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 seemto 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 18F-2-fluoro-2-deoxyd-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.
In the course of metformin treatment, staging abdominal cancer lesions with (18)F-FDG PET images is often hindered by the presence of a high bowel radioactivity. The present study aimed to verify the ...mechanism underlying this phenomenon.
Fifty-three mice were submitted to dynamic acquisitions of (18)F-FDG kinetics under fasting conditions. Three small-animal PET scans were obtained over a 4-mo study period. The animals were subdivided into 4 groups according to the following metformin administration protocol: group 1, untreated mice (n = 15); group 2, mice exposed to metformin treatment (750 mg/kg/d) for the 48 h before each PET study (pulsed, n = 10); group 3, mice treated for the whole study period (prolonged, n = 10); and group 4, mice in which prolonged treatment was interrupted 48 h before PET (interrupted, n = 8). The rate constant of (18)F-FDG uptake was estimated by Patlak analysis. At the end of the study, the ileum and colon were harvested, washed, and counted ex vivo. Two further groups, of 5 animals each, were included to evaluate the effect of prolonged metformin treatment on phosphorylated adenosine monophosphate (AMP)-activated protein kinase (pAMPK) form and gene expression for thioredoxin-interacting protein (TXNIP).
Pulsed treatment did not modify gut tracer retention with respect to the untreated group. Conversely, prolonged treatment induced a progressive increase in (18)F-FDG uptake that selectively involved the colonic wall, without any significant contamination of bowel content. This effect persisted after a complete drug washout in the interrupted group. These responses were paralleled by increased pAMPK availability and by reduced expression of TXNIP messenger RNA in colonic enterocytes exposed to prolonged metformin treatment.
Metformin causes a selective increase in colonic (18)F-FDG uptake. This effect appears after a relatively long period of treatment and persists soon after drug washout. Accordingly, the increased bowel glucose metabolism reflects a biologic response to chronic metformin treatment characterized by increased levels of pAMPK and reduced levels of TXNIP.
AIM: To compare 2-deoxy-2-(18F)fluoro-D-glucose(18FFDG) and 18F-sodium(18F-NaF) positron emission tomography/computed tomography（PET/CT） accuracy in breast cancer patients with ...clinically/radiologically suspected or known bone metastases.METHODS: A total of 45 consecutive patients with breast cancer and the presence or clinical/biochemical or radiological suspicion of bone metastatic disease underwent 18F-FDG and 18F-fluoride PET/CT. Imaging results were compared with histopathology when available, or clinical and radiological follow-up of at least 1 year. For each technique we calculated: Sensitivity（Se）, specificity（Sp）, overall accuracy, positive and negative predictive values, error rate, and Youden’s index. Mc Nemar’s χ2 test was used to test the difference in sensitivity and specificity between the two diagnostic methods. All analyses were computed on a patient basis, and then on a lesion basis, with consideration ofthe density of independent lesions on the coregistered CT（sclerotic, lytic, mixed, no-lesions） and the divergent site of disease（skull, spine, ribs, extremities, pelvis）. The impact of adding 18F-Na F PET/CT to the work-up of patients was also measured in terms of change in their management due to 18F-Na F PET/CT findings. RESULTS: The two imaging methods of 18F-FDG and 18F-fluoride PET/CT were significantly different at the patient-based analysis: Accuracy was 86.7% and 84.4%, respectively（Mc Nemar’s χ2 = 6.23, df = 1, P = 0.01）. Overall, 244 bone lesions were detected in our analysis. The overall accuracy of the two methods was significantly different at lesion-based analysis（Mc Nemar’s χ2 = 93.4, df = 1, P < 0.0001）. In the lesion density-based and site-based analysis, 18F-FDG PET/CT provided more accurate results in the detection of CT-negative metastasis（P < 0.002） and vertebral localizations（P < 0.002）; 18F-Na F PET/CT was more accurate in detecting sclerotic（P < 0.005） and rib lesions（P < 0.04）. 18F-Na F PET/CT led to a change of management in 3 of the 45 patients（6.6%） by revealing findings that were not detected at 18F-FDG PET/CT. CONCLUSION: 18F-FDG PET/CT is a reliable imaging tool in the detection of bone metastasis in most cases, with a diagnostic accuracy that is slightly, but significantly, superior to that of 18F-Na F PET/CT in the general population of breast cancer patients. However, the extremely high sensitivity of 18F-fluoride PET/CT can exploit its diagnostic potential in specific clinical settings(i.e., small CT-evident sclerotic lesions, high clinical suspicious of relapse, and negative 18F-FDG PET and conventional imaging).
