Sunitha B. Thakur

Integration of 2-hydroxyglutarate-proton magnetic resonance spectroscopy into clinical practice for disease monitoring in isocitrate dehydrogenase-mutant glioma

BACKGROUND The majority of WHO grades II and III gliomas harbor a missense mutation in the metabolic gene isocitrate dehydrogenase (IDH) and accumulate the metabolite R-2-hydroxyglutarate (R-2HG). Prior studies showed that this metabolite can be detected in vivo using proton magnetic-resonance spectroscopy (MRS), but the sensitivity of this methodology and its clinical implications are unknown. METHODS We developed an MR imaging protocol to integrate 2HG-MRS into routine clinical glioma imaging and examined its performance in 89 consecutive glioma patients. RESULTS Detection of 2-hydroxyglutarate (2HG) in IDH-mutant gliomas was closely linked to tumor volume, with sensitivity ranging from 8% for small tumors (<3.4 mL) to 91% for larger tumors (>8 mL). In patients undergoing 2HG-MRS prior to surgery, tumor levels of 2HG corresponded with tumor cellularity but not with tumor grade or mitotic index. Cytoreductive therapy resulted in a gradual decrease in 2HG levels with kinetics that closely mirrored changes in tumor volume. CONCLUSIONS Our study demonstrates that 2HG-MRS can be linked with routine MR imaging to provide quantitative measurements of 2HG in glioma and may be useful as an imaging biomarker to monitor the abundance of IDH-mutant tumor cells noninvasively during glioma therapy and disease monitoring.

Discrimination of Benign and Malignant Breast Lesions by Using Shutter-Speed Dynamic Contrast-enhanced MR Imaging

PURPOSE To assess the accuracy of the shutter-speed approach compared with standard approach dynamic contrast material-enhanced magnetic resonance (MR) imaging pharmacokinetic analysis for breast cancer diagnosis. MATERIALS AND METHODS This study was approved by the institutional review board and was HIPAA compliant. Informed consent was obtained from 89 high-risk women (age range, 28-83 years) who had 92 suspicious lesions with negative findings at mammography (but visible at MR imaging). Each underwent a research dynamic contrast-enhanced MR imaging examination just prior to a clinical MR imaging-guided interventional procedure. Tumor region of interest (ROI) averaged and (for some) pixel-by-pixel dynamic contrast-enhanced time-course data, together with mean arterial input function, were subjected to serial standard and shutter-speed approach analyses to extract pharmacokinetic parameters, including rate constant for passive contrast reagent transfer between plasma and interstitium (K(trans)) and interstitial space volume fraction, or v(e). Pathologic findings were used as reference standards. Diagnostic accuracy was assessed with receiver operating characteristic analyses. RESULTS The pathologic analyses revealed 20 malignant and 72 benign lesions. Positive predictive value of the institutional clinical breast MR imaging protocol was 22%. At 100% sensitivity, ROI-averaged shutter-speed approach K(trans) had significantly (P = .008) higher diagnostic specificity than standard approach K(trans): 86.1% versus 77.8%. The difference in the ROI-averaged K(trans) parameter value, or ΔK(trans) (≡ K(trans) [shutter-speed approach] - K(trans) [standard approach]), had even higher specificity (88.9%). Combined use of ROI analysis and pixel-by-pixel mapping of ΔK(trans) achieved 98.6% specificity at 100% sensitivity. CONCLUSION The use of the shutter-speed dynamic contrast-enhanced MR imaging method has the potential to improve breast cancer diagnostic accuracy and reduce putatively unnecessary biopsy procedures that yield benign pathologic findings. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11102413/-/DC1.

Metabolic imaging: a link between lactate dehydrogenase A, lactate, and tumor phenotype.

