Comparison of [18F]fluorodeoxyglucose uptake with glucose transporter-1 expression and proliferation rate in human glioma and non-small-cell lung cancer

To clarify the biological significance of [18F]fluorodeoxyglucose (18F-FDG) accumulation in patients with cancer, we assessed the relationships between 18F-FDG uptake and glucose transporter-1 (GLUT-1) expression and proliferation rate in human glioma and lung cancer. We obtained FDG PET images and measured standardized uptake values (SUVs) of primary tumours in 13 patients with brain glioma and 25 patients with non-small-cell lung cancer. After surgery, portions of respected tumours were obtained, and the proliferation rate was measured as proliferation index (per cent of (S+G2+M)/(G0+G1+S+G2+M)) using DNA flow cytometry. The expression of GLUT-1 in a tumour was evaluated by using immunostaining. We classified GLUT-1 expression as grade 0 (no positive cell), grade 1 (< 10% cells positive), grade 2 (11-50% cells positive) and grade 3 (51-100% cells positive). Based on the expression of GLUT-1, cases with grades 0, 1, 2 and 3 showed SUVs of 6.1 +/- 2.8, 5.0 +/- 3.2, 8.3 +/- 3.3 and 10.4 +/- 6.6, respectively (P < 0.05). Non-small-cell lung cancer showed higher FDG uptake (SUV, 8.5 +/- 5.1) and higher GLUT-1 expression (grade, 2.0 +/- 1.0) than did brain glioma (SUV, 4.7 +/- 2.5; grade, 0.8 +/- 0.8). Based on the total number of cases, SUVs did not relate to proliferation index (r = 0.19). In non-small-cell lung cancer, SUVs did not correlate with proliferation index, whereas in glioma, SUVs were strongly related to proliferation index (r = 0.79, P < 0.01). In conclusion, FDG uptake generally correlated with GLUT-1 expression in non-small-cell lung cancer and glioma. In the case of glioma, FDG uptake also indicated increased cellular proliferation, which was not demonstrated in non-small-cell lung cancer.     

Insulin action on heart and skeletal muscle FDG uptake in patients with hypertriglyceridemia.

Abnormal heart and skeletal muscle 18F-fluorodeoxyglucose (FDG) uptake in patients with insulin resistance has been demonstrated. Although the existence of whole-body insulin resistance has been reported in hypertriglyceridemics, its specific role in heart and skeletal muscle FDG uptake in hypertriglyceridemics has not been clarified. METHODS: We compared heart and skeletal muscle FDG uptake using PET and the whole-body glucose disposal rate (GDR) during insulin clamping in 17 hypertriglyceridemics and 12 age-matched control subjects to increase our knowledge of whole-body insulin resistance and its relationship to heart and skeletal muscle FDG uptake in hypertriglyceridemics. RESULTS: GDR was significantly reduced in hypertriglyceridemics compared with control subjects (4.50 +/- 1.37 mg/min/kg versus 10.0 +/- 2.97 mg/min/kg, P = 0.00001), as were the skeletal muscle FDG Ki = (k1 x k3)/(k2 + k3) (SFKi: 0.007 +/- 0.003 mL/min/g versus 0.018 +/- 0.01 mL/min/g, P = 0.0001) and skeletal muscle FDG uptake ([SMFU] 0.725 +/- 0.282 mg/min/100 g versus 1.86 +/- 1.06 mg/min/100 g, P = 0.00023). However, myocardial FDG Ki (MFKi) tended to be reduced in hypertriglyceridemics compared with that in control subjects (0.062 +/- 0.017 mL/min/g versus 0.068 +/- 0.015 mL/min/g), but the difference was statistically insignificant (P = 0.3532). Moreover, myocardial FDG uptake (MFU) in hypertriglyceridemics (6.47 +/- 1.72 mg/min/100 g) tended to be reduced compared with that in control subjects (6.97 +/- 1.73 mg/min/100 g), but the difference was statistically insignificant (P = 0.4485). GDR was significantly correlated with SFKi (r = 0.69, P = 0.0022), SMFU (r = 0.612, P = 0.009), MFKi (r = 0.57, P = 0.0174) and MFU (r = 0.505, P = 0.0385) in hypertriglyceridemics. CONCLUSION: Both heart and skeletal muscle glucose utilization were related to insulin resistance in hypertriglyceridemics. However, the less severe reduction in MFU (compared with SMFU) suggests that myocardium may have a mechanism to oppose insulin resistance in hypertriglyceridemics.     

Repetitive supply-demand ischemia with dobutamine increases glucose uptake in postischemic and remote myocardium.

The goal of this study was to determine whether myocardial glucose uptake after repetitive ischemia differs in response to coronary occlusion-reperfusion versus supply-demand ischemia induced by dobutamine. Although glucose metabolism is increased after myocardial ischemia, the metabolic effect of supply-demand ischemia induced by dobutamine may increase glucose metabolism within remote myocardium. This would make it difficult to discriminate postischemic from remote myocardium with glucose tracers. METHODS: Eighteen swine with a hydraulic occluder and flow probe on the circumflex artery underwent repetitive ischemia. In group 1 (n = 9), the circumflex artery was occluded, whereas in group 2 (n = 9), circumflex flow was decreased by 30% before dobutamine (40 micro g/kg/min intravenously). Each pig underwent 15 min of ischemia, twice per day for 5 d. Echocardiography and PET to determine myocardial glucose ((18)F-FDG) uptake were performed after final ischemia, and tissue was later analyzed for activation of Akt, p38 mitogen-activated protein, and adenosine monophosphate (AMP) kinase. RESULTS: Wall thickening in the circumflex region was lower than in remote regions in both groups. (18)F-FDG uptake in the circumflex region was similar in groups 1 and 2 (0.22 +/- 0.03 and 0.23 +/- 0.04 micro mol/min/g, respectively; not statistically significant). In the remote region, (18)F-FDG uptake was lower than in the circumflex region in group 1 (0.14 +/- 0.03 micro mol/min/g; P < 0.05) but was similar to that in the circumflex region in group 2 (0.20 +/- 0.03 micro mol/min/g; not statistically significant). AMP kinase activity in the remote region was significantly lower than in the circumflex region in group 1 but was similar to that in the circumflex region in group 2. CONCLUSION: Unlike repetitive coronary artery occlusion-reperfusion, repetitive supply-demand ischemia with dobutamine alters glucose uptake within the remote myocardium, possibly as a result of AMP kinase activation. Clinically, these data suggest that (18)F-FDG studies have a limited role in discriminating postischemic from remote myocardium after dobutamine stress.     

