The plasma glutamate concentration as a complementary tool to differentiate benign PET-positive lung lesions from lung cancer.

BACKGROUND: Pulmonary imaging often identifies suspicious abnormalities resulting in supplementary diagnostic procedures. This study aims to investigate whether the metabolic fingerprint of plasma allows to discriminate between patients with lung inflammation and patients with lung cancer. METHODS: Metabolic profiles of plasma from 347 controls, 269 cancer patients and 108 patients with inflammation were obtained by 1H-NMR spectroscopy. Models to discriminate between groups were trained by PLS-LDA. A test set was used for independent validation. A ROC curve was built to evaluate the diagnostic performance of potential biomarkers. RESULTS: Sensitivity, specificity, PPV and NPV of PET-CT to diagnose cancer are 96, 23, 76 and 71%. Metabolic profiles differentiate between cancer and inflammation with a sensitivity of 89%, a specificity of 87% and a MCE of 12%. Removal of the glutamate metabolite results in an increase of MCE (38%) and a decrease of both sensitivity and specificity (62%), demonstrating the importance of glutamate for discrimination. At the cut-off point 0.31 on the ROC curve, the relative glutamate concentration discriminates between cancer and inflammation with a sensitivity of 85%, a specificity of 81%, and an AUC of 0.88. PPV and NPV are 92 and 69%. In PET-positive patients with a relative glutamate level ≤ 0.31 the sensitivity to diagnose cancer reaches 100% with a PPV of 94%. In PET-negative patients, a relative glutamate level > 0.31 increases the specificity of PET from 23% to 58% and results in a high NPV of 100%. In case of discrepancy between SUVmax and the glutamate concentration, lung cancer is missed in 19% of the cases. CONCLUSION: This study indicates that the 1H-NMR-derived relative plasma concentration of glutamate allows discrimination between lung cancer and lung inflammation. A glutamate level ≤ 0.31 in PET-positive patients corresponds to the diagnosis of lung cancer with a higher specificity and PPV than PET-CT. Glutamate levels > 0.31 in patients with PET negative lung lesions is likely to correspond with inflammation. Caution is needed for patients with conflicting SUVmax values and glutamate concentrations. Confirmation is needed in a prospective study with external validation and by another analytical technique such as HPLC-MS.

Metabolic phenotyping of human blood plasma: a powerful tool to discriminate between cancer types?

BACKGROUND: Accumulating evidence has shown that cancer cell metabolism differs from that of normal cells. However, up to now it is not clear whether different cancer types are characterized by a specific metabolite profile. Therefore, this study aims to evaluate whether the plasma metabolic phenotype allows to discriminate between lung and breast cancer. PATIENTS AND METHODS: The proton nuclear magnetic resonance spectrum of plasma is divided into 110 integration regions, representing the metabolic phenotype. These integration regions reflect the relative metabolite concentrations and were used to train a classification model in discriminating between 80 female breast cancer patients and 54 female lung cancer patients, all with an adenocarcinoma. The validity of the model was examined by permutation testing and by classifying an independent validation cohort of 60 female breast cancer patients and 81 male lung cancer patients, all with an adenocarcinoma. RESULTS: The model allows to classify 99% of the breast cancer patients and 93% of the lung cancer patients correctly with an area under the curve (AUC) of 0.96 and can be validated in the independent cohort with a sensitivity of 89%, a specificity of 82% and an AUC of 0.94. Decreased levels of sphingomyelin and phosphatidylcholine (phospholipids with choline head group) and phospholipids with short, unsaturated fatty acid chains next to increased levels of phospholipids with long, saturated fatty acid chains seem to indicate that cell membranes of lung tumors are more rigid and less sensitive to lipid peroxidation. The other discriminating metabolites are pointing to a more pronounced response of the body to the Warburg effect for lung cancer. CONCLUSION: Metabolic phenotyping of plasma allows to discriminate between lung and breast cancer, indicating that the metabolite profile reflects more than a general cancer marker. CLINICAL TRIAL REGISTRATION NUMBER: NCT02362776.

Relation between different methods for analysing ST segment deviation and infarct size as assessed by positron emission tomography.

OBJECTIVE: To study the relation between resolution of ST segment deviation and infarct size using positron emission tomography. METHODS: 45 patients with ST segment elevation acute myocardial infarction treated with thrombolysis or percutaneous coronary intervention were studied prospectively. An ECG was taken before and at (mean (SD)) 100 (45) min after reperfusion therapy. ECGs were analysed by three methods. Residual ST segment deviation, obtained from the ECG immediately after completion of reperfusion therapy, was defined by summation for each of the three methods. Relative resolution of ST segment deviation was defined as the absolute resolution divided by the ST segment deviation score at baseline x 100 (%). After 29 (14) hours, myocardial blood flow was measured with 13NH3. For each patient, the regions with a myocardial blood flow < 80% of normally perfused myocardium ( = hypoperfusion) and < 50% ( = no reflow) were automatically delineated. RESULTS: Substantial differences were found between different ECG analysis methods. There were moderate correlations between the area with myocardial hypoperfusion and ST segment deviation scores at baseline and after reperfusion therapy. After reperfusion therapy, residual ST segment deviation in the single lead with maximum ST segment deviation was as good at discriminating between tertiles of myocardial damage as summed ST segment elevation. Relative ST segment resolution did not discriminate between different degrees of myocardial damage. CONCLUSIONS: In the individual patient, residual ST segment deviation after reperfusion in the single lead with maximum ST segment deviation is at least as good as summed ST elevation in predicting final myocardial damage.

