Whole-Body PET/CT Evaluation of Tumor Perfusion Using Generator-Based 62Cu-Ethylglyoxal Bis(Thiosemicarbazonato)Copper(II): Validation by Direct Comparison to 15O-Water in Metastatic Renal Cell Carcinoma

Fletcher, James; Logan, Theodore F.; Eitel, Jacob; Mathias, Carla J.; Ng, Yen; Lacy, Jeffrey L.; Hutchins, Gary D.; Green, Mark

doi:10.2967/jnumed.114.148106

Cited by 11 publications

(6 citation statements)

References 29 publications

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“…In the perfused system, the vascular input function was modeled as a gamma variate; extravasation (k ve ) was assumed to be 0.02-s −1 (Ref. 36) and v e = 0.91. Total SNR for these dynamic data sets was defined as the sum of the half-height full-width area of noise-free spectral peaks over all time points divided by the standard deviation of the Gaussian noise that is subsequently added.…”

Section: C Simulationsmentioning

confidence: 99%

A novel perfused Bloch–McConnell simulator for analyzing the accuracy of dynamic hyperpolarized MRS

et al. 2016

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Purpose: Magnetic resonance spectroscopy of hyperpolarized agents allows real-time detection of metabolism in vivo. However, the nonrenewable nature of these signals necessitates data acquisitions that differ significantly from conventional magnetic resonance imaging. Signal evolution is permanently altered by the data acquisition scheme, potentially leading to sequence parameter-dependent bias in quantification. The authors have developed a novel simulation environment to characterize the effects of sequence parameters on magnetic resonance spectroscopy-based chemical exchange measurements using hyperpolarized pyruvate. Methods: Conventional Bloch-McConnell equations were coupled with a pharmacokinetic model for perfusion to allow realistic simulation of in vivo dynamic hyperpolarized signal evolution. In this study, simulations were conducted to explore effects of excitation angle and repetition time on the observed signal and subsequent parametric analysis. Both high and low apparent exchange rates were modeled under assumption of both perfused and closed systems. Bias due to sampling strategy bias was subsequently tested in vivo. Results: Simulation of dynamic magnetic resonance spectroscopy studies using hyperpolarized pyruvate demonstrated that for closed systems, accurate measurement of the apparent exchange rate was possible over a wide range of sequence parameters. This was true for both high and low apparent exchange rates, although a low exchange rate was associated with larger errors when excitation angles were high. When effects of perfusion were included to account for pyruvate delivery, a more restricted range of settings led to accurate quantification of exchange rates. Perfusion alleviated some of the errors seen at high excitation angles for low exchange rates. Residuals from parametric analysis did not generally correlate with fit accuracy, implying that the quality of the analysis model was not a major driver of error. Animal studies acquired with sequence parameters that are predicted to impart bias showed a significant under estimation of exchange rates (P < 0.035) compared to parameter combinations that are not expected to bias measurements. Conclusions: The authors' results suggest that great care must be taken when measuring dynamic processes by magnetic resonance spectroscopy of hyperpolarized substrates. When comparing apparent exchange rates, choice of sequence parameters will affect the results. Bias introduced by parameters of more advanced acquisition and reconstruction schemes will likely increase compared to the relatively simple dynamic spectroscopy methods tested herein. The modified Bloch-McConnell equations the authors describe will be crucial tools for characterizing and optimizing the performance of these more advanced techniques. C

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Section: C Simulationsmentioning

confidence: 99%

A novel perfused Bloch–McConnell simulator for analyzing the accuracy of dynamic hyperpolarized MRS

et al. 2016

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“…Perfusion of A375 melanoma xenografts was investigated by dynamic small animal PET using the widely available PET tracer [ 18 F]FDG ( Figure 3 A) [ 54 ]. Since [ 18 F]FDG is only a surrogate marker for perfusion, in a subset of nine mice we further used the previously little noticed experimental perfusion tracer [ 64 Cu]Cu-ETS, showing a microsphere-like behavior ( Figure 3 B) [ 55 ]. Tracer kinetic analysis revealed a significantly decreased perfusion-associated rate constant K1 in A375-EphB4 tumors in comparison to mock tumors for [ 18 F]FDG, but not for [ 64 Cu]Cu-ETS ( Figure 4 A,B).…”

