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.     

Comparison of microsphere-equivalent blood flow (15O-water PET) and relative perfusion (99mTc-tetrofosmin SPECT) in myocardium showing metabolism-perfusion mismatch.

Myocardial perfusion imaging with (99m)Tc-tetrofosmin is based on the assumption of a linear correlation between myocardial blood flow (MBF) and tracer uptake. However, it is known that (99m)Tc-tetrofosmin uptake is directly related to energy-dependent transport processes, such as Na(+)/H(+) ion channel activity, as well as cellular and mitochondrial membrane potentials. Therefore, cellular alterations that affect these energy-dependent transport processes ought to influence (99m)Tc-tetrofosmin uptake independently of blood flow. Because metabolism ((18)F-FDG)-perfusion ((99m)Tc-tetrofosmin) mismatch myocardium (MPMM) reflects impaired but viable myocardium showing cellular alterations, MPMM was chosen to quantify the blood flow-independent effect of cellular alterations on (99m)Tc-tetrofosmin uptake. Therefore, we compared microsphere-equivalent MBF (MBF_micr; (15)O-water PET) and (99m)Tc-tetrofosmin uptake in MPMM and in "normal" myocardium. METHODS: Forty-two patients with severe coronary artery disease, referred for myocardial viability diagnostics, were examined using (18)F-FDG PET and (99m)Tc-tetrofosmin perfusion SPECT. Relative (18)F-FDG and (99m)Tc-tetrofosmin uptake values were calculated using 18 segments per patient. Normal myocardium and MPMM myocardium were classified using a previously validated (99m)Tc-tetrofosmin SPECT/(18)F-FDG PET score. In addition, (15)O-water PET was performed to assess kinetic-modeled MBF (MBF_kin), the water-perfusable tissue fraction (PTF), and the resulting MBF_micr (MBF_kin x PTF), which is comparable to tracer uptake values. (99m)Tc-tetrofosmin uptake and MBF_micr values were calculated for all normal and MPMM segments and averaged within their respective classifications. RESULTS: Mean relative (99m)Tc-tetrofosmin uptake was 86% +/- 1% in normal myocardium and 56% +/- 1% in MPMM, showing a significant difference (P < 0.001), as was expected from the classification. Contrary to these findings, mean MBF_micr in MPMM myocardium was 0.60 +/- 0.03 mL x min(-1) x mL(-1), which did not significantly differ from normal myocardium (0.64 +/- 0.01 mL x min(-1) x mL(-1)). All values are given as mean +/- SEM. CONCLUSION: Differences between reduced (99m)Tc-tetrofosmin uptake and the unchanged MBF_micr in MPMM myocardium suggest that the pathophysiologic basis of MPMM is not a blood flow reduction but cellular alterations that affect uptake and retention of (99m)Tc-tetrofosmin independently of blood flow. Therefore, it seems that perfusion deficits in MPMM myocardium are greatly overestimated by (99m)Tc-tetrofosmin and that it tends to give false-positive findings.     

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.     

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.     

Electromechanical properties of perfusion/metabolism mismatch: comparison of nonfluoroscopic electroanatomic mapping with 18F-FDG PET.

