses to amyloid-beta and tau pathologies in mouse models of Alzheimer's disease and related disorders.

Core pathologies of Alzheimers disease (AD) are aggregated amyloid-β peptides (Aβ) and tau, and the latter is also characteristic of diverse neurodegenerative tauopathies. These amyloid lesions provoke microglial activation, and recent neuroimaging technologies have enabled visualization of this response in living brains using radioligands for the peripheral benzodiazepine receptor also known as the 18 kDa translocator protein (TSPO). Here, we elucidated contributions of Aβ and tau deposits to in vivo TSPO signals in pursuit of mechanistic and diagnostic significance of TSPO imaging in AD and other tauopathies. A new antibody to human TSPO revealed induction of TSPO-positive microgliosis by tau fibrils in tauopathy brains. Emergence of TSPO signals before occurrence of brain atrophy and thioflavin-S-positive tau amyloidosis was also demonstrated in living mice transgenic for mutant tau by positron emission tomography (PET) with two classes of TSPO radioligands, [11C]AC-5216 and [18F]fluoroethoxy-DAA1106. Meanwhile, only modest TSPO elevation was observed in aged mice modeling Aβ plaque deposition, despite the notably enhanced in vivo binding of amyloid radiotracer, [11C]Pittsburgh Compound-B, to plaques. In these animals, [11C]AC-5216 yielded better TSPO contrasts than [18F]fluoroethoxy-DAA1106, supporting the possibility of capturing early neurotoxicity with high-performance TSPO probes. Furthermore, an additional line of mice modeling intraneuronal Aβ accumulation displayed elevated TSPO signals following noticeable neuronal loss, unlike TSPO upregulation heralding massive neuronal death in tauopathy model mice. Our data corroborate the utility of TSPO-PET imaging as a biomarker for tau-triggered toxicity, and as a complement to amyloid scans for diagnostic assessment of tauopathies with and without Aβ pathologies.

A clinical evaluation of FDG-PET to assess the response in radiation therapy for bronchogenic carcinoma

The clinical usefulness of FDG-PET in the prediction and assessment of response to radiation therapy in patients with bronchogenic carcinoma was evaluated. Thirty patients with untreated bronchogenic carcinoma were included in the study. All patients received FDG-PET before the initiation of radiation therapy, while 20 also received it after completing the therapy. The tumor to muscle ratio (TMR) was used as an index of the FDG uptake. The tumor response to therapy was classified as either a partial response (PR, n = 21) or no change (NC, n = 9) according to changes in the tumor size. Prognosis was made 6 months after the initiation of therapy, and was classified as either relapse (n = 19) or non-relapse (n = 9). The FDG uptakes both before and after therapy were compared with tumor response and prognosis. A high FDG uptake was noted in all 30 lesions before therapy. No significant differences in the uptake before therapy was observed according to the histological types nor T factors (UICC). The lesions with a higher uptake (TMR more than 7) responded better to therapy than those with a lower uptake (p < 0.05). The decrease in the uptake after therapy tended to be more prominent in the PR group than in the NC group. The rate of relapse was higher in lesions with a higher uptake before therapy (TMR more than 10) than in those with a lower uptake. The relapse group also showed a higher uptake after therapy than the non-relapse group. In addition, all 6 lesions showing a higher uptake (TMR more than 5) after therapy eventually relapsed (p < 0.05). Two lesions demonstrating a lower uptake both before and after therapy did not relapse, although no tumor regression due to the therapy was observed. These results indicate that FDG-PET plays a complementary role in both predicting and assessing the therapeutic response and prognosis in patients with bronchogenic carcinoma.

Differences in the reduced 18F-Dopa uptakes of the caudate and the putamen in Parkinson's disease: correlations with the three main symptoms

