The role of 18F-FDG PET in the assessment of a benign hematological disorder: polycythemia.

Fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging was conceived in the early 1970 by investigators at the University of Pennsylvania as a research technique to measure brain metabolism and function by employing a non-invasive imaging approach. Soon after the introduction of whole-body PET instruments, 18F-FDG was utilized in the assessment of a variety of solid tumors and certain hematological malignancies. Yet, the role of 18F-FDG in assessing benign and uncommon malignant disorders of the bone marrow has not been investigated to a great extent. Fluorine-18-FDG as a molecular probe has the proven capacity to reflect the abnormal glycolytic activities inherent to a variety of disorders, where such information may serve as a guide to the clinical course of the respective disease. Recent efforts have studied bone marrow and extra-medullary disease activity in certain malignancies like chronic lymphocytic leukemia. Nonetheless, few studies have explored the role of 18F-FDG in assessing the metabolic basis of benign disorders of red marrow. Moreover, the introduction of novel imaging analysis schemes in recent years has allowed for the global assessment of red marrow disease, which can provide a superior means for characterizing the systemic nature and burden of these disorders. Accordingly, semi-quantitative global analysis techniques as applied to the skeletal structures in 18F-FDG PET may provide a tool to better understand these complex marrow abnormalities. Functional imaging of red bone marrow may also reveal critical information specifically regarding the extra-medullary extension of such hematological disorders that cannot be assessed by other diagnostic or imaging techniques. Myleoproliferative neoplasms (MPN) are an apt category of hematological disease that confer significantly altered systemic metabolic rates of hematopoietic stem cells (HSC) in the marrow, as such they are primed for exploration with 18F-FDG PET. The hallmark of such disorders involves the excess production of particular cellular components in blood. After a period of excess production, scar tissue may develop in place of the HSC leading to myleofibrosis and decreased hematopoietic activity. One of the least studied disorders within the larger category of MPN with respect to the nuclear medicine is polycythemia. Polycythemia may be either primary, polycythemia vera (PV), or secondary. PV involves a JAK2+ in HSC which allows for the excessive proliferation of immature erythrocytes and depressed erythropoietin levels as a result. Secondary polycythemia occurs in response to decreased oxygen intake, often as a result of smoking, which results in increased erythropoietin and hematocrit levels. Primary and secondary polycythemia lead to an increase in overall red marrow activity and a diffusion of active red marrow into the appendicular skeleton. Clinical presentation often includes redness or irritation of the skin along with headache, fatigue and excessive bleeding. Based upon the mentioned precedent, it is evident that PET imaging with 18F-FDG and other tracers will play a meaningful role in assessing diffuse bone marrow disorders such as hematological malignancies and myeloproliferative abnormalities. Semi-quantification studies of global bone marrow activity in such an application will be a vital means in accurately assessing the systematic nature and global burden of such benign hematological disorders such a polycythemia. Accordingly, the derived metabolic data projects to be a useful tool in the prospective clinical and scientific aspects of the diagnosis of these benign hematological disorders and the assessment of disease progression in light of relevant biological treatments. Given the nature of the disease and the enumerated capabilities of 18F-FDG PET it is expected that one would be able to capture the systematic abnormalities inherent to the disease. Moreover, the handful of case studies supports this possibility. Three case studies have all illustrated diffuse elevated 18F-FDG uptake throughout the axial and appendicular skeleton that reflects the hyper-metabolic red bone marrow as related to polycythemia. Moreover, the use of various functional imaging tracers, in addition to 18F-FDG, may indirectly reflect hypermetabolism in red bone marrow through abnormal tracer accumulation in the skeletons of patients. The whole body 18F-FDG scan of a JAK2+ PV patient before treatment (a) as compared to a matched subject (b) is found below; of note is the PV patient's elevated uptake in the pelvis, femur and spine.

Association between age, uptake of 18F-fluorodeoxyglucose and of 18F-sodium fluoride, as cardiovascular risk factors in the abdominal aorta.

OBJECTIVE: We aimed to assess the feasibility of quantifying fluorine-18-fluorodexoglucose (18F-FDG) and 18F-sodium fluoride (18F-NaF) uptake in abdominal aorta and examine their association with age and cardiovascular risk factors. SUBJECTS AND METHODS: Our study comprised 123 subjects (48±14 years of age, 62 men) including 78 healthy volunteers and 45 patients with chest pain syndrome, who originally enrolled in the CAMONA study in Odense, Denmark (NCT01724749). All subjects underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) and 18F-NaF PET/CT on separate days, 180min and 90min after administration of tracers, respectively. The global tracer uptake value (GTUV) in the abdominal aorta was determined as sum of the product of each slice area and its corresponding average standardized uptake value (SUV mean), divided by the sum of those slice areas. In addition, for each subject, the 10 years Framingham risk score (FRS) was calculated. The correlations between 18F-NaF and 18F-FDG GTUV with age and 10 years FRS were assessed in all, healthy and patient subjects. RESULTS: There was a significant, positive correlation between subjects' age and 18F-NaF GTUV (r=0.35, P<0.001), but not 18F-FDG GTUV (r=0.06, P=0.53). Also, there was a significant, positive correlation between 10 years FRS and 18F-NaF GTUV (r=0.30, P<0.001), but not 18F-FDG GTUV (r=0.01, P=0.95). Individual differences in 18F-FDG and 118F-NaF uptake were large in both healthy subjects and patients. CONCLUSION: In this study, the global uptake of 18F-NaF in abdominal aorta was positively associated with age and 10 years FRS in all subjects, healthy and patient groups, whereas the global uptake of 18F-FDG was not.

