Metformin and cancer: Technical and clinical implications for FDG-PET imaging

Metformin is the most widely used hypoglycemic agent. Besides its conventional indications, increasing evidence demonstrate a potential efficacy of this biguanide as an anticancer drug. Possible mechanisms of actions seem to be independent from its hypoglycemic effect and seem to involve the interference with key pathways in cellular proliferation and glycolysis. To date, many clinical trials implying the use of metformin in cancer treatment are on-going. The increasing use of (18)F-2-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in cancer evaluation raises a number of questions about the possible interference of the biguanide on FDG distribution. In particular, the interferences exerted by metformin on AMP-activated protein kinase pathway (the cellular energy sensor), on insulin levels and on Hexokinase could potentially have repercussion on glucose handling and thus on FDG distribution. A better comprehension of the impact of metformin on FDG uptake is needed in order to optimize the use of PET in this setting. This evaluation would be useful to ameliorate scans interpretation in diabetic patients under chronic metformin treatment and to critically interpret images in the context of clinical trials. Furthermore, collecting prospective data in this setting would help to verify whether FDG-PET could be a valid tool to appreciate the anticancer effect of this new therapeutic approach

Comparative diagnostic accuracy of 18F-FDG PET/CT for breast cancer recurrence

In the last decades, in addition to conventional imaging techniques and magnetic resonance imaging (MRI), 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) has been shown to be relevant in the detection and management of breast cancer recurrence in doubtful cases in selected groups of patients. While there are no conclusive data indicating that imaging tests, including FDG PET/CT, produce a survival benefit in asymptomatic patients, FDG PET/CT can be useful for identifying the site of relapse when traditional imaging methods are equivocal or conflicting and for identifying or confirming isolated loco-regional relapse or isolated metastatic lesions. The present narrative review deals with the potential role of FDG PET in these clinical settings by comparing its accuracy and impact with conventional imaging modalities such as CT, ultrasound, bone scan, 18F-sodium fluoride PET/CT (18F-NaF PET/CT) as well as MRI. Patient-focused perspectives in terms of patients\ue2\u80\u99 satisfaction and acceptability are also discussed

Comparisons between glucose analogue 2-deoxy-2-((18)F)fluoro-D-glucose and (18)F-sodium fluoride positron emission tomography/computed tomography in breast cancer patients with bone lesions

To compare 2-deoxy-2-((18)F)fluoro-D-glucose((18)F-FDG) and (18)F-sodium ((18)F-NaF) positron emission tomography/computed tomography (PET/CT) accuracy in breast cancer patients with clinically/radiologically suspected or known bone metastases

Intrabone Transplant of Cord Blood Stem Cells Establishes a Local Engraftment Store: A Functional PET/FDG Study

Background. Despite advancements in comprehension of molecular mechanisms governing bone marrow (BM) homing of hematopoietic stem cells, cord blood transplant (CBT) suffers from a slow rate of hematopoietic recovery. Intrabone (IB) injection has been proposed as a method able to improve speed of BM engraftment with respect to conventional IV protocols. However, the mechanisms underlying this benefit are largely unknown. Aim. To verify whether IB-CBT determines a local engraftment able to predict the reconstitution of recipient hematopoiesis. Design and Methods. Twenty-one patients with hematologic malignancies received IB injection into both iliac crests of 3.2±0.68 * 107/kg cord blood cells. One month following IB-CBT, PET-CT imaging was performed. Maximal standardized uptake values (SUVs) were assessed in BM of both iliac crests and in all lumbar vertebrae. Results. Maximal SUV within iliac crests was higher than in lumbar vertebrae (4.1±1.7 versus 3.2±0.7, resp., P=0.01). However, metabolic activity in these two different BM districts was significantly correlated (r=0.7, P<0.001). Moreover, FDG uptake values within the injection site closely predicted platelet recovery 100 days after IB-CBT (r=0.72, P<0.01). Conclusions. The metabolic activity of injected BM predicts the subsequent rate of hematopoietic recovery after IB-CBT, suggesting a pivotal role of the local engraftment in the reconstitution of recipient hematopoiesis

Divergent targets of glycolysis and oxidative phosphorylation result in additive effects of metformin and starvation in colon and breast cancer

Emerging evidence demonstrates that targeting energy metabolism is a promising strategy to fight cancer. Here we show that combining metformin and short-term starvation markedly impairs metabolism and growth of colon and breast cancer. The impairment in glycolytic flux caused by starvation is enhanced by metformin through its interference with hexokinase II activity, as documented by measurement of 18F-fluorodeoxyglycose uptake. Oxidative phosphorylation is additively compromised by combined treatment: metformin virtually abolishes Complex I function; starvation determines an uncoupled status of OXPHOS and amplifies the activity of respiratory Complexes II and IV thus combining a massive ATP depletion with a significant increase in reactive oxygen species. More importantly, the combined treatment profoundly impairs cancer glucose metabolism and virtually abolishes lesion growth in experimental models of breast and colon carcinoma. Our results strongly suggest that energy metabolism is a promising target to reduce cancer progression