It has been reported that the F-Dopa (FD) uptake in patients with idiopathic Parkinsons disease (PD) decreased significantly in the caudate and putamen when compared to controls. The FD uptake severely decreased in the putamen, while it was relatively spared in the caudate nucleus. We also previously reported that atypical parkinsonism with no or little tremor showed a homogeneously reduced FD uptake in both the caudate and the putamen. In this study we evaluated the caudate and the putaminal FD uptakes in relation to the three main symptoms in PD. The FD uptake was measured by PET with 6-L-[18F]fluorodopa in 17 patients with PD. The caudate and the putaminal FD uptake ratios to the cerebellum at 120 min were evaluated. The caudate and the putaminal FD uptake ratios in the patients with PD decreased as their clinical stages advanced. These decreases also correlated with the degree of rigidity and bradykinesia. However, such decreases did not correlate with the degree of tremor. The caudate-putamen index (CPI)(%), which was calculated by a formula based on the difference in the uptakes of the caudate and putamen divided by the caudate uptake, indicated 11.6 +/- 3.6, 16.5 +/- 5.5 and 18.3 +/- 4.1 in the group of no, mild and moderate tremor, respectively, and increased as the degree of tremor advanced. The CPI in the group of moderate tremor significantly increased from that in the group of no tremor (P < 0.04). However, the CPI did not correlate with the clinical stage, the degree of rigidity or the degree of bradykinesia. The FD/PET study therefore effectively demonstrated the severity of the clinical symptoms of rigidity and bradykinesia in patients with PD in correlation with a decrease in the FD uptakes in the caudate and the putamen, and it also demonstrated that the severity of tremor might have a different mechanism from that of such other symptoms as rigidity and bradykinesia.

Differentiating between multiple system atrophy and Parkinson’s disease by positron emission tomography with18F-dopa and18F-FDG

Both the striatal18F-dopa uptake and brain glucose metabolism were studied by PET with 6-l-[18F]fluorodopa (FD) and [18F]fluorodeoxyglucose (FDG) in 9 patients with multiple system atrophy (MSA) and 15 patients with idiopathic Parkinson’s disease (PD). Five of the 9 MSA patients were diagnosed as having olivopontocerebellar atrophy, whereas 2 had striatonigral degeneration and 2 demonstrated Shy-Drager syndrome. The FD uptake ratios to the occipital cortex in the MSA patients at 120 min after the administration of FD were 2.07 ± 0.31 (mean ± SD) and 1.96 ± 0.29 in the caudate and the putamen, respectively, and decreased compared to those in the controls (2.72 ± 0.11, 2.71 ± 0.10). The same ratios in the PD patients were 2.07 ± 0.36 and 1.74 ± 0.24, respectively, which also decreased, but the decreased uptake in the putamen was more prominent. The caudate-putamen index (CPI) (%), which was calculated by a formula based on the difference in the uptakes in the caudate and putamen divided by the caudate uptake, indicated 5.6 ± 4.6 in the MSA patients and 14.8 ± 5.4 in the PD patients. The CPI for all PD patients was more than 7.0, which was the mean + 2SD for the controls, but the CPI for 3 MSA patients was more than 7.0 (accuracy: 88%). The glucose metabolic rates for each region in the PD patients showed no difference from the normal controls. The frontal and the temporal cortical glucose metabolism and the caudate, the putaminal, the cerebellar and the brainstem glucose metabolism in the MSA patients decreased significantly in comparison to those in the controls. But, as the glucose metabolic rates in such regions of each patient overlapped in the two groups, the accuracy of the FDG study for differentiation was lower than that of the FD study. The putaminal glucose metabolic rates, for example, in 3 PD patients were less than 6.8 (mg/min/100 ml), which was the mean — 2SD for the controls, while those in 3 MSA patients were more than 6.8 (accuracy: 75%). In addition, the combination of these two methods slightly improved the accuracy. The glucose metabolism is useful for evaluating the regional metabolic activity of the brain, and the FD study, which is specific to the dopamine system, seems to be more useful for differentiating between MSA and PD.

Glucose metabolism in the cortical and subcortical brain structures in multiple system atrophy and Parkinson's disease: A positron emission tomographic study

The brain glucose metabolism was studied by PET with 18F-FDG in 11 patients with multiple system atrophy (MSA) and 12 patients with idiopathic Parkinsons disease (PD). Seven of the 11 MSA patients were diagnosed as having olivopontocerebellar atrophy, two had striatonigral degeneration, while two demonstrated Shy-Drager syndrome. The glucose metabolic rates for each region in the PD patients showed no difference from the normal controls. The frontal, temporal and parietal cortical glucose metabolic rates and the caudate, the putaminal, the cerebellar and the brainstem glucose metabolic rates in the MSA patients decreased significantly from the controls. The atrophy of the cerebellum and the brainstem in the MSA patients were scored by MRI. The cerebellar and brainstem glucose metabolism in the MSA patients decreased as the atrophy score in such regions advanced in each group; however, some patients with no atrophy showed a decreased glucose metabolism. Although the cerebellar and the brainstem glucose metabolism decreased in all MSA patients, such a decrease was not observed in the SND patients. The decrease in the glucose metabolism for the non-cortical regions in the MSA patients seems to be due to a diffuse depletion of the neurons not restricted to the nigrostriatal neurons. Deafferentation to the cerebral cortices seems to result in a decreased cortical metabolism. The differences in the glucose metabolism between MSA and PD as assessed by PET may be caused by the pathophysiological differences between MSA and PD, and such differences therefore appear to be useful when making a differential diagnosis between MSA and PD. The relative sparing of the brainstem and cerebellar glucose metabolism is considered to be a feature of patients with SND.

