F]-2-fluoro-2-deoxy-D-glucose Uptake Research Articles

Molecular imaging as a tool to investigate heterogeneity of advanced HER2-positive breast cancer and to predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial

Only human epidermal growth factor receptor (HER)2 status determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) has been validated to predict efficacy of HER2-targeting antibody-drug-conjugate trastuzumab emtansine (T-DM1). We propose molecular imaging to explore intra-/interpatient heterogeneity in HER2 mapping of metastatic disease and to identify patients unlikely to benefit from T-DM1. HER2-positive mBC patients with IHC3+ or FISH ≥ 2.2 scheduled for T-DM1 underwent a pretreatment HER2-positron emission tomography (PET)/computed tomography (CT) with (89)Zr-trastuzumab. [(18)F]2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT was performed at baseline and before T-DM1 cycle 2. Patients were grouped into four HER2-PET/CT patterns according to the proportion of FDG-avid tumor load showing relevant (89)Zr-trastuzumab uptake (>blood pool activity): patterns A and B were considered positive (>50% or all of the tumor load 'positive'); patterns C and D were considered negative (>50% or all of the tumor load 'negative'). Early FDG-PET/CT was defined as nonresponding when >50% of the tumor load showed no significant reduction of FDG uptake (<15%). Negative (NPV) and positive predictive values (PPV) of HER2-PET/CT, early FDG response and their combination were assessed to predict morphological response (RECIST 1.1) after three T-DM1 cycles and time-to-treatment failure (TTF). In the 56 patients analyzed, 29% had negative HER2-PET/CT while intrapatient heterogeneity (patterns B and C) was found in 46% of patients. Compared with RECIST1.1, respective NPV/PPV for HER2-PET/CT were 88%/72% and 83%/96% for early FDG-PET/CT. Combining HER2-PET/CT and FDG-PET/CT accurately predicted morphological response (PPV and NPV: 100%) and discriminated patients with a median TTF of only 2.8 months [n = 12, 95% confidence interval (CI) 1.4-7.6] from those with a TTF of 15 months (n = 25, 95% CI 9.7-not calculable). Pretreatment imaging of HER2 targeting, combined with early metabolic response assessment holds great promise for improving the understanding of tumor heterogeneity in mBC and for selecting patients who will/will not benefit from T-DM1. NCT01565200.

Increased 18F-FDG uptake suggests synovial inflammatory reaction with osteoarthritis: preliminary in-vivo results in humans.

The aim of this prospective study was to compare the metabolic activity of the knee joints of a group of patients with painful knees clinically (such as recurrent joint pain, joint instability, and functional limitations) consistent with osteoarthritis and those of another group of patients without such complaints, using [F]-2-fluoro-2-deoxy-D-glucose (F-FDG)-PET imaging. A total of 97 patients who participated in either painful joint prosthesis or diabetic foot research studies involving F-FDG-PET scans were asked to complete a knee pain questionnaire. The patients were asked whether they experienced pain in any joint, and if so, which joints were affected. A total of 18 knee joints without prosthesis were reported to be painful. The maximum standardized uptake values (SUVmax) of the middle joint space and lateral synovial tissue of these 18 knees were measured and compared with those of a set of patients with control asymptomatic knees. The average SUVmax of the middle part of the joint space in the painful knees was 1.35±0.59 compared with an average SUVmax value of 0.86±0.14 in the control group (P=0.0176). The average SUVmax of the synovium in the lateral part of the painful joints was 1.17±0.49 compared with 0.73±0.31 in the control group (P=0.0161). These data indicate that increased F-FDG uptake is associated with knee pain in osteoarthritis patients and that there is a positive relationship between the two parameters.

Involvement of Subcortical Brain Structures During Olfactory Stimulation in Multiple Chemical Sensitivity.

