Dariya I. Malyarenko

Multi-system repeatability and reproducibility of apparent diffusion coefficient measurement using an ice-water phantom

To determine quantitative quality control procedures to evaluate technical variability in multi‐center measurements of the diffusion coefficient of water as a prerequisite to use of the biomarker apparent diffusion coefficient (ADC) in multi‐center clinical trials.

Demonstration of nonlinearity bias in the measurement of the apparent diffusion coefficient in multicenter trials.

Characterize system‐specific bias across common magnetic resonance imaging (MRI) platforms for quantitative diffusion measurements in multicenter trials.

The Impact of Arterial Input Function Determination Variations on Prostate Dynamic Contrast-Enhanced Magnetic Resonance Imaging Pharmacokinetic Modeling: A Multicenter Data Analysis Challenge

Pharmacokinetic analysis of dynamic contrast-enhanced (DCE) MRI data allows estimation of quantitative imaging biomarkers such as Ktrans (rate constant for plasma/interstitium contrast reagent (CR) transfer) and ve (extravascular and extracellular volume fraction). However, the use of quantitative DCE-MRI in clinical practice is limited with uncertainty in arterial input function (AIF) determination being one of the primary reasons. In this multicenter study to assess the effects of AIF variations on pharmacokinetic parameter estimation, DCE-MRI data acquired at one center from 11 prostate cancer patients were shared among nine centers. Individual AIF from each data set was determined by each center and submitted to the managing center. These AIFs, along with a literature population averaged AIF, and their reference-tissue-adjusted variants were used by the managing center to perform pharmacokinetic data analysis using the Tofts model (TM). All other variables, including tumor region of interest (ROI) definition and pre-contrast T1, were kept constant to evaluate parameter variations caused solely by AIF discrepancies. Considerable parameter variations were observed with the within-subject coefficient of variation (wCV) of Ktrans obtained with unadjusted AIFs being as high as 0.74. AIF-caused variations were larger in Ktrans than ve and both were reduced when reference-tissue-adjusted AIFs were used. These variations were largely systematic, resulting in nearly unchanged parametric map patterns. The intravasation rate constant, kep (= Ktrans/ve), was less sensitive to AIF variation than Ktrans (wCV for unadjusted AIFs: 0.45 vs. 0.74), suggesting that it might be a more robust imaging biomarker of prostate microvasculature than Ktrans.

Multi-site clinical evaluation of DW-MRI as a treatment response metric for breast cancer patients undergoing neoadjuvant chemotherapy

Purpose To evaluate diffusion weighted MRI (DW-MR) as a response metric for assessment of neoadjuvant chemotherapy (NAC) in patients with primary breast cancer using prospective multi-center trials which provided MR scans along with clinical outcome information. Materials and Methods A total of 39 patients with locally advanced breast cancer accrued from three different prospective clinical trials underwent DW-MR examination prior to and at 3–7 days (Hull University), 8–11 days (University of Michigan) and 35 days (NeoCOMICE) post-treatment initiation. Thirteen patients, 12 of which participated in treatment response study, from UM underwent short interval (<1hr) MRI examinations, referred to as “test-retest” for examination of repeatability. To further evaluate stability in ADC measurements, a thermally controlled diffusion phantom was used to assess repeatability of diffusion measurements. MRI sequences included contrast-enhanced T1-weighted, when appropriate, and DW images acquired at b-values of 0 and 800 s/mm2. Histogram analysis and a voxel-based analytical technique, the Parametric Response Map (PRM), were used to derive diffusion response metrics for assessment of treatment response prediction. Results Mean tumor apparent diffusion coefficient (ADC) values generated from patient test-retest examinations were found to be very reproducible (|ΔADC|<0.1x10-3mm2/s). This data was used to calculate the 95% CI from the linear fit of tumor voxel ADC pairs of co-registered examinations (±0.45x10-3mm2/s) for PRM analysis of treatment response. Receiver operating characteristic analysis identified the PRM metric to be predictive of outcome at the 8–11 (AUC = 0.964, p = 0.01) and 35 day (AUC = 0.770, p = 0.05) time points (p<.05) while whole-tumor ADC changes where significant at the later 35 day time interval (AUC = 0.825, p = 0.02). Conclusion This study demonstrates the feasibility of performing a prospective analysis of DW-MRI as a predictive biomarker of NAC in breast cancer patients. In addition, we provide experimental evidence supporting the use of sensitive analytical tools, such as PRM, for evaluating ADC measurements.

Molecular, dynamic, and structural origin of inhomogeneous magnetization transfer in lipid membranes.

To elucidate the dynamic, structural, and molecular properties that create inhomogeneous magnetization transfer (ihMT) contrast.

Analysis and correction of gradient nonlinearity bias in apparent diffusion coefficient measurements

Gradient nonlinearity of MRI systems leads to spatially dependent b‐values and consequently high non‐uniformity errors (10–20%) in apparent diffusion coefficient (ADC) measurements over clinically relevant field‐of‐views. This work seeks practical correction procedure that effectively reduces observed ADC bias for media of arbitrary anisotropy in the fewest measurements.