FDG metabolism and uptake versus blood flow in women with untreated primary breast cancers

The aim of this study was to determine the relationship between tumor blood flow and glucose utilization in women with untreated primary breast carcinomas. Noninvasive determinations of blood flow and glucose utilization with positron emission tomography (PET) were performed in 101 regions of tumor from nine women with untreated primary breast carcinoma. [(15)O]H(2)O PET scans of tumor blood flow were compared with fluorine-18 fluoro-2-deoxy- D-glucose (FDG) PET scans of tumor glucose metabolism. Modeling of multiple parameters was undertaken and flow and glucose utilization compared. Mean whole-tumor blood flow was 14.9 ml dl(-1) min(-1), but ranged from 7.6 to 29.2 ml dl(-1) min(-1). Mean whole-tumor standardized uptake value corrected for lean body mass, SUV-lean (50-60 min), was 2.32+/-0.19 while mean K(i) was 1.2 ml dl(-1) min(-1) for FDG. SUV-lean and blood flow were strongly correlated (r=0.82, P=0.007) as were K(1) for FDG and flow (r=0.84, P=0.004). In these women with untreated breast cancers, FDG uptake (SUV-lean) and tumor blood flow are strongly correlated. The slope of FDG uptake versus blood flow appears higher at low flow rates, suggesting the possible presence of areas of tumor hypoxia.     

In vitro studies on the signal transduction of thyroidal uptake of 18F-FDG and 131I-Iodide.

Glucose metabolism in radioiodine-negative metastases of differentiated thyroid carcinomas (DTC) may still be increased by thyroid-stimulating hormone (TSH) as demonstrated by PET with 18F-FDG. The mechanisms of signal transduction involved in that process are as yet not completely understood. Therefore, the aim of this study was to investigate the effects of TSH, of an analog of cyclic adenosine monophosphate (dibutyryl cyclic AMP (Bu)2cAMP), and of inhibitors of the phosphatidylinositol 3-kinase (PI3-kinase) and of the protein kinase A (PKA) on 18F-FDG and radioiodide uptake in the thyroid cell line FRTL-5. METHODS: FRTL-5 cells were cultured in the presence of hormones with or without 1 mU/ mL TSH. Glucose carrier (GLUT-1) was determined by Western blot analysis. Cells were incubated with 0.5-1.0 MBq/mL 18F-FDG for 1 h or 18-37 kBq/mL 131I for 45 min, respectively, and tracer uptake was related to protein concentration. (Bu)2cAMP (1 mmol/L) was used as cAMP enhancer, H89 (0.25-25 micromol/L) as selective PKA inhibitor, and wortmannin (1 micromol/L) as inhibitor of PI3-kinase. RESULTS: TSH induced a 2.6-fold +/- 0.5 increase of radioiodide uptake in FRTL-5 cells (P < 0.001, n = 8). The use of wortmannin inhibited TSH-induced uptake of 131I only moderately by 21.1% +/- 3.5% (P < 0.05, n = 8), whereas H89 markedly blocked the effect of TSH by 53.8% +/- 16.7% (P < 0.001, n = 8). TSH enhanced GLUT-1 concentration of FRTL-5 cell membrane preparations by a factor of 1.6 (n = 3). TSH-treated cells showed a 2.6-fold increased uptake of 18F-FDG (P < 0.001, n = 20). Stimulation by (Bu)2cAMP analogously increased 18F-FDG uptake (P < 0.001, n = 20). Wortmannin, but not H89, significantly inhibited TSH- and (Bu)2cAMP-stimulation of 18F-FDG uptake by 42% +/- 25% (P < 0.001, n = 20) and 42% +/- 31% (P < 0.001, n = 20), respectively. CONCLUSION: The effect of TSH and cAMP on 18F-FDG uptake by FRTL-5 cells is mediated by PI3-kinase and not by PKA, thus differing from the mechanism of radioiodide accumulation of this cell line. This observation is one possible explanation for the persistence of TSH-dependent 18F-FDG uptake in radioiodine-negative metastases of DTC.     

Comparison of integrin alphaVbeta3 expression and glucose metabolism in primary and metastatic lesions in cancer patients: a PET study using 18F-galacto-RGD and 18F-FDG.