Purpose: We compared the metabolic profiles and the association between LDH-A expression and lactate production in two isogenic murine breast cancer cell lines and tumors (67NR and 4T1). These cell lines were derived from a single mammary tumor and have different growth and metabolic phenotypes. Experimental Design: LDH-A expression, lactate concentration, glucose utilization, and oxygen consumption were measured in cells, and the potential relationship between tumor lactate levels [measured by magnetic resonance spectroscopic imaging (MRSI)] and tumor glucose utilization [measured by [18F]2-deoxy-2-fluoro-d-glucose positron emission tomography ([18F]FDG-PET)] was assessed in orthotopic breast tumors derived from these cell lines. Results: We show a substantial difference in LDH-A expression between 67NR and 4T1 cells under normoxia and hypoxia. We also show that small orthotopic 4T1 tumors generate 10-fold more lactate than corresponding 67NR tumors. The high lactate levels in small primary 4T1 tumors are associated with intense pimonidazole staining (a hypoxia indicator). Less-intense hypoxia staining was observed in the larger 67NR tumors and is consistent with the gradual increase and plateau of lactate concentration in enlarging 67NR tumors. Conclusions: Lactate-MRSI has a greater dynamic range than [18F]FDG-PET and may be a more sensitive measure with which to evaluate the aggressive and metastatic potential of primary breast tumors. Clin Cancer Res; 17(19); 6250–61. ©2011 AACR.

Intravoxel Incoherent Motion Diffusion-Weighted MRI at 3.0 T Differentiates Malignant Breast Lesions From Benign Lesions and Breast Parenchyma

To study the differentiation of malignant breast lesions from benign lesions and fibroglandular tissue (FGT) using apparent diffusion coefficient (ADC) and intravoxel incoherent motion (IVIM) parameters.

Breast Cancer Subtype Intertumor Heterogeneity: MRI-Based Features Predict Results of a Genomic Assay

To investigate the association between a validated, gene‐expression‐based, aggressiveness assay, Oncotype Dx RS, and morphological and texture‐based image features extracted from magnetic resonance imaging (MRI).

In vivo 19F magnetic resonance spectroscopy and chemical shift imaging of tri-fluoro-nitroimidazole as a potential hypoxia reporter in solid tumors

Purpose: 2-Nitro-α-[(2,2,2-trifluoroethoxy)methyl]-imidazole-1-ethanol (TF-MISO) was investigated as a potential noninvasive marker of tissue oxygen levels in tumors using 19F magnetic resonance spectroscopy (MRS) and 19F chemical shift imaging. Experimental Designs:In vitro data were obtained using high-performance liquid chromatography on tumor cells incubated under varying oxygen conditions to determine the oxygen-binding characteristics. In vivo data were obtained using a well-characterized hypoxic murine breast tumor (MCa), in addition to studies on a rat prostate tumor model (R3327-AT) implanted in nude mice. Detection of intratumor 19F signal from TF-MISO was done using MRS for up to 10 h following a 75 mg/kg i.v. injection. Localized distribution of the compound in the implanted MCa tumor has been imaged using slice-selective two-dimensional chemical shift imaging 6 h after injection. Results: The in vitro results showed that TF-MISO preferentially accumulates in cells incubated under anoxic conditions. The in vivo 19F MR spectral features (line width and chemical shift) were recorded as a function of time after injection, and the results indicate that the fluorine atoms are indeed sensitive to changes in the local environment while still providing a detectable MR signal. Ex vivo spectra were collected and established the visibility of the 19F signal under conditions of maximum hypoxia. Late time point (>6 h) tumor tissue concentrations, as obtained from 19F MRS, suggest that TF-MISO is reduced and retained in hypoxic tumor. The feasibility of obtaining TF-MISO tumor distribution maps in a reasonable time frame was established. Conclusions: Based on the results presented herein, it is suggested that TF-MISO has the potential to be a valid magnetic resonance hypoxia imaging reporter for both preclinical hypoxia studies and hypoxia-directed clinical therapy.