Magnetic resonance imaging-based partial volume-corrected 18F-sodium fluoride positron emission tomography in the femoral neck.

OBJECTIVES: 18F-sodium fluoride (NaF) is a radiotracer used in PET that reflects calcium metabolism and osteoblastic activity. In this study, we assessed the construct validity of a novel application of global assessment to measure NaF uptake in the femoral neck as a method of evaluating physiologic changes in osteoblastic metabolism with age. METHODS: Whole-body NaF-PET/computed tomography (CT) images and MRI of 24 male patients with a history of nonmetastatic prostate cancer between the ages of 36 and 82 years (67.8 ± 9.6) were analyzed. A region of interest delineated the entire femoral neck on the PET/CT image to determine the mean standardized uptake value (SUVmean). Correction for the partial volume effect was performed by measuring the volume of inert yellow bone marrow by MRI segmentation. Multiple linear regression was used to assess the relationship of uptake with age and body weight. RESULTS: The SUVmean with and without partial volume correction decreased with respect to age (P = 0.001 and P = 0.002, respectively). Body weight was not significantly related to any measured PET parameter. CONCLUSION: Our results support the use of global NaF uptake with magnetic resonance-derived partial volume correction in the femoral neck. Because osteoblastic metabolism is known to decrease with normal aging, the observed decrease in NaF uptake constitutes evidence for convergent validity, indicating that the proposed methodology likely reflects systemic osteoblastic activity. Future studies of this methodology are warranted in other instances of varying osteoblastic activity such as in metabolic bone diseases and for the evaluation of therapy targeting osteoblastic metabolism.

Role of 18F-NaF-PET in assessing aortic valve calcification with age.

Aortic valve calcification is a slow and progressive pathological process that can manifest in various degrees from mild thickening of the valve known as aortic sclerosis to severe calcification that hinders the leaflet motion, known as aortic stenosis. The evolving concept of aortic calcification is thought to result from infiltration of macrophages and T-lymphocytes. Moreover, the incidence of aortic valve calcification increases with age, in particular over the age of 50. In this study, we aimed to assess 18F-sodium fluoride (18F-NaF) uptake by the aortic valve on PET/CT scans performed in two age groups; 25-35 and 50-75 years of age. We hypothesized that patients aged 50-75, comprising of both healthy and high risk for cardiovascular disease (CVD), would have higher uptake of 18F-NaF than patients aged 25-35 and further that in the former group those who were at high risk for CVD had also higher 18F-NaF uptake. The 25-35-year group comprised of 6 males and 6 females, mean age 30 ± 3.5 years, while the 50-75-year group included 18 males and 20 females, mean age 61 ± 6.2 years. All underwent PET/CT imaging 90 minutes following the injection of 2.2 MBq of 18F-NaF per kg body weight. Aortic valve analysis was performed on axial sections using standard guided computer software (OsiriX MD software, version 9.0.02). The average aortic valve SUVmean was calculated for each patient. Univariate regression models stratified by age group were employed to determine the association of SUVmean with age. In the 50-75-year group, explanatory multivariable regression modeling was applied using available demographic and baseline information. SUVmean was found to be higher in the 50-75 age group than in the 25-35 age group: 0.91 ± 0.25 and 0.86 ± 0.26, respectively. The association of SUVmean with age was much stronger in individuals aged 50-75 years (r = 0.64, P<0.001) than individuals aged 25-35 years (r = 0.20, P = 0.53). In addition, in the 50-75 age group the association was much stronger in subjects with a high risk of CVD than in individuals without: r = 0.68, P = 0.001 versus r = 0.48, P = 0.042. Furthermore, the SUVmean was found to be higher in the high-risk group aged 50-75 than in the low-risk healthy group aged 50-75: 0.98 ± 0.32 and 0.83 ± 0.13. Aortic valve 18F-NaF uptake was higher in patients belonging to the age group of 50-75 years and correlated positively with age and high risk of CVD. These data provide evidence for a potential role of 18F-NaF PET/CT in identifying calcific changes in the aortic valve and may help direct therapeutic intervention prior to the development of symptomatic valvular disease.

NaF-PET/CT global assessment in detecting and quantifying subclinical cardiac atherosclerosis and its association with blood pressure in non-dyslipidemic individuals.

BACKGROUND: We used 18F-sodium fluoride (NaF) to assess early atherosclerosis in the global heart in asymptomatic individuals with a coronary calcium score of zero and without a formal diagnosis of hypertension. We hypothesized that these individuals might present with subclinical atherosclerosis that correlates with systolic, diastolic and mean arterial pressure (SBP, DBP, and MAP). METHODS: We identified 20 asymptomatic individuals (41.6 ± 13.8 years, 8 females) from the CAMONA trial with C-reactive protein ≥3 mg/L, no smoking history, diabetes (fasting blood glucose <126 mg/dl) and dyslipidemia per the Adult Treatment Panel III Guidelines: untreated LDL <160 mg/dL, total cholesterol <240 mg/dL, HDL >40 mg/dL. All underwent PET/CT imaging 90 minutes after NaF injection (2.2 Mbq/Kg). The global cardiac average SUVmean (aSUVmean) was calculated for each individual. Correlation coefficients and linear regression models were employed for statistical analysis. RESULTS: Significant positive correlation was revealed between global cardiac NaF uptake and all blood pressures: SBP (r=0.44, P=0.05), DBP (r=0.64, P=0.002), and MAP (r=0.59, P=0.007). After adjusting for age and gender, DBP and MAP were independent predictors of higher global cardiac NaF uptake. CONCLUSION: NaF-PET/CT for detecting and quantifying subclinical atherosclerosis in asymptomatic individuals revealed that cardiac NaF uptake correlated independently with DBP and MAP.