Magnetization transfer in lamellar liquid crystals

This study examines the relationship between quantitative magnetization transfer (qMT) parameters and the molecular composition of a model lamellar liquid crystal (LLC) system composed of 1‐decyl alcohol (decanol), sodium dodecyl sulfate (SDS), and water.

Practical estimate of gradient nonlinearity for implementation of apparent diffusion coefficient bias correction.

To describe an efficient procedure to empirically characterize gradient nonlinearity and correct for the corresponding apparent diffusion coefficient (ADC) bias on a clinical magnetic resonance imaging (MRI) scanner.

Proteotranscriptomic analysis reveals stage specific changes in the molecular landscape of clear-cell renal cell carcinoma

Renal cell carcinoma comprises 2 to 3% of malignancies in adults with the most prevalent subtype being clear-cell RCC (ccRCC). This type of cancer is well characterized at the genomic and transcriptomic level and is associated with a loss of VHL that results in stabilization of HIF1. The current study focused on evaluating ccRCC stage dependent changes at the proteome level to provide insight into the molecular pathogenesis of ccRCC progression. To accomplish this, label-free proteomics was used to characterize matched tumor and normal-adjacent tissues from 84 patients with stage I to IV ccRCC. Using pooled samples 1551 proteins were identified, of which 290 were differentially abundant, while 783 proteins were identified using individual samples, with 344 being differentially abundant. These 344 differentially abundant proteins were enriched in metabolic pathways and further examination revealed metabolic dysfunction consistent with the Warburg effect. Additionally, the protein data indicated activation of ESRRA and ESRRG, and HIF1A, as well as inhibition of FOXA1, MAPK1 and WISP2. A subset analysis of complementary gene expression array data on 47 pairs of these same tissues indicated similar upstream changes, such as increased HIF1A activation with stage, though ESRRA and ESRRG activation and FOXA1 inhibition were not predicted from the transcriptomic data. The activation of ESRRA and ESRRG implied that HIF2A may also be activated during later stages of ccRCC, which was confirmed in the transcriptional analysis. This combined analysis highlights the importance of HIF1A and HIF2A in developing the ccRCC molecular phenotype as well as the potential involvement of ESRRA and ESRRG in driving these changes. In addition, cofilin-1, profilin-1, nicotinamide N-methyltransferase, and fructose-bisphosphate aldolase A were identified as candidate markers of late stage ccRCC. Utilization of data collected from heterogeneous biological domains strengthened the findings from each domain, demonstrating the complementary nature of such an analysis. Together these results highlight the importance of the VHL/HIF1A/HIF2A axis and provide a foundation and therapeutic targets for future studies. (Data are available via ProteomeXchange with identifier PXD003271 and MassIVE with identifier MSV000079511.)

Effect of Gadoxetate Disodium on Arterial Phase Respiratory Waveforms Using a Quantitative Fast Fourier Transformation–Based Analysis

OBJECTIVE The purpose of this study is to investigate the effect of gadoxetate disodium administration on arterial phase respiratory waveforms. SUBJECTS AND METHODS From 2013 to 2015, 107 subjects undergoing liver MRI with either gadoxetate disodium (10 mL diluted 1:1 with saline; injection rate, 2 mL/s; n = 40) or gadobenate dimeglumine (0.2 mL/kg; maximum, 20 mL; injection rate, 2 mL/s; n = 67) were enrolled. Respiratory waveforms obtained during unenhanced and dynamic contrast-enhanced phases were filtered by a physicist, who was blinded to contrast agent and imaging phase, to eliminate electronic and cardiac noise using fast Fourier transformation. The average root-mean-square difference of two intrasubject control phases (unenhanced and late dynamic) was termed D1, and the root-mean-square deviation of the arterial phase referent to the control record mean was termed D2. D1, D2, and their difference were compared across agents with the Mann-Whitney U test. Bland-Altman plots were generated for D1 and D2 values. RESULTS D1 values were similar for both agents (mean [± SD], 232 ± 203 for gadoxetate vs 201 ± 230 for gadobenate; p = 0.48), indicating similar intercohort baseline breath-holding capability. D2 was greater and more variable for the gadoxetate cohort (438 ± 381) than for the gadobenate cohort (167 ± 167; p < 0.001), indicating larger and more unpredictable respiratory waveform deviations isolated to the arterial phase (subject-level rate, 48% [19/40] for gadoxetate vs 1% [1/67] for gadobenate; p < 0.001). Aberrant respiratory waveform peaks in the arterial phase were usually associated with transient tachypnea (mean maximum arterial phase respiratory rate for the gadoxetate cohort, 27 breaths/min; range, 11-40 breaths/min). CONCLUSION Fixed-dose gadoxetate disodium (10 mL; 1:1 dilution with 10 mL of saline; injection rate, 2 mL/s) transiently reduces breath-holding capacity during the arterial phase and is accompanied by brief transient tachypnea.