Relationships between LDH-A, Lactate, and Metastases in 4T1 Breast Tumors

Purpose: To investigate the relationship between lactate dehydrogenase A (LDH-A) expression, lactate concentration, cell metabolism, and metastases in murine 4T1 breast tumors. Experimental Design: Inhibition of LDH-A expression and protein levels were achieved in a metastatic breast cancer cell line (4T1) using short hairpin RNA (shRNA) technology. The relationship between tumor LDH-A protein levels and lactate concentration (measured by magnetic resonance spectroscopic imaging, MRSI) and metastases was assessed. Results: LDH-A knockdown cells (KD9) showed a significant reduction in LDH-A protein and LDH activity, less acid production, decreased transwell migration and invasion, lower proliferation, reduced glucose consumption and glycolysis, and increase in oxygen consumption, reactive oxygen species (ROS), and cellular ATP levels, compared with control (NC) cells cultured in 25 mmol/L glucose. In vivo studies showed lower lactate levels in KD9, KD5, and KD317 tumors than in NC or 4T1 wild-type tumors (P < 0.01), and a linear relationship between tumor LDH-A protein expression and lactate concentration. Metastases were delayed and primary tumor growth rate decreased. Conclusions: We show for the first time that LDH-A knockdown inhibited the formation of metastases, and was accompanied by in vivo changes in tumor cell metabolism. Lactate MRSI can be used as a surrogate to monitor targeted inhibition of LDH-A in a preclinical setting and provides a noninvasive imaging strategy to monitor LDH-A–targeted therapy. This imaging strategy can be translated to the clinic to identify and monitor patients who are at high risk of developing metastatic disease. Clin Cancer Res; 19(18); 5158–69. ©2013 AACR.

Breast cancer molecular subtype classifier that incorporates MRI features.

To use features extracted from magnetic resonance (MR) images and a machine‐learning method to assist in differentiating breast cancer molecular subtypes.

Lactate MRSI and DCE MRI as surrogate markers of prostate tumor aggressiveness

Longitudinal studies of lactate MRSI and dynamic contrast‐enhanced MRI were performed at 4.7 T in two prostate tumor models grown in rats, Dunning R3327‐AT (AT) and Dunning R3327‐H (H), to determine the potential of lactate and the perfusion/permeability parameter Akep as markers of tumor aggressiveness. Subcutaneous AT (n = 12) and H (n = 6) tumors were studied at different volumes between 100 and 2900 mm3 (Groups 1–5). Lactate concentration was determined using selective multiple quantum coherence MRSI with the phantom substitution method. Tumor enhancement after the administration of gadolinium diethylenetriaminepenta‐acetic acid was analyzed using the Brix–Hoffmann model and the Akep parameter was used as a measure of tumor perfusion/permeability. Lactate was not detected in the smallest AT tumors (Group 1; 100–270 mm3). In larger AT tumors, the lactate concentration increased from 2.8 ± 1.0 mm (Group 2; 290–700 mm3) to 8.4 ± 2.9 mm (Group 3; 1000–1340 mm3) and 8.2 ± 2.2 mm (Group 4; 1380–1750 mm3), and then decreased to 5.0 ± 1.7 mm (Group 5; 1900–2500 mm3), and was consistently higher in the tumor core than in the rim. Lactate was not detected in any of the H tumors. The mean tumor Akep values decreased with increasing volume in both tumor types, but were significantly higher in H tumors. In AT tumors, the Akep values were significantly higher in the rim than in the core. Histological hypoxic and necrotic fractions in AT tumors increased with volume from 0% in Group 1 to about 20% and 30%, respectively, in Group 5. Minimal amounts of hypoxia and necrosis were found in H tumors of all sizes. Thus, the presence of lactate and heterogeneous perfusion/permeability are signatures of aggressive, metabolically deprived tumors. Copyright

Diagnostic usefulness of water-to-fat ratio and choline concentration in malignant and benign breast lesions and normal breast parenchyma: An in vivo 1H MRS study†

To compare total choline concentrations ([Cho]) and water‐to‐fat (W/F) ratios of subtypes of malignant lesions, benign lesions, and normal breast parenchyma and determine their usefulness in breast cancer diagnosis. Reference standard was histology.