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Background: Glass 90 Y microspheres are produced with known radionuclide impurities. These impurities are not independently monitored. Clinical instruments, including ionization chamber dose calibrators and positron emmission tomography (PET) cameras, can be much more sensitive in detecting signals from these impurities than to signals from 90 Y itself., Purpose: The "typical" levels of 90 Y impurities have been studied to assess their impact on dosimetry during internal implantation, and for the management of waste. However, unaccounted-for decay spectra of impurities can also have an impact on dose calibrator and PET readings. Thus, even what might be considered negligibly small impurity fractions, can in principle cause substantial overestimates of the amount of 90 Y activity present in a sample. To our knowledge, quantitative effects of radionuclide impurities in glass microspheres on activity measurements have not been documented in the field. As activity quantitation for dosimetry and its correlations with outcome becomes more prevalent, the effects of impurities on measurements may remain unaccounted for in dosimetry studies., Methods: In this letter, we review theoretical and physical considerations that will result in asymmetric errors in quantitation from 90 Y impurities and estimate their typical and potential impact on clinical utilization. Among the common impurities 88 Y is of particular concern for its impact on 90 Y dose measurements because of its decay characteristics, along with other isotopes 91 Y and 46 Sc which can also impact measurements., Results: The typical level of 88 Y impurities reported by the manufacturer should only cause small errors in dose calibrator and PET measurements made within the 12-day label-specified use-by period, up to 2.0% and 1.6%, respectively. However, the product specification max allowable impurity levels, specified by the manufacturer, leave open the potential for much greater bias from within the 12-day use-by period, potentially as high as 13.2% for dose calibrator measurements and 10.6% for PET from the 88 Y impurities., Conclusions: While typical levels of impurities appear to have acceptable impact on patient absorbed dose, it should be noted that they can have adverse effects on 90 Y radioactivity measurements. Furthermore, there is currently minimal independent verification and/or monitoring of impurity levels within the field., (© 2023 American Association of Physicists in Medicine.)

Background: The majority of radiopharmaceuticals for use in disease detection and targeted treatment undergo a single radioactive transition (decay) to reach a stable ground state. Complex emitters, which produce a series of daughter radionuclides, are emerging as novel radiopharmaceuticals. The need for validation of chemical and radiopurity with such agents using common quality control instrumentation is an area of active investigation. Here, we demonstrate novel methods to characterize 227 Th and 223 Ra. Materials and Methods: A radio-TLC scanner and a γ-counter, two common and widely accessible technologies, as well as a solid-state α-particle spectral imaging camera were evaluated for their ability to characterize and distinguish 227 Th and 223 Ra. We verified these results through purity evaluation of a novel 227 Th-labeled protein construct. Results: The γ-counter and α-camera distinguished 227 Th from 223 Ra, enabling rapid and quantitative determination of radionuclidic purity. The radio-TLC showed limited ability to describe purity, although use under α-particle-specific settings enhanced resolution. All three methods were able to distinguish a pure from impure 227 Th-labeled protein. Conclusions: The presented quality control evaluation for 227 Th and 223 Ra on three different instruments can be applied to both research and clinical settings as new alpha particle therapies are developed.

Purpose: To devise a new body-habitus normalizer to be used in the calculation of an SUV that is specific to the PET tracer 18F-FDG., Methods: A cohort of 481-patients was selected for analysis of 18F-FDG uptake into tissues unaffected by their disease. Among these, 65-patients had only brain concentrations measured and the remaining 416 were randomly divided into an 86-patient test set and a 330-patient training set. Within the test set, normal liver, spleen and blood measures were made. In the training set, only normal liver concentrations were measured. Using data from the training set, a simple polynomial function of height and weight was selected and optimized in a fitting procedure to predict each patient's mean liver %ID/ml. This function, when used as a normalizer, defines a new SUV metric (SUVfdg) which we compared to SUV metrics normalized by body weight (SUVbw), lean-body mass (SUVlbm) and body surface-area (SUVbsa) in a five-fold cross-validation. SUVfdg was also evaluated in the independent brain-only and whole-body test sets., Results: For patients of all sizes including pediatric patients, the normal range of liver 18F-FDG uptake at 60 minutes post injection in units of SUVfdg is 1.0 ± 0.16. Liver, blood, and spleen SUVfdg in all comparisons had lower coefficients of variation compared to SUVbw SUVlbm and SUVbsa. Blood had a mean SUVfdg of 0.8 ± 0.11 and showed no correlation with age, height, or weight. Brain SUVfdg measures were significantly higher (P<0.01) in pediatric patients (4.7 ± 0.9) compared to adults (3.1 ± 0.6)., Conclusion: A new SUV metric, SUVfdg, is proposed. It is hoped that SUVfdg will prove to be better at classifying tumor lesions compared to SUV metrics in current use. Other tracers may benefit from similarly tracer-specific body habitus normalizers., Competing Interests: The authors have declared that no competing interests exist.

Diseases are a manifestation of how thousands of proteins interact. In several diseases, such as cancer and Alzheimer's disease, proteome-wide disturbances in protein-protein interactions are caused by alterations to chaperome scaffolds termed epichaperomes. Epichaperome-directed chemical probes may be useful for detecting and reversing defective chaperomes. Here we provide structural, biochemical, and functional insights into the discovery of epichaperome probes, with a focus on their use in central nervous system diseases. We demonstrate on-target activity and kinetic selectivity of a radiolabeled epichaperome probe in both cells and mice, together with a proof-of-principle in human patients in an exploratory single group assignment diagnostic study (ClinicalTrials.gov Identifier: NCT03371420). The clinical study is designed to determine the pharmacokinetic parameters and the incidence of adverse events in patients receiving a single microdose of the radiolabeled probe administered by intravenous injection. In sum, we introduce a discovery platform for brain-directed chemical probes that specifically modulate epichaperomes and provide proof-of-principle applications in their use in the detection, quantification, and modulation of the target in complex biological systems., (© 2021. The Author(s).)

Background: The goal of this work was to determine the quantitative accuracy and optimal reconstruction parameters for 124 I-PET imaging in the presence of therapeutic levels of 131 I. In this effort, images were acquired on a GE D710 PET/CT scanner using a NEMA IEC phantom with spheres containing 124 I and increasing amounts of 131 I activity in the background. At each activity level, two scans were acquired, one with the phantom centered in the field of view (FOV) and one 11.2 cm off-center. Reconstructions used an ordered subset expectation maximization algorithm with up to 100 iterations of 16 subsets, with and without time-of-flight (TOF) information. Results were evaluated visually and by comparing the 124 I activity relative to the scan performed in the absence of 131 I., Results: 131 I within the FOV added to the randoms rate, to dead time, and to pile-up within the detectors. Using our standard clinical reconstruction parameters, the image quality and quantitative accuracy suffered at 131 I activities above 1.4 GBq. Convergence rates slowed progressively in the presence of increasing amounts of 131 I for both TOF and nonTOF reconstructions. TOF reconstructions converged more quickly than nonTOF but often towards erroneous concentrations. Iterating nonTOF reconstructions to convergence produced quantitatively accurate images except for the off-center phantom at the very highest level of background 131 I tested., Conclusions: This study shows that quantitative PET is feasible in the presence of large amounts of 131 I. The high randoms fractions resulted in slow reconstruction convergence and negatively impacted TOF corrections and/or the accuracy of TOF information. Therefore, increased iterations and nonTOF reconstructions are recommended., (© 2021. The Author(s).)

Despite the known influence of anatomic variability on internal dosimetry, dosimetry for 18 F-FDG and other diagnostic radiopharmaceuticals is routinely derived using reference phantoms, which embody population-averaged morphometry for a given age and sex. Moreover, phantom format affects dosimetry estimates to varying extent. Here, we applied newly developed mesh format reference phantoms and a patient-dependent phantom library to assess the impact of height, weight, and body contour variation on dosimetry of 18 F-FDG. We compared the mesh reference phantom dosimetry estimates with corresponding estimates from common software to identify differences related to phantom format or software implementation. Our study serves as an example of how more precise patient size-dependent dosimetry methodology could be performed. Methods: Absorbed dose coefficients were computed for the adult mesh reference phantoms and derivative patient-dependent phantom series by Monte Carlo simulation using the PHITS radiation transport code within PARaDIM software. The dose coefficients were compared with reference absorbed dose coefficients obtained from ICRP Publication 128, or generated using software including OLINDA 2.1, OLINDA 1.1, and IDAC-dose 2.1. Results: Differences in dosimetry arising from anatomical variations were shown to be significant, with detriment-weighted dose coefficients for the percentile-specific phantoms varying by up to ±40% relative to the corresponding reference phantom effective dose coefficients, irrespective of phantom format. Similar variations were seen in the individual organ absorbed dose coefficients for the percentile-specific phantoms relative to the reference phantoms. The effective dose coefficient for the mesh reference adult was 0.017 mSv/MBq, which was 5% higher than estimated by a corresponding voxel phantom, and 10% lower than estimated by the stylized phantom format. Conclusion: We observed notable variability in 18 F-FDG dosimetry across morphometrically different patients, supporting the use of patient-dependent phantoms for more accurate dosimetric estimations relative to standard reference dosimetry. These data may help in optimizing imaging protocols and research studies, in particular when longer-lived isotopes are employed., (Copyright © 2021 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Purpose: Paired imaging/therapy with radiolabeled somatostatin receptor (SSTR) antagonists is a novel approach in neuroendocrine tumors (NETs). The aim of this study was to compare tumor uptake of 68 Ga-DOTA-JR11 and 177 Lu-satoreotide tetraxetan ( 177 Lu-DOTA-JR11) in patients with NETs., Methods: As part of a prospective clinical trial, 20 patients with metastatic NETs underwent 68 Ga-DOTA-JR11 PET/CT and serial imaging with 177 Lu-satoreotide tetraxetan. PET/CT and SPECT/CT parameters for lesion uptake and absorbed dose of 177 Lu-satoreotide tetraxetan in lesions were compared using linear regression analysis and Pearson correlation., Results: A total of 95 lesions were analyzed on 68 Ga-DOTA-JR11 PET/CT and 177 Lu-satoreotide tetraxetan SPECT/CT. SUVs and tumor-to-normal-tissue ratios on PET/CT and SPECT/CT were significantly correlated (p < 0.01), but the degree of correlation was modest with Pearson correlation coefficients ranging from 0.3 to 0.7. Variation in intrapatient lesional correlation was observed. Nevertheless, in all patients, the lesion SUVpeak uptake ratio for 177 Lu-satoreotide tetraxetan vs. 68 Ga-DOTA-JR11 was high; even in those with low uptake on 68 Ga-DOTA-JR11 PET/CT (SUVpeak ≤ 10), a ratio of 8.0 ± 5.2 was noted. Correlation of SUVpeak of 68 Ga-DOTA-JR11 with projected 177 Lu-satoreotide tetratexan-absorbed dose (n = 42) was modest (r = 0.5, p < 0.01), while excellent correlation of SUVpeak of 177 Lu-satoreotide tetraxetan with projected 177 Lu-satoreotide tetraxetan-absorbed dose was noted (r = 0.9, p < 0.0001)., Conclusion: Our study shows that 68 Ga-DOTA-JR11 PET can be used for patient selection and PRRT and that low tumor uptake on PET should not preclude patients from treatment with 177 Lu-satoreotide tetraxetan. The ability to use single time-point SPECT/CT for absorbed dose calculations could facilitate dosimetry regimens, save costs, and improve patient convenience.

We developed a first-of-kind dasatinib-derivative imaging agent, 18 F-SKI-249380 ( 1 8 F-SKI), and validated its use for noninvasive in vivo tyrosine kinase-targeted tumor detection in preclinical models. In this study, we assessed the feasibility of using 18 F-SKI for PET imaging in patients with malignancies. Methods: Five patients with a prior diagnosis of breast cancer, renal cell cancer, or leukemia underwent whole-body PET/CT imaging 90 min after injection of 18 F-SKI (mean, 241.24 ± 116.36 MBq) as part of a prospective study. In addition, patients underwent either a 30-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney ( n = 2) or three 10-min whole-body PET/CT scans ( n = 3) immediately after injection and blood-based radioactivity measurements to determine the time course of tracer distribution and facilitate radiation dose estimates. A subset of 3 patients had a delayed whole-body PET/CT scan at 180 min. Biodistribution, dosimetry, and tumor uptake were quantified. Absorbed doses were calculated using OLINDA/EXM 1.0. Results: No adverse events occurred after injection of 18 F-SKI. In total, 27 tumor lesions were analyzed, with a median SUV peak of 1.4 (range, 0.7-2.3) and tumor-to-blood ratios of 1.6 (range, 0.8-2.5) at 90 min after injection. The intratumoral drug concentrations calculated for 4 reference lesions ranged from 0.03 to 0.07 nM. In all reference lesions, constant tracer accumulation was observed between 30 and 90 min after injection. A blood radioassay indicated that radiotracer clearance from blood and plasma was initially rapid (blood half-time, 1.31 ± 0.81 min; plasma, 1.07 ± 0.66 min; n = 4), followed variably by either a prolonged terminal phase (blood half-time, 285 ± 148.49 min; plasma, 240 ± 84.85 min; n = 2) or a small rise to a plateau ( n = 2). Like dasatinib, 18 F-SKI underwent extensive metabolism after administration, as evidenced by metabolite analysis. Radioactivity was predominantly cleared via the hepatobiliary route. The highest absorbed dose estimates (mGy/MBq) in normal tissues were to the right colon (0.167 ± 0.04) and small intestine (0.153 ± 0.03). The effective dose was 0.0258 mSv/MBq (SD, 0.0034 mSv/MBq). Conclusion: 18 F-SKI demonstrated significant tumor uptake, distinct image contrast despite low injected doses, and rapid clearance from blood., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: 124 I-PU-H71 is an investigational first-in-class radiologic agent specific for imaging tumor epichaperome formations. The intracellular epichaperome forms under cellular stress and is a clinically validated oncotherapeutic target. We conducted a first-in-human study of microdose 124 I-PU-H71 for PET to study in vivo biodistribution, pharmacokinetics, metabolism, and safety; and the feasibility of epichaperome-targeted tumor imaging., Experimental Design: Adult patients with cancer ( n = 30) received 124 I-PU-H71 tracer (201±12 MBq, <25 μg) intravenous bolus followed by PET/CT scans and blood radioassays., Results: 124 I-PU-H71 PET detected tumors of different cancer types (breast, lymphoma, neuroblastoma, genitourinary, gynecologic, sarcoma, and pancreas). 124 I-PU-H71 was retained by tumors for several days while it cleared rapidly from bones, healthy soft tissues, and blood. Radiation dosimetry is favorable and patients suffered no adverse effects., Conclusions: Our first-in-human results demonstrate the safety and feasibility of noninvasive in vivo detection of tumor epichaperomes using 124 I-PU-H71 PET, supporting clinical development of PU-H71 and other epichaperome-targeted therapeutics., (©2020 American Association for Cancer Research.)

Purpose: The aim of our study was to investigate the efficacy of 18 F-Fluciclovine brain PET imaging in recurrent gliomas, and to compare the utility of these images to that of contrast enhanced magnetic resonance imaging (MRI) and to [ 11 C-methyl]-L-methionine ( 11 C-Methionine) PET imaging. We also sought to gain insight into the factors affecting the uptake of 18 F-FACBC in both tumors and normal brain, and specifically to evaluate how the uptake in these tissues varied over an extended period of time post injection., Methods: Twenty-seven patients with recurrent or progressive primary brain tumor (based on clinical and MRI/CT data) were studied using dynamic 18 F-Fluciclovine brain imaging for up to 4 h. Of these, 16 patients also had 11 C-Methionine brain scans. Visual findings, semi-quantitative analyses and pharmacokinetic modeling of a subset of the 18 F-Fluciclovine images was conducted. The information derived from these analyses were compared to data from 11 C-Methionine and to contrast-enhanced MRI., Results: 18 F-Fluciclovine was positive for all 27 patients, whereas contrast MRI was indeterminate for three patients. Tumor 18 F-Fluciclovine SUVmax ranged from 1.5 to 10.5 (average: 4.5 ± 2.3), while 11 C-Methionine's tumor SUVmax ranged from 2.2 to 10.2 (average: 5.0 ± 2.2). Image contrast was higher with 18 F-Fluciclovine compared to 11 C-Methionine (p < 0.0001). This was due to 18 F-Fluciclovine's lower background in normal brain tissue (0.5 ± 0.2 compared to 1.3 ± 0.4 for 11 C-Methionine). 18 F-Fluciclovine uptake in both normal brain and tumors was well described by a simple one-compartment (three-parameter: V b ,k 1 ,k 2 ) model. Normal brain was found to approach transient equilibrium with a half-time that varied greatly, ranging from 1.5 to 8.3 h (mean 2.7 ± 2.3 h), and achieving a consistent final distribution volume averaging 1.4 ± 0.2 ml/cc. Tumors equilibrated more rapidly (t 1/2 ranging from 4 to 148 min, average 57 ± 51 min), with an average distribution volume of 3.2 ± 1.1 ml/cc. A qualitative comparison showed that the rate of normal brain uptake of 11 C-Methionine was much faster than that of 18 F-Fluciclovine., Conclusion: Tumor uptake of 18 F-Fluciclovine correlated well with the established brain tumor imaging agent 11 C-Methionine but provided significantly higher image contrast. 18 F-Fluciclovine may be particularly useful when the contrast MRI is non-diagnostic. Based on the data gathered, we were unable to determine whether Fluciclovine uptake was due solely to recurrent tumor or if inflammation or other processes also contributed.

Purpose: Radiographic changes of brain metastases after stereotactic radiosurgery (SRS) can signify tumor recurrence and/or radiation necrosis (RN); however, standard imaging modalities cannot easily distinguish between these two entities. We investigated whether 18 F-Fluorocholine uptake in surgical samples of the resected lesions correlates with pathologic evidence of recurrent tumor and PET imaging., Methods: About 14 patients previously treated with SRS that developed radiographic changes were included. All patients underwent a preoperative 40-min dynamic PET/CT concurrent with 392 ± 11 MBq bolus injection of 18 F-Fluorocholine. 18 F-Fluorocholine pharmacokinetics were evaluated by standardized uptake value (SUV), graphical analysis (Patlak plot; K i P ) and an irreversible two-compartment model (K 1 , k 2 , k 3 , and K i ). 12 out of 14 patients were administered an additional 72 ± 14 MBq injection of 18 F-Fluorocholine 95 ± 26 minutes prior to surgical resection. About 113 resected samples from 12 patients were blindly reviewed by a neuropathologist to assess the viable tumor and necrotic content, microvascular proliferation, reactive gliosis, and mono- and polymorphonuclear inflammatory infiltrates. Correlation between these metrics 18 F-Fluorocholine SUV was investigated with a linear mixed model. Comparison of survival distributions of two groups of patients (population median split of PET SUV max ) was performed with the log-rank test., Results: Exactly 10 out of 12 patients for which surgical samples were acquired exhibited pathologic recurrence. Strong correlation was observed between SUV max as measured from a surgically removed sample with highest uptake and by PET (Pearson's r = 0.66). Patients with 18 F-Fluorocholine PET SUV max > 6 experienced poor survival. Surgical samples with viable tumor had higher 18 F-fluorocholine uptake (SUV) than those without tumor (4.5 ± 3.7 and 2.6 ± 3.0; p = 0.01). 18 F-fluorocholine count data from surgical samples is driven not only by the percentage viable tumor but also by the degree of inflammation and reactive gliosis (p ≤ 0.02; multivariate regression)., Conclusions: 18 F-Fluorocholine accumulation is increased in viable tumor; however, inflammation and gliosis may also lead to elevated uptake. Higher 18 F-Fluorocholine PET uptake portends worse prognosis. Kinetic analysis of dynamic 18 F-Fluorocholine PET imaging supports the adequacy of the simpler static SUV metric.

18 F-fluorodihydrotestosterone ( 18 F-FDHT) PET/CT potentially provides a noninvasive method for assessment of androgen receptor expression in patients with metastatic castration-resistant prostate cancer (mCRPC). The objective of this study was to assess simplified methods for quantifying 18 F-FDHT uptake in mCRPC patients and to assess effects of tumor perfusion on these 18 F-FDHT uptake metrics. Methods: Seventeen mCRPC patients were included in this prospective observational multicenter study. Test and retest 30-min dynamic 18 F-FDHT PET/CT scans with venous blood sampling were performed in 14 patients. In addition, arterial blood sampling and dynamic 15 O-H 2 O scans were obtained in a subset of 6 patients. Several simplified methods were assessed: Patlak plots; SUV normalized to body weight (SUV BW ), lean body mass (SUV LBM ), whole blood (SUV WB ), parent plasma activity concentration (SUV PP ), area under the parent plasma curve (SUV AUC,PP ), and area under the whole-blood input curve (SUV AUC,WB ); and SUV BW corrected for sex hormone-binding globulin levels (SUV SHBG ). Results were correlated with parameters derived from full pharmacokinetic 18 F-FDHT and 15 O-H 2 O. Finally, the repeatability of individual quantitative uptake metrics was assessed. Results: Eighty-seven 18 F-FDHT-avid lesions were evaluated. 18 F-FDHT uptake was best described by an irreversible 2-tissue-compartment model. Replacing the continuous metabolite-corrected arterial plasma input function with an image-derived input function in combination with venous sample data provided similar K i results ( R 2 = 0.98). Patlak K i and SUV AUC,PP showed an excellent correlation ( R 2 > 0.9). SUV BW showed a moderate correlation to K i ( R 2 = 0.70, presumably due to fast 18 F-FDHT metabolism. When calculating SUV SHBG , correlation to K i improved ( R 2 = 0.88). The repeatability of full kinetic modeling parameters was inferior to that of simplified methods (repeatability coefficients > 36% vs. < 28%, respectively). 18 F-FDHT uptake showed minimal blood flow dependency. Conclusion: 18 F-FDHT kinetics in mCRPC patients are best described by an irreversible 2-tissue-compartment model with blood volume parameter. SUV AUC,PP showed a near-perfect correlation with the irreversible 2-tissue-compartment model analysis and can be used for accurate quantification of 18 F-FDHT uptake in whole-body PET/CT scans. In addition, SUV SHBG could potentially be used as an even simpler method to quantify 18 F-FDHT uptake when less complex scanning protocols and accuracy are required., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Androgen ablating drugs increase life expectancy in men with metastatic prostate cancer, but resistance inevitably develops. In a majority of these recurrent tumors, the androgen axis is reactivated in the form of increased androgen receptor (AR) expression. Targeting proteins that are expressed as a down-stream effect of AR activity is a promising rationale for management of this disease. The humanized IgG1 antibody hu11B6 internalizes into prostate and prostate cancer (PCa) cells by binding to the catalytic cleft of human kallikrein 2 (hK2), a prostate specific enzyme governed by the AR-pathway. In a previous study, hu11B6 conjugated with Actinium-225 ( 225 Ac), a high linear energy transfer (LET) radionuclide, was shown to generate an AR-upregulation driven feed-forward mechanism that is believed to enhance therapeutic efficacy. We assessed the efficacy of hu11B6 labeled with a low LET beta-emitter, Lutetium-177 ( 177 Lu) and investigated whether similar tumor killing and AR-enhancement is produced. Moreover, single-photon emission computed tomography (SPECT) imaging of 177 Lu is quantitatively accurate and can be used to perform treatment planning. [ 177 Lu]hu11B6 therefore has significant potential as a theranostic agent. Materials and Methods : Subcutaneous PCa xenografts (LNCaP s.c.) were grown in male mice. Biokinetics at 4-336 h post injection and uptake as a function of the amount of hu11B6 injected at 72 h were studied. Over a 30 to 120-day treatment period the therapeutic efficacy of different activities of [ 177 Lu]hu11B6 were assessed by volumetric tumor measurements, blood cell counts, molecular analysis of the tumor as well as SPECT/CT imaging. Organ specific mean absorbed doses were calculated, using a MIRD-scheme, based on biokinetic data and rodent specific S-factors from a modified MOBY phantom. Tumor tissues of treated xenografts were immunohistochemically (IHC) stained for Ki-67 (proliferation) and AR, SA-β-gal activity (senescence) and analyzed by digital autoradiography (DAR). Results : Organ-to-blood and tumor-to-blood ratios were independent of hu11B6 specific activity except for the highest amount of antibody (150 µg). Tumor accumulation of [ 177 Lu]hu11B6 peaked at 168 h with a specific uptake of 29 ± 9.1 percent injected activity per gram (%IA/g) and low accumulation in normal organs except in the submandibular gland (15 ± 4.5 %IA/g), attributed to a cross-reaction with mice kallikreins in this organ, was seen. However, SPECT imaging with therapeutic amounts of [ 177 Lu]hu11B6 revealed no peak in tumor accumulation at 7 d, probably due to cellular retention of 177 Lu and decreasing tumor volumes. For [ 177 Lu]hu11B6 treated mice, tumor decrements of up to 4/5 of the initial tumor volume and reversible myelotoxicity with a nadir at 12 d were observed after a single injection. Tumor volume reduction correlated with injected activity and the absorbed dose. IHC revealed retained expression of AR throughout treatment and that Ki-67 staining reached a nadir at 9-14 d which coincided with high SA- β-gal activity (14 d). Quantification of nuclei staining showed that Ki-67 expression correlated negatively with activity uptake. AR expression levels in cells surviving therapy compared to previous timepoints and to controls at 30 d were significantly increased (p = 0.017). Conclusions : This study shows that hu11B6 labeled with the low LET beta-emitting radionuclide 177 Lu can deliver therapeutic absorbed doses to prostate cancer xenografts with transient hematological side-effects. The tumor response correlated with the absorbed dose both on a macro and a small scale dosimetric level. Analysis of AR staining showed that AR protein levels increased late in the study suggesting a therapeutic mechanism, a feed forward mechanism coupled to AR driven response to DNA damage or clonal lineage selection, similar to that reported in high LET alpha-particle therapy using 225 Ac labeled hu11B6, however emerging at a later timepoint., Competing Interests: Competing interests: Sven-Erik Strand, David Ulmert and Dan Thorek are shareholders in Diaprost AB who owns the commercial rights for hu11B6 and hold patents for its applications. Sven-Erik Strand and David Ulmert are authors on several patents protecting the use of radiolabeled 11B6. Oskar Vilhelmsson Timmermand and Thuy Tran are the co-authors of a patent, held by Diaprost AB, on humanized 11B6.

Purpose: Somatostatin receptor antagonists have shown promise for imaging neuroendocrine tumors (NETs) in preclinical studies, but clinical data is still very limited. In this study, we assess the feasibility of using the novel somatostatin antagonist 68 Ga-DOTA-JR11 for PET imaging of NETs., Methods: Twenty patients with advanced NETs underwent whole-body PET/CT imaging 60 min after injection of 169 MBq (median) 68 Ga-DOTA-JR11 as part of a prospective study. Volumes of interest were drawn around up to four 68 Ga-DOTA-JR11-avid lesions per patient (with uptake greater than liver) and standardized uptake values were estimated. Additionally, target-to-normal tissue ratios were calculated. A subset of six patients had additional imaging (25-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney, and a whole-body PET/CT scan at 30 min post-injection) to determine the time course of tracer distribution and facilitate radiation dose estimates. Absorbed doses were calculated using OLINDA/EXM 1.0., Results: In contrast to the known biodistribution of somatostatin receptor agonists, little or no uptake above background was seen in the pituitary gland, spleen, adrenals, and uninvolved liver; e.g., median spleen SUV mean 1.4 (range: 0.7-1.8), liver SUV mean 1.1 (0.7-1.9). A total of 42 tumor lesions were analyzed with median SUV max 13.0 (range: 2.9-94), TNR blood 9.3 (1.8-87), TNR spleen 4.9 (1.9-48), TNR kidney 2.2 (0.52-28), and TNR liver 10.5 (2.3-107). Tumor uptake reached plateau levels by 20-30 min post-injection. The highest absorbed dose estimates (mGy/MBq) to normal tissues were: urinary bladder wall (0.30; SD 0.06) and kidneys (0.050; SD 0.013). The effective dose (ICRP 103) was 0.022 (SD 0.003) mSv/MBq., Conclusions: 68 Ga-DOTA-JR11 demonstrated rapid tumor uptake, high tumor/background ratios, and rapid clearance from blood. The low liver background is advantageous and may facilitate detection of liver metastases. Dosimetric data compare favorably with published data for 68 Ga-DOTATATE and 68 Ga-DOTATOC.

Objectives: The phantom filling procedures currently specified by the American College of Radiology (ACR) for its PET accreditation program unnecessarily limit how tight the tolerances can be made on the accuracy requirements for the concentrations measured in the resultant images., Methods: New procedures are proposed to improve the accuracy and consistency of the concentrations within the phantom at the time of imaging. These improvements are gained by exchanging the difficult process of accurately measuring a dose with the more easily achieved accurate measurements of time and liquid volume to control final radioactivity concentrations. A comparison of the results when following the two filling procedures is made., Results: The variability in metrics specified by the ACR was approximately halved by following the new procedures., Conclusion: These improvements allow tighter thresholds to be applied when evaluating image quality and quantitative accuracy of the PET images. These changes also render this phantom data more suitable for inter-PET-scanner harmonization and improve its utility for comparing image reconstruction methods., (© 2019 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

18 F-fluorodihydrotestosterone ( 18 F-FDHT) is a radiolabeled analog of the androgen receptor's primary ligand that is currently being credentialed as a biomarker for prognosis, response, and pharmacodynamic effects of new therapeutics. As part of the biomarker qualification process, we prospectively assessed its reproducibility and repeatability in men with metastatic castration-resistant prostate cancer. Methods: We conducted a prospective multiinstitutional study of metastatic castration-resistant prostate cancer patients undergoing 2 (test/retest) 18 F-FDHT PET/CT scans on 2 consecutive days. Two independent readers evaluated all examinations and recorded SUVs, androgen receptor-positive tumor volumes, and total lesion uptake for the most avid lesion detected in each of 32 predefined anatomic regions. The relative absolute difference and reproducibility coefficient (RC) of each metric were calculated between the test and retest scans. Linear regression analyses, intraclass correlation coefficients (ICCs), and Bland-Altman plots were used to evaluate repeatability of 18 F-FDHT metrics. The coefficient of variation and ICC were used to assess interobserver reproducibility. Results: Twenty-seven patients with 140 18 F-FDHT-avid regions were included. The best repeatability among 18 F-FDHT uptake metrics was found for SUV metrics (SUV max, SUV mean , and SUV peak ), with no significant differences in repeatability among them. Correlations between the test and retest scans were strong for all SUV metrics ( R 2 ≥ 0.92; ICC ≥ 0.97). The RCs of the SUV metrics ranged from 21.3% (SUV peak ) to 24.6% (SUV max ). The test and retest androgen receptor-positive tumor volumes and TLU, respectively, were highly correlated ( R 2 and ICC ≥ 0.97), although variability was significantly higher than that for SUV (RCs > 46.4%). The prostate-specific antigen levels, Gleason score, weight, and age did not affect repeatability, nor did total injected activity, uptake measurement time, or differences in uptake time between the 2 scans. Including the most avid lesion per patient, the 5 most avid lesions per patient, only lesions 4.2 mL or more, only lesions with an SUV of 4 g/mL or more, or normalizing of SUV to area under the parent plasma activity concentration-time curve did not significantly affect repeatability. All metrics showed high interobserver reproducibility (ICC > 0.98; coefficient of variation < 0.2%-10.8%). Conclusion: Uptake metrics derived from 18 F-FDHT PET/CT show high repeatability and interobserver reproducibility., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose To assess the clinical safety, pharmacokinetics, and tumor imaging characteristics of fluorine 18-(2S,4R)-4-fluoroglutamine (FGln), a glutamine analog radiologic imaging agent. Materials and Methods This study was approved by the institutional review board and conducted under a U.S. Food and Drug Administration-approved Investigational New Drug application in accordance with the Helsinki Declaration and the Health Insurance Portability and Accountability Act. All patients provided written informed consent. Between January 2013 and October 2016, 25 adult patients with cancer received an intravenous bolus of FGln tracer (mean, 244 MBq ± 118, <100 μg) followed by positron emission tomography (PET) and blood radioassays. Patient data were summarized with descriptive statistics. FGln biodistribution and plasma amino acid levels in nonfasting patients (n = 13) were compared with those from patients who fasted at least 8 hours before injection (n = 12) by using nonparametric one-way analysis of variance with Bonferroni correction. Tumor FGln avidity versus fluorodeoxyglucose (FDG) avidity in patients with paired PET scans (n = 15) was evaluated with the Fisher exact test. P < .05 was considered indicative of a statistically significant difference. Results FGln PET depicted tumors of different cancer types (breast, pancreas, renal, neuroendocrine, lung, colon, lymphoma, bile duct, or glioma) in 17 of the 25 patients, predominantly clinically aggressive tumors with genetic mutations implicated in abnormal glutamine metabolism. Acute fasting had no significant effect on FGln biodistribution and plasma amino acid levels. FGln-avid tumors were uniformly FDG-avid but not vice versa (P = .07). Patients experienced no adverse effects. Conclusion Preliminary human FGln PET trial results provide clinical validation of abnormal glutamine metabolism as a potential tumor biomarker for targeted radiotracer imaging in several different cancer types. © RSNA, 2018 Online supplemental material is available for this article. Clinical trial registration no. NCT01697930.

Human kallikrein peptidase 2 (hK2) is a prostate specific enzyme whose expression is governed by the androgen receptor (AR). AR is the central oncogenic driver of prostate cancer (PCa) and is also a key regulator of DNA repair in cancer. We report an innovative therapeutic strategy that exploits the hormone-DNA repair circuit to enable molecularly-specific alpha particle irradiation of PCa. Alpha-particle irradiation of PCa is prompted by molecularly specific-targeting and internalization of the humanized monoclonal antibody hu11B6 targeting hK2 and further accelerated by inherent DNA-repair that up-regulate hK2 (KLK2) expression in vivo. hu11B6 demonstrates exquisite targeting specificity for KLK2. A single administration of actinium-225 labeled hu11B6 eradicates disease and significantly prolongs survival in animal models. DNA damage arising from alpha particle irradiation induces AR and subsequently KLK2, generating a unique feed-forward mechanism, which increases binding of hu11B6. Imaging data in nonhuman primates support the possibility of utilizing hu11B6 in man.

Brain tumor patients treated with radiotherapy (RT) often develop cognitive dysfunction, and recent studies suggest that the APOE ε-4 allele may influence cognitive outcome. The ε-4 allele is known to promote beta (β) amyloid deposition in the cortex, and preliminary evidence suggests that RT may be associated with this process. However, it is unknown whether β-amyloid accumulation contributes to treatment neurotoxicity. In this pilot study, we assessed neuropsychological functions and β-amyloid retention using 18 F-florbetaben (FBB) PET in a subset of brain tumor patients who participated in our study of APOE polymorphisms and cognitive functions. Twenty glioma patients treated with conformal RT ± chemotherapy participated in the study: 6 were APOE ε-4 carriers and 14 were non-ε-4 carriers. Patients completed a neuropsychological re-evaluation (mean time interval = 5 years, SD = 0.83) and brain MRI and FBB PET scans. Wilcoxon signed-rank test comparisons between prior and current neuropsychological assessments showed a significant decline in attention (Brief Test of Attention, p = 0.018), and a near significant decline in verbal learning (Hopkins Verbal learning Test-Learning, p = 0.07). Comparisons by APOE status showed significant differences over time in attention/working memory (WAIS-III digits forward, p = 0.028 and digits backward, p = 0.032), with a decline among APOE ε-4 carriers. There were no significant differences in any of the FBB PET analyses between APOE ε-4 carriers and non-ε-4 carriers. The findings suggest that glioma patients may experience worsening in attention and executive functions several years after treatment, and that the APOE ε-4 allele may modulate cognitive decline, but independent of increased β-amyloid deposition.

Purpose: There is growing recognition that biologic features of the tumor microenvironment affect the response to cancer therapies and the outcome of cancer patients. In head and neck cancer (HNC) one such feature is hypoxia. We investigated the utility of 18 F-fluoromisonidazole (FMISO) dynamic positron emission tomography (dPET) for monitoring the early microenvironmental response to chemoradiotherapy in HNC., Experimental Design: Seventy-two HNC patients underwent FMISO dPET scans in a customized immobilization mask (0-30 min dynamic acquisition, followed by 10 min static acquisitions starting at ∼95 min and ∼160 min post-injection) at baseline and early into treatment where patients have already received one cycle of chemotherapy and anywhere from five to ten fractions of 2 Gy per fraction radiation therapy. Voxelwise pharmacokinetic modeling was conducted using an irreversible one-plasma two-tissue compartment model to calculate surrogate biomarkers of tumor hypoxia (k 3 and Tumor-to-Blood Ratio (TBR)), perfusion (K 1 ) and FMISO distribution volume (DV). Additionally, Tumor-to-Muscle Ratios (TMR) were derived by visual inspection by an experienced nuclear medicine physician, with TMR > 1.2 defining hypoxia., Results: One hundred and thirty-five lesions in total were analyzed. TBR, k 3 and DV decreased on early response scans, while no significant change was observed for K 1 . The k 3 -TBR correlation decreased substantially from baseline scans (Pearson's r = 0.72 and 0.76 for mean intratumor and pooled voxelwise values, respectively) to early response scans (Pearson's r = 0.39 and 0.40, respectively). Both concordant and discordant examples of changes in intratumor k 3 and TBR were identified; the latter partially mediated by the change in DV. In 13 normoxic patients according to visual analysis (all having lesions with TMR = 1.2), subvolumes were identified where k 3 indicated the presence of hypoxia., Conclusion: Pharmacokinetic modeling of FMISO dynamic PET reveals a more detailed characterization of the tumor microenvironment and assessment of response to chemoradiotherapy in HNC patients than a single static image does. In a clinical trial where absence of hypoxia in primary tumor and lymph nodes would lead to de-escalation of therapy, the observed disagreement between visual analysis and pharmacokinetic modeling results would have affected patient management in <20% cases. While simple static PET imaging is easily implemented for clinical trials, the clinical applicability of pharmacokinetic modeling remains to be investigated.

Nanomedicine rests at the nexus of medicine, bioengineering, and biology with great potential for improving health through innovation and development of new drugs and devices. Carbon nanotubes are an example of a fibrillar nanomaterial poised to translate into medical practice. The leading candidate material in this class is ammonium-functionalized carbon nanotubes (fCNT) that exhibits unexpected pharmacological behavior in vivo with important biotechnology applications. Here, we provide a multi-organ evaluation of the distribution, uptake and processing of fCNT in nonhuman primates using quantitative whole body positron emission tomography (PET), compartmental modeling of pharmacokinetic data, serum biomarkers and ex vivo pathology investigation. Kidney and liver are the two major organ systems that accumulate and excrete [86Y]fCNT in nonhuman primates and accumulation is cell specific as described by compartmental modeling analyses of the quantitative PET data. A serial two-compartment model explains renal processing of tracer-labeled fCNT; hepatic data fits a parallel two-compartment model. These modeling data also reveal significant elimination of the injected activity (>99.8%) from the primate within 3 days (t1/2 = 11.9 hours). These favorable results in nonhuman primates provide important insight to the fate of fCNT in vivo and pave the way to further engineering design considerations for sophisticated nanomedicines to aid late stage development and clinical use in man.

Purpose: Performance of the preconditioned alternating projection algorithm (PAPA) using relaxed ordered subsets (ROS) with a non-smooth penalty function was investigated in positron emission tomography (PET). A higher order total variation (HOTV) regularizer was applied and a method for unsupervised selection of penalty weights based on the measured data is introduced., Methods: A ROS version of PAPA with HOTV penalty (ROS-HOTV-PAPA) for PET image reconstruction was developed and implemented. Two-dimensional PET data were simulated using two synthetic phantoms (geometric and brain) in geometry similar to GE D690/710 PET/CT with uniform attenuation, and realistic scatter (25%) and randoms (25%). Three count levels (high/medium/low) corresponding to mean information densities (ID¯s) of 125, 25, and 5 noise equivalent counts (NEC) per support voxel were reconstructed using ROS-HOTV-PAPA. The patients' brain and whole body PET data were acquired at similar ID¯s on GE D690 PET/CT with time-of-fight and were reconstructed using ROS-HOTV-PAPA and available clinical ordered-subset expectation-maximization (OSEM) algorithms. A power-law model of the penalty weights' dependence on ID¯ was semi-empirically derived. Its parameters were elucidated from the data and used for unsupervised selection of the penalty weights within a reduced search space. The resulting image quality was evaluated qualitatively, including reduction of staircase artifacts, image noise, spatial resolution and contrast, and quantitatively using root mean squared error (RMSE) as a global metric. The convergence rates were also investigated., Results: ROS-HOTV-PAPA converged rapidly, in comparison to non-ROS-HOTV-PAPA, with no evidence of limit cycle behavior. The reconstructed image quality was superior to optimally post-filtered OSEM reconstruction in terms of noise, spatial resolution, and contrast. Staircase artifacts were not observed. Images of the measured phantom reconstructed using ROS-HOTV-PAPA showed reductions in RMSE of 5%-44% as compared with optimized OSEM. The greatest improvement occurred in the lowest count images. Further, ROS-HOTV-PAPA reconstructions produced images with RMSE similar to images reconstructed using optimally post-filtered OSEM but at one-quarter the NEC., Conclusion: Acceleration of HOTV-PAPA was achieved using ROS. This was accompanied by an improved RMSE metric and perceptual image quality that were both superior to that obtained with either clinical or optimized OSEM. This may allow up to a four-fold reduction of the radiation dose to the patients in a PET study, as compared with current clinical practice. The proposed unsupervised parameter selection method provided useful estimates of the penalty weights for the selected phantoms' and patients' PET studies. In sum, the outcomes of this research indicate that ROS-HOTV-PAPA is an appropriate candidate for clinical applications and warrants further research., (© 2017 American Association of Physicists in Medicine.)

Tumor hypoxia and perfusion are independent prognostic indicators of patient outcome. We developed the methodology for and investigated the utility of multiparametric imaging of tumor hypoxia and perfusion with 18 F-fluoromisonidazole ( 18 F-FMISO) dynamic PET (dPET) in head and neck cancer. Methods: One hundred twenty head and neck cancer patients underwent 0- to 30-min 18 F-FMISO dPET in a customized immobilization mask, followed by 10-min static acquisitions starting at 93 ± 6 and 160 ± 13 min after injection. A total of 248 lesions (≥2 cm 3 ) were analyzed. Voxelwise pharmacokinetic modeling was conducted using an irreversible 1-plasma 2-tissue-compartment model to calculate surrogate biomarkers of tumor hypoxia ( k 3 ), perfusion ( K 1 ), and 18 F-FMISO distribution volume. The analysis was repeated with truncated dPET datasets. Results: Substantial inter- and intratumor heterogeneity was observed for all investigated metrics. Equilibration between the blood and unbound 18 F-FMISO was rapid in all tumors. 18 F-FMISO distribution volume deviated from the expected value of unity, causing discrepancy between k 3 maps and total 18 F-FMISO uptake and reducing the dynamic range of total 18 F-FMISO uptake for quantifying the degree of hypoxia. Both positive and negative trends between hypoxia and perfusion were observed in individual lesions. All investigated metrics were reproducible when calculated from a truncated 20-min dataset. Conclusion: 18 F-FMISO dPET provides the data necessary to generate parametric maps of tumor hypoxia, perfusion, and radiotracer distribution volume. These data clarify the ambiguity in interpreting 18 F-FMISO uptake and improve the characterization of lesions. We show total acquisition times can be reduced to 20 min, facilitating the translation of 18 F-FMISO dPET into the clinic., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: To develop and evaluate a fast and simple tool called dpetstep (Dynamic PET Simulator of Tracers via Emission Projection), for dynamic PET simulations as an alternative to Monte Carlo (MC), useful for educational purposes and evaluation of the effects of the clinical environment, postprocessing choices, etc., on dynamic and parametric images., Methods: The tool was developed in matlab using both new and previously reported modules of petstep (PET Simulator of Tracers via Emission Projection). Time activity curves are generated for each voxel of the input parametric image, whereby effects of imaging system blurring, counting noise, scatters, randoms, and attenuation are simulated for each frame. Each frame is then reconstructed into images according to the user specified method, settings, and corrections. Reconstructed images were compared to MC data, and simple Gaussian noised time activity curves (GAUSS)., Results: dpetstep was 8000 times faster than MC. Dynamic images from dpetstep had a root mean square error that was within 4% on average of that of MC images, whereas the GAUSS images were within 11%. The average bias in dpetstep and MC images was the same, while GAUSS differed by 3% points. Noise profiles in dpetstep images conformed well to MC images, confirmed visually by scatter plot histograms, and statistically by tumor region of interest histogram comparisons that showed no significant differences (p < 0.01). Compared to GAUSS, dpetstep images and noise properties agreed better with MC., Conclusions: The authors have developed a fast and easy one-stop solution for simulations of dynamic PET and parametric images, and demonstrated that it generates both images and subsequent parametric images with very similar noise properties to those of MC images, in a fraction of the time. They believe dpetstep to be very useful for generating fast, simple, and realistic results, however since it uses simple scatter and random models it may not be suitable for studies investigating these phenomena. dpetstep can be downloaded free of cost from https://github.com/CRossSchmidtlein/dPETSTEP.

RNA interference has tremendous yet unrealized potential to treat a wide range of illnesses. Innovative solutions are needed to protect and selectively deliver small interfering RNA (siRNA) cargo to and within a target cell to fully exploit siRNA as a therapeutic tool in vivo. Herein, we describe ammonium-functionalized carbon nanotube (fCNT)-mediated transport of siRNA selectively and with high efficiency to renal proximal tubule cells in animal models of acute kidney injury (AKI). fCNT enhanced siRNA delivery to tubule cells compared to siRNA alone and effectively knocked down the expression of several target genes, includingTrp53,Mep1b,Ctr1, andEGFP A clinically relevant cisplatin-induced murine model of AKI was used to evaluate the therapeutic potential of fCNT-targeted siRNA to effectively halt the pathogenesis of renal injury. Prophylactic treatment with a combination of fCNT/siMep1band fCNT/siTrp53significantly improved progression-free survival compared to controls via a mechanism that required concurrent reduction of meprin-1β and p53 expression. The fCNT/siRNA was well tolerated, and no toxicological consequences were observed in murine models. Toward clinical application of this platform, fCNTs were evaluated for the first time in nonhuman primates. The rapid and kidney-specific pharmacokinetic profile of fCNT in primates was comparable to what was observed in mice and suggests that this approach is amenable for use in humans. The nanocarbon-mediated delivery of siRNA provides a therapeutic means for the prevention of AKI to safely overcome the persistent barrier of nephrotoxicity during medical intervention., Competing Interests: A patent was filed in July 2015: “Method and composition for targeted delivery of therapeutic agents.”, (Copyright © 2016, American Association for the Advancement of Science.)

Purpose: This work describes PETSTEP (PET Simulator of Tracers via Emission Projection): a faster and more accessible alternative to Monte Carlo (MC) simulation generating realistic PET images, for studies assessing image features and segmentation techniques., Methods: PETSTEP was implemented within Matlab as open source software. It allows generating three-dimensional PET images from PET/CT data or synthetic CT and PET maps, with user-drawn lesions and user-set acquisition and reconstruction parameters. PETSTEP was used to reproduce images of the NEMA body phantom acquired on a GE Discovery 690 PET/CT scanner, and simulated with MC for the GE Discovery LS scanner, and to generate realistic Head and Neck scans. Finally the sensitivity (S) and Positive Predictive Value (PPV) of three automatic segmentation methods were compared when applied to the scanner-acquired and PETSTEP-simulated NEMA images., Results: PETSTEP produced 3D phantom and clinical images within 4 and 6 min respectively on a single core 2.7 GHz computer. PETSTEP images of the NEMA phantom had mean intensities within 2% of the scanner-acquired image for both background and largest insert, and 16% larger background Full Width at Half Maximum. Similar results were obtained when comparing PETSTEP images to MC simulated data. The S and PPV obtained with simulated phantom images were statistically significantly lower than for the original images, but led to the same conclusions with respect to the evaluated segmentation methods., Conclusions: PETSTEP allows fast simulation of synthetic images reproducing scanner-acquired PET data and shows great promise for the evaluation of PET segmentation methods., (Copyright © 2015 Associazione Italiana di Fisica Medica. All rights reserved.)

Because of their chemical properties and multiday half lives, iodine-124 and zirconium-89 are being used in a growing number of PET imaging studies. Some aspects of their quantitation, however, still need attention. For (89)Zr the PET images should, in principle, be as quantitatively accurate as similarly reconstructed 18F measurements. We found, however, that images of a 20 cm well calibration phantom containing (89)Zr underestimated the activity by approximately 10% relative to a dose calibrator measurement (Capintec CRC-15R) using a published calibration setting number of 465. PET images of (124)I, in contrast, are complicated by the contribution of decays in cascade that add spurious coincident events to the PET data. When these cascade coincidences are properly accounted for, quantitatively accurate images should be possible. We found, however, that even with this correction we still encountered what appeared to be a large variability in the accuracy of the PET images when compared to dose calibrator measurements made using the calibration setting number, 570, recommended by Capintec. We derive new calibration setting numbers for (89)Zr and (124)I based on their 511 keV photon peaks as measured on an HPGe detector. The peaks were calibrated relative to an 18F standard, the activity level of which was precisely measured in a dose calibrator under well-defined measurement conditions. When measuring (89)Zr on a Capintec CRC-15R we propose the use of calibration setting number 517. And for (124)I, we recommend the use of a copper filter surrounding the sample and the use of calibration setting number 494. The new dose calibrator measurement procedures we propose will result in more consistent and accurate radioactivity measurements of (89)Zr and (124)I. These and other positron emitting radionuclides can be accurately calibrated relative to 18F based on measurements of their 511 keV peaks and knowledge of their relative positron abundances.

Introduction: The increasing use of molecular imaging probes as biomarkers in oncology emphasizes the need for robust and stable methods for quantifying tracer uptake in PET imaging. The primary motivation for this research was to find an accurate method to quantify the total tumor uptake. Therefore we developed a histogram-based method to calculate the background subtracted lesion (BSL) activity and validated BSL by comparing the quantitative consistency with the total lesion glycolysis (TLG) in phantom and patient studies., Methods: A thorax phantom and a PET-ACR quality assurance phantom were scanned with increasing FDG concentrations. Volumes of interest (VOIs) were placed over each chamber. TLG was calculated with a fixed threshold at SUV 2.5 (TLG2.5) and a relative threshold at 42% of SUVmax (TLG42%). The histogram for each VOI was built and BSL was calculated. Comparison with the total injected FDG activity (TIA) was performed using concordance correlation coefficients (CCC) and the slope (a). Fifty consecutive patients with FDG-avid lung tumors were selected under an IRB waiver. TLG42%, TLG2.5 and BSL were compared to the reference standard calculating CCC and the slope., Results: In both phantoms, the CCC for lesions with a TIA ≤50ml*SUV between TIA and BSL was higher and the slope closer to 1 (CCC=0.933, a=1.189), than for TLG42% (CCC=0.350, a=0.731) or TLG2.5 (CCC=0.761, a=0.727). In 50 lung lesions BSL had a slope closer to 1 compared to the reference activity than TLG42% (a=1.084 vs 0.618 - for high activity lesions) and also closer to 1 than TLG2.5 (a=1.117 vs 0.548 - for low activity lesions)., Conclusion: The histogram based BSL correlated better with TIA in both phantom studies than TLG2.5 or TLG42%. Also in lung tumors, the BSL activity is overall more accurate in quantifying the lesion activity compared to the two most commonly applied TLG quantification methods., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: In this pilot study we explored the feasibility of (89)Zr labeled J591 monoclonal antibody positron emission tomography of localized prostate cancer., Materials and Methods: Before scheduled radical prostatectomy 11 patients were injected intravenously with (89)Zr-J591, followed 6 days later by whole body positron emission tomography. Patients underwent surgery the day after imaging. Specimens were imaged by ex vivo micro positron emission tomography and a custom 3 Tesla magnetic resonance scanner coil. Positron emission tomography images and histopathology were correlated., Results: Median patient age was 61 years (range 47 to 68), median prostate specific antigen was 5.2 ng/ml (range 3.5 to 12.0) and median biopsy Gleason score of the 11 index lesions was 7 (range 7 to 9). On histopathology 22 lesions were identified. Median lesion size was 5.5 mm (range 2 to 21) and median Gleason score after radical prostatectomy was 7 (range 6 to 9). Eight of 11 index lesions (72.7%) were identified by in vivo positron emission tomography. Lesion identification improved with increasing lesion size for in vivo and ex vivo positron emission tomography (each p <0.0001), and increasing Gleason score (p = 0.14 and 0.01, respectively). Standardized uptake values appeared to correlate with increased Gleason score but not significantly (p = 0.19)., Conclusions: To our knowledge this is the first report of (89)Zr-J591/prostate specific membrane antigen positron emission tomography in localized prostate cancer cases. In this setting (89)Zr-J591 bound to tumor foci in situ and positron emission tomography identified primarily Gleason score 7 or greater and larger tumors, likely corresponding to clinically significant disease warranting definitive therapy. A future, larger clinical validation trial is planned to better define the usefulness of (89)Zr-J591 positron emission tomography for localized prostate cancer., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Although disorders of consciousness (DOCs) demonstrate widely varying clinical presentations and patterns of structural injury, global down-regulation and bilateral reductions in metabolism of the thalamus and frontoparietal network are consistent findings. We test the hypothesis that global reductions of background synaptic activity in DOCs will associate with changes in the pattern of metabolic activity in the central thalamus and globus pallidus. We compared 32 [(18)F]fluorodeoxyglucose PETs obtained from severely brain-injured patients (BIs) and 10 normal volunteers (NVs). We defined components of the anterior forebrain mesocircuit on high-resolution T1-MRI (ventral, associative, and sensorimotor striatum; globus pallidus; central thalamus and noncentral thalamus). Metabolic profiles for BI and NV demonstrated distinct changes in the pattern of uptake: ventral and association striatum (but not sensorimotor) were significantly reduced relative to global mean uptake after BI; a relative increase in globus pallidus metabolism was evident in BI subjects who also showed a relative reduction of metabolism in the central thalamus. The reversal of globus pallidus and central thalamus profiles across BIs and NVs supports the mesocircuit hypothesis that broad functional (or anatomic) deafferentation may combine to reduce central thalamus activity and release globus pallidus activity in DOCs. In addition, BI subjects showed broad frontoparietal metabolic down-regulation consistent with prior studies supporting the link between central thalamic/pallidal metabolism and down-regulation of the frontoparietal network. Recovery of left hemisphere frontoparietal metabolic activity was further associated with command following.

Many common PET segmentation methods for malignant lesions use surrounding background activity as a reference. To date, background has to be measured by drawing a second volume of interest (VOI) in nearby, undiseased tissue. This is time consuming as two VOIs have to be determined for each lesion. The aim of our study was to analyse whether background activity in different organs and body regions could be calculated from the tumour VOI by histogram analyses. The institutional review board waived informed consent for this retrospective study. For each of the following tumour types and areas - head and neck (neck), lung, hepatic metastasis (liver), melanoma (skin), and cervix (pelvis) - 10 consecutive patients with biopsy-proven tumours who underwent (18)F-fluorodeoxyglucose-PET in January 2012 were retrospectively selected. One lesion was selected and two readers drew a cubical VOI around the lesion (VOItumour) and over the background (VOIBG). The mean value of VOIBG was compared with the mode of the histogram, using equivalence testing with an equivalence margin of ±0.5 SUV. Inter-reader agreement was analysed for the mean background, and the mode of the VOItumour histogram was assessed using the concordance correlation coefficient. For both readers, the mode of VOItumour was equivalent to the mean of VOIBG (P<0.0001 for R1 and R2). The inter-reader agreement was almost perfect, with a concordance correlation coefficient of greater than 0.92 for both the mode of VOItumour and the mean of VOIBG. Background activity determined within a tumour VOI using histogram analysis is equivalent to separately measured mean background values, with an almost perfect inter-reader agreement. This could facilitate PET quantification methods based on background values without increasing workload.

In the era of personalized medicine, there is an urgent need for in vivo techniques able to sensitively detect and quantify molecular activities. Sensitive imaging of gamma rays is widely used; however, radioactive decay is a physical constant, and its signal is independent of biological interactions. Here, we introduce a framework of previously uncharacterized targeted and activatable probes that are excited by a nuclear decay-derived signal to identify and measure molecular signatures of disease. We accomplished this by using Cerenkov luminescence, the light produced by β-particle-emitting radionuclides such as clinical positron emission tomography (PET) tracers. Disease markers were detected using nanoparticles to produce secondary Cerenkov-induced fluorescence. This approach reduces background signal compared to conventional fluorescence imaging. In addition to tumor identification from a conventional PET scan, we demonstrate the medical utility of our approach by quantitatively determining prognostically relevant enzymatic activity. This technique can be applied to monitor other markers and represents a shift toward activatable nuclear medicine agents.

Purpose: Dual-modality PET/MR platforms add a new dimension to patient diagnosis with high resolution, functional, and anatomical imaging. The full potential of this emerging hybrid modality could be realized by using a corresponding dual-modality probe. Here, we report pegylated liposome (LP) formulations, housing a MR T(1) contrast agent (Gd) and the positron-emitting (89)Zr (half-life: 3.27 days), for simultaneous PET and MR tumor imaging capabilities., Methods: (89)Zr oxophilicity was unexpectedly found advantageous for direct radiolabeling of preformed paramagnetic LPs. LPs were conjugated with octreotide to selectively target neuroendocrine tumors via human somatostatin receptor subtype 2 (SSTr2). (89)Zr-Gd-LPs and octreotide-conjugated homolog were physically, chemically and biologically characterized., Results: (89)Zr-LPs showed reasonable stability over serum proteins and chelator challenges for proof-of-concept in vitro and in vivo investigations. Nuclear and paramagnetic tracking quantified superior SSTr2-recognition of octreotide-LP compared to controls., Conclusions: This study demonstrated SSTr2-targeting specificity along with direct chelator-free (89)Zr-labeling of LPs and dual PET/MR imaging properties.

Unlabelled: (18)F-fluoromisonidazole PET, a noninvasive means of identifying hypoxia in tumors, has been widely applied but with mixed results, raising concerns about its accuracy. The objective of this study was to determine whether kinetic analysis of dynamic (18)F-fluoromisonidazole data provides better discrimination of tumor hypoxia than methods based on a simple tissue-to-plasma ratio., Methods: Eleven Dunning R3327-AT prostate tumor-bearing nude rats were immobilized in custom-fabricated whole-body molds, injected intravenously with (18)F-fluoromisonidazole, and imaged dynamically for 105 min. They were then transferred to a robotic system for image-guided measurement of intratumoral partial pressure of oxygen (Po(2)). The dynamic (18)F-fluoromisonidazole uptake data were fitted with 2 variants of a 2-compartment, 3-rate-constant model, one constrained to have K(1) equal to k(2) and the other unconstrained. Parametric images of the rate constants were generated. The Po(2) measurements were compared with spatially registered maps of kinetic rate constants and tumor-to-plasma ratios., Results: The constrained pharmacokinetic model variant was shown to provide fits similar to that of the unconstrained model and did not introduce significant bias in the results. The trapping rate constant, k(3), of the constrained model provided a better discrimination of low Po(2) than the tissue-to-plasma ratio or the k(3) of the unconstrained model., Conclusion: The use of kinetic modeling on a voxelwise basis can identify tumor hypoxia with improved accuracy over simple tumor-to-plasma ratios. An effective means of controlling noise in the trapping rate constant, k(3), without introducing significant bias, is to constrain K(1) equal to k(2) during the fitting process.

Unlabelled: The lymphatic system plays a critical role in the maintenance of healthy tissues. Its function is an important indicator of the presence and extent of disease. In oncology, metastatic spread to local lymph nodes (LNs) is a strong predictor of poor outcome. Clinical methods for the visualization of LNs involve regional injection and tracking of (99m)Tc-sulfur colloid ((99m)Tc-SC) along with absorbent dyes. Intraoperatively, these techniques suffer from the requirement of administration of multiple contrast media ((99m)Tc-SC and isosulfan blue), unwieldy γ-probes, and a short effective surgical window for dyes. Preclinically, imaging of transport through the lymphatics is further hindered by the resolution of lymphoscintigraphy and SPECT. We investigated multimodal imaging in animal models using intradermal administration of (18)F-FDG for combined diagnostic and intraoperative use. PET visualizes LNs with high sensitivity and resolution and low background. Cerenkov radiation (CR) from (18)F-FDG was evaluated to optically guide surgical resection of LNs., Methods: Imaging of (18)F-FDG uptake used PET and sensitive luminescent imaging equipment (for CR). Dynamic PET was performed in both sexes and multiple strains (NCr Nude, C57BL/6, and Nu/Nu) of mice. Biodistribution confirmed the uptake of (18)F-FDG and was compared with that of (99m)Tc-SC. Verification of uptake and the ability to use (18)F-FDG CR to guide nodal removal were confirmed histologically., Results: Intradermal injection of (18)F-FDG clearly revealed lymphatic vessels and LNs by PET. Dynamic imaging revealed rapid and sustained labeling of these structures. Biodistribution of the radiotracer confirmed the active transport of radioglucose in the lymphatics to the local LNs and over time into the general circulation. (18)F-FDG also enabled visualization of LNs through CR, even before surgically revealing the site, and guided LN resection., Conclusion: Intradermal (18)F-FDG can enhance the preclinical investigation of the lymphatics through dynamic, high-resolution, and quantitative tomographic imaging. Clinically, combined PET/Cerenkov imaging has significant potential as a single-dose, dual-modality tracer for diagnostics (PET/CT) and guided resection of LNs (Cerenkov optical).

There has been recent and growing interest in applying Cerenkov radiation (CR) for biological applications. Knowledge of the production efficiency and other characteristics of the CR produced by various radionuclides would help in accessing the feasibility of proposed applications and guide the choice of radionuclides. To generate this information we developed models of CR production efficiency based on the Frank-Tamm equation and models of CR distribution based on Monte-Carlo simulations of photon and β particle transport. All models were validated against direct measurements using multiple radionuclides and then applied to a number of radionuclides commonly used in biomedical applications. We show that two radionuclides, Ac-225 and In-111, which have been reported to produce CR in water, do not in fact produce CR directly. We also propose a simple means of using this information to calibrate high sensitivity luminescence imaging systems and show evidence suggesting that this calibration may be more accurate than methods in routine current use.

Cerenkov luminescence imaging (CLI) is an emerging hybrid modality that utilizes the light emission from many commonly used medical isotopes. Cerenkov radiation (CR) is produced when charged particles travel through a dielectric medium faster than the speed of light in that medium. First described in detail nearly 100 years ago, CR has only recently applied for biomedical imaging purposes. The modality is of considerable interest as it enables the use of widespread luminescence imaging equipment to visualize clinical diagnostic (all PET radioisotopes) and many therapeutic radionuclides. The amount of light detected in CLI applications is significantly lower than other that in other optical imaging techniques such as bioluminescence and fluorescence. However, significant advantages include the use of approved radiotracers and lack of an incident light source, resulting in high signal to background ratios. As well, multiple subjects may be imaged concurrently (up to 5 in common bioluminescent equipment), conferring both cost and time benefits. This review summarizes the field of Cerenkov luminescence imaging to date. Applications of CLI discussed include intraoperative radionuclide-guided surgery, monitoring of therapeutic efficacy, tomographic optical imaging capabilities, and the ability to perform multiplexed imaging using fluorophores excited by the Cerenkov radiation. While technical challenges still exist, Cerenkov imaging has materialized as an important molecular imaging modality.

Introduction: Potential confounding factors in bioluminescence imaging (BLI)-quantification need to be identified to improve its accuracy and repeatability., Purpose: The aim of this study was to study the degree to which plasma protein binding of BLI substrates influences signal intensity and quantification, both in vitro and in vivo., Procedures: Protein binding was assessed using ultrafiltration and spectrophotometry. Effects of increasing serum protein concentrations were studied in vitro, in intact cells expressing Firefly or Renilla luciferase, and in vivo, in a doxorubicin-induced hypoalbuminemia mouse model., Results: Increasing concentrations of serum proteins showed an important negative effect on BLI signal intensity, both for D-luciferin and coelenterazine-dependent reactions. This was due to a decrease in the free fraction of the substrate in the presence of serum proteins of up to 88%. In vivo, hypoalbuminemia was associated with higher BLI signal intensity, although this was only significant in animals with a major decrease in albumin (<2 g/dL). Important kinetic differences, including earlier peak luminescence and a more rapid decline in luminescence, were observed for coelenterazine-dependent BLI under hypoalbuminemic conditions. Changes in protein concentrations can significantly influence BLI quantification and its presence decreases sensitivity in vitro. In vivo, effects on signal intensity and kinetics are only noted at severe hypoalbuminemia and can be neglected in most experimental designs. These findings again emphasize the need for careful interpretation of BLI quantification data.

The purpose of this study was to develop a paradigm for quantitative molecular imaging of bone cell activity. We hypothesized the feasibility of non-invasive imaging of the osteoblast enzyme alkaline phosphatase (ALP) using a small imaging molecule in combination with (19)Flourine magnetic resonance spectroscopic imaging ((19)FMRSI). 6, 8-difluoro-4-methylumbelliferyl phosphate (DiFMUP), a fluorinated ALP substrate that is activatable to a fluorescent hydrolysis product was utilized as a prototype small imaging molecule. The molecular structure of DiFMUP includes two Fluorine atoms adjacent to a phosphate group allowing it and its hydrolysis product to be distinguished using (19)Fluorine magnetic resonance spectroscopy ((19)FMRS) and (19)FMRSI. ALP-mediated hydrolysis of DiFMUP was tested on osteoblastic cells and bone tissue, using serial measurements of fluorescence activity. Extracellular activation of DiFMUP on ALP-positive mouse bone precursor cells was observed. Concurringly, DiFMUP was also activated on bone derived from rat tibia. Marked inhibition of the cell and tissue activation of DiFMUP was detected after the addition of the ALP inhibitor levamisole. (19)FMRS and (19)FMRSI were applied for the non-invasive measurement of DiFMUP hydrolysis. (19)FMRS revealed a two-peak spectrum representing DiFMUP with an associated chemical shift for the hydrolysis product. Activation of DiFMUP by ALP yielded a characteristic pharmacokinetic profile, which was quantifiable using non-localized (19)FMRS and enabled the development of a pharmacokinetic model of ALP activity. Application of (19)FMRSI facilitated anatomically accurate, non-invasive imaging of ALP concentration and activity in rat bone. Thus, (19)FMRSI represents a promising approach for the quantitative imaging of bone cell activity during bone formation with potential for both preclinical and clinical applications.

The purpose of this study is to establish and validate a methodology for estimating the standard deviation of voxels with large activity concentrations within a PET image using replicate imaging that is immediately available for use in the clinic. To do this, ensembles of voxels in the averaged replicate images were compared to the corresponding ensembles in images derived from summed sinograms. In addition, the replicate imaging noise estimate was compared to a noise estimate based on an ensemble of voxels within a region. To make this comparison two phantoms were used. The first phantom was a seven-chamber phantom constructed of 1 liter plastic bottles. Each chamber of this phantom was filled with a different activity concentration relative to the lowest activity concentration with ratios of 1:1, 1:1, 2:1, 2:1, 4:1, 8:1 and 16:1. The second phantom was a GE Well-Counter phantom. These phantoms were imaged and reconstructed on a GE DSTE PET/CT scanner with 2D and 3D reprojection filtered backprojection (FBP), and with 2D- and 3D-ordered subset expectation maximization (OSEM). A series of tests were applied to the resulting images that showed that the region and replicate imaging methods for estimating standard deviation were equivalent for backprojection reconstructions. Furthermore, the noise properties of the FBP algorithms allowed scaling the replicate estimates of the standard deviation by a factor of 1/square root N, where N is the number of replicate images, to obtain the standard deviation of the full data image. This was not the case for OSEM image reconstruction. Due to nonlinearity of the OSEM algorithm, the noise is shown to be both position and activity concentration dependent in such a way that no simple scaling factor can be used to extrapolate noise as a function of counts. The use of the Well-Counter phantom contributed to the development of a heuristic extrapolation of the noise as a function of radius in FBP. In addition, the signal-to-noise ratio for high uptake objects was confirmed to be higher with backprojection image reconstruction methods. These techniques were applied to several patient data sets acquired in either 2D or 3D mode, with (18)F (FLT and FDG). Images of the standard deviation and signal-to-noise ratios were constructed and the standard deviations of the tumors' uptake were determined. Finally, a radial noise extrapolation relationship deduced in this paper was applied to patient data.

We have developed a dual bioluminescent reporter system allowing noninvasive, concomitant imaging of T-cell trafficking, expansion, and activation of nuclear factor of activated T cells (NFAT) in vivo. NFAT activation plays an important role in T-cell activation and T-cell development. Therefore we used this system to determine spatial-temporal activation patterns of (1) proliferating T lymphocytes during graft-versus-host disease (GVHD) and (2) T-cell precursors during T-cell development after allogeneic hematopoietic stem cell transplantation (HSCT). In the first days after HSCT, donor T cells migrated to the peripheral lymph nodes and the intestines, whereas the NFAT activation was dominant in the intestines, suggesting an important role for the intestines in the early stages of alloactivation during development of GVHD. After adoptive transfer of in vitro-derived T-cell receptor (TCR) H-Y transgenic T-cell precursors into B6 (H-2(b)) hosts of both sexes, NFAT signaling and development into CD4(+) or CD8(+) single-positive cells could only be detected in the thymus of female recipients indicating either absence of positive selection or prompt depletion of double-positive thymocytes in the male recipients. Because NFAT plays an important role in a wide range of cell types, our system could provide new insights into a variety of biologic processes.

Background and Purpose: Gd-enhancement provides essential information in the assessment of brain tumors. However, enhancement does not always correlate with histology or disease activity, especially in the setting of current therapies. Our aim was to compare FDG-PET scans to ADC maps and Gd-enhanced MR images in patients with glial neoplasms to assess whether DWI might offer information not available on routine MR imaging sequences and whether such findings have prognostic significance., Materials and Methods: Institutional review board approval was obtained for this retrospective review, which was conducted in full compliance with HIPAA regulations. Twenty-one patients (11 men and 10 women) with glial tumors underwent FDG-PET and MR imaging, including ADC and Gd- enhancement. Subjectively, regions of interest were drawn around the following areas: 1) increased FDG uptake, 2) decreased signal intensity on ADC maps, and 3) Gd-enhancement. Objectively, FDG-PET and MR images were co-registered, and pixel-by-pixel comparison of ADC to PET values was made for all regions of interest. Correlation coefficients (r values) were calculated for each region of interest. Percentage overlap between regions of interest was calculated for each case., Results: Subjective evaluation showed 60% of patients with excellent or good correlation between ADC maps and FDG-PET. Pixel-by-pixel comparison demonstrated r values that ranged from -0.72 to -0.21. There was significantly greater overlap between decreased ADC and increased FDG-PET uptake (67.1 +/- 15.5%) versus overlap between Gd-enhancement and increased FDG-PET uptake (54.4 +/- 27.5%) (P < .05). ADC overlap was greater with increased FDG-PET than with Gd-enhancement in 8/9 cases. Survival data revealed that the presence of restricted diffusion on ADC correlated with patient survival (P < .0001)., Conclusions: ADC maps in patients with brain tumors provide unique information that is analogous to FDG-PET. There is a greater overlap between ADC and FDG-PET compared with Gd-enhancement. ADC maps can serve to approximate tumor grade and predict survival.

Unlabelled: The aim of this study was to develop a clinically applicable noninvasive method to quantify changes in androgen receptor (AR) levels based on (18)F-16beta-fluoro-5alpha-dihydrotestosterone ((18)F-FDHT) PET in prostate cancer patients undergoing therapy., Methods: Thirteen patients underwent dynamic (18)F-FDHT PET over a selected tumor. Concurrent venous blood samples were acquired for blood metabolite analysis. A second cohort of 25 patients injected with (18)F-FDHT underwent dynamic PET of the heart. These data were used to generate a population-based input function, essential for pharmacokinetic modeling. Linear compartmental pharmacokinetic models of increasing complexity were tested on the tumor tissue data. Four suitable models were applied and compared using the Bayesian information criterion (BIC). Model 1 consisted of an instantaneously equilibrating space, followed by a unidirectional trap. Models 2a and 2b contained a reversible space between the instantaneously equilibrating space and the trap, into which metabolites were excluded (2a) or allowed (2b). Model 3 built on model 2b with the addition of a second reversible space preceding the unidirectional trap and from which metabolites were excluded., Results: The half-life of the (18)F-FDHT in blood was between 6 and 7 min. As a consequence, the uptake of (18)F-FDHT in prostate cancer lesions reached a plateau within 20 min as the blood-borne activity was consumed. Radiolabeled metabolites were shown not to bind to ARs in in vitro studies with CWR22 cells. Model 1 produced reasonable and robust fits for all datasets and was judged best by the BIC for 16 of 26 tumor scans. Models 2a, 2b, and 3 were judged best in 7, 2, and 1 cases, respectively., Conclusion: Our study explores the clinical potential of using (18)F-FDHT PET to estimate free AR concentration. This process involved the estimation of a net uptake parameter such as the k(trap) of model 1 that could serve as a surrogate measure of AR expression in metastatic prostate cancer. Our initial studies suggest that a simple body mass-normalized standardized uptake value correlates reasonably well to model-based k(trap) estimates, which we surmise may be proportional to AR expression. Validation studies to test this hypothesis are underway.

Purpose: Bioluminescence imaging is a research tool for studying gene expression levels in small animal models of human disease. Bioluminescence light, however, is strongly scattered in biological tissue and no direct image of the light-emitting reporter probe's location can be obtained. Therefore, the authors have developed a linear image reconstruction method for bioluminescence tomography (BLT) that recovers the three-dimensional spatial bioluminescent source distribution in small animals., Methods: The proposed reconstruction method uses third-order simplified spherical harmonics (SP3) solutions to the equation of radiative transfer for modeling the bioluminescence light propagation in optically nonuniform tissue. The SP3 equations and boundary conditions are solved with a finite-difference (FD) technique on a regular grid. The curved geometry of the animal surface was taken into account with a blocking-off region method for regular grids. Coregistered computed tomography (CT) and magnetic resonance (MR) images provide information regarding the geometry of the skin surface and internal organs. The inverse source problem is defined as an algebraic system of linear equations for the unknown source distribution and is iteratively solved given multiview and multispectral boundary measurements. The average tissue absorption parameters, which are used for the image reconstruction process, were calculated with an evolution strategy (ES) from in vivo measurements using an implanted pointlike source of known location and spectrum. Moreover, anatomical information regarding the location of the internal organs and other tissue structures within the animal's body are provided by coregistered MR images., Results: First, the authors recovered the wavelength-dependent absorption coefficients (average error of 14%) with the ES under ideal conditions by using a numerical mouse model. Next, they reconstructed the average absorption coefficient of a small animal by using an artificial implanted light source and the validated ES. Last, they conducted two in vivo animal experiments and recovered the spatial location of the implanted light source and the spatial distribution of a bioluminescent reporter system located in the kidneys. The source reconstruction results were coregistered to CT and MR images. They further found that accurate bioluminescence image reconstructions could be obtained when segmenting a voidlike cyst with low-scattering and absorption parameters, whereas inaccurate image reconstructions were obtained when assuming a uniform optical parameter distribution instead. The image reconstructions were completed within 23 min on a 3 GHz Intel processor., Conclusions: The authors demonstrated on in vivo examples that the combination of anatomical coregistration, accurate optical tissue properties, multispectral acquisition, and a blocking-off FD-SP3 solution of the radiative transfer model significantly improves the accuracy of the BLT reconstructions.

The procedures we propose make possible the mapping of two-dimensional (2-D) bioluminescence image (BLI) data onto a skin surface derived from a three-dimensional (3-D) anatomical modality [magnetic resonance (MR) or computed tomography (CT)] dataset. This mapping allows anatomical information to be incorporated into bioluminescence tomography (BLT) reconstruction procedures and, when applied using sources visible to both optical and anatomical modalities, can be used to evaluate the accuracy of those reconstructions. Our procedures, based on immobilization of the animal and a priori determined fixed projective transforms, should be more robust and accurate than previously described efforts, which rely on a poorly constrained retrospectively determined warping of the 3-D anatomical information. Experiments conducted to measure the accuracy of the proposed registration procedure found it to have a mean error of 0.36+/-0.23 mm. Additional experiments highlight some of the confounds that are often overlooked in the BLT reconstruction process, and for two of these confounds, simple corrections are proposed.

We present a three-dimensional (3D) bioluminescence image reconstruction method with MRI and CT co-registration for small animal molecular imaging. The multi-spectral light intensity distribution of an optical luciferase-luciferin reporter system is measured at the tissue surface of a small animal for the purpose of 3D image reconstruction. The reporter probe distribution inside tissue is calculated with a linear matrix inversion method and a light propagation model based on the simplified spherical harmonics equations. The animal's surface geometry and anatomy is determined from co-registered CT and MR images in order to locate the reconstructed source distribution relative to the animal's anatomy. We present in vivo bioluminescence reconstruction results that demonstrate the performance of our co-registration method.

The successful translation of gene therapy for clinical application will require the assessment of transgene activity as a measure of the biological function of a therapeutic transgene. Although current imaging permits the noninvasive detection of transgene expression, the critical need for quantitative imaging of the action of the expressed transgene has not been met. In vivo magnetic resonance spectroscopic imaging (MRSI) was applied to quantitatively delineate both the concentration and activity of a cytosine deaminase-uracil phosphoribosyltransferase (CD-UPRT) fusion enzyme expressed from a transgene. MRSI enabled the generation of anatomically accurate maps of the intratumoral heterogeneity in fusion enzyme activity. We observed an excellent association between the CD-UPRT concentration and activity and the percentage of CD-UPRT(+) cells. Moreover, the regional levels of UPRT activity, as measured by imaging, correlated well with the biological affect of the enzyme. This study presents a translational imaging paradigm for precise, in vivo measurements of transgene activity with potential applications in both preclinical and clinical settings.

Multimodality scanners that allow the acquisition of both functional and structural image sets on a single system have recently become available for animal research use. Although the resultant registered functional/structural image sets can greatly enhance the interpretability of the functional data, the cost of multimodality systems can be prohibitive, and they are often limited to two modalities, which generally do not include magnetic resonance imaging. Using a thin plastic wrap to immobilize and fix a mouse or other small animal atop a removable bed, we are able to calculate registrations between all combinations of four different small animal imaging scanners (positron emission tomography, single-photon emission computed tomography, magnetic resonance, and computed tomography [CT]) at our disposal, effectively equivalent to a quadruple-modality scanner. A comparison of serially acquired CT images, with intervening acquisitions on other scanners, demonstrates the ability of the proposed procedures to maintain the rigidity of an anesthetized mouse during transport between scanners. Movement of the bony structures of the mouse was estimated to be 0.62 mm. Soft tissue movement was predominantly the result of the filling (or emptying) of the urinary bladder and thus largely constrained to this region. Phantom studies estimate the registration errors for all registration types to be less than 0.5 mm. Functional images using tracers targeted to known structures verify the accuracy of the functional to structural registrations. The procedures are easy to perform and produce robust and accurate results that rival those of dedicated multimodality scanners, but with more flexible registration combinations and while avoiding the expense and redundancy of multimodality systems.