The aim of this study was to compare nonfluoroscopic electroanatomic mapping (NOGA), SPECT perfusion imaging, and PET metabolic imaging for assessment of myocardial viability. In particular, we sought to elucidate differences of electromechanical properties between the perfusion/metabolism mismatch as an indicator of a potentially reversible ischemic injury and the perfusion/metabolism match indicating irreversibly damaged myocardial tissue. METHODS: Twenty-one patients with coronary artery disease underwent NOGA mapping of endocardial unipolar voltage, cardiac 18F-FDG PET of glucose utilization, and resting 201Tl SPECT of myocardial perfusion. RESULTS: Electrical activity was 10.8 +/- 4.6 mV (mean +/- SD) in normal myocardium and was unchanged in hypoperfused segments with maintained glucose metabolism (perfusion/metabolism mismatch), 9.3 +/- 3.4 mV (P = not significant). In contrast, hypoperfused segments with a perfusion/metabolism match and nonviable segments showed significantly lower voltage (6.9 +/- 3.1 mV, P < 0.0001 and 4.1 +/- 1.1 mV, P < 0.0001 vs. normal). In hypoperfused segments, metabolic activity was more closely related to endocardial voltage than was myocardial perfusion (201Tl vs. voltage: r = 0.38, SEE = 3.2, P < 0.001; 18F-FDG PET vs. voltage: r = 0.6, SEE = 2.8, P < 0.0001). CONCLUSION: In hypoperfused myocardium, electrical activity by NOGA mapping is more closely related to PET metabolic activity than to SPECT myocardial perfusion. As NOGA mapping does not differentiate hypoperfused myocardium with enhanced glucose utilization from normal myocardium, results from NOGA mapping need to be correlated with results from perfusion imaging to identify hypoperfused, yet viable, myocardium and to stratify patients for revascularization procedures.     

Dynamic 13N-ammonia PET: a new imaging method to diagnose hypopituitarism.

We have developed a new imaging method to evaluate the blood perfusion and ammonia metabolism of the pituitary gland, and we preliminarily assessed its role in the diagnosis of hypopituitarism. METHODS: Six female healthy volunteers (age range, 20-46 y) and 6 female patients (age range, 23-42 y) were enrolled in this study. Dynamic (13)N-NH(3) PET was performed. Time-activity curves for the pituitary gland and internal carotid artery were generated by setting regions of interest on the transverse planes of the pituitary gland. The standardized uptake value of the pituitary gland, the radioactive ratio of pituitary to thalamus (P/T), and the first-pass uptake rate of ammonia in the pituitary gland were calculated. RESULTS: (13)N-Ammonia was extracted rapidly by pituitary tissue in the first 120 s after injection and trapped in pituitary tissue in the healthy volunteers. Three to 20 min after injection, the pituitary gland was clearly seen in the healthy volunteers, and the mean (+/-SD) size of the pituitary gland on (13)N-ammonia PET images was (1.09 +/- 0.17 cm) x (1.08 +/- 0.14 cm) x (1.12 +/- 0.09 cm). However, in patients with hypopituitarism, the first-pass uptake rate of ammonia in the pituitary gland was significantly lower than that in healthy volunteers (0.35 +/- 0.10 vs. 0.75 +/- 0.07). On images of patients, the pituitary gland was absent or could not clearly be found, was small or malformed, and showed significantly lower uptake of (13)N-NH(3) than in healthy volunteers (standardized uptake value, 1.15 +/- 0.34 vs. 3.74 +/- 1.44; P/T, 0.65 +/- 0.23 vs. 1.24 +/- 0.34). CONCLUSION: Dynamic (13)N-ammonia PET can provide information on blood perfusion and metabolism of the pituitary gland and is useful in early monitoring of damage to the pituitary gland and in diagnosing hypopituitarism.     

An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fluoro-6-thia-heptadecanoic acid and [18F]FDG in Patients with Congestive Heart Failure.

Understanding the metabolic consequences of heart failure is important in evaluating potential mechanisms for disease progression and assessing targets for therapies designed to improve myocardial metabolism in patients with heart failure. PET is uniquely suited to noninvasively evaluate myocardial metabolism. In this study, we investigated the kinetics of 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (FTHA) and [18F]FDG in patients with stable New York Heart Association functional class III congestive heart failure and a left ventricular ejection fraction of no more than 35%. METHODS: Twelve fasting patients underwent dynamic PET studies using [18F]FTHA and FDG. From the dynamic image data, the fractional uptake rates (Ki) were determined for [18F]FTHA and FDG. Subsequently, serum free fatty acid and glucose concentrations were used to calculate the myocardial free fatty acid and glucose uptake rates, respectively. Uptake rates were compared with reported values for [18F]FTHA and FDG in subjects with normal left ventricular function. RESULTS: The average Ki for [18F]FTHA was 19.7 +/- 9.3 mL/100 g/min (range, 7.2-36.0 ml/100 g/min). The average myocardial fatty acid use was 19.3 +/- 2.3 mmol/100 g/min. The average Ki for FDG was 1.5 +/- 0.37 mL/100 g/min (range, 0.1-3.3 mL/100 g/min), and the average myocardial glucose use was 12.3 +/- 2.3 mmol/100 g/min. CONCLUSION: Myocardial free fatty acid and glucose use in heart failure can be quantitatively assessed using PET with [18F]FTHA and FDG. Myocardial fatty acid uptake rates in heart failure are higher than expected for the normal heart, whereas myocardial glucose uptake rates are lower. This shift in myocardial substrate use may be an indication of impaired energy efficiency in the failing heart, providing a target for therapies directed at improving myocardial energy efficiency.     