Multiple chemical sensitivity (MCS) patients usually react to odour compounds and the majority of neuroimaging studies assessed, especially at the cortical level, many olfactory-related correlates. The purpose of the present study was to depict sub-cortical metabolic changes during a neutral (NC) and pure (OC) olfactory stimulation by using a recently validated (18)F-2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography/computer tomography procedure in 26 MCS and 11 healthy (HC) resting subjects undergoing a battery of clinical tests. Twelve subcortical volumes of interest were identified by the automated anatomical labeling library and normalized to thalamus FDG uptake. In both groups, when comparing OC to NC, the within-subjects ANOVA demonstrated a relative decreased metabolism in bilateral putamen and hippocampus and a relative increased metabolism in bilateral amygdala, olfactory cortex (OLF), caudate and pallidum. The between-groups ANOVA demonstrated in MCS a significant higher metabolism in bilateral OLF during NC. As in HC subjects negative correlations were found in OC between FDG uptake in bilateral amygdala and hippocampus and odor pleasantness scale, the latter positively correlated with MCS subjects' bilateral putamen FDG uptake in OC. Besides FDG uptake resemblances in both groups were found, for the first time a relative higher metabolism increase in OLF in MCS subjects at rest with respect to HC was found. When merging this aspect to the different subcortical FDG uptake correlations patterns in the two groups, the present study demonstrated to describe a peculiar metabolic index of behavioral and neurological aspects of MCS complaints.

Spatiotemporal Uptake Characteristics of [ 18 ]F-2-Fluoro-2-Deoxy- d -Glucose in a Rat Middle Cerebral Artery Occlusion Model

Alterations of cerebral glucose metabolism are well anticipated during cerebral ischemia. However, detailed spatiotemporal characteristics of disturbed cerebral glucose metabolism during acute ischemia remain largely elusive. This study aims to delineate spatiotemporal distributions of [18]F-2-fluoro-2-deoxy-D-glucose (FDG) uptake using positron emission tomography imaging, particularly at the peri-ischemic zone, and its correlation with tissue outcome. The intraluminal suture middle cerebral artery occlusion model was used to induce focal cerebral ischemia in rats (n=48). All animals underwent sequential MRI and FDG positron emission tomography imaging at different times (30-150 minutes) after middle cerebral artery occlusion. MR and positron emission tomography images were coregistered. FDG uptake in the peri-ischemic zone was assessed in relation to middle cerebral artery occlusion duration, cerebral blood flow, apparent diffusion coefficient, and 24-hour T2 lesions. Elevated FDG uptake was consistently observed at the peri-ischemic zone surrounding the presumed ischemic core with low FDG uptake. Both the spatial volume and the uptake level of the hyper-uptake region were inversely correlated with the duration of middle cerebral artery occlusion. The hyper-uptake regions exhibited a mild reduction of cerebral blood flow (28.2±3.2%) and apparent diffusion coefficient (9.1±1.4%) when compared with that in the contralateral hemisphere. Colocalization analysis revealed that, with reperfusion, an average of 12.1±1.7% of the hyper-uptake volume was recruited into final infarction. Elevated FDG uptake at the peri-ischemic zone is consistently observed during acute cerebral ischemia. The region with elevated FDG uptake likely reflects viable tissues that can be salvaged with reperfusion. Therefore, acute FDG positron emission tomography imaging might hold promise in the management of patients with acute stroke.

Quantification of Atherosclerotic Plaque Activity and Vascular Inflammation using [18-F] Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT)

Conventional non-invasive imaging modalities of atherosclerosis such as coronary artery calcium (CAC) and carotid intimal medial thickness (C-IMT) provide information about the burden of disease. However, despite multiple validation studies of CAC, and C-IMT, these modalities do not accurately assess plaque characteristics, and the composition and inflammatory state of the plaque determine its stability and, therefore, the risk of clinical events. [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG) imaging using positron-emission tomography (PET)/computed tomography (CT) has been extensively studied in oncologic metabolism. Studies using animal models and immunohistochemistry in humans show that FDG-PET/CT is exquisitely sensitive for detecting macrophage activity, an important source of cellular inflammation in vessel walls. More recently, we and others have shown that FDG-PET/CT enables highly precise, novel measurements of inflammatory activity of activity of atherosclerotic plaques in large and medium-sized arteries. FDG-PET/CT studies have many advantages over other imaging modalities: 1) high contrast resolution; 2) quantification of plaque volume and metabolic activity allowing for multi-modal atherosclerotic plaque quantification; 3) dynamic, real-time, in vivo imaging; 4) minimal operator dependence. Finally, vascular inflammation detected by FDG-PET/CT has been shown to predict cardiovascular (CV) events independent of traditional risk factors and is also highly associated with overall burden of atherosclerosis. Plaque activity by FDG-PET/CT is modulated by known beneficial CV interventions such as short term (12 week) statin therapy as well as longer term therapeutic lifestyle changes (16 months). The current methodology for quantification of FDG uptake in atherosclerotic plaque involves measurement of the standardized uptake value (SUV) of an artery of interest and of the venous blood pool in order to calculate a target to background ratio (TBR), which is calculated by dividing the arterial SUV by the venous blood pool SUV. This method has shown to represent a stable, reproducible phenotype over time, has a high sensitivity for detection of vascular inflammation, and also has high inter-and intra-reader reliability. Here we present our methodology for patient preparation, image acquisition, and quantification of atherosclerotic plaque activity and vascular inflammation using SUV, TBR, and a global parameter called the metabolic volumetric product (MVP). These approaches may be applied to assess vascular inflammation in various study samples of interest in a consistent fashion as we have shown in several prior publications.