Multicentre multi-device hybrid imaging study of coronary artery disease: results from the EValuation of INtegrated Cardiac Imaging for the Detection and Characterization of Ischaemic Heart Disease (EVINCI) hybrid imaging population

AIMS: Hybrid imaging provides a non-invasive assessment of coronary anatomy and myocardial perfusion. We sought to evaluate the added clinical value of hybrid imaging in a multi-centre multi-vendor setting. METHODS AND RESULTS: Fourteen centres enrolled 252 patients with stable angina and intermediate (20-90%) pre-test likelihood of coronary artery disease (CAD) who underwent myocardial perfusion scintigraphy (MPS), CT coronary angiography (CTCA), and quantitative coronary angiography (QCA) with fractional flow reserve (FFR). Hybrid MPS/CTCA images were obtained by 3D image fusion. Blinded core-lab analyses were performed for CTCA, MPS, QCA and hybrid datasets. Hemodynamically significant CAD was ruled-in non-invasively in the presence of a matched finding (myocardial perfusion defect co-localized with stenosed coronary artery) and ruled-out with normal findings (both CTCA and MPS normal). Overall prevalence of significant CAD on QCA (&gt;70% stenosis or 30-70% with FFR 640.80) was 37%. Of 1004 pathological myocardial segments on MPS, 246 (25%) were reclassified from their standard coronary distribution to another territory by hybrid imaging. In this respect, in 45/252 (18%) patients, hybrid imaging reassigned an entire perfusion defect to another coronary territory, changing the final diagnosis in 42% of the cases. Hybrid imaging allowed non-invasive CAD rule-out in 41%, and rule-in in 24% of patients, with a negative and positive predictive value of 88% and 87%, respectively. CONCLUSION: In patients at intermediate risk of CAD, hybrid imaging allows non-invasive co-localization of myocardial perfusion defects and subtending coronary arteries, impacting clinical decision-making in almost one every five subjects

PET/CT in nononcological lung diseases: current applications and future perspectives

Positron emission tomography (PET) combined with computed tomography (CT) is an established diagnostic modality that has become an essential imaging tool in oncological practice. However, thanks to its noninvasive nature and its capability to provide physiological information, the main applications of this technique have significantly expanded. 18F-labelled fluorodeoxyglucose (FDG) is the most commonly used radiopharmaceutical for PET scanning and demonstrates metabolic activity in various tissues. Since activated inflammatory cells, like malignant cells, predominantly metabolise glucose as a source of energy and increase expression of glucose transporters when activated, FDG-PET/CT can be successfully used to detect and monitor a variety of lung diseases, such as infections and several inflammatory conditions. The added value of FDG-PET/CT as a molecular imaging technique relies on its capability to identify disease in very early stages, long before the appearance of structural changes detectable by conventional imaging. Furthermore, by detecting the active phase of infectious or inflammatory processes, disease progression and treatment efficacy can be monitored. This review will focus on the clinical use of FDG-PET/CT in nonmalignant pulmonary diseases

A new compartmental method for the analysis of liver FDG kinetics in small animal models

BACKGROUND: Compartmental analysis is a standard method to quantify metabolic processes using fluorodeoxyglucose-positron emission tomography (FDG-PET). For liver studies, this analysis is complex due to the hepatocyte capability to dephosphorylate and release glucose and FDG into the blood. Moreover, a tracer is supplied to the liver by both the hepatic artery and the portal vein, which is not visible in PET images. This study developed an innovative computational approach accounting for the reversible nature of FDG in the liver and directly computing the portal vein tracer concentration by means of gut radioactivity measurements. METHODS: Twenty-one mice were subdivided into three groups: the control group 'CTR' (n = 7) received no treatment, the short-term starvation group 'STS' (n = 7) was submitted to food deprivation with free access to water within 48 h before imaging, and the metformin group 'MTF' (n = 7) was treated with metformin (750 mg/Kg per day) for 1 month. All mice underwent a dynamic micro-PET study for 50 min after an (18)F-FDG injection. The compartmental analysis considered two FDG pools (phosphorylated and free) in both the gut and liver. A tracer was carried into the liver by the hepatic artery and the portal vein, and tracer delivery from the gut was considered as the sole input for portal vein tracer concentration. Accordingly, both the liver and gut were characterized by two compartments and two exchange coefficients. Each one of the two two-compartment models was mathematically described by a system of differential equations, and data optimization was performed by applying a Newton algorithm to the inverse problems associated to these differential systems. RESULTS: All rate constants were stable in each group. The tracer coefficient from the free to the metabolized compartment in the liver was increased by STS, while it was unaltered by MTF. By contrast, the tracer coefficient from the metabolized to the free compartment was reduced by MTF and increased by STS. CONCLUSIONS: Data demonstrated that our method was able to analyze FDG kinetics under pharmacological or pathophysiological stimulation, quantifying the fraction of the tracer trapped in the liver or dephosphorylated and released into the bloodstream