The expression of alpha(v)beta(3) and glucose metabolism are upregulated in many malignant lesions, and both are known to correlate with an aggressive phenotype. We evaluated whether assessment of alpha(v)beta(3) expression and of glucose metabolism with PET using (18)F-galacto-RGD and (18)F-FDG provides complementary information in cancer patients. METHODS: Eighteen patients with primary or metastatic cancer (non-small cell lung cancer [NSCLC], n = 10; renal cell carcinoma, n = 2; rectal cancer, n = 2; others, n = 4) were examined with PET using (18)F-galacto-RGD and (18)F-FDG. Standardized uptake values (SUVs) were derived by volume-of-interest analysis. (18)F-Galacto-RGD and (18)F-FDG PET results were compared using linear regression analysis for all lesions (n = 59; NSCLC, n = 39) and for primaries (n = 14) and metastases to bone (n = 11), liver (n = 10), and other organs (n = 24) separately. RESULTS: The sensitivity of (18)F-galacto-RGD PET compared with clinical staging was 76%. SUVs for (18)F-FDG ranged from 1.3 to 23.2 (mean +/- SD, 7.6 +/- 4.9) and were significantly higher than SUVs for (18)F-galacto-RGD (range, 0.3-6.8; mean +/- SD, 2.7 +/- 1.5; P < 0.001). There was no significant correlation between the SUVs for (18)F-FDG and (18)F-galacto-RGD for all lesions (r = 0.157; P = 0.235) or for primaries, osseous or soft-tissue metastases separately (P > 0.05). For the subgroup of lesions in NSCLC, there was a weak correlation between (18)F-FDG and (18)F-galacto-RGD uptake (r = 0.353; P = 0.028). CONCLUSION: Tracer uptake of (18)F-galacto-RGD and (18)F-FDG does not correlate closely in malignant lesions. Whereas (18)F-FDG PET is more sensitive for tumor staging, (18)F-galacto-RGD PET warrants further evaluation for planning and response evaluation of targeted molecular therapies with antiangiogenic or alpha(v)beta(3)-targeted drugs.     

Comparison of 1-(11)C-glucose and (18)F-FDG for quantifying myocardial glucose use with PET.

In this study, we compared the accuracy of the rate of myocardial glucose use (rMGU) measured using PET and 1-(11)C-glucose with the rate measured using PET and the more conventional tracer (18)F-FDG. METHODS: PET measurements of myocardial tracer uptake (K, in mL/g/min) and rMGU (in nmol/g/min) were obtained with 1-(11)C-glucose and (18)F-FDG in 21 dogs using kinetic modeling and the Patlak graphical method, respectively. Eighteen dogs were studied during hyperinsulinemic-euglycemic clamp performed either at rest or combined with phenylephrine, dobutamine, intralipid infusion, or intralipid infusion and dobutamine. Three dogs were studied during intralipid infusion alone under resting conditions. Arterial-coronary sinus sampling was performed to measure the K of both tracers (n = 14) and rMGU by the Fick method (n = 21). RESULTS: PET-derived values for K from either 1-(11)C-glucose or (18)F-FDG correlated closely with directly measured tracer K values (glucose: y = 0.98x + 0.01, r = 0.79, P < 0.001; (18)F-FDG: y = 0.74x + 0.03, r = 0.77, P < 0.001). In contrast, correlation with K values of unlabeled glucose measured directly was better for 1-(11)C-glucose (y = 0.92x + 0.02, r = 0.96, P < 0.0001) than for (18)F-FDG (y = 0.66x + 0.05, r = 0.72, P < 0.01) (P < 0.001 for comparison of correlation coefficients). As a consequence, PET-derived values for rMGU correlated more closely with Fick-derived measurements of unlabeled glucose using 1-(11)C-glucose (y = 0.82x + 168, r = 0.97, P < 0.0001) than with (18)F-FDG (y = 0.81x + 278, r = 0.79, P < 0.001) (P < 0.001 for comparison of correlation coefficients). CONCLUSION: Over a wide range of conditions, PET-derived measurements of rMGU are obtained more accurately with 1-(11)C-glucose than with (18)F-FDG.     

Relationships between oxygen and glucose metabolism in human liver tumours: positron emission tomography using (15)O and (18)F-deoxyglucose

BACKGROUND: Recently, investigators have measured glucose utilization in liver tumours using F-deoxyglucose positron emission tomography (FDG PET) in order to characterize tumours and predict therapeutic effects. However, the detectability of liver tumours by this method remains unclear. In addition, no study has examined the association between oxygen and glucose metabolism in liver tumours using PET. AIM: To evaluate these associations in human liver tumours in vivo using O and FDG. METHODS: Thirteen patients with liver tumours were studied: six with hepatocellular carcinoma (HCC), one with cholangiocarcinoma (CCC) and six with metastatic colon cancer (MET). We measured regional tumour blood flow (Ft), regional oxygen extraction fraction (OEF) and regional metabolic rate of oxygen (MRO2) using O PET. Using FDG PET, we determined a standardized uptake value (SUV) for liver tumours as an index of glucose metabolism. RESULTS: The mean values (mean+/-SE) for Ft, OEF, MRO2 and SUV were 42.5+/-7.0 ml x (100 g) x min, 43.4+/-4.9%, 2.57+/-0.39 ml x (100g) x min and 4.01+/-0.36, respectively. SUV for MET (4.44+/-0.48) was higher than that for HCC (3.52+/-0.59), and the blood flow in MET [31.4+/-4.1 ml x (100 g) x min] was lower than that in HCC [57.1+/-12.4 ml x (100 g) x min]. Significant negative correlations were noted between MRO2 and SUV (r=-0.741, P=0.004), and between Ft and SUV (r=-0.713, P=0.006). No correlation was apparent between Ft and OEF (r=-0.348, P=0.24), or between OEF and SUV (r=-0.023, P=0.94). CONCLUSION: O and FDG PET showed a significant negative correlation between MRO2 and SUV in human liver tumours. In addition, MRO2 depends on Ft rather than on OEF.     