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%ᆟ% at 5 days and 85%ᆞ% at 3 months (P<0.00001). Absolute blood flow in this region was 75ᆭ ml/min per 100 g at 5 days and 80ᆧ ml/min per 100 g at 3 months. At 5 days, normalized ¹⁸F-FDG uptake in the infarct-related region was decreased (51%ᆠ%). At 3 months, ¹⁸F-FDG uptake in this region had significantly recovered (75%ᆟ%, P<0.00001). In the infarct-related region, absolute FDG metabolism was 17Lj µmol/min per 100 g at 5 days and 26Nj µmol/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%ᆡ% 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%lj% of the left ventricle at that time. The ratio of ¹⁸F-FDG uptake to ¹³NH₃ uptake in the infarct-related region increased from 0.67ǂ.8 at 5 days to 0.88ǂ.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 2.5ǂ.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.     

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.     

Relationship between 18F-FDG uptake and breast density in women with normal breast tissue.

Breast density affects the mammographic detectability of breast cancer. The study aimed to evaluate the impact of breast density on the (18)F-FDG uptake of normal breast tissue. METHODS: The study population consisted of 45 women (median age, 54 y; age range, 42-77 y). All underwent whole-body (18)F-FDG PET for various indications other than breast cancer, and all underwent mammography within a mean of 6.6 +/- 4.9 mo of PET. On the basis of mammographic findings, breasts were categorized as extremely dense, heterogeneously dense, primarily fatty, or entirely fatty. Regions of interest were drawn on every PET image in which breast tissue was visualized. Average and peak standardized uptake values (SUVs) were calculated for the left and right breasts. RESULTS: Mammography showed that 20 of the 45 women had heterogeneously dense breasts, 1 had extremely dense breasts, 20 had primarily fatty breasts, and 4 had entirely fatty breasts. In dense breasts, the average SUV was 0.39 +/- 0.05 (right breast) and 0.36 +/- 0.07 (left breast) and the peak SUV was 0.93 +/- 0.16 and 0.89 +/- 0.18, respectively. The average and peak SUVs were significantly lower for primarily fatty breasts than for dense breasts (P < 0.01). Peak and average SUVs of entirely fatty breasts also differed significantly from peak and average SUVs of dense and primarily fatty breasts (P < 0.01). The impact of hormonal status on SUV was significant but less than the impact of breast density. No significant relationship between average SUV or peak SUV and age or serum glucose level was observed. CONCLUSION: Breast density and hormonal status affect the uptake of (18)F-FDG. Dense breasts exhibit, on average, significantly higher (18)F-FDG uptake than do nondense breasts. However, the highest peak SUV observed in dense breasts was 1.39, which is well below the SUV of 2.5 commonly used as a cutoff between benign and malignant tissue. Therefore, breast density is unlikely to affect the ability of (18)F-FDG PET to discriminate between benign and malignant breast lesions.     

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.     

Dual-time-point 18F-FDG PET for the evaluation of gallbladder carcinoma.

