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1.
Proc Natl Acad Sci U S A ; 117(4): 2092-2098, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31964840

RESUMO

Our purpose is to investigate the feasibility of imaging tumor metabolism in breast cancer patients using 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C label exchange between injected [1-13C]pyruvate and the endogenous tumor lactate pool. Treatment-naïve breast cancer patients were recruited: four triple-negative grade 3 cancers; two invasive ductal carcinomas that were estrogen and progesterone receptor-positive (ER/PR+) and HER2/neu-negative (HER2-), one grade 2 and one grade 3; and one grade 2 ER/PR+ HER2- invasive lobular carcinoma (ILC). Dynamic 13C MRSI was performed following injection of hyperpolarized [1-13C]pyruvate. Expression of lactate dehydrogenase A (LDHA), which catalyzes 13C label exchange between pyruvate and lactate, hypoxia-inducible factor-1 (HIF1α), and the monocarboxylate transporters MCT1 and MCT4 were quantified using immunohistochemistry and RNA sequencing. We have demonstrated the feasibility and safety of hyperpolarized 13C MRI in early breast cancer. Both intertumoral and intratumoral heterogeneity of the hyperpolarized pyruvate and lactate signals were observed. The lactate-to-pyruvate signal ratio (LAC/PYR) ranged from 0.021 to 0.473 across the tumor subtypes (mean ± SD: 0.145 ± 0.164), and a lactate signal was observed in all of the grade 3 tumors. The LAC/PYR was significantly correlated with tumor volume (R = 0.903, P = 0.005) and MCT 1 (R = 0.85, P = 0.032) and HIF1α expression (R = 0.83, P = 0.043). Imaging of hyperpolarized [1-13C]pyruvate metabolism in breast cancer is feasible and demonstrated significant intertumoral and intratumoral metabolic heterogeneity, where lactate labeling correlated with MCT1 expression and hypoxia.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Isótopos de Carbono/química , Isótopos de Carbono/metabolismo , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/metabolismo , Imageamento por Ressonância Magnética/instrumentação , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Ácido Pirúvico/química , Ácido Pirúvico/metabolismo , Simportadores/genética , Simportadores/metabolismo
2.
Neuroimage ; 189: 171-179, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30639333

RESUMO

Hyperpolarized 13C Magnetic Resonance Imaging (13C-MRI) provides a highly sensitive tool to probe tissue metabolism in vivo and has recently been translated into clinical studies. We report the cerebral metabolism of intravenously injected hyperpolarized [1-13C]pyruvate in the brain of healthy human volunteers for the first time. Dynamic acquisition of 13C images demonstrated 13C-labeling of both lactate and bicarbonate, catalyzed by cytosolic lactate dehydrogenase and mitochondrial pyruvate dehydrogenase respectively. This demonstrates that both enzymes can be probed in vivo in the presence of an intact blood-brain barrier: the measured apparent exchange rate constant (kPL) for exchange of the hyperpolarized 13C label between [1-13C]pyruvate and the endogenous lactate pool was 0.012 ±â€¯0.006 s-1 and the apparent rate constant (kPB) for the irreversible flux of [1-13C]pyruvate to [13C]bicarbonate was 0.002 ±â€¯0.002 s-1. Imaging also revealed that [1-13C]pyruvate, [1-13C]lactate and [13C]bicarbonate were significantly higher in gray matter compared to white matter. Imaging normal brain metabolism with hyperpolarized [1-13C]pyruvate and subsequent quantification, have important implications for interpreting pathological cerebral metabolism in future studies.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Isótopos de Carbono , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Ácido Pirúvico , Adulto , Feminino , Humanos , Masculino
3.
NMR Biomed ; 29(4): 387-99, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27414749

RESUMO

Dissolution dynamic nuclear polarization (DNP) enables the metabolism of hyperpolarized (13)C-labelled molecules, such as the conversion of [1-(13)C]pyruvate to [1-(13)C]lactate, to be dynamically and non-invasively imaged in tissue. Imaging of this exchange reaction in animal models has been shown to detect early treatment response and correlate with tumour grade. The first human DNP study has recently been completed, and, for widespread clinical translation, simple and reliable methods are necessary to accurately probe the reaction in patients. However, there is currently no consensus on the most appropriate method to quantify this exchange reaction. In this study, an in vitro system was used to compare several kinetic models, as well as simple model-free methods. Experiments were performed using a clinical hyperpolarizer, a human 3 T MR system, and spectroscopic imaging sequences. The quantitative methods were compared in vivo by using subcutaneous breast tumours in rats to examine the effect of pyruvate inflow. The two-way kinetic model was the most accurate method for characterizing the exchange reaction in vitro, and the incorporation of a Heaviside step inflow profile was best able to describe the in vivo data. The lactate time-to-peak and the lactate-to-pyruvate area under the curve ratio were simple model-free approaches that accurately represented the full reaction, with the time-to-peak method performing indistinguishably from the best kinetic model. Finally, extracting data from a single pixel was a robust and reliable surrogate of the whole region of interest. This work has identified appropriate quantitative methods for future work in the analysis of human hyperpolarized (13)C data.