Tumor chemoresistance is associated with high aerobic glycolysis rates and reduced oxidative phosphorylation, a phenomenon called "Warburg effect" whose reversal could impair the ability of a wide ...range of cancer cells to survive in the presence or absence of chemotherapy. In previous studies, Short-term-starvation (STS) was shown to protect normal cells and organs but to sensitize different cancer cell types to chemotherapy but the mechanisms responsible for these effects are poorly understood. We tested the cytotoxicity of Oxaliplatin (OXP) combined with a 48hour STS on the progression of CT26 colorectal tumors. STS potentiated the effects of OXP on the suppression of colon carcinoma growth and glucose uptake in both in vitro and in vivo models. In CT26 cells, STS down-regulated aerobic glycolysis, and glutaminolysis, while increasing oxidative phosphorylation. The STS-dependent increase in both Complex I and Complex II-dependent O(2) consumption was associated with increased oxidative stress and reduced ATP synthesis. Chemotherapy caused additional toxicity, which was associated with increased succinate/Complex II-dependent O(2) consumption, elevated oxidative stress and apoptosis .These findings indicate that the glucose and amino acid deficiency conditions imposed by STS promote an anti-Warburg effect characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis.
The choice of imaging techniques in patients with suspected coronary artery disease (CAD) varies between countries, regions, and hospitals. This prospective, multicenter, comparative effectiveness ...study was designed to assess the relative accuracy of commonly used imaging techniques for identifying patients with significant CAD.
A total of 475 patients with stable chest pain and intermediate likelihood of CAD underwent coronary computed tomographic angiography and stress myocardial perfusion imaging by single photon emission computed tomography or positron emission tomography, and ventricular wall motion imaging by stress echocardiography or cardiac magnetic resonance. If ≥1 test was abnormal, patients underwent invasive coronary angiography. Significant CAD was defined by invasive coronary angiography as >50% stenosis of the left main stem, >70% stenosis in a major coronary vessel, or 30% to 70% stenosis with fractional flow reserve ≤0.8. Significant CAD was present in 29% of patients. In a patient-based analysis, coronary computed tomographic angiography had the highest diagnostic accuracy, the area under the receiver operating characteristics curve being 0.91 (95% confidence interval, 0.88-0.94), sensitivity being 91%, and specificity being 92%. Myocardial perfusion imaging had good diagnostic accuracy (area under the curve, 0.74; confidence interval, 0.69-0.78), sensitivity 74%, and specificity 73%. Wall motion imaging had similar accuracy (area under the curve, 0.70; confidence interval, 0.65-0.75) but lower sensitivity (49%, P<0.001) and higher specificity (92%, P<0.001). The diagnostic accuracy of myocardial perfusion imaging and wall motion imaging were lower than that of coronary computed tomographic angiography (P<0.001).
In a multicenter European population of patients with stable chest pain and low prevalence of CAD, coronary computed tomographic angiography is more accurate than noninvasive functional testing for detecting significant CAD defined invasively.
http://www.clinicaltrials.gov. Unique identifier: NCT00979199.
Objectives
Increased detection of prostate cancer (PCa) recurrences using
68
GaGa-PSMA-11 PET/CT has been reported by adding forced diuresis or late-phase imaging to the standard protocol. However, ...the combination of these procedures in the clinical setting is still not standardized.
Methods
One hundred prospectively recruited biochemical recurrent PCa patients were restaged with dual-phase
68
GaGa-PSMA-11 PET/CT from September 2020 to October 2021. All patients received a standard scan (60 min), followed by diuretics (140 min) and a late-phase abdominopelvic scan (180 min). PET readers with low (
n
= 2), intermediate (
n
= 2), or high (
n
= 2) experience rated (i) standard and (ii) standard + forced diuresis late-phase images in a stepwise fashion according to E-PSMA guidelines, scoring their level of confidence. Study endpoints were (i) accuracy against a composite reference standard, (ii) reader’s confidence level, and (iii) interobserver agreement.
Results
Forced diuresis late-phase imaging increased the reader’s confidence category for local and nodal restaging (both
p
< 0.0001), and the interobserver agreement in identifying nodal recurrences (from moderate to substantial,
p
< 0.01). However, it significantly increased diagnostic accuracy exclusively for local uptakes rated by low-experienced readers (from 76.5 to 84%,
p
= 0.05) and for nodal uptakes rated as uncertain at standard imaging (from 68.1 to 78.5%,
p
< 0.05). In this framework, SUVmax kinetics resulted in an independent predictor of PCa recurrence compared to standard metrics, potentially guiding the dual-phase PET/CT interpretation.