Section: Resultsmentioning

confidence: 99%

“…PET, by contrast, allows for non-invasive characterization of parameters like tumor perfusion and hypoxia, which may better reflect the true functional status of a tumor vasculature. Therefore, we investigated perfusion of A375 melanoma xenografts by dynamic small animal PET imaging using [ 18 F]FDG and [ 64 Cu]Cu-ETS, representing a surrogate marker for perfusion and a previously little noticed experimental perfusion tracer, respectively [ 54 , 55 , 68 , 69 ].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Receptor Tyrosine Kinase EphB4 Triggers Tumor Growth and Hypoxia in A375 Melanoma Xenografts: Insights from Multitracer Small Animal Imaging Experiments

et al. 2018

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Experimental evidence has associated receptor tyrosine kinase EphB4 with tumor angiogenesis also in malignant melanoma. Considering the limited in vivo data available, we have conducted a systematic multitracer and multimodal imaging investigation in EphB4-overexpressing and mock-transfected A375 melanoma xenografts. Tumor growth, perfusion, and hypoxia were investigated by positron emission tomography. Vascularization was investigated by fluorescence imaging in vivo and ex vivo. The approach was completed by magnetic resonance imaging, radioluminography ex vivo, and immunohistochemical staining for blood and lymph vessel markers. Results revealed EphB4 to be a positive regulator of A375 melanoma growth, but a negative regulator of tumor vascularization. Resulting in increased hypoxia, this physiological characteristic is considered as highly unfavorable for melanoma prognosis and therapy outcome. Lymphangiogenesis, by contrast, was not influenced by EphB4 overexpression. In order to distinguish between EphB4 forward and EphrinB2, the natural EphB4 ligand, reverse signaling a specific EphB4 kinase inhibitor was applied. Blocking experiments show EphrinB2 reverse signaling rather than EphB4 forward signaling to be responsible for the observed effects. In conclusion, functional expression of EphB4 is considered a promising differentiating characteristic, preferentially determined by non-invasive in vivo imaging, which may improve personalized theranostics of malignant melanoma.

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“…The kit-based [ 62 Cu]Cu-ETS synthesis method has proven to be convenient, rapid, reliable, and robust. Analysis and validation of the performance of [ 62 Cu]Cu-ETS in whole-body tumor perfusion imaging is in progress (Fletcher, et al, 2014). …”

Section: Discussionmentioning

confidence: 99%

Performance of a 62Zn/62Cu microgenerator in kit-based synthesis and delivery of [62Cu]Cu–ETS for PET perfusion imaging

Lacy

Fletcher

et al. 2014

Applied Radiation and Isotopes

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The performance of a commercially produced 62Zn/62Cu microgenerator system, and an associated kit-based radiopharmaceutical synthesis method, was evaluated for clinical site production of [62Cu]Cu-ETS (ethylglyoxal bis(thiosemicarbazonato)copper(II)), an investigational agent for PET perfusion imaging. Using 37 generators, containing 1.84 ± 0.23 GBq 62Zn at 9:00 AM on the day of clinical use, a total of 45 patient doses of [62Cu]Cu-ETS (672 ± 172 MBq) were delivered without difficulty. 62Cu elution yields were high (approximately 90%), accompanied by extremely low 62Zn breakthrough (<0.001%). Radiopharmaceutical preparation, from the start-of-elution to time-of-injection, consumed less than five minutes. The 62Zn/62Cu microgenerator was a dependable source of short-lived positron-emitting 62Cu, and the kit-based synthesis proved to be rapid, robust, and highly reliable for “on-demand” delivery of [62Cu]Cu-ETS for PET perfusion imaging.

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Whole-Body PET/CT Evaluation of Tumor Perfusion Using Generator-Based ⁶²Cu-Ethylglyoxal Bis(Thiosemicarbazonato)Copper(II): Validation by Direct Comparison to ¹⁵O-Water in Metastatic Renal Cell Carcinoma

Cited by 11 publications

References 29 publications

A novel perfused Bloch–McConnell simulator for analyzing the accuracy of dynamic hyperpolarized MRS

A novel perfused Bloch–McConnell simulator for analyzing the accuracy of dynamic hyperpolarized MRS

Overexpression of Receptor Tyrosine Kinase EphB4 Triggers Tumor Growth and Hypoxia in A375 Melanoma Xenografts: Insights from Multitracer Small Animal Imaging Experiments

Performance of a 62Zn/62Cu microgenerator in kit-based synthesis and delivery of [62Cu]Cu–ETS for PET perfusion imaging

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