Since its introduction in the early nineties as a promising functional imaging technique in the management of neoplastic disorders, FDG-PET, and subsequently FDG-PET/CT, has become a cornerstone in several oncologic procedures such as tumor staging and restaging, treatment efficacy assessment during or after treatment end and radiotherapy planning. Moreover, the continuous technological progress of image generation and the introduction of sophisticated software to use PET scan as a biomarker paved the way to calculate new prognostic markers such as the metabolic tumor volume (MTV) and the total amount of tumor glycolysis (TLG). FDG-PET/CT proved more sensitive than contrast-enhanced CT scan in staging of several type of lymphoma or in detecting widespread tumor dissemination in several solid cancers, such as breast, lung, colon, ovary and head and neck carcinoma. As a consequence the stage of patients was upgraded, with a change of treatment in 10%–15% of them. One of the most evident advantages of FDG-PET was its ability to detect, very early during treatment, significant changes in glucose metabolism or even complete shutoff of the neoplastic cell metabolism as a surrogate of tumor chemosensitivity assessment. This could enable clinicians to detect much earlier the effectiveness of a given antineoplastic treatment, as compared to the traditional radiological detection of tumor shrinkage, which usually takes time and occurs much later.

The present translational study aimed to verify whether serial F-FDG PET/CT predicts doxorubicin cardiotoxicity. Fifteen athymic mice were treated intravenously with saline ( = 5) or with 5 or 7.5 mg of doxorubicin per kilogram ( = 5 each) and underwent dynamic small-animal PET beforehand and afterward to estimate left ventricular (LV) metabolic rate of glucose (MRGlu). Thereafter, we retrospectively identified 69 patients who had been successfully treated with a regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine for Hodgkin disease (HD) and had undergone 4 consecutive F-FDG PET/CT scans. Volumes of interest were drawn on LV myocardium to quantify mean SUV. All patients were subsequently interviewed by telephone (median follow-up, 30 mo); 36 of them agreed to undergo electrocardiography and transthoracic echocardiography. In mice, LV MRGlu was 17.9 ± 4.4 nmol × min × g at baseline. Doxorubicin selectively and dose-dependently increased this value in the standard-dose (27.9 ± 9 nmol × min × g, < 0.05 vs. controls) and high-dose subgroups (37.2 ± 7.8 nmol × min × g, < 0.01 vs. controls, < 0.05 vs. standard-dose). In HD patients, LV SUV showed a progressive increase during doxorubicin treatment that persisted at follow-up. New-onset cardiac abnormalities appeared in 11 of 36 patients (31%). In these subjects, pretherapy LV SUV was markedly lower with respect to the remaining patients (1.53 ± 0.9 vs. 3.34 ± 2.54, respectively, < 0.01). Multivariate analysis confirmed the predictive value of baseline LV SUV for subsequent cardiac abnormalities. Doxorubicin dose-dependently increases LV MRGlu, particularly in the presence of low baselineF-FDG uptake. These results imply that low myocardial F-FDG uptake before the initiation of doxorubicin chemotherapy in HD patients may predict the development of chemotherapy-induced cardiotoxicity, suggesting that prospective clinical trials are warranted to test this hypothesis.

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ObjectivesThe present study aims to verify the relationship between glucose consumption and uptake of 18F-2-deoxy-glucose (FDG) in the skeletal muscle (SM) of experimental models of streptozotocin-induced diabetes mellitus (STZ-DM).MethodsThe study included 36 Balb/c mice. Two weeks after intraperitoneal administration of saline (control group, n = 18) or 150 mg streptozotocin (STZ-DM group, n = 18), the two cohorts were submitted to an oral glucose tolerance test and were further subdivided into three groups (n = 6 each): untreated and treated with metformin (MTF) at low or high doses (10 or 750 mg/kg daily, respectively). Two weeks thereafter, all mice were submitted to dynamic micro–positron emission tomography (PET) imaging after prolonged fasting. After sacrifice, enzymatic pathways and response to oxidative stress were evaluated in harvested SM.ResultsOn PET imaging, the FDG uptake rate in hindlimb SM was significantly lower in nondiabetic mice as compared with STZ-DM–untreated mice. MTF had no significant effect on SM FDG uptake in untreated mice; however, its high dose induced a significant decrease in STZ-DM animals. Upon conventional analysis, the SM standard uptake value was higher in STZ-DM mice, while MTF was virtually ineffective in either control or STZ-DM models. This metabolic reprogramming was not explained by any change in cytosolic glucose metabolism. By contrast, it closely agreed with the catalytic function of hexose-6P-dehydrogenase (H6PD; i.e., the trigger of a specific pentose phosphate pathway selectively located within the endoplasmic reticulum). In agreement with this role, the H6PD enzymatic response to both STZ-DM and MTF matched the activation of the NADPH-dependent antioxidant responses to the increased generation of reactive oxygen species caused by chronic hyperglycemia. Ex vivo analysis of tracer kinetics confirmed that the enhanced SM avidity for FDG occurred despite a significant reduction in glucose consumption, while it was associated with increased radioactivity transfer to the endoplasmic reticulum.ConclusionsThese data challenge the current dogma linking FDG uptake to the glycolytic rate. They instead introduce a new model considering a strict link between the uptake of this glucose analog, H6PD reticular activity, and oxidative damage in diabetes, at least under fasting condition.