Conclusions
The present results do not support the systematic combination of forced diuresis and late-phase imaging in the clinical setting, but allow the identification of patients-, lesions-, and reader-based scenarios that might benefit from it.
Key Points
• Increased detection of prostate cancer recurrences has been reported by adding diuretics administration or an additional late abdominopelvic scan to the standard
68
GaGa-PSMA-11 PET/CT procedure.
• We verified the added value of combined forced diuresis and delayed imaging, showing that this protocol only slightly increases the diagnostic accuracy of
68
GaGa-PSMA-11 PET/CT, thus not justifying its systematic use in clinics.
• However, it can be helpful in specific clinical scenarios, e.g., when PET/CT is reported by low-experienced readers. Moreover, it increased the reader's confidence and the agreement among observers.
Purpose
The endoplasmic reticulum (ER) contains hexose-6P-dehydrogenase (H6PD). This enzyme competes with glucose-6P-phosphatase for processing a variety of phosphorylated hexoses including 2DG-6P. ...The present study aimed to verify whether this ER glucose-processing machinery contributes to brain FDG uptake.
Methods
Effect of the H6PD inhibitor metformin on brain 18F-FDG accumulation was studied, in vivo, by microPET imaging. These data were complemented with the in vitro estimation of the lumped constant (LC). Finally, reticular accumulation of the fluorescent 2DG analogue 2-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino-2-deoxyglucose (2NBDG) and its response to metformin was studied by confocal microscopy in cultured neurons and astrocytes.
Results
Metformin halved brain 18F-FDG accumulation without altering whole body tracer clearance. Ex vivo, this same response faced the doubling of both glucose consumption and lactate release. The consequent fall in LC was not explained by any change in expression or activity of its theoretical determinants (GLUTs, hexokinases, glucose-6P-phosphatase), while it agreed with the drug-induced inhibition of H6PD function. In vitro, 2NBDG accumulation selectively involved the ER lumen and correlated with H6PD activity being higher in neurons than in astrocytes, despite a lower glucose consumption.
Conclusions
The activity of the reticular enzyme H6PD profoundly contributes to brain 18F-FDG uptake. These data challenge the current dogma linking 2DG/FDG uptake to the glycolytic rate and introduce a new model to explain the link between 18-FDG uptake and neuronal activity.
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.
To compare the diagnostic value of striatal (123) I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ((123) I-FP-CIT) single photon emission computed tomography (SPECT) and (123) ...I-metaiodobenzylguanidine ((123) I-MIBG) myocardial scintigraphy in differentiating dementia with Lewy bodies (DLB) from other dementia types.
This prospective longitudinal study included 30 patients with a clinical diagnosis of DLB and 29 patients with non-DLB dementia (Alzheimer disease, n = 16; behavioral variant frontotemporal dementia, n = 13). All patients underwent (123) I-FP-CIT SPECT and (123) I-MIBG myocardial scintigraphy within a few weeks of clinical diagnosis. All diagnoses at each center were agreed upon by the local clinician and an independent expert, both unaware of imaging data, and re-evaluated after 12 months. Each image was visually classified as either normal or abnormal by 3 independent nuclear physicians blinded to patients' clinical data.
Overall, sensitivity and specificity to DLB were respectively 93% and 100% for (123) I-MIBG myocardial scintigraphy, and 90% and 76% for (123) I-FP-CIT SPECT. Lower specificity of striatal compared to myocardial imaging was due to decreased (123) I-FP-CIT uptake in 7 non-DLB subjects (3 with concomitant parkinsonism) who had normal (123) I-MIBG myocardial uptake. Notably, in our non-DLB group, myocardial imaging gave no false-positive readings even in those subjects (n = 7) with concurrent medical illnesses (diabetes and/or heart disease) supposed to potentially interfere with (123) I-MIBG uptake.
(123) I-FP-CIT SPECT and (123) I-MIBG myocardial scintigraphy have similar sensitivity for detecting DLB, but the latter appears to be more specific for excluding non-DLB dementias, especially when parkinsonism is the only "core feature" exhibited by the patient. Our data also indicate that the potential confounding effects of diabetes and heart disease on (123) I-MIBG myocardial scintigraphy results might have been overestimated. Ann Neurol 2016;80:368-378.
PDF