Correlation of metabolism/hypoxia markers and fluorodeoxyglucose uptake in oral squamous cell carcinomas

The objective of this study was to analyze the relationship between the uptake of (18)F-2-fluoro-2-deoxy-d-glucose (FDG) by positron emission tomography-computerized tomography (PET-CT) and glucose metabolism/hypoxia markers in oral squamous cell carcinoma (OSCC). Thirty-six patients with OSCC (tongue [n = 23], buccal mucosa [n = 7], and floor of the mouth [n = 6]) were assessed and underwent incisional biopsy and subsequently received FDG-PET-CT. Expressions of hypoxia-inducible factor 1α (HIF-1α), glucose transporter protein 1 (GLUT-1), hexokinase-II (HK-II), and glucose-6-phosphatase (G6Pase) were immunohistochemically quantified, and FDG uptake was evaluated by the maximum standardized uptake values (SUV(max)) at the primary tumor site. FDG uptake was found to be significantly correlated with the T classification of OSCC but not with other clinicopathologic characteristics, such as the N classification, clinical type, and histologic grade of malignancy. In the early-stage (T1 and T2) tumor, FDG uptake was significantly associated with the expression levels of GLUT-1, HK II, and HIF-1α, and the expression levels of GLUT-1 and HK-II significantly correlated with HIF-1α expression levels. However, there were no correlations between the expression levels of these molecules and SUV(max) in the late-stage (T3 and T4) tumor. FDG uptake was significantly associated with the expression levels of glucose metabolism-related molecules, such as GLUT-1, HK II, and HIF-1α, especially in early-stage tumors.

Surgical resection of pulmonary metastases from meningioma: Report of a case

Meningiomas rarely metastasize, and little information on pulmonary metastasectomy from meningioma has been documented. We herein report a case of a potentially curative resection for meningioma that metastasized to the lung. A 67-year-old woman was admitted to our hospital because of two masses in the right lung. In 1993, when the patient was 52 years old, she underwent a craniotomy for an atypical meningioma. The meningioma recurred once in the local site and was re-excised in 1997. In 2008, a screening chest X-ray detected two lung nodules in the right lung field. A computed tomographic scan demonstrated round masses with sharp borders, in the right S2 (2.2 cm in diameter) and S4 (1.1 cm in diameter) regions. A whole-body [(18)F]2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography/CT examination revealed intense focal FDG uptake (maximum standard uptake value [SUV(max)] = 6.9) in the larger mass, and weak FDG uptake (SUV(max) = 2.3) in the smaller mass. A wedge resection of S2 and a middle lobectomy of the right lung were performed, and the final diagnosis was pulmonary metastases from an intracranial meningioma. The patient is presently doing well 20 months after the surgery without any signs of recurrence. Our case demonstrates that surgery should be considered when pulmonary metastases are deemed completely resectable by a preoperative radiological examination, and that a good clinical outcome can be achieved.

Measuring the “Unmeasurable”: Assessment of Bone Marrow Response to Therapy Using FDG-PET in Patients with Lymphoma