Fatty Acid Synthase Is a Key Target in Multiple Essential Tumor Functions of Prostate Cancer: Uptake of Radiolabeled Acetate as a Predictor of the Targeted Therapy Outcome

Fatty acid synthase (FASN) expression is elevated in several cancers, and this over-expression is associated with poor prognosis. Inhibitors of FASN, such as orlistat, reportedly show antitumor effects against cancers that over-express FASN, making FASN a promising therapeutic target. However, large variations in FASN expression levels in individual tumors have been observed, and methods to predict FASN-targeted therapy outcome before treatment are required to avoid unnecessary treatment. In addition, how FASN inhibition affects tumor progression remains unclear. Here, we showed the method to predict FASN-targeted therapy outcome using radiolabeled acetate uptake and presented mechanisms of FASN inhibition with human prostate cancer cell lines, to provide the treatment strategy of FASN-targeted therapy. We revealed that tumor uptake of radiolabeled acetate reflected the FASN expression levels and sensitivity to FASN-targeted therapy with orlistat in vitro and in vivo. FASN-targeted therapy was noticeably effective against tumors with high FASN expression, which was indicated by high acetate uptake. To examine mechanisms, we established FASN knockdown prostate cancer cells by transduction of short-hairpin RNA against FASN and investigated the characteristics by analyses on morphology and cell behavior and microarray-based gene expression profiling. FASN inhibition not only suppressed cell proliferation but prevented pseudopodia formation and suppressed cell adhesion, migration, and invasion. FASN inhibition also suppressed genes involved in production of intracellular second messenger arachidonic acid and androgen hormones, both of which promote tumor progression. Collectively, our data demonstrated that uptake of radiolabeled acetate is a useful predictor of FASN-targeted therapy outcome. This suggests that [1-11C]acetate positron emission tomography (PET) could be a powerful tool to accomplish personalized FASN-targeted therapy by non-invasive visualization of tumor acetate uptake and selection of responsive tumors. FASN-targeted therapy could be an effective treatment to suppress multiple steps related to tumor progression in prostate cancers selected by [1-11C]acetate PET.

In vivo evaluation of P-glycoprotein and breast cancer resistance protein modulation in the brain using [11C]gefitinib

Gefitinib (Iressa) is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase. Recent studies confirmed that gefitinib interacted with the breast cancer resistance protein (BCRP) at submicromolar concentrations, whereas other multidrug transporters, including P-glycoprotein (P-gp), showed much lower reactivity toward gefitinib. Recently, many tracers for positron emission tomography (PET) have been prepared to study P-gp function in vivo; however, PET tracers had not been evaluated for both P-gp and BCRP modulation in the brain. Therefore, we evaluated in vivo brain penetration-mediated P-gp and BCRP in mice using [(11)C]gefitinib. Co-injection with gefitinib (over 50 mg/kg), a nonspecific P-gp modulator cyclosporin A (50 mg/kg), and the dual P-gp and BCRP modulator GF120918 (over 5 mg/kg) induced an increase in the brain uptake of [(11)C]gefitinib in mice 30 min after injection. In the PET study of mice, the radioactivity level in the brain with co-injection of GF120918 (5 mg/kg) was three- to fourfold higher than that in control after initial uptake. The radioactivity level in the brain in P-gp and Bcrp knockout mice was approximately eightfold higher than that in wild-type mice 60 min after injection. In conclusion, [(11)C]gefitinib is a promising PET tracer to evaluate the penetration of gefitinib into the brain by combined therapy with P-gp or BCRP modulators, and into brain tumors. Furthermore, PET study with GF120918 is a promising approach for evaluating brain penetration-mediated P-gp and BCRP.