PET "reversed mismatch pattern" early after acute myocardial infarction: follow-up of flow, metabolism and function

The aim of this study was to evaluate changes of flow, metabolism and left ventricular function in patients revealing a "reversed mismatch" pattern (reduced glucose uptake relative to perfusion) on positron emission tomography (PET) early after myocardial infarction. In 19 out of 68 patients (28%), prospectively included in the GUSTO-I or STAR studies, a PET reversed mismatch pattern in the infarct-related region was found. All patients received thrombolytic therapy within 3 h after onset of pain and coronary angiography 90 min later. 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG)/nitrogen-13-labelled ammonia (13NH3) PET was performed after 5 days and 3 months. In 12 of the 19 patients, functional recovery was investigated with two-dimensional echocardiography at the same time points. In the infarct-related region, normalized 13NH3 uptake was 76% +/- 11% at 5 days and 85% +/- 10% at 3 months (P < 0.00001). Absolute blood flow in this region was 75 +/- 25 ml/min per 100 g at 5 days and 80 +/- 19 ml/min per 100 g at 3 months. At 5 days, normalized 18F-FDG uptake in the infarct-related region was decreased (51% +/- 12%). At 3 months, 18F-FDG uptake in this region had significantly recovered (75% +/- 11%, P < 0.00001). In the infarct-related region, absolute FDG metabolism was 17 +/- 6 mumol/min per 100 g at 5 days and 26 +/- 9 mumol/min per 100 g at 3 months (P < 0.0001). At 5 days, normalized 18F-FDG uptake was more severely decreased as compared to the normalized 13NH3 uptake (P < 0.00001) in the infarct-related region, resulting in a reversed mismatch pattern (25% +/- 13% of the left ventricle). At 3 months, 18F-FDG metabolism had partially recovered, giving rise to a change into a PET match pattern. Reversed mismatch regions were present in only 7% +/- 7% of the left ventricle at that time. The ratio of 18F-FDG uptake to 13NH3 uptake in the infarct-related region increased from 0.67 +/- 0.8 at 5 days to 0.88 +/- 0.09 at 3 months (P < 0.00001). No functional recovery was observed in the infarct-related region (the 5-day and 3-month wall motion scores were both 2.5 +/- 0.5). In patients with a myocardial infarction showing a PET reversed mismatch pattern 5 days after thrombolytic therapy, recovery of 18F-FDG uptake was found but no functional recovery was observed at 3-month follow-up.     

Insulin stimulates liver glucose uptake in humans: an 18F-FDG PET Study.

The liver is vital for the regulation of glucose metabolism, but inaccessibility of the organ for direct assessments has limited the study of its metabolic role in vivo. METHODS: The effect of insulin and insulin sensitivity (IS) on hepatic glucose uptake was investigated using PET, (18)F-FDG, and graphical analysis and 3-compartment modeling in humans. We studied 16 healthy sedentary men (normal IS), 8 athletes (high IS), and 7 patients with coronary artery disease (low IS) either during fasting (n = 14) or during euglycemic hyperinsulinemia (n = 24). RESULTS: Whole-body insulin-mediated glucose uptake was 35 +/- 7 micro mol/min/kg for normal-IS subjects, 65 +/- 8 micro mol/min/kg for high-IS subjects (P < 0.05 vs. normal IS), and 24 +/- 3 micro mol/min/kg for low-IS subjects (P < 0.05 vs. normal IS and high IS). Hyperinsulinemia enhanced hepatic glucose influx (2.3 +/- 0.9 vs. 1.5 +/- 0.7 micro mol x min(-1) x 100 mL(-1), P < 0.05) and phosphorylation rates (0.55 +/- 0.24 vs. 0.36 +/- 0.19 min(-1) x 10(-2), P < 0.05) similarly in insulin-sensitive and -resistant subjects. During hyperinsulinemia, however, the glucose phosphorylation-to-dephosphorylation ratio was significantly lower in the low-IS group than in normal-IS subjects (P < 0.05) or high-IS subjects (P < 0.01); correspondingly, whole-body insulin-mediated glucose disposal was directly related to this ratio (r = 0.45; P < 0.05). Furthermore, glucose influx rates were inversely correlated with fasting plasma free fatty acids (P < 0.05). Both compartmental modeling and the graphical approach accurately described the data, though the latter yielded slightly lower estimates of glucose influx rates during fasting. CONCLUSION: Our study provided evidence that physiologic hyperinsulinemia enhances hepatic glucose uptake and that IS is related to the glucose phosphorylation-to-dephosphorylation balance in the liver. Graphical analysis and modeling proved to be applicable and complementary tools for the investigation of glucose metabolism in the liver.     

Myocardial glucose uptake after dobutamine stress in chronic hibernating swine myocardium

BACKGROUND: In patients with hibernating myocardium, regional uptake of the glucose analog 2-fluorine 18-fluoro-2-deoxy-d-glucose (FDG) is increased under resting conditions. It is unclear whether the degree of increased FDG uptake correlates with the degree of impaired blood flow response and whether chronic changes in the glucose transporters may play a role in the enhanced FDG uptake under fasted conditions. METHODS AND RESULTS: Twelve swine were instrumented with a constrictor on the left anterior descending (LAD) artery. Serial echocardiography and positron emission tomography studies were done to assess temporal changes in myocardial function, blood flow, and FDG uptake. One week after surgery (early study), wall thickening, blood flow, and postdobutamine FDG uptake in LAD and remote territories were similar. By approximately 6 weeks (late study), baseline wall thickening in the LAD region was lower than in remote regions (20% +/- 7% and 36% +/- 6%, P <.05), as was dobutamine-stimulated blood flow (0.92 +/- 0.16 mL. min(-1). g(-1) and 1.17 +/- 0.20 mL. min(-1). g(-1) in LAD and remote regions, respectively; P <.05). After the dobutamine infusion, FDG uptake in the LAD region during fasted conditions was higher than in remote regions (0.128 +/- 0.053 micromol. min(-1). g(-1) and 0.098 +/- 0.044 micromol. min(-1). g(-1), respectively; P <.05), and the increase was proportional to the impairment in dobutamine blood flow (r(2) = 0.62, P <.001). After the animals were killed, the LAD region showed a higher content of GLUT4 by immunoblots and a greater degree of translocation as estimated by immunohistochemistry. In 5 additional hibernating pigs studied under resting fasted conditions, FDG uptake and GLUT4 translocation were also higher in the LAD region, in the absence of dobutamine stimulation. CONCLUSIONS: In hibernating myocardium, regional FDG uptake under fasting conditions is higher than in remote regions, both at rest and after an infusion of dobutamine. The degree of poststress FDG uptake is proportional to the impaired stress-induced blood flow. Total GLUT4 content as well as membrane-bound protein is higher in the hibernating tissue, and these changes may facilitate the observed increase in FDG uptake.     