Conventional imaging techniques such as ultrasonography, CT, and MRI are able to detect gallbladder abnormalities but are not always able to differentiate a malignancy from other disease processes such as cholecystitis. The purpose of the present study was to evaluate the efficacy of dual-time-point (18)F-FDG PET for differentiating malignant from benign gallbladder disease. METHODS: The study evaluated 32 patients who were suspected of having gallbladder tumors. (18)F-FDG PET (whole body) was performed at 62 +/- 8 min (early) after (18)F-FDG injection and was repeated 146 +/- 14 min (delayed) after injection only in the abdominal region. We evaluated the (18)F-FDG uptake both visually and semiquantitatively. Semiquantitative analysis using the standardized uptake value (SUV) was performed for both early and delayed images (SUV(early) and SUV(delayed), respectively). The retention index (RI) was calculated according to the equation (SUV(delayed) - SUV(early)) x 100/SUV(early). The tumor-to-liver ratio was also calculated. Results: The final diagnosis was gallbladder carcinoma in 23 patients and benign disease in 9 patients. For visual analysis of gallbladder carcinoma, delayed (18)F-FDG PET images improved the specificity of diagnosis in 2 patients. When an SUV(early) of 4.5, SUV(delayed) of 2.9, and RI of -8 were chosen as arbitrary cutoffs for differentiating between malignant and benign conditions, sensitivity increased from 82.6% to 95.7% and 100% for delayed imaging and combined early and delayed imaging (i.e., RI), respectively. With the same criteria, specificity decreased from 55.6% to 44.4% for delayed imaging and combined early and delayed imaging, respectively. The specificity of (18)F-FDG PET improved to 80% in the group with a normal level of C-reactive protein (CRP) and decreased to 0% in the group with an elevated CRP level. For gallbladder carcinoma, both SUV and tumor-to-liver ratios derived from delayed images were significantly higher than the ratios derived from early images (P < 0.0001). CONCLUSION: Delayed (18)F-FDG PET is more helpful than early (18)F-FDG PET for evaluating malignant lesions because of increased lesion uptake and increased lesion-to-background contrast. However, the diagnostic performance of (18)F-FDG PET depends on CRP levels.     

Early prediction of response to chemotherapy in metastatic breast cancer using sequential 18F-FDG PET.

Chemotherapy is currently the treatment of choice for patients with high-risk metastatic breast cancer. Clinical response is determined after several cycles of chemotherapy by changes in tumor size as assessed by conventional imaging procedures including CT, MRI, plain film radiography, or ultrasound. The aim of this study was to evaluate the use of sequential 18F-FDG PET to predict response after the first and second cycles of standardized chemotherapy for metastatic breast cancer. METHODS: Eleven patients with 26 metastatic lesions underwent 31 (18)F-FDG PET examinations (240-400 MBq of 18F-FDG; 10-min 2-dimensional emission and transmission scans). Clinical response, as assessed by conventional imaging after completion of chemotherapy, served as the reference. 18F-FDG PET images after the first and second cycles of chemotherapy were analyzed semiquantitatively for each metastatic lesion using standardized uptake values (SUVs) normalized to patients' blood glucose levels. In addition, whole-body 18F-FDG PET images were viewed for overall changes in the 18F-FDG uptake pattern of metastatic lesions within individual patients and compared with conventional imaging results after the third and sixth cycles of chemotherapy. RESULTS: After completion of chemotherapy, 17 metastatic lesions responded, as assessed by conventional imaging procedures. In those lesions, SUV decreased to 72% +/- 21% after the first cycle and 54% +/- 16% after the second cycle, when compared with the baseline PET scan. In contrast, 18F-FDG uptake in lesions not responding to chemotherapy (n = 9) declined only to 94% +/- 19% after the first cycle and 79% +/- 9% after the second cycle. The differences between responding and nonresponding lesions were statistically significant after the first (P = 0.02) and second (P = 0.003) cycles. Visual analysis of 18F-FDG PET images correctly predicted the response in all patients as early as after the first cycle of chemotherapy. As assessed by 18F-FDG PET, the overall survival in nonresponders (n = 5) was 8.8 mo, compared with 19.2 mo in responders (n = 6). CONCLUSION: In patients with metastatic breast cancer, sequential 18F-FDG PET allowed prediction of response to treatment after the first cycle of chemotherapy. The use of 18F-FDG PET as a surrogate endpoint for monitoring therapy response offers improved patient care by individualizing treatment and avoiding ineffective chemotherapy.     