Dissociation of cardiomyocyte apoptosis and dedifferentiation in infarct border zones.

AIMS: Cardiomyocyte apoptosis is known to occur in infarct border zones, where cardiomyocyte dedifferentiation, as seen in hibernating myocardium, can also be observed. The aim of the study is to determine whether dedifferentiated cardiomyocytes represent a population of cells stably surviving or undergoing apoptosis. METHODS AND RESULTS: Microinfarctions were induced in sheep (n=8) by intracoronary injection of polymer macrobeads. The sheep were killed when cardiac function was gradually decreased (ejection fraction 37+/-6%, mean+/-SEM), but not earlier than 6 weeks after embolization. Transmural biopsies were taken from embolized and remote areas, based on flow measurements with positron emission tomography. Cells were classified as dedifferentiated when sarcomere content was depleted by >10% and glycogen content increased. Apoptosis was detected using the Tdt-mediated nick-end labelling (TUNEL) method and activated caspase-3 immunolabelling. Dedifferentiated cardiomyocytes were identified by morphology and by immunohistochemical evaluation of dedifferentiation related expression patterns of desmin, titin, cardiotin and alpha-smooth muscle actin. Cardiomyocyte apoptosis was detected in both the infarction border zones and remote areas. Dedifferentiated cardiomyocytes accounted for up to 30% of the cells in embolized areas and were almost exclusively non-apoptotic. CONCLUSION: In embolization induced microinfarcted tissue, dedifferentiated cardiomyocytes are preferentially spared to undergo apoptosis. It is hypothesized that dedifferentiated cardiomyocytes and apoptotic cardiomyocytes represent two different cell populations. The dedifferentiated cells can be considered as stable surviving cells.

PET reversed mismatch in an experimental model of subacute myocardial infarction.

The aim of this study was to evaluate the relationship between flow/metabolism, histology and functional follow-up in a sheep model of subacute myocardial infarction. In eight juvenile sheep, a myocardial infarction was induced by intracoronary injection of macrobeads. Left ventricular function was evaluated using echocardiography. 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG)/nitrogen-13-labelled ammonia (13NH3) positron emission tomography (PET) was performed at 6 weeks and 16 weeks after embolization. In five sheep, a dynamic carbon-11 acetate study was performed. In each animal, two regions of interest were defined on the polar map, corresponding to the embolized and the non-embolized region. After the final measurements, the hearts were processed for histological evaluation. PET revealed a moderately decreased flow and oxidative metabolism in the embolized region at 6 weeks, without significant changes at follow-up. At 6 weeks, 18F-FDG uptake in the embolized area was more severely decreased as compared to the flow index in the embolized area (P < 0.05). At 16 weeks, 18F-FDG metabolism had significantly recovered (P < 0.05). Serial echocardiography showed a persistent decrease in global and regional left ventricular function. Histology revealed a mix of micro-infarcted and viable tissue in the embolized region. In this model of subacute myocardial infarction, a PET "reversed mismatch" pattern was observed, with partial recovery of 18F-FDG uptake at follow-up. The histological counterpart of this PET pattern appears to be patchy necrosis.

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.

Surgical correction of vesicoureteral reflux: 5-year follow-up with 99Tcm-DMSA scintigraphy.

AIM: To evaluate kidney function before and after surgical correction of vesicoureteral reflux. The long-term effect was measured with quantitative nephro-scintigraphy using 99Tcm labelled dimercaptosuccinic acid (99Tcm-DMSA). METHODS: Forty-five children with a history of urinary tract infections due to vesicoureteral reflux (VUR) were studied. VUR grade was determined with contrast voiding cystourethrography. Planar scintigraphy was performed with 99Tcm-DMSA and uptake measured as a percentage of injected dose. Kidney function was evaluated at baseline and 5 years after corrective surgery. RESULTS: Three months after surgery, persistent mild reflux was found in eight of 76 treated renal units. Kidney uptake at 5-year follow-up was unchanged in the majority of children, indicating preservation of renal function found at baseline. The split renal function showed an excellent correlation (r = 0.99) between baseline and follow-up studies (regression slope 1.01). Percentage uptake had a regression slope of 0.89 significantly different from unity (P<0.05). Empirical kidney-depth correction techniques were compared. The scintigraphic pattern worsened in six kidneys, indicative of increased scarring in a minority of children. CONCLUSION: Planar nephro-scintigraphy with 99Tcm-DMSA was well tolerated in our paediatric population, and appeared appropriate to evaluate kidney function in time. After surgical correction of VUR, the baseline function was maintained in 94% of kidneys.