Correlation of Glut-1 glucose transporter expression with

Positron emission tomography (PET) with [18F]2-fluoro-2-deoxy-D-glucose (FDG) may show negative results for bronchioloalveolar lung carcinoma. We investigated the correlation of Glut-1 glucose transporter expression with [18F]FDG uptake in non-small cell lung cancer. Thirty-two patients with 34 non-small cell lung cancers (7 bronchioloalveolar carcinomas, 23 non-bronchioloalveolar adenocarcinomas, 3 squamous cell carcinomas, and 1 adenosquamous cell carcinoma) were studied. Final diagnoses were established by histology (via thoracotomy) in all patients. [18F]FDG PET was performed 40 min after i.v. injection of 185 MBq [18F]FDG. For semi-quantitative analysis of [18F]FDG uptake, standardized uptake values (SUVs) were calculated. Glut-1 expression was studied in terms of the immunohistochemistry of paraffin sections using anti-Glut-1 antibody to determine the intensity (0-3) of Glut-1 immunoreactivity and percentage of the Glut-1-positive area. Of seven bronchioloalveolar carcinomas, six (85.7%) were negative for the expression of Glut-1, while only one (4.3%) of 23 non-bronchioloalveolar adenocarcinomas was negative (P < 0.0001). The percentages of Glut-1-positive area, as well as the SUVs, were significantly lower in bronchioloalveolar carcinomas (n = 7) (2.86% +/- 7.56% and 1.25 +/- 0.75, respectively) than in non-bronchioloalveolar adenocarcinomas (n = 23) (54.83% +/- 25.64%, P < 0.0001, and 3.94 +/- 1.93, P = 0.001, respectively). The degree of cell differentiation correlated with the percentage of Glut-1-positive area and SUVs in adenocarcinoma of the lung. Correlations between SUVs and the intensity of Glut-1 immunoreactivity were also significant (intensities 0 and 1, n = 11, SUV 1.47 +/- 0.63; intensities 2 and 3, n=23, SUV 4.78 +/- 2.13; P < 0.0001). The percentage of Glut-1-positive area correlated significantly with SUVs (n = 34, r = 0.658, P < 0.01). Overexpression of Glut-1 correlated with high [18F]FDG uptake. These findings suggest that Glut-1 expression is related to [18F]FDG uptake in non-small cell lung cancer. Glut-1 expression, as well as [18F]FDG uptake, correlated with the degree of cell differentiation in adenocarcinomas, and both Glut-1 expression and [18F]FDG uptake were significantly lower in bronchioloalveolar carcinomas than in non-bronchioloalveolar carcinomas.     

Correlation of regional metabolic rates of glucose with glasgow coma scale after traumatic brain injury.

After traumatic brain injury (TBI), subcortical white matter damage may induce a functional disconnection leading to a dissociation of regional cerebral metabolic rate of glucose (CMRglc) between the cerebral cortex and deeper brain regions. Therefore, thalamic and brain stem CMRglc may have a closer correlation than does the cerebral cortex with depth of coma after TBI. METHODS: Eleven adult healthy volunteers and 23 adult patients with TBI (median initial Glasgow Coma Scale score [GCSini], 8) underwent (18)F-FDG PET within 5 d after injury. The CMRglc of cortical areas (remote from hemorrhagic lesions), striatum, thalamus, brain stem, cerebellar cortex, and whole brain was compared with severity of injury and the level of consciousness evaluated using GCSini and the Glasgow Coma Scale score at the time of PET (GCSpet). RESULTS: The regional CMRglc of the brain stem is relatively unaffected by the TBI. Compared with healthy volunteers, TBI patients exhibited significantly depressed CMRglc in the striatum (3.9 +/- 1.3 vs. 5.1 +/- 0.9 mg/100 g/min, P < 0.05) and thalamus (3.1 +/- 1.0 vs. 4.3 +/- 0.9 mg/100 g/min, P < 0.05). CMRglc levels were not statistically lower in the cerebellum (2.9 +/- 0.8 vs. 3.5 +/- 0.8 mg/100 g/min, P = NS) and brain stem (2.5 +/- 0.5 vs. 2.6 +/- 0.5 mg/100 g/min, P = NS). However, compared between comatose and noncomatose patients, CMRglc values in the thalamus (2.7 +/- 0.7 vs. 3.6 +/- 1.2 mg/100 g/min, P < 0.05), brain stem (2.2 +/- 0.4 vs. 2.8 +/- 0.5 mg/100 g/min, P < 0.01), and cerebellar cortex (2.6 +/- 0.5 vs. 3.4 +/- 1.0 mg/100 g/min, P < 0.05) were significantly lower in comatose patients. When individual values of regional CMRglc were plotted against posttraumatic level of consciousness, CMRglc values for the thalamus, brain stem, and cerebellum significantly correlated with the level of consciousness at the time of PET (r = 0.58, P < 0.01; r = 0.66, P < 0.01; r = 0.64, P < 0.01, respectively). CT or MRI findings were normal for the analyzed structures except for 3 patients with diffuse axonal injury of the brain stem. The presence of shear injury was associated with poor GCSini (P < 0.05.) but was not related to GCSpet and brain stem CMRglc. CONCLUSION: A PET investigation using (18)F FDG demonstrated a significant difference in glucose metabolism in the thalamus, brain stem, and cerebellum between comatose and noncomatose patients acutely after TBI. The metabolic rate of glucose in these regions significantly correlated with the level of consciousness at the time of PET.     

18F-FDG small-animal PET for monitoring the therapeutic effect of CT-guided radiofrequency ablation on implanted VX2 lung tumors in rabbits.

The primary goals of this study were to investigate the behavior of normal lung tissues after radiofrequency ablation (RFA) and to determine the suitability of 18F-FDG PET, using a dedicated small-animal scanner, for monitoring the early therapeutic effects of RFA on VX2 lung tumors (VX2s) in rabbits. METHODS: Fourteen Japanese white rabbits with normal lungs underwent RFA, followed by 18F-FDG PET at 1 d and at 1, 2, 4, and 8 wk. In addition, 7 rabbits with untreated VX2s underwent 18F-FDG PET, and 13 rabbits with RFA-treated VX2s underwent 18F-FDG PET at 1 d (n = 7) or 1 wk (n = 6) after the treatment. RESULTS: After RFA of normal lungs, ring-shaped accumulations of 18F-FDG, which coincided with inflammation caused by ablation, were observed. The mean early- (40-60 min after injection) and delayed (100-120 min)-phase ablated lesion-to-muscle ratios were, respectively, 2.9 +/- 1.0 and 3.3 +/- 0.8 (1 d), 4.1 +/- 0.6 and 5.2 +/- 0.9 (1 wk), 4.1 +/- 1.0 and 5.3 +/- 1.5 (2 wk), 3.1 +/- 0.5 and 3.6 +/- 1.1 (4 wk), and 1.8 +/- 0.1 and 2.3 +/- 0.1 (8 wk). At 4 and 8 wk, the uptake was less than that at 1 and 2 wk (P < 0.05). VX2s showed mean tumor-to-muscle ratios of 6.6 +/- 2.1 and 8.6 +/- 3.3 at the early and delayed phases, respectively. For ablated tumors, the respective ratios were 0.8 +/- 0.4 and 1.1 +/- 0.7 (1 d) and 1.2 +/- 0.5 and 1.5 +/- 0.7 (1 wk). These values were significantly lower than those for nonablated tumors (P < 0.001). Histopathologic examination confirmed the absence of viable tumors. 18F-FDG accumulation around ablated tumors reflected thermally damaged normal tissues and was significantly lower than that of control VX2s (P < 0.01). CONCLUSION: Our data suggest that 18F-FDG PET is promising for evaluating the therapeutic response of lung malignancies to RFA: Accumulation of 18F-FDG in surrounding normal tissues appears to be time dependent, and the data suggest that, clinically, 18F-FDG PET should be performed 4 wk or more after RFA. Delayed-phase images seem to better distinguish tumor from inflammation than do early-phase images.     

Relationship between retention index in dual-phase (18)F-FDG PET, and hexokinase-II and glucose transporter-1 expression in pancreatic cancer.

Recently, some studies have shown that delayed scanning with (18)F-FDG PET may help to differentiate malignant from benign pancreatic lesions. However, no study has evaluated the relationship between temporal changes in (18)F-FDG uptake and expression of hexokinase or glucose transporter. METHODS: Twenty-one consecutive patients with pancreatic cancer were studied preoperatively by dual-phase (18)F-FDG PET, performed 1 and 2 h after injection of (18)F-FDG. The standardized uptake value (SUV) of the pancreatic cancer was determined, and the retention index (RI) (%) was calculated by subtracting the SUV at 1 h (SUV1) from the SUV at 2 h (SUV2) and dividing by SUV1. The percentages of cells strongly expressing hexokinase type-II (HK-II) and glucose transporter-1 (GLUT-1) were scored on a 5-point scale (1 = 0%-20%, 2 = 20%-40%, 3 = 40%-60%, 4 = 60%-80%, 5 = 80%-100%) by visual analysis of immunohistochemical staining of paraffin sections from the tumor specimens using anti-HK-II and anti-GLUT-1 antibody (HK-index and G-index, respectively). RESULTS: SUV2 (mean +/- SD, 5.7 +/- 2.6) was higher than SUV1 (5.1 +/- 2.1), with an RI of 8.5 +/- 11.0. Four cases of cancer, in which SUV2 showed a decline from SUV1, showed a low HK-index (1.8 +/- 1.1), whereas 4 cases with an RI of > or =20 and 13 cases with an intermediate RI (0-20) showed significantly higher HK-indices (4.3 +/- 0.7 and 3.1 +/- 1.5, respectively; P < 0.05). RI showed a positive correlation with HK-index, with an R(2) of 0.27 (P < 0.05), but no significant correlation with the G-index. SUV1 showed no relationship with the HK-index but showed a weak positive correlation with the G-index, with an R(2) of 0.05 (P = 0.055). CONCLUSION: These preliminary findings suggest that the RI obtained from dual-phase (18)F-FDG PET can predict HK-II expression and that the SUV (at 1 h) has a positive correlation with GLUT-1 expression but not with HK-II expression.     

^11C-胆碱和^18F—FDG PET反映兔VX2肺肿瘤增殖活性的对比研究

目的探讨^11C-胆碱和^18F-脱氧葡萄糖（FDG）PET反映实验性兔VX2肺肿瘤细胞增殖活性的价值。方法新西兰大白兔60只,6只用于传代,另54只于全身麻醉状态下,采用经皮穿刺法于右肺注射VX2肿瘤活细胞悬液0．5ml,10～11d后行PET检查。胆碱PET于静脉注射37MBq^11C-胆碱5rain后进行,^18F—FDG PET于静脉注射18．5MBq^18F—FDG后60min、^11C-胆碱注射后120min进行。测量肿瘤最大标准摄取值（SUVmax）。HE染色观察肿瘤细胞密度,增殖细胞核抗原（PCNA）免疫组织化学染色评价肿瘤细胞增殖活性。^11C-胆碱SUVmax和^18F—FDG SUVmax的比较采用配对t检验,SUVmax与肿瘤细胞密度及PCNA指数之间进行Pearson直线相关分析。结果33只实验兔成功种植VX2肿瘤,并完成所有影像学检查。肿瘤的^11C-胆碱SUVmax为4．02±3．07（1．4～12．2）,^18F-FDG SUVmax为5．70±3．45（1．0～13．0）,后者明显高于前者（t=-3．188,P：0．003）,二者呈正相关（r=0．578,P〈0．05）。高倍光学显微镜下（×200,0．739mm^2视野）,肿瘤细胞密度为（547．36±64．78,413～708）个,PCNA指数为（42．34±15．26）％（3．23％-75．87％）。^11C-胆碱SUVmax与PCNA指数呈正相关（r=0.786,P〈0．05）,r^2=0．617,但与肿瘤细胞密度之间不具有相关性（r=-0．176,P=0．327）。FDG SUVmax与PCNA指数呈正相关（r=0．551,P=0．001）,r^2=0．281,与肿瘤细胞密度之间不具有相关性（r=-0．105,P=0．561）。结论^11C-胆碱与^18F—FDG PET均可反映肿瘤细胞增殖活性,以^11C-胆碱PET的准确性更高。     

Enhanced apoptotic reaction correlates with suppressed tumor glucose utilization after cytotoxic chemotherapy: use of 99mTc-Annexin V, 18F-FDG, and histologic evaluation.

Cancer chemotherapy enhances the apoptosis, whereas apoptosis is a suicidal mechanism requiring energy. We determined the relationship between apoptosis and glucose utilization during cancer chemotherapy using (99m)Tc-annexin V ((99m)Tc-annexin A5) and (18)F-FDG and compared their uptake with histologic findings in a rat tumor model. METHODS: Allogenic hepatoma cells (KDH-8) were inoculated into the left calf muscle of male Wistar rats (WKA). Eleven days after the inoculation, the rats were randomly divided into 3 groups: The first group (n = 7) received a single dose of gemcitabine (90 mg/kg, intravenously), the second group (n = 8) received cyclophosphamide (150 mg/kg, intraperitoneally), and the third group (n = 7) was untreated and served as the control group. We injected (99m)Tc-annexin V 48 h after the chemotherapy and then injected (18)F-FDG to all rats 1 h before sacrifice. Six hours after (99m)Tc-annexin V injection, the rats were sacrificed and the organs, including the tumor, were removed and radioactivity was counted. The radioactivities of (18)F and (99m)Tc in the organs were determined using normalization by tissue weight. Histologic evaluation by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) method and the immunostaining of glucose transporter-1 (GLUT-1) were also performed to obtain the indices of apoptosis and glucose utilization, respectively. The rate of positively stained cells was calculated and analyzed statistically. RESULTS: After chemotherapy using gemcitabine and cyclophosphamide, the (99m)Tc-annexin V uptake (percentage injected dose per gram x kg [(%ID/g) x kg]; mean +/- SD) in tumor increased significantly (0.062 +/- 0.012 (%ID/g) x kg in the gemcitabine-treated group and 0.050 +/- 0.012 (%ID/g) x kg in the cyclophosphamide group vs. 0.031 +/- 0.005 (%ID/g) x kg in the control group; P < 0.01). In contrast, the (18)F-FDG in tumor decreased significantly (0.483 +/- 0.118 (%ID/g) x kg in the gemcitabine group and 0.583 +/- 0.142 (%ID/g) x kg in the cyclophosphamide group) compared with that in the control group (0.743 +/- 0.084 (%ID/g) x kg; P < 0.01). In addition, (18)F-FDG uptake in tumor negatively correlated with (99m)Tc-annexin V uptake (r = -0.75; P < 0.01). In the gemcitabine and cyclophosphamide groups, the rate of TUNEL positively stained cells was significantly higher than that in the control group (10.2% +/- 1.7% and 8.0% +/- 1.5% vs. 5.2% +/- 1.5%; P < 0.01), whereas the GLUT-1 expression level showed no definite changes in histologic analyses. CONCLUSION: These data indicate that an enhanced apoptotic reaction correlated with suppressed tumor glucose utilization after cytotoxic chemotherapy as determined using radiotracers and histologic evaluation. The increase in (99m)Tc-annexin V and the decrease in (18)F-FDG in tumor can be useful markers for predicting therapeutic outcomes and for prognosis at the early stage of chemotherapy.     