To determine if anatomically "nonmeasurable" disease in bone marrow (BM) is assessable for response to therapy by [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT). FDG PET/CT images of 27 patients with lymphoma, FDG-avid bone marrow (BM) lesions, and >or=1 FDG-avid, tumor-involved lymph node (LN) at baseline were retrospectively reviewed. FDG uptake in target LNs and BM foci was determined pre- and posttherapy using the standardized uptake value corrected for lean body mass (SUL(mean)). Size of the same target LNs was measured pre- and posttherapy on CT. Percentage decreases of LN size and LN and BM SUL were calculated. Response was classified according to revised International Workshop Criteria (IWC) with and without modification for metabolic evaluation of BM and correlated to overall survival. Statistical analyses were performed using paired t-tests, Pearson correlation coefficients, and z-tests. LN size, LN SUL(mean), and BM SUL(mean) were significantly higher pre- versus posttherapy (2337 mm(2) +/- 1810 vs. 309 mm(2) +/- 323; 6.94 +/- 4.96 vs. 1.02 +/- 1.00; and 6.81 +/- 4.58 to 1.84 +/- 1.58, all P < .001, respectively). After therapy, significant correlation was found between percentage declines of LN size and SUL(mean) of LNs (r = 0.84, P < .001) or BM (r = 0.56, P = .002) and SUL(mean) of LN and BM (r = 0.76, P < .001). Including a metabolic assessment of BM correctly altered overall response assessment in 5/27 (19%) patients and better predicted overall survival than revised IWC. Anatomically "unmeasurable" BM infiltration with lymphoma behaves similarly to LN disease after therapy and is "measurable" by FDG PET/CT. FDG PET/CT is valuable for monitoring tumor response in "measurable" disease and BM, which was previously considered "unmeasurable" by anatomical imaging.

A Comparison between Radiolabeled Fluorodeoxyglucose Uptake and Hyperpolarized 13C-Labeled Pyruvate Utilization as Methods for Detecting Tumor Response to Treatment

Detection of early tumor responses to treatment can give an indication of clinical outcome. Positron emission tomography measurements of the uptake of the glucose analog, [(18)F] 2-fluoro-2-deoxy-D-glucose (FDG), have demonstrated their potential for detecting early treatment response in the clinic. We have shown recently that (13)C magnetic resonance spectroscopy and spectroscopic imaging measurements of the uptake and conversion of hyperpolarized [1-(13)C]pyruvate into [1-(13)C]lactate can be used to detect treatment response in a murine lymphoma model. The present study compares these magnetic resonance measurements with changes in FDG uptake after chemotherapy. A decrease in FDG uptake was found to precede the decrease in flux of hyperpolarized (13)C label between pyruvate and lactate, both in tumor cells in vitro and in tumors in vivo. However, the magnitude of the decrease in FDG uptake and the decrease in pyruvate to lactate flux was comparable at 24 hours after drug treatment. In cells, the decrease in FDG uptake was shown to correlate with changes in plasma membrane expression of the facilitative glucose transporters, whereas the decrease in pyruvate to lactate flux could be explained by an increase in poly(ADP-ribose) polymerase activity and subsequent depletion of the NAD(H) pool. These results show that measurement of flux between pyruvate and lactate may be an alternative to FDG-positron emission tomography for imaging tumor treatment response in the clinic.

Variability and reproducibility of hepatic FDG uptake measured as SUV as well as tissue‐to‐blood background ratio using positron emission tomography in healthy humans

To investigate variability and reproducibility of hepatic [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG) uptake in healthy individuals. Static images were obtained 70 min after the injection of 160 MBq FDG in six healthy subjects at two occasions with 13 days' interval. FDG uptake was adjusted for tissue-to-blood background ratio (T/B), or measured as standardized uptake value (SUV). Small regions of interest (ROIs) of 10 cm(3) in two different hepatic regions were analysed as well as the total liver. Mean SUV was 1.16 +/- 0.15 and mean T/B corrected values was 1.87 +/- 0.17. The maximal values were 2.70 (SUV) and 4.67 (T/B). Reproducibility was 6.7% for the mean SUV and 0.2% for the max SUV values. The corresponding figures for the T/B corrected mean values were 6.4% and for the max T/B values 13.0%. In general, the small ROIs had a comparable or even lower CV% for SUV values, but a higher CV% for T/B corrected values. In normal subjects hepatic FDG-uptake is high and homogeneous with a low CV% between days. T/B corrected values are largely comparable to SUV values but not superior, probably due to the standardization of procedures and homogeneity of the subjects. The T/B corrected method is theoretically superior in a more inhomogeneous population or when using different scanners and is shown here to be easy to apply. Small ROIs of 10 cm(3) are representative with respect to mean FDG uptake in the total liver and reproducibility, but do not identify the max FDG uptake.