Early assessment of regional myocardial blood flow and metabolism in thrombolysis in myocardial infarction flow grade 3 reperfused myocardial infarction using carbon-11-acetate.

OBJECTIVES: The aim of this study was to investigate the prognostic value of carbon-11-acetate (acetate) positron emission tomography (PET) after successful reperfusion of myocardial infarction (MI). BACKGROUND: Acetate PET allows the measurement of both myocardial flow and oxidative metabolism. The prognostic value of acetate measurements performed early (within 24 h) after Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 reperfused MI is unknown. METHODS: In 18 patients with TIMI flow grade 3 reperfusion of their first MI, a dynamic acetate study was performed within 24 h of the acute event. At five days, nitrogen-13-NH3 (NH3) and fluorine-18-labeled fluorodeoxyglucose (FDG) PET studies were performed. Infarct-related areas were classified as "PET viable" or "PET nonviable," as assessed with NH3 and FDG, according to previously established criteria. At five days and three months, radionuclide angiography was performed for evaluation of left ventricular (LV) function. RESULTS: In infarct-related regions, myocardial blood flow, FDG uptake and oxygen consumption were decreased, compared with remote regions. However, oxygen consumption values, as measured with acetate in both PET-viable and PET-nonviable areas, as assessed with NH3 and FDG, were not significantly different (p = NS). A significant linear correlation was observed between global LV ejection fraction at three months and oxidative metabolism in the infarct-related area (r = 0.8, p < 0.0001). Multivariate analysis revealed that oxidative metabolism measurements in reperfused myocardium was the only significant predictor for recovery of LV function at three months (p < 0.05). CONCLUSIONS: Measurement of oxidative metabolism early after TIMI flow grade 3 reperfusion of MI offers important prognostic value concerning LV function at follow-up.

Self-injection ictal SPECT during partial seizures.

The authors compared ictal SPECT injection performed by medical personnel with self-injection ictal SPECT in six patients with refractory temporal lobe epilepsy. Self-injection was safe and started faster. Self-injection subtraction ictal SPECT coregistered to MRI (SISCOM) was localizing in three patients who had a complex partial seizure, but only one of three patients who had a simple partial seizure, which may limit its usefulness in clinical practice. The localizing information of self-injection was better in three patients, and obviated the need for depth-EEG studies in one patient.

Chronic heart failure model induced by coronary embolization in sheep.

OBJECTIVE: To create a model of chronic heart failure in a large animal. METHODS: Heart failure was induced in sheep by single intracoronary injection of polymer macrobeads, which were administered into left main coronary artery (n=3) or selectively into left anterior descending (n=4) or left circumflex (n=5) coronary artery. The animals were followed by echocardigraphy for 20 weeks. Measurements comprised fractional area change (FAC), and diastolic ventricular area (EDVA) and regional wall-thickening fraction (WT%). RESULTS: EDVA increased from 14.2+/-2.1 cm2 prior to embolization to 16.9+/-3.1 cm2 on day 1 (p<0.05), and remained significantly increased until completion of the follow-up period. FAC dropped from 47.9+/-4.6% at baseline to 29.3+/-4.4% on day 1 (p<0.001) and remained significantly depressed until 20 weeks later. In 9 selectively embolized animals WT% of the embolized area decreased from 33.8+/-8.0% at baseline to 5.3+/-2.6% on day 1 and remained significantly decreased. CONCLUSIONS: A simple model of chronic heart failure was developed. It shows relatively high stability over time and may prove beneficial in experimental work on ventricular assist devices.

Nuclear cardiology, Part IV: Viability.

After reading Part IV of this series of nuclear cardiology articles, the reader should be able to describe: (a) the differences between SPECT and PET techniques; (b) the various radiopharmaceuticals and imaging protocols used for detecting viability with SPECT; (c) the different radiopharmaceuticals and imaging protocols used for detecting viability with PET; and (d) the imaging patterns observed after reconstructing myocardial images.

Nuclear cardiology, Part III: Scintigraphic evaluation of cardiac perfusion.

OBJECTIVE: After reading Part III of this series of nuclear cardiology articles, the technologist should be able to: (a) compare and contrast radiopharmaceuticals used for myocardial perfusion imaging; (b) describe imaging protocols used for detecting coronary artery disease; and (c) describe imaging patterns seen following reconstruction of myocardial images.

Nuclear cardiology, Part II: Scintigraphic evaluation of cardiac function.

OBJECTIVE: Different methods are currently available to assess cardiac function, especially left ventricular ejection fraction, using either planar or tomographic imaging, first-pass or equilibrium techniques, and blood-pool or myocardial perfusion agents. This is the second article of a four-part series on nuclear cardiology. In this article the authors review the most widely used radiopharmaceuticals and methodologies.

Nuclear cardiology, Part I: Anatomy and function of the normal heart.

This is the first article of a four-part series on nuclear cardiology. This article introduces and reviews the anatomy and function of the normal heart. Future articles will develop the contribution of nuclear medicine techniques in evaluating myocardial perfusion, function and viability. This article describes the external and internal features of the heart and its vascularization, conducting system and physiological function. After reading this article, the reader should understand the anatomy and the function of the normal heart.