Assuntos
Espectroscopia de Ressonância Magnética/métodos , Ácido Pirúvico/metabolismo , Animais , Isótopos de Carbono , Feminino , Neoplasias Mamárias Animais/patologia , Modelos Biológicos , Ratos Endogâmicos F344 , Tela Subcutânea/patologia
4.
Radiol Imaging Cancer ; 4(4): e210076, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35838532

RESUMO

Purpose To evaluate glioblastoma (GBM) metabolism by using hyperpolarized carbon 13 (13C) MRI to monitor the exchange of the hyperpolarized 13C label between injected [1-13C]pyruvate and tumor lactate and bicarbonate. Materials and Methods In this prospective study, seven treatment-naive patients (age [mean ± SD], 60 years ± 11; five men) with GBM were imaged at 3 T by using a dual-tuned 13C-hydrogen 1 head coil. Hyperpolarized [1-13C]pyruvate was injected, and signal was acquired by using a dynamic MRI spiral sequence. Metabolism was assessed within the tumor, in the normal-appearing brain parenchyma (NABP), and in healthy volunteers by using paired or unpaired t tests and a Wilcoxon signed rank test. The Spearman ρ correlation coefficient was used to correlate metabolite labeling with lactate dehydrogenase A (LDH-A) expression and some immunohistochemical markers. The Benjamini-Hochberg procedure was used to correct for multiple comparisons. Results The bicarbonate-to-pyruvate (BP) ratio was lower in the tumor than in the contralateral NABP (P < .01). The tumor lactate-to-pyruvate (LP) ratio was not different from that in the NABP (P = .38). The LP and BP ratios in the NABP were higher than those observed previously in healthy volunteers (P < .05). Tumor lactate and bicarbonate signal intensities were strongly correlated with the pyruvate signal intensity (ρ = 0.92, P < .001, and ρ = 0.66, P < .001, respectively), and the LP ratio was weakly correlated with LDH-A expression in biopsy samples (ρ = 0.43, P = .04). Conclusion Hyperpolarized 13C MRI demonstrated variation in lactate labeling in GBM, both within and between tumors. In contrast, bicarbonate labeling was consistently lower in tumors than in the surrounding NABP. Keywords: Hyperpolarized 13C MRI, Glioblastoma, Metabolism, Cancer, MRI, Neuro-oncology Supplemental material is available for this article. Published under a CC BY 4.0 license.


Assuntos
Glioblastoma , Bicarbonatos , Glioblastoma/diagnóstico por imagem , Humanos , Lactato Desidrogenase 5 , Ácido Láctico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ácido Pirúvico/metabolismo
5.
IEEE Trans Med Imaging ; 37(4): 840-850, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28880161

RESUMO

Hyperpolarized MRI with 13C-labelled compounds is an emerging clinical technique allowing in vivo metabolic processes to be characterized non-invasively. Accurate quantification of 13C data, both for clinical and research purposes, typically relies on the use of region-of-interest analysis to detect and compare regions of altered metabolism. However, it is not clear how this should be determined from the five-dimensional data produced and most standard methodologies are unable to exploit the multidimensional nature of the data. Here we propose a solution to the novel problem of 13C image segmentation using a hybrid Markov random field model with continuous fuzzy logic. The algorithm fully utilizes the multi-dimensional data format in order to classify each voxel into one of six distinct classes based on its metabolic characteristics. Bayesian priors fully incorporate spatial, temporal and ratiometric contextual information whilst image contrast from multiple spectral dimensions are considered concurrently by using an analogy from color image segmentation. Performance of the algorithm is demonstrated on in silico data, where the superiority of the approach over a reference thresholding method is consistently observed. Application to in vivo animal data from a pre-clinical subcutaneous tumor model illustrates the ability of the MRF algorithm to successfully detect tumor location whilst avoiding image artifacts. This work has the potential to assist the analysis of human hyperpolarized 13C data in the future.


Assuntos
Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Aprendizado de Máquina não Supervisionado , Algoritmos , Animais , Isótopos de Carbono/química , Simulação por Computador , Meios de Contraste , Lógica Fuzzy , Cadeias de Markov , Modelos Estatísticos , Neoplasias Experimentais/diagnóstico por imagem , Imagens de Fantasmas , Ratos
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