Imaging gastric cancer with PET and the radiotracers 18F-FLT and 18F-FDG: a comparative analysis.

In this pilot study, we evaluated 3'-deoxy-3'-(18)F-fluorothymidine (FLT) PET for the detection of gastric cancer and compared the diagnostic accuracy with that of (18)F-FDG PET. METHODS: Forty-five patients (31 male and 14 female) with histologically proven locally advanced gastric cancer underwent attenuation-corrected whole-body (18)F-FLT PET and (18)F-FDG PET/CT (low-dose CT). (18)F-FLT emission images were acquired on a full-ring PET scanner 45 min after the injection of 270-340 MBq of (18)F-FLT. (18)F-FDG PET/CT was performed 60 min after the injection of 300-370 MBq of (18)F-FDG. Mean standardized uptake values for (18)F-FLT and (18)F-FDG were calculated using circular ROIs (diameter, 1.5 cm) in the primary tumor manifestation site, in a reference segment of the liver, and in the bone marrow and were compared on a lesion-by-lesion basis. RESULTS: According to the Lauren classification, 15 tumors (33%) were of the intestinal subtype and 30 (67%) of the nonintestinal subtype. (18)F-FLT PET images showed high contrast for the primary tumor and proliferating bone marrow. In all patients (45/45), focal (18)F-FLT uptake could be detected in the primary tumor. In contrast, 14 primary tumors were negative for (18)F-FDG uptake, with lesional (18)F-FDG uptake lower than or similar to background activity. The mean standardized uptake value for (18)F-FLT in malignant primaries was 6.0 +/- 2.5 (range, 2.4-12.7). In the subgroup of (18)F-FDG-positive patients, the mean value for (18)F-FDG was 8.4 +/- 4.1 (range, 3.8/19.0), versus 6.8 +/- 2.6 for (18)F-FLT (Wilcoxon test: P = 0.03). Comparison of mean (18)F-FLT and (18)F-FDG uptake in tumors with signet ring cells revealed no statistically significant difference between the tracers (6.2 +/- 2.1 for (18)F-FLT vs. 6.4 +/- 2.8 for (18)F-FDG; Wilcoxon test: P = 0.94). CONCLUSION: The results of this study indicate that imaging gastric cancer with the proliferation marker (18)F-FLT is feasible. (18)F-FLT PET was more sensitive than (18)F-FDG PET, especially in tumors frequently presenting without or with low (18)F-FDG uptake, and may improve early evaluation of response to neoadjuvant treatment.     

Assessment of myocardial metabolism in diabetic rats using small-animal PET: a feasibility study.

This feasibility study was undertaken to determine whether kinetic modeling in conjunction with small-animal PET could noninvasively quantify alterations in myocardial perfusion and substrate metabolism in rats. METHODS: All small-animal PET was performed on either of 2 tomographs. Myocardial blood flow and substrate metabolism were measured in 10 male Zucker diabetic fatty rats (ZDF, fa/fa) and 10 lean littermates (Lean, Fa/+) using (15)O-water, 1-(11)C-glucose, 1-(11)C-acetate, and 1-(11)C-palmitate. Animals were 12.0 +/- 1.4-wk old. RESULTS: Consistent with a type 2 diabetic phenotype, the ZDF animals showed higher plasma hemoglobin A(1c), insulin, glucose, and free fatty acid (FFA) levels than their lean controls. Myocardial glucose uptake (mL/g/min) was not significantly different between the 2 groups. However, higher glucose plasma levels in the ZDF rats resulted in higher myocardial glucose utilization (nmol/g/min) (Lean, 629 +/- 785, vs. ZDF, 1,737 +/- 1,406; P = 0.06). Similarly, myocardial FFA uptake (mL/g/min) was not significantly different between the 2 groups, (Lean, 0.51 +/- 28, vs. ZDF, 0.72 +/- 0.19; P = not significant) However, due to higher FFA plasma levels, utilization and oxidation (nmol/g/min) were significantly higher in the ZDF group (Lean, 519 +/- 462, vs. ZDF, 1,623 +/- 712, P < .001; and Lean, 453 +/- 478, vs. ZDF, 1,636 +/- 730, P < .01). CONCLUSION: Noninvasive measurements of myocardial substrate metabolism in ZDF rats using small-animal PET are consistent with the expected early metabolic abnormalities that occur in this well-characterized model of type 2 diabetes mellitus. Thus, small-animal PET demonstrates significant promise in providing a means to link the myocardial metabolic abnormalities that occur in rat of disease with the human condition.     

Detection of Klatskin's tumor in extrahepatic bile duct strictures using delayed 18F-FDG PET/CT: preliminary results for 22 patient studies.

Detection of cholangiocarcinoma in extrahepatic bile duct strictures is a continuing challenge in clinical practice because brush cytology taken at endoscopic retrograde cholangiography has an average sensitivity of 50%. The aim of this study was to evaluate the effectiveness of dual-modality PET/CT using (18)F-FDG for noninvasive differentiation of extrahepatic bile duct strictures. METHODS: Twenty-two PET/CT studies were performed on 20 patients (10 women, 10 men; mean age +/- SD, 63 +/- 14 y) with extrahepatic bile duct strictures on endoscopic retrograde cholangiography. PET imaging was started 101 +/- 22 min after injection of 369 +/- 48 MBq of 18F-FDG. Blood glucose was 100 +/- 20 mg/dL. PET images were reconstructed iteratively with attenuation correction based on a rescaling of the CT image. CT was performed within 1 min before the PET study, with the patient in the same position. CT was used to place a volume of interest 5 cm in diameter at the liver hilus for quantitative evaluation of PET images by means of standardized uptake values (SUVs). RESULTS: Final diagnosis was histologically proven cholangiocarcinoma in 14 cases and benign causes of strictures in 8 cases without evidence of malignancy during a follow-up of 18 +/- 3 mo. All patients with cholangiocarcinoma presented with focal increased uptake in the liver hilus with an SUV of 6.8 +/- 3.3 (range, 3.9-15.8), compared with 2.9 +/- 0.3 (range, 2.5-3.3) in patients with benign causes of strictures (P = 0.003). There was a clear cutoff SUV of 3.6 for detection of malignancy in the liver hilus. CONCLUSION: 18F-FDG PET/CT provided high accuracy for noninvasive detection of perihilar cholangiocarcinoma in extrahepatic bile duct strictures.     

Treatment monitoring by 18F-FDG PET/CT in patients with sarcomas: interobserver variability of quantitative parameters in treatment-induced changes in histopathologically responding and nonresponding tumors

