Phantoms for Quantitative Body MRI: a review and discussion of the phantom value.

In this paper, we review the value of phantoms for body MRI in the context of their uses for quantitative MRI methods research, clinical trials, and clinical imaging. Certain uses of phantoms are common throughout the body MRI community, including measuring bias, assessing reproducibility, and training. In addition to these uses, phantoms in body MRI methods research are used for novel methods development and the design of motion compensation and mitigation techniques. For clinical trials, phantoms are an essential part of quality management strategies, facilitating the conduct of ethically sound, reliable, and regulatorily compliant clinical research of both novel MRI methods and therapeutic agents. In the clinic, phantoms are used for development of protocols, mitigation of cost, quality control, and radiotherapy. We briefly review phantoms developed for quantitative body MRI, and finally, we review open questions regarding the most effective use of a phantom for body MRI.

Breast imaging with an ultra-low field MRI scanner: a pilot study.

Breast cancer screening is necessary to reduce mortality due to undetected breast cancer. Current methods have limitations, and as a result many women forego regular screening. Magnetic resonance imaging (MRI) can overcome most of these limitations, but access to conventional MRI is not widely available for routine annual screening. Here, we used an MRI scanner operating at ultra-low field (ULF) to image the left breasts of 11 women (mean age, 35 years ±13 years) in the prone position. Three breast radiologists reviewed the imaging and were able to discern the breast outline and distinguish fibroglandular tissue (FGT) from intramammary adipose tissue. Additionally, the expert readers agreed on their assessment of the breast tissue pattern including fatty, scattered FGT, heterogeneous FGT, and extreme FGT. This preliminary work demonstrates that ULF breast MRI is feasible and may be a potential option for comfortable, widely deployable, and low-cost breast cancer diagnosis and screening.

Iron oxide nanoparticles as positive T1 contrast agents for low-field magnetic resonance imaging at 64 mT.

We have investigated the efficacy of superparamagnetic iron oxide nanoparticles (SPIONs) as positive T1 contrast agents for low-field magnetic resonance imaging (MRI) at 64 millitesla (mT). Iron oxide-based agents, such as the FDA-approved ferumoxytol, were measured using a variety of techniques to evaluate T1 contrast at 64 mT. Additionally, we characterized monodispersed carboxylic acid-coated SPIONs with a range of diameters (4.9-15.7 nm) in order to understand size-dependent properties of T1 contrast at low-field. MRI contrast properties were measured using 64 mT MRI, magnetometry, and nuclear magnetic resonance dispersion (NMRD). We also measured MRI contrast at 3 T to provide comparison to a standard clinical field strength. SPIONs have the capacity to perform well as T1 contrast agents at 64 mT, with measured longitudinal relaxivity (r1) values of up to 67 L mmol-1 s-1, more than an order of magnitude higher than corresponding r1 values at 3 T. The particles exhibit size-dependent longitudinal relaxivities and outperform a commercial Gd-based agent (gadobenate dimeglumine) by more than eight-fold at physiological temperatures. Additionally, we characterize the ratio of transverse to longitudinal relaxivity, r2/r1 and find that it is ~ 1 for the SPION based agents at 64 mT, indicating a favorable balance of relaxivities for T1-weighted contrast imaging. We also correlate the magnetic and structural properties of the particles with models of nanoparticle relaxivity to understand generation of T1 contrast. These experiments show that SPIONs, