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Clinical Characteristics of patients imaged with [18F]DASA-23

Imaging of IC-2

Purpose:Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel PET tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and patients with GBM.Experimental Design:[18F]DASA-23 was synthesized with a molar activity of 100.47 ± 29.58 GBq/μmol and radiochemical purity >95%. We performed initial testing of [18F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next, we produced [18F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers and a pilot cohort of patients with glioma.Results:In mouse imaging studies, [18F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio of 3.6 ± 0.5. In human volunteers, [18F]DASA-23 crossed the intact blood–brain barrier and was rapidly cleared. In patients with GBM, [18F]DASA-23 successfully outlined tumors visible on contrast-enhanced MRI. The uptake of [18F]DASA-23 was markedly elevated in GBMs compared with normal brain, and it identified a metabolic nonresponder within 1 week of treatment initiation.Conclusions:We developed and translated [18F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [18F]DASA-23 to assess its utility for imaging therapy–induced normalization of aberrant cancer metabolism.

Purpose: Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel PET tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and patients with GBM. Experimental Design: [18F]DASA-23 was synthesized with a molar activity of 100.47 ± 29.58 GBq/μmol and radiochemical purity >95%. We performed initial testing of [18F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next, we produced [18F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers and a pilot cohort of patients with glioma. Results: In mouse imaging studies, [18F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio of 3.6 ± 0.5. In human volunteers, [18F]DASA-23 crossed the intact blood–brain barrier and was rapidly cleared. In patients with GBM, [18F]DASA-23 successfully outlined tumors visible on contrast-enhanced MRI. The uptake of [18F]DASA-23 was markedly elevated in GBMs compared with normal brain, and it identified a metabolic nonresponder within 1 week of treatment initiation. Conclusions: We developed and translated [18F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [18F]DASA-23 to assess its utility for imaging therapy–induced normalization of aberrant cancer metabolism.

PURPOSE: While sampled or short-frame realizations have shown the potential power of deep learning to reduce radiation dose for PET images, evidence in true injected ultra-low-dose cases is lacking. Therefore, we evaluated deep learning enhancement using a significantly reduced injected radiotracer protocol for amyloid PET/MRI. METHODS: Eighteen participants underwent two separate (18)F-florbetaben PET/MRI studies in which an ultra-low-dose (6.64 ± 3.57 MBq, 2.2 ± 1.3% of standard) or a standard-dose (300 ± 14 MBq) was injected. The PET counts from the standard-dose list-mode data were also undersampled to approximate an ultra-low-dose session. A pre-trained convolutional neural network was fine-tuned using MR images and either the injected or sampled ultra-low-dose PET as inputs. Image quality of the enhanced images was evaluated using three metrics (peak signal-to-noise ratio, structural similarity, and root mean square error), as well as the coefficient of variation (CV) for regional standard uptake value ratios (SUVRs). Mean cerebral uptake was correlated across image types to assess the validity of the sampled realizations. To judge clinical performance, four trained readers scored image quality on a five-point scale (using 15% non-inferiority limits for proportion of studies rated 3 or better) and classified cases into amyloid-positive and negative studies. RESULTS: The deep learning–enhanced PET images showed marked improvement on all quality metrics compared with the low-dose images as well as having generally similar regional CVs as the standard-dose. All enhanced images were non-inferior to their standard-dose counterparts. Accuracy for amyloid status was high (97.2% and 91.7% for images enhanced from injected and sampled ultra-low-dose data, respectively) which was similar to intra-reader reproducibility of standard-dose images (98.6%). CONCLUSION: Deep learning methods can synthesize diagnostic-quality PET images from ultra-low injected dose simultaneous PET/MRI data, demonstrating the general validity of sampled realizations and the potential to reduce dose significantly for amyloid imaging.

Cerebrovascular reactivity (CVR) reflects the capacity of the brain to meet changing physiological demands and can predict the risk of cerebrovascular diseases. CVR can be obtained by measuring the change in cerebral blood flow (CBF) during a brain stress test where CBF is altered by a vasodilator such as acetazolamide. Although the gold standard to quantify CBF is PET imaging, the procedure is invasive and inaccessible to most patients. Arterial spin labeling (ASL) is a non-invasive and quantitative MRI method to measure CBF, and a consensus guideline has been published for the clinical application of ASL. Despite single post labeling delay (PLD) pseudo-continuous ASL (PCASL) being the recommended ASL technique for CBF quantification, it is sensitive to variations to the arterial transit time (ATT) and labeling efficiency induced by the vasodilator in CVR studies. Multi-PLD ASL controls for the changes in ATT, and velocity selective ASL is in theory insensitive to both ATT and labeling efficiency. Here we investigate CVR using simultaneous 15O-water PET and ASL MRI data from 19 healthy subjects. CVR and CBF measured by the ASL techniques were compared using PET as the reference technique. The impacts of blood T1 and labeling efficiency on ASL were assessed using individual measurements of hematocrit and flow velocity data of the carotid and vertebral arteries measured using phase-contrast MRI. We found that multi-PLD PCASL is the ASL technique most consistent with PET for CVR quantification (group mean CVR of the whole brain=42±19% and 40±18% respectively). Single-PLD ASL underestimated the CVR of the whole brain significantly by 15±10% compared with PET (p

PURPOSE: Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel positron emission tomography (PET) tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[(18)F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([(18)F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and GBM patients. EXPERIMENTAL DESIGN: [(18)F]DASA-23 was synthesized with a molar activity of 100.47 ± 29.58 GBq/μmol and radiochemical purity >95%. We performed initial testing of [(18)F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next we produced [(18)F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers, and a pilot cohort of glioma patients. RESULTS: In mouse imaging studies, [(18)F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio (TBR) of 3.6 ± 0.5. In human volunteers, [(18)F]DASA-23 crossed the intact blood-brain barrier and was rapidly cleared. In GBM patients, [(18)F]DASA-23 successfully outlined tumors visible on contrast-enhanced magnetic resonance imaging (MRI). The uptake of [(18)F]DASA-23 was markedly elevated in GBMs compared to normal brain, and it identified a metabolic non-responder within 1-week of treatment initiation. CONCLUSION: We developed and translated [(18)F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [(18)F]DASA-23 to assess its utility for imaging therapy-induced normalization of aberrant cancer metabolism.

Cerebrovascular reactivity (CVR) reflects the capacity of the brain to meet changing physiological demands and can predict the risk of cerebrovascular diseases. CVR can be obtained by measuring the change in cerebral blood flow (CBF) during a brain stress test where CBF is altered by a vasodilator such as acetazolamide. Although the gold standard to quantify CBF is PET imaging, the procedure is invasive and inaccessible to most patients. Arterial spin labeling (ASL) is a non-invasive and quantitative MRI method to measure CBF, and a consensus guideline has been published for the clinical application of ASL. Despite single post labeling delay (PLD) pseudo-continuous ASL (PCASL) being the recommended ASL technique for CBF quantification, it is sensitive to variations to the arterial transit time (ATT) and labeling efficiency induced by the vasodilator in CVR studies. Multi-PLD ASL controls for the changes in ATT, and velocity selective ASL is in theory insensitive to both ATT and labeling efficiency. Here we investigate CVR using simultaneous 15O-water PET and ASL MRI data from 19 healthy subjects. CVR and CBF measured by the ASL techniques were compared using PET as the reference technique. The impacts of blood T1 and labeling efficiency on ASL were assessed using individual measurements of hematocrit and flow velocity data of the carotid and vertebral arteries measured using phase-contrast MRI. We found that multi-PLD PCASL is the ASL technique most consistent with PET for CVR quantification (group mean CVR of the whole brain = 42 ± 19% and 40 ± 18% respectively). Single-PLD ASL underestimated the CVR of the whole brain significantly by 15 ± 10% compared with PET (p

Thirty-five samples of vitamin E supplement softgels, obtained from store shelves, were analyzed for 17 dioxin and furan congeners. Of these samples, 14 were identified as natural vitamin E, containing D- α -tocopherol, as well as lesser amounts of β -, α -, and δ -tocopherols, and the remaining 21 were labeled as synthetic vitamin E, containing a mixture of D- and L- α -tocopherol. The supplements were collected during the years of 2002 and 2004. The seven natural vitamin E supplements collected in 2002 were found to contain significant quantities of dioxins and furans, with an average total toxic equivalence (TEQ) of 0.79 pg/g, compared to 0.10 g/g for the 2004 natural vitamin E supplements. The 21 synthetic vitamin E supplements collected during the same time period showed little or no contamination, with an average TEQ of 0.057 pg/g. Eight samples of deodorizer distillate, from which natural vitamin E is derived, were also collected and analyzed. The distillates exhibit an overall congener pattern similar to that found in the natural vitamin E, but at a much higher average TEQ of 3.4 pg/g. This suggests the possibility of carryover of contamination to the vitamin E samples from the deodorizer distillate during the extraction process. The natural vitamin E supplements collected in 2004 have much lower levels of contamination, suggesting that improved extraction processes may be in use, effectively reducing contamination.

13C NMR data have been correlated to Toxic Equivalency Factors (TEFs) of the 29 PCDDs, PCDFs, or PCBs for which non-zero TEFs have been defined. Such correlations are called quantitative spectrometric data-activity relationship (QSDAR) models. An improved QSDAR model predicted TEFs of 0.037 and 0.004, respectively, for 1,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 1,2,3,4,7-pentachlorodibenzo-p-dioxin (PeCDD), both among the 390 congeners for which zero value TEFs are assumed. A QSDAR model of Relative Potency (REP) values estimated the corresponding values as 0.115 and 0.020. Results from both models indicated that these two congeners may exhibit significant dioxin-like toxicity. If other such congeners have non-zero toxicity, TEF-based risk assessments of some dioxin-, furan-, or PCB-contaminated sites or foods may underestimate toxicity. Both models were extensively cross-validated and the TEF model was externally validated. We confirmed the predictions by an independent in vitro method, a luciferase gene expression assay based on mouse liver cells that found REPs of 0.027 and 0.013, respectively, for 1,3,7,8-TCDD and 1,2,3,4,7-PeCDD. The QSDAR-estimated and gene-expression assayed values agreed. The models were used to predict activity for an applicability domain including 108 non-2,3,7,8 dioxin, furan, or PCB congeners and 2,3,7,8-tetrachlorophenothiazine, a dioxin analog proposed as a drug candidate. This study showed that QSDAR prediction followed by a relatively inexpensive in vitro assay could be used to nominate a few candidates among hundreds for further investigation. It suggested that in silico and in vitro nomination protocols may facilitate practical risk assessment when chemical family members exhibit different degrees of toxicity operating via a common mechanism.

This paper is a case study calibrating well log derived lithology indicators with productivity attributes from modern production logs. More than thirty wells drilled thirty years ago into the South Ellwood Field were completed based on limited understanding of the well log responses in the complex Monterey Formation. From a retrospective study of well productivity, Wylie, Ershaghi and Christensen1 presented a pattern recognition technique for identifying productive intervals. Availability of recently obtained state-of-the-art production logs has provided invaluable information about the relevance of the well log derived potential zones to positively tested productive and undamaged intervals. This paper includes an analysis of the information processing from the Flow View and Gas Holdup Sensor Tool. A calibration of production log data and well log lithology pattern studies is the basis of designing a re-development strategy for untapped intervals not perforated in the initial completion work. Furthermore, the calibration methodology is extended to a nearby field with similar geology for reassessment of reserves potential.

Oxidation of lidocaine and its principal metabolites, monoethylglycine xylidide and glycine xylidide, at glassy carbon electrodes was employed to permit electrochemical detection of these compounds following separation by high-performance liquid chromatography. The absolute detection limits found for these compounds were 2 ng, 5 ng, and 4 ng injected, respectively. The resulting assay was suitable for the routine quantitation of lidocaine and these metabolites in blood serum over the entire therapeutic range, 1-6 micrograms/ml. Total analysis time is 10-15 min.

Cobalt phthalocyanine-containing carbon paste electrodes are used as electrocatalytic amperometric sensors for 6-mercaptopurine, 6-thioguanine, and several related thiopurines in blood plasma after separation by liquid chromatography. Required sample preparation is minimal, and total quantitation time is 8 min or less. Detection limits are 1.5–8 pmol, approximately an order of magnitude better than that obtained with ultraviolet or fluorescence detection.

Les electrodes du titre catalysent l'electrooxydation de composes tel que la cysteine, l'homocysteine, la N-acetylcysteine et le glutathion. Ces electrodes utilisees comme electrodes sensibles pour la detection amperometrique qui suit une chromatographie en phase liquide permettent la detection de ces composes