Measurements of tumor glucose use by (18)F-FDG PET need to be standardized within and across institutions. Various parameters are used for measuring changes in tumor glucose metabolic activity with (18)F-FDG PET in response to cancer treatments. However, it is unknown which of these provide the lowest variability between observers. Knowledge of the interobserver variability of quantitative parameters is important in sarcomas as these tumors are frequently large and demonstrate heterogeneous (18)F-FDG uptake. METHODS: A total of 33 patients (16 men, 17 women; mean age, 47 +/- 18 y) with high-grade sarcomas underwent (18)F-FDG PET/CT scans before and after neoadjuvant chemotherapy. Two independent investigators measured the following parameters on the pretreatment and posttreatment scans: maximum standardized uptake value (SUVmax), peak SUV (SUVpeak), mean SUV (SUVmean), SUVmean in an automatically defined volume (SUVauto), and tumor-to-background ratio (TBR). The variability of the different parameters was compared by concordance correlation coefficient (CCC), variability effect coefficient, and Bland-Altman plots. RESULTS: Baseline SUVmax, SUVpeak, SUVmean, SUVauto, and TBR averaged 10.36, 7.78, 4.13, and 6.22 g/mL and 14.67, respectively. They decreased to 5.36, 3.80, 1.79, and 3.25 g/mL and 6.62, respectively, after treatment. SUVmax, SUVpeak, and SUVauto measurements and their changes were reproducible (CCC > or = 0.98). However, SUVauto poorly differentiated between responding and nonresponding tumors. The high intratumoral heterogeneity of (18)F-FDG resulted in frequent failure of the thresholding algorithm, which necessitated manual corrections that in turn resulted in a higher interobserver variability of SUVmean (CCCs for follow-up and change were 0.96 and 0.91, respectively; P < 0.005). TBRs also showed a significantly higher variability than did SUVpeak (CCCs for follow-up and change were 0.94 and 0.86, respectively; P < 0.005). CONCLUSION: SUVmax and SUVpeak provided the most robust measurements of tumor glucose metabolism in sarcomas. Delineation of the whole-tumor volume by semiautomatic thresholding did not decrease the variability of SUV measurements. TBRs were significantly more observer-dependent than were absolute SUVs. These findings should be considered for standardization of clinical (18)F-FDG PET/CT trials.     

Comparative 18F-FDG PET of experimental Staphylococcus aureus osteomyelitis and normal bone healing.

PET using (18)F-FDG is a promising imaging modality for bone infections, based on intensive consumption of glucose by mononuclear cells and granulocytes. The method may have limitations in distinguishing uncomplicated bone healing from osteomyelitis. Bone healing involves an inflammatory phase that represents a highly activated state of cell metabolism and glucose consumption, mimicking infection on PET images. This laboratory study of a standardized model was designed to compare the (18)F-FDG PET characteristics of normal bone healing with those of local osteomyelitis. METHODS: A localized osteomyelitis model of the rabbit tibia was created by modifying a previously reported canine model. In the osteomyelitic group (n = 8), a standardized metaphyseal defect of the proximal right tibia was surgically created and filled with a block of orthopedic bone cement, followed by injection of a predetermined amount (0.1 mL) of Staphylococcus aureus (strain 52/52A/80, 1 x 10(5)/mL) into the space around the cement. The control group of animals with normal bone healing (n = 8) underwent the same procedure, but the bacterial injection was replaced by a sterile saline injection. The bone cement was surgically removed during debridement at 2 wk. Osteomyelitis was confirmed with positive bacterial cultures during the debridement and 6 wk later at the time of sacrifice. (18)F-FDG PET and peripheral quantitative CT were performed 3 and 6 wk after the debridement. The presence of osteomyelitic bone changes on plain radiographs was classified according to a previously published system. RESULTS: Before surgery, the standardized uptake values of (18)F-FDG did not differ markedly between the right and left tibias. In the control animals, uncomplicated bone healing was associated with a temporary increase in (18)F-FDG uptake at 3 wk (P = 0.007), but it returned almost to normal by 6 wk. In the experimental animals, localized osteomyelitis resulted in an intense continuous uptake of (18)F-FDG, which was higher than that of healing and intact bones at 3 wk (P = 0.014 and P < 0.001, respectively) and at 6 wk (P < 0.001). CONCLUSION: (18)F-FDG PET seems to be an efficient tool in the differentiation of uneventful bone healing from bone healing complicated by localized osteomyelitis.     

18F-FET PET compared with 18F-FDG PET and CT in patients with head and neck cancer.