Role of insulin resistance in heart and skeletal muscle F-18 fluorodeoxyglucose uptake in patients with noninsulin-dependent diabetes mellitus

BACKGROUND: Altered heart and skeletal glucose usage has been reported in patients with non-insulin-dependent diabetes mellitus (NIDDM). Although elevations in plasma free fatty acid (FFA) concentrations have been implicated in reduced myocardial 18fluorine-fluoro-2-deoxy-D-glucose uptake (MFU), the specific role of whole-body insulin resistance in MFU in patients with NIDDM compared with skeletal muscle metabolism remains controversial. PURPOSE: MFU and skeletal muscle 18fluorine-fluoro-2-deoxy-D-glucose uptake (SMFU) were compared with positron emission tomography and the whole-body glucose disposal rate (GDR) during hyperinsulinemic euglycemic clamping in 26 normotensive asymptomatic patients with NIDDM who were not taking medication. These factors were also compared in 12 age-matched control subjects to increase the knowledge of the influence of whole-body insulin resistance on MFU. In addition, independent factors for both SMFU and MFU were investigated. RESULTS: GDR in control subjects (10.0 +/- 2.97 mg/min per kilogram) was significantly higher than in patients with NIDDM (4.05 +/- 2.37 mg/min per kilogram, P < .01). SMFU in patients with NIDDM (0.826 +/- 0.604 mg/min per 100 g) was significantly lower than that in control subjects (1.86 +/- 1.06 mg/min per 100 g, P < .01). MFU in patients with NIDDM (5.35 +/- 2.10 mg/min per 100 g) was also significantly lower than that of control subjects (7.05 +/- 1.66 mg/min per 100 g, P = .0182). SMFU significantly correlated with GDR (r = .727, P < .01) and FFA (r = -.52, P < .01) in patients with NIDDM. MFU also correlated with GDR (r = .778, P < .01) and FFA (r = -.72, P < .01) in patients with NIDDM. Multivariate stepwise regression analysis showed that GDR (F = 36.8) was independently related to MFU (r = .85, P < .01) whereas FFA was not (F = 1.763), where F is the value for statistical analysis of multivariate stepwise regression analysis. CONCLUSION: Insulin resistance is the most essential factor for both heart and skeletal muscle FDG uptake in patients with NIDDM.     

Short dynamic FDG-PET imaging protocol for patients with lung cancer

This positron emission tomography (PET) study was designed to compare 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) kinetic parameters of tumours derived from imaging frames of 0-60 min post FDG injection with those derived from shorter imaging frames of 0-30 min. Dynamic FDG-PET scans were performed on 20 patients with primary lung cancers for 1 h after intravenous injection of FDG. Images were reconstructed with attenuation correction using transmission images obtained with a germanium-68 ring source immediately before FDG injection. A region of interest (ROI) was placed on the plane of the maximal tumour FDG uptake. Arterial input function was estimated from an ROI defined in the left atrium. Based on the standard three-compartment metabolic model, we calculated the rate constants (K1-k3) and influx constant Ki = K1k3/(k2+k3) using the imaging frames for 60 min and 30 min post FDG injection. The standardized uptake value (SUV) of tumour was measured using the imaging frame of 50-60 min post injection. High correlations were observed between kinetic parameters (K1, k2, k3 and Ki) derived from imaging frames of 0-60 min and 0-30 min [0.231+/-0.114 vs 0.260+/-0.174 (r=0.958), 1.149+/-1.038 vs 1.565+/-2.027 (r=0.968), 0.259+/-0.154 vs 0.311+/-0.194 (r=0.886) and 0.044+/-0.022 vs 0.048+/-0.023 (r=0.961), respectively, P<0.001]. Ki showed an excellent agreement between the two methods (y=-0.0041+0.9831x). Mean SUV of the lung cancers was 6.58+/-2.85. It is concluded that the briefer 30-min acquisition may yield essentially the same results as the standard 60-min imaging protocol, thus offering a time saving in dynamic PET studies in which the model parameters are desired.     

Dissociation of glucose tracer uptake and glucose transporter distribution in the regionally ischaemic isolated rat heart: application of a new autoradiographic technique

Fluorine-18 fluoro-2-deoxyglucose ((18)FDG) and carbon-14 2-deoxyglucose ((14)C-2-DG) are both widely used tracers of myocardial glucose uptake and phosphorylation. We have recently shown, using positron emission tomography (PET) and nuclear magnetic resonance, that ischaemia-reperfusion (I-R) causes differential changes in their uptake. We describe here the novel application of an autoradiographic technique allowing the investigation of this phenomenon at high resolution, using tracer concentrations of both analogues in the dual-perfused isolated rat heart. We also investigate the importance of glucose transporter (GLUT 1 and GLUT 4) distribution in governing the observed phosphorylated analogue accumulation. Hearts ( n=5) were perfused with Krebs buffer for 40 min, made regionally zero-flow ischaemic for 40 min and reperfused for 60 min with Krebs containing tracer (18)FDG (200 MBq) and tracer (14)C-2-DG (0.37 MBq). Hearts were then frozen and five sections (10 micro m) were cut per heart, fixed and exposed on phosphor storage plates for 18 h (for (18)FDG) and then for a further 9 days (for (14)C-2-DG). Quantitative digital images of tracer accumulation were obtained using a phosphor plate reader. The protocol was repeated in a second group of hearts and GLUT 1 and GLUT 4 distribution analysed. Post-ischaemic accumulation of (18)FDG-6-P was inhibited by 38.2%+/-1.7% and (14)C-DG-6-P by 19.0%+/-2.2%, compared with control ( P<0.05). After placing seven "lines of interrogation" across each heart section and analysing the phosphorylated tracer accumulation along them, a transmural gradient of both tracers was observed; this was highest at the endocardium and lowest at the epicardium. GLUT 4 translocated to the sarcolemma in the ischaemic/reperfused region (from 24%+/-3% to 59%+/-5%), while there was no cellular redistribution of GLUT 1. We conclude that since decreased phosphorylated tracer accumulation occurs after ischaemia-reperfusion, despite greater externalisation of GLUT 4, hexokinase or the affinities of the GLUT transporters are changed under these conditions.