In vivo MRS measurement of 2‐hydroxyglutarate in patient‐derived IDH‐mutant xenograft mouse models versus glioma patients

Abstract

Purpose:To generate a preclinical model of isocitrate dehydrogenase (IDH) mutant gliomas from glioma patients and design a MRS method to test the compatibility of 2-hydroxyglutarate (2HG) production between the preclinical model and patients. Methods: Five patient-derived xenograft (PDX) mice were generated from two glioma patients with IDH1 R132H mutation. A PRESS sequence was tailored at 9.4 T, with computer simulation and phantom analyses, for improving 2HG detection in mice. 2HG and other metabolites in the PDX mice were measured using the optimized MRS at 9.4 T and compared with 3 T MRS measurements of the metabolites in the parental-tumor patients. Spectral fitting was performed with LCModel using in-house basis spectra. Metabolite levels were quantified with reference to water. Results: The PRESS TE was optimized to be 96 ms, at which the 2HG 2.25 ppm signal was narrow and inverted, thereby leading to unequivocal separation of the 2HG resonance from adjacent signals from other metabolites. The optimized MRS provided precise detection of 2HG in mice compared to short-TE MRS at 9.4 T. The 2HG estimates in PDX mice were in excellent agreement with the 2HG measurements in the patients.

In vivo characterization of physiological and metabolic changes related to isocitrate dehydrogenase 1 mutation expcression by multiparametric MRI and MRS in a rat model with orthotopically grafted human‐derived glioblastoma cell lines

“…34 Further compounding the issue is the fact that the main 2-HG resonances overlap with the NAA and GLU signals in the in vivo MRS spectra at the magnetic field used (4.7 T) and are thus difficult to observe. 35 However, it should be noted that GLU synthesis was shown to be impaired with a higher production of 2-HG in gliomas, which is in line with our observations of reduced GLU in ex vivo HR-MAS and reduced GSH for both in vivo MRS and ex vivo HR-MAS in IDH1+ tumors. 36 For these reasons, a number of MRS studies have recently proposed using metabolites other than 2-HG for IDH1 mutation detection.…”

The Value of Enhanced MR Radiomics in Estimating the IDH1 Genotype in High‐Grade Gliomas

“…Next, we will conduct more extensive and in-depth research with other research centers to verify the reliability of the model. In addition, some new imaging techniques have been used to predict IDH genotypes in gliomas, such as quantitative imaging of D-2-hydroxyglutarate [ 21 ] and MRI-based deep learning method [ 22 ]; these noninvasive highly accurate methods for the determination of IDH status can predict IDH status thereby facilitating clinical translation. However, our research is only based on the radiomic model for noninvasive prediction of glioma IDH genotypes, lacking of multiparameter deep learning method.…”

Utilidad de la Espectroscopía por Resonancia Magnética para la diferenciación de gliomas de alto y bajo grado.

“…24 La espectroscopía por resonancia magnética es capaz de detectar este oncometabolito 25 que resuena a 2,25 ppm y utilizarlo para predecir la mutación IDH1/2 en la lesión de manera no invasiva. 26,27 Esto nos haría capaces dar un pronóstico temprano al paciente y la guía terapéutica tanto quirúrgica como medicamentosa. Además el aumento de 2HG en progresión del tumor y la disminución del mismo en respuesta al tratamiento sería de utilidad para el control de estas lesiones y el manejo posttratamiento.…”