Early response evaluation of therapy with AP23573 (an mTOR inhibitor) in sarcoma using [18F]2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) scan

9028 Background: AP23573 (AP) is a non-prodrug rapamycin analog, which potently inhibits mTOR, a downstream effector of the PI3K/Akt pathway. AP has demonstrated some anti-tumor efficacy in sarcoma in phase I study. The relationship between mTOR and the glycolytic pathway provides mechanistic rationale for the use of PET as a non-invasive indicator of mTOR activity. Early response evaluation by PET was studied in this phase 2 trial in advanced sarcoma pts. Methods: AP is dosed at 12.5 mg IV daily X 5 days every 2 weeks (1 course). PET scan was done on D1 and D5 of the first course of AP using a CTI Viewer 16 PET/CT scanner with LSO crystals (11 pts) or a Siemens Biograph 2 PET/CT scanner with LSO crystals (14 pts). The five areas with highest FDG accumulation at baseline were selected as target lesions. Percent difference in sum of maximum standard uptake values (SUVmax) were compared for each patient on D1 and D5. These values represent a measure of FDG uptake. Response criteria used were recommended by the EORTC PET Study Group (Eur J Cancer. 1999; 35; 1773–1782). In the targeted lesions D5, SUVmax normalization was considered as complete metabolic response (CMR), while >25% SUVmax reduction was considered partial metabolic response (PMR). Stable metabolic response (SMR) was defined by an SUVmax change less then ±25% and increased metabolic response (IMR) was considered >25% increase in SUVmax. Further evaluation with PET scan is planned after 4 courses of AP. Results: 25 pts (14M/11F) were enrolled (age 18–76 yrs, median 57 yrs). Two pts showed no abnormal 18-FDG accumulation on D1, hence D5 PET was omitted. Of the remaining 23 pts, 9 pts (39%) showed PMR (SUV decreased by 25.3–58.7%). 14 pts (61%) had SMR (9 pts had SUV decrease by 4.7–21.6% and 5 pts had SUV increase by 0.7–5.5%). None of the patients had IMR or CMR. 5/9 pts with PET evidence of PMR showed clinical improvement as demonstrated by reduced symptoms of pain, shortness of breath and cough. Conclusions: This is the first known report of the use of PET to evaluate mTOR inhibition in non-GIST sarcomas. PET appears to be valuable in initial evaluation of patient response to treatment with AP. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ariad Ariad Ariad

Imaging gliomas with positron emission tomography and single-photon emission computed tomography

Over the last two decades the large volume of research involving various brain tracers has shed invaluable light on the pathophysiology of cerebral neoplasms. Yet the question remains as to how best to incorporate this newly acquired insight into the clinical context. Thallium is the most studied radiotracer with the longest track record. Many, but not all studies, show a relationship between 201Tl uptake and tumor grade. Due to the overlap between tumor uptake and histologic grades, 201Tl cannot be used as the sole noninvasive diagnostic or prognostic tool in brain tumor patients. However, it may help differentiating a high-grade tumor recurrence from radiation necrosis. MIBI is theoretically a better imaging agent than 201Tl but it has not convincingly been shown to differentiate tumors according to grade. MDR-1 gene expression as demonstrated by MIBI does not correlate with chemoresistance in high grade gliomas. Currently, MIBI's clinical role in brain tumor imaging has yet to be defined. IMT, a radio-labeled amino acid analog, may be useful for identifying postoperative tumor recurrence and, in this application, appears to be a cheaper, more widely available tool than positron emission tomography (PET). However, its ability to accurately identify tumor grade is limited. 18 F-2-Fluoro-2-deoxy- d-glucose (FDG) PET predicts tumor grade, and the metabolic activity of brain tumors has a prognostic significance. Whether FDG uptake has an independent prognostic value above that of histology remains debated. FDG-PET is effective in differentiating recurrent tumor from radiation necrosis for high-grade tumors, but has limited value in defining the extent of tumor involvement and recurrence of low-grade lesions. Amino-acid tracers, such as MET, perform better for this purpose and thus play a complementary role to FDG. Given the poor prognosis of patients with gliomas, particularly with high-grade lesions, the overall clinical utility of single photon emission computed tomography (SPECT) and PET in characterizing recurrent lesions remains dependent on the availability of effective treatments. These tools are thus mostly suited to the evaluation of treatment response in experimental protocols designed to improve the patients' outcome. © 2003 Elsevier Inc. All rights reserved.