Recent studies suggest a somewhat selective uptake of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) in cerebral gliomas and in squamous cell carcinoma (SCC) and a good distinction between tumor and inflammation. The aim of this study was to investigate the diagnostic potential of 18F-FET PET in patients with SCC of the head and neck region by comparing that tracer with 18F-FDG PET and CT. METHODS: Twenty-one patients with suspected head and neck tumors underwent 18F-FET PET, 18F-FDG PET, and CT within 1 wk before operation. After coregistration, the images were evaluated by 3 independent observers and an ROC analysis was performed, with the histopathologic result used as a reference. Furthermore, the maximum standardized uptake values (SUVs) in the lesions were determined. RESULTS: In 18 of 21 patients, histologic examination revealed SCC, and in 2 of these patients, a second SCC tumor was found at a different anatomic site. In 3 of 21 patients, inflammatory tissue and no tumor were identified. Eighteen of 20 SCC tumors were positive for both 18F-FDG uptake and 18F-FET uptake, one 0.3-cm SCC tumor was detected neither with 18F-FDG PET nor with 18F-FET PET, and one 0.7-cm SCC tumor in a 4.3-cm ulcer was overestimated as a 4-cm tumor on 18F-FDG PET and missed on 18F-FET PET. Inflammatory tissue was positive for 18F-FDG uptake (SUV, 3.7-4.7) but negative for 18F-FET uptake (SUV, 1.3-1.6). The SUVs of 18F-FDG in SCC were significantly higher (13.0 +/- 9.3) than those of 18F-FET (4.4 +/- 2.2). The ROC analysis showed significantly superior detection of SCC with (18)F-FET PET or 18F-FDG PET than with CT. No significant difference (P = 0.71) was found between 18F-FDG PET and 18F-FET PET. The sensitivity of 18F-FDG PET was 93%, specificity was 79%, and accuracy was 83%. 18F-FET PET yielded a lower sensitivity of 75% but a substantially higher specificity of 95% (accuracy, 90%). CONCLUSION: 18F-FET may not replace 18F-FDG in the PET diagnostics of head and neck cancer but may be a helpful additional tool in selected patients, because 18F-FET PET might better differentiate tumor tissue from inflammatory tissue. The sensitivity of 18F-FET PET in SCC, however, was inferior to that of 18F-FDG PET because of lower SUVs.     

Dual time point 18F-FDG PET imaging detects breast cancer with high sensitivity and correlates well with histologic subtypes.

This prospective study was designed to assess the utility of the dual time point imaging technique by (18)F-FDG PET in detecting primary breast cancer and to determine whether there is a relationship between (18)F-FDG uptake and its change over time and the histopathologic subtypes. METHODS: One hundred fifty-two patients with newly diagnosed breast cancer underwent 2 sequential PET scans (dual time point imaging) for preoperative staging. The maximum standardized uptake value (SUVmax) of (18)F-FDG was measured from both time points. The percent change in SUVmax (Delta%SUVmax) between time points 1 (SUVmax1) and 2 (SUVmax2) was calculated. Patients were divided into 2 groups according to histopathology as invasive and noninvasive. Invasive tumors were also divided into 2 groups (>10 mm and 4-10 mm). The tumor-to-contralateral normal breast (background) ratios of SUVmax at both time points for groups were measured and the Delta%SUVmax values were calculated. RESULTS: The mean +/- SD of the SUVmax1, the SUVmax2, and the Delta%SUVmax were 3.9 +/- 3.7, 4.3 +/- 4.0, and 8.3% +/- 11.5% for invasive; 2.0 +/- 0.6, 2.1 +/- 0.6, and 3.4% +/- 13.0% for noninvasive; and were 1.2 +/- 0.3, 1.1 +/- 0.2, and -10.0% +/- 10.8% for the contralateral normal breast groups, respectively. In the comparison of SUVmax1, Delta%SUVmax, and the tumor-to-background ratios among groups, all results were significant (P < 0.001). Visual assessment revealed that the sensitivity of dual time point imaging was 90.1% for invasive cancer >10 mm, 82.7% for invasive breast cancers 4-10 mm, and 76.9% for noninvasive breast cancers. CONCLUSION: Dual time point imaging is a simple and noninvasive method that may improve the sensitivity and accuracy of (18)F-FDG PET in assessing patients with primary breast cancer. The changes that are noted in SUVs in dual time point imaging vary depending on the histopathologic type of primary breast cancer.