Toxicology evaluation of radiotracer doses of 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) for human PET imaging: Laboratory analysis of serial blood samples and comparison to previously investigated therapeutic FLT doses

Background: 18F-FLT is a novel PET radiotracer which has demonstrated a strong potential utility for imaging cellular proliferation in human tumors in vivo. To facilitate future regulatory approval of 18F-FLT for clinical use, we wished to demonstrate the safety of radiotracer doses of 18F-FLT administered to human subjects, by: 1) performing an evaluation of the toxicity of 18F-FLT administered in radiotracer amounts for PET imaging, 2) comparing a radiotracer dose of FLT to clinical trial doses of FLT. Methods: Twenty patients gave consent to a 18F-FLT injection, subsequent PET imaging, and blood draws. For each patient, blood samples were collected at multiple times before and after 18F-FLT PET. These samples were assayed for a comprehensive metabolic panel, total bilirubin, complete blood and platelet counts. 18F-FLT doses of 2.59 MBq/Kg with a maximal dose of 185 MBq (5 mCi) were used. Blood time-activity curves were generated for each patient from dynamic PET data, providing a measure of the area under the FLT concentration curve for 12 hours (AUC12). Results: No side effects were reported. Only albumin, red blood cell count, hematocrit and hemoglobin showed a statistically significant decrease over time. These changes are attributed to IV hydration during PET imaging and to subsequent blood loss at surgery. The AUC12 values estimated from imaging data are not significantly different from those found from serial measures of FLT blood concentrations (p = 0.66). The blood samples-derived AUC12 values range from 0.232 ng*h/mL to 1.339 ng*h/mL with a mean of 0.802 � 0.303 ng*h/mL. This corresponds to 0.46% to 2.68% of the lowest and least toxic clinical trial AUC12 of 50 ng*h/mL reported by Flexner et al (1994). This single injection also corresponds to a nearly 3,000-fold lower cumulative dose than in Flexner's twice daily trial. Conclusion: This study shows no evidence of toxicity or complications attributable to 18F-FLT injected intravenously.This study was supported by NIH grant R01 CA115559, 1R01 CA107264, and 1R01 CA80907

Hypermethylation of CCND2 May Reflect a Smoking-Induced Precancerous Change in the Lung

It remains unknown whether tobacco smoke induces DNA hypermethylation as an early event in carcinogenesis or as a late event, specific to overt cancer tissue. Using MethyLight assays, we analyzed 316 lung tissue samples from 151 cancer-free subjects (121 ever-smokers and 30 never-smokers) for hypermethylation of 19 genes previously observed to be hypermethylated in nonsmall cell lung cancers. Only APC (39%), CCND2 (21%), CDH1 (7%), and RARB (4%) were hypermethylated in >2% of these cancer-free subjects. CCND2 was hypermethylated more frequently in ever-smokers (26%) than in never-smokers (3%). CCND2 hypermethylation was also associated with increased age and upper lobe sample location. APC was frequently hypermethylated in both ever-smokers (41%) and never-smokers (30%). BVES, CDH13, CDKN2A (p16), CDKN2B, DAPK1, IGFBP3, IGSF4, KCNH5, KCNH8, MGMT, OPCML, PCSK6, RASSF1, RUNX, and TMS1 were rarely hypermethylated (<2%) in all subjects. Hypermethylation of CCND2 may reflect a smoking-induced precancerous change in the lung

Assessment of Cardiac, Vascular, and Pulmonary Pathobiology In Vivo During Acute COVID-19.

Background Acute COVID-19-related myocardial, pulmonary, and vascular pathology and how these relate to each other remain unclear. To our knowledge, no studies have used complementary imaging techniques, including molecular imaging, to elucidate this. We used multimodality imaging and biochemical sampling in vivo to identify the pathobiology of acute COVID-19. Specifically, we investigated the presence of myocardial inflammation and its association with coronary artery disease, systemic vasculitis, and pneumonitis. Methods and Results Consecutive patients presenting with acute COVID-19 were prospectively recruited during hospital admission in this cross-sectional study. Imaging involved computed tomography coronary angiography (identified coronary disease), cardiac 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron emission tomography/computed tomography (identified vascular, cardiac, and pulmonary inflammatory cell infiltration), and cardiac magnetic resonance (identified myocardial disease) alongside biomarker sampling. Of 33 patients (median age 51 years, 94% men), 24 (73%) had respiratory symptoms, with the remainder having nonspecific viral symptoms. A total of 9 patients (35%, n=9/25) had cardiac magnetic resonance-defined myocarditis. Of these patients, 53% (n=5/8) had myocardial inflammatory cell infiltration. A total of 2 patients (5%) had elevated troponin levels. Cardiac troponin concentrations were not significantly higher in patients with and without myocarditis (8.4 ng/L [interquartile range, IQR: 4.0-55.3] versus 3.5 ng/L [IQR: 2.5-5.5]; P=0.07) or myocardial cell infiltration (4.4 ng/L [IQR: 3.4-8.3] versus 3.5 ng/L [IQR: 2.8-7.2]; P=0.89). No patients had obstructive coronary artery disease or vasculitis. Pulmonary inflammation and consolidation (percentage of total lung volume) was 17% (IQR: 5%-31%) and 11% (IQR: 7%-18%), respectively. Neither were associated with the presence of myocarditis. Conclusions Myocarditis was present in a third patients with acute COVID-19, and the majority had inflammatory cell infiltration. Pneumonitis was ubiquitous, but this inflammation was not associated with myocarditis. The mechanism of cardiac pathology is nonischemic and not attributable to a vasculitic process. Registration URL: https://www.isrctn.com; Unique identifier: ISRCTN12154994

Semi-quantitative metabolic values on FDG PET/CT including extracardiac sites of disease as a predictor of treatment course in patients with cardiac sarcoidosis

Abstract Background Cardiac sarcoidosis is associated with major adverse cardiac events including cardiac arrest, for which anti-inflammatory treatment is indicated. Oral corticosteroid is the mainstay among treatment options; however, adverse effects are a major concern with long-term use. It would be beneficial for providers to predict treatment response and prognosis for proper management strategy of sarcoidosis, though it remains challenging. Fluorine (F)-18 fluorodeoxyglucose (FDG)-positron emission tomography(PET)/computed tomography(CT) has an advantage over anatomical imaging in providing semi-quantitative functional parameters such as standard uptake value (SUV), metabolic volume, and total lesion glycolysis (TLG), which are well-established biomarkers in oncology. However, the relationship between these parameters and treatment response has not been fully investigated in cardiac sarcoidosis. Also, the prognostic value of extracardiac active inflammation noted on FDG-PET/CT in the setting of cardiac sarcoidosis is unclear. The aim of this retrospective study was to investigate the prognostic value of semi-quantitative values of both cardiac and extracardiac disease sites derived from FDG-PET/CT in predicting treatment course in cardiac sarcoidosis. Methods Sixteen consecutive patients with suspected cardiac sarcoidosis, who demonstrated abnormal myocardial activity on cardiac-inflammation FDG-PET/CT encompassing the entire chest/upper abdomen and subsequently underwent corticosteroid therapy for diagnosis of active cardiac sarcoidosis, were included. Semi-quantitative values of hypermetabolic lesions were derived from all visualized organ system and were compared to daily corticosteroid dose at 6 months. Results  Of the 16 patients, 81.3% (13/16) of the patients showed extracardiac involvement. The lesion with the greatest SUV was identified in the heart in 11 patients (68.7%), in the liver in 1 patient (6.3%), and in lymph nodes in 4 patients (25%). The maximum SUV across all visualized organ systems including the heart were 8.8 ± 3.1 for the patients with corticosteroid dose ≤ 10 mg and 12.5 ± 3.3 for those with > 10 mg (P = 0.04). Metabolic volume and TLG across all visualized organ systems or any values in the heart alone showed no significant statistical difference between the two groups. Conclusions Maximum SUV across all involved organ-systems of the chest and upper abdomen, not that of the heart alone, could be a predictor of treatment course of steroid therapy at 6 months in patients with active cardiac sarcoidosis

Toxicology evaluation of radiotracer doses of 3'-deoxy-3'-Ffluorothymidine (F-FLT) for human PET imaging: Laboratory analysis of serial blood samples and comparison to previously investigated therapeutic FLT doses-0

<p><b>Copyright information:</b></p><p>Taken from "Toxicology evaluation of radiotracer doses of 3'-deoxy-3'-[F]fluorothymidine (F-FLT) for human PET imaging: Laboratory analysis of serial blood samples and comparison to previously investigated therapeutic FLT doses"</p><p>http://www.biomedcentral.com/1471-2385/7/3</p><p>BMC Nuclear Medicine 2007;7():3-3.</p><p>Published online 3 Jul 2007</p><p>PMCID:PMC1931583.</p><p></p>�24 h), between day 1 and 7 (1–7 d) and later than one week (>1 wk) after FLT injection. Lines link all values for an individual patient over time. On Figure F (same data as Figure E) the mean +/- standard deviation for albumin is plotted over time. Dotted horizontal lines illustrate the upper and lower normal limits (reference range) for each test