68Ga-EDTA PET/CT imaging and plasma clearance for glomerular filtration rate quantification: comparison to conventional 51Cr-EDTA.

UNLABELLED: Glomerular filtration rate (GFR) can accurately be determined using (51)Cr-ethylenediaminetetraacetic acid (EDTA) plasma clearance counting but is time-consuming and requires technical skills and equipment not always available in imaging departments. (68)Ga-EDTA can be readily available using an onsite generator, and PET/CT enables both imaging of renal function and accurate camera-based quantitation of clearance of activity from blood and its appearance in the urine. This study aimed to assess agreement between (68)Ga-EDTA GFR ((68)Ga-GFR) and (51)Cr-EDTA GFR ((51)Cr-GFR), using serial plasma sampling and PET imaging. METHODS: (68)Ga-EDTA and (51)Cr-EDTA were injected concurrently in 31 patients. Dynamic PET/CT encompassing the kidneys was acquired for 10 min followed by 3 sequential 3-min multibed step acquisitions from kidneys to bladder. PET quantification was performed using renal activity at 1-2 min (PETinitial), renal excretion at 2-10 min (PETearly), and, subsequently, urinary excretion into the collecting system and bladder (PETlate). Plasma sampling at 2, 3, and 4 h was performed, with (68)Ga followed by (51)Cr counting after positron decay. The level of agreement for GFR determination was calculated using a Bland-Altman plot and Pearson correlation coefficient (PCC). RESULTS: (51)Cr-GFR ranged from 10 to 220 mL/min (mean, 85 mL/min). There was good agreement between (68)Ga-GFR and (51)Cr-GFR using serial plasma sampling, with a Bland-Altman bias of -14 ± 20 mL/min and a PCC of 0.94 (95% confidence interval, 0.88-0.97). Of the 3 methods used for camera-based quantification, the strongest correlation was for plasma sampling-derived GFR with PETlate (PCC of 0.90; 95% confidence interval, 0.80-0.95). CONCLUSION: (68)Ga-GFR agreed well with (51)Cr-GFR for estimation of GFR using serial plasma counting. PET dynamic imaging provides a method to estimate GFR without plasma sampling, with the additional advantage of enabling renal imaging in a single study. Additional validation in a larger cohort is warranted to further assess utility.

Analysis of 177Lu-DOTA-octreotate therapy-induced DNA damage in peripheral blood lymphocytes of patients with neuroendocrine tumors.

UNLABELLED: Ionizing radiation-induced DNA double-strand breaks (DSBs) can lead to cell death, genome instability, and carcinogenesis. Immunofluorescence detection of phosphorylated histone variant H2AX (γ-H2AX) is a reliable and sensitive technique to monitor external-beam ionizing radiation-induced DSBs in peripheral blood lymphocytes (PBLs). Here, we investigated whether γ-H2AX could be used as an in vivo marker to assess normal-tissue toxicity after extended internal irradiation with (177)Lu-DOTA-octreotate (LuTate) peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors. METHODS: We analyzed the kinetics of γ-H2AX foci in PBLs of 11 patients undergoing PRRT. The number of γ-H2AX foci was determined before and up to 72 h after treatment. These values were compared with the estimated absorbed dose to blood, spleen, bone marrow, and tumor and with subsequent PBL reduction. RESULTS: The decrease in (177)Lu activity in blood with time followed a biexponential kinetic pattern, with approximately 90% of circulating activity in blood cleared within 2 h. Absorbed dose to blood, but not to spleen or bone marrow, correlated with the administered (177)Lu activity. PRRT increased γ-H2AX foci in lymphocytes in all patients, relative to pretherapy values. The response varied significantly between patients, but the average number of foci indicated a general trend toward an increase at 0.5-4 h with a subsequent decrease by 24-72 h after treatment. The peak number of foci correlated with the absorbed dose to tumor and bone marrow and the extent of PBL reduction. CONCLUSION: γ-H2AX can be exploited in the LuTate PRRT as a biomarker of PBL cytotoxicity. Long-term follow-up studies investigating whether elevated residual γ-H2AX values are associated with acute myelotoxicity and secondary blood malignancy may be worthwhile.

Validation of a 4D-PET maximum intensity projection for delineation of an internal target volume.

PURPOSE: The delineation of internal target volumes (ITVs) in radiation therapy of lung tumors is currently performed by use of either free-breathing (FB) (18)F-fluorodeoxyglucose-positron emission tomography-computed tomography (FDG-PET/CT) or 4-dimensional (4D)-CT maximum intensity projection (MIP). In this report we validate the use of 4D-PET-MIP for the delineation of target volumes in both a phantom and in patients. METHODS AND MATERIALS: A phantom with 3 hollow spheres was prepared surrounded by air then water. The spheres and water background were filled with a mixture of (18)F and radiographic contrast medium. A 4D-PET/CT scan was performed of the phantom while moving in 4 different breathing patterns using a programmable motion device. Nine patients with an FDG-avid lung tumor who underwent FB and 4D-PET/CT and >5 mm of tumor motion were included for analysis. The 3 spheres and patient lesions were contoured by 2 contouring methods (40% of maximum and PET edge) on the FB-PET, FB-CT, 4D-PET, 4D-PET-MIP, and 4D-CT-MIP. The concordance between the different contoured volumes was calculated using a Dice coefficient (DC). The difference in lung tumor volumes between FB-PET and 4D-PET volumes was also measured. RESULTS: The average DC in the phantom using 40% and PET edge, respectively, was lowest for FB-PET/CT (DCAir = 0.72/0.67, DCBackground 0.63/0.62) and highest for 4D-PET/CT-MIP (DCAir = 0.84/0.83, DCBackground = 0.78/0.73). The average DC in the 9 patients using 40% and PET edge, respectively, was also lowest for FB-PET/CT (DC = 0.45/0.44) and highest for 4D-PET/CT-MIP (DC = 0.72/0.73). In the 9 lesions, the target volumes of the FB-PET using 40% and PET edge, respectively, were on average 40% and 45% smaller than the 4D-PET-MIP. CONCLUSION: A 4D-PET-MIP produces volumes with the highest concordance with 4D-CT-MIP across multiple breathing patterns and lesion sizes in both a phantom and among patients. Freebreathing PET/CT consistently underestimates ITV when compared with 4D PET/CT for a lesion affected by respiration.

In vivo tracking of dendritic cells in patients with multiple myeloma.

Dendritic cell (DC) immunotherapy is being actively studied in multiple myeloma (MM). We aimed to use positron emission tomography or single positron emission tomography to determine the in vivo distribution of monocyte-derived nonmatured DC or matured DC (mDC) administered to patients with MM. Eligible patients had stable or slowly progressive MM and elevated serum MUC-1 or MUC-1 expression on marrow plasma cells. DCs were derived from granulocyte-macrophage colony-stimulating factor+ interleukin-13 stimulated autologous monocytes, pulsed with mannan-MUC1 fusion protein, and matured by FMKp and interferon-gamma. Before injection, DCs were labeled with either 18fluorine-fluorodeoxyglucose, 111indium-oxine or 64copper-pyruvaldehyde-bis-N-4-methylthiosemicarbazone. Labeled DCs were given either as a single intravenous dose or by concurrent subcutaneous (SC), intradermal (ID), and intranodal routes. 18Fluorine-fluorodeoxyglucose tracking was unsuccessful owing to high radiolabel efflux. 64Copper-pyruvaldehyde-bis-N-4-methylthiosemicarbazone-labeled mDC (n=2 patients) demonstrated tracking to regional nodes but quantitation was also limited owing to cellular efflux. 111Indium-oxine, however, gave reproducible tracking of both nmDc and mDC (n=6) to regional lymph node after either SC or ID administration, with mDC revealing superior migration to regional lymph node. SC and ID routes produced similar levels of DC migration.

Relationship of hepatic functional imaging to irinotecan pharmacokinetics and genetic parameters of drug elimination.

PURPOSE: The marked variability of irinotecan (Ir) clearance warrants individualized dosing based on hepatic drug handling. The aims of this trial were to identify parameters from functional hepatic nuclear imaging (HNI) that correlate with (1) Ir pharmacology, and (2) single-nucleotide polymorphisms (SNPs) for the ABCB1 (P-glycoprotein) and UGT-1A1 genes, known to influence Ir handling. METHODS: Patients underwent genotyping for ABCB1 SNPs and UTUGT-1A1*28 carriage and HNI with 99mTc-DIDA (acetanilidoiminodiacetic acid)/99mTc-DISIDA (disofenin) and MIBI (99mTc-sestamibi) scans, probes for biliary transport proteins ABCC1 and -2, and ABCB1 function. HNI data were analyzed by noncompartmental and deconvolutional analysis to provide hepatic extraction and biliary excretion parameters. Patients received Ir, fluorouracil, and folinic acid using a weekly x2, every-3-weeks schedule. Plasma was taken for Ir and SN-38 analysis on day 1, cycle 1. RESULTS: Of the 21 patients accrued, Ir pharmacokinetics data were obtained from 16 patients. 99mTc-DIDA/DISIDA percent retention at 1 hour (1-hour RET) correlated to baseline serum bilirubin (P = .008). Both 99mTc-DIDA/DISIDA and MIBI 1-hour RET correlated with SN-38 area under the curve (AUC; P < .01). On multiple regression analysis, SN-38 AUC = -215 + 18.68 x bilirubin + 4.27 x MIBI 1-hour RET (P = .009, R2 = 44.2%). HNI parameters did not correlate with Ir toxicity or UGT1A1*28 carriage. MIBI excretion was prolonged in patients with the ABCB1 exon 26 TT variant allele relative to wild-type (P = .015). CONCLUSION: Functional imaging of hepatic uptake and excretory pathways may have potential to predict Ir pharmacokinetics. Evaluation of a larger cohort as well as polymorphisms in other biliary transporters and UGT1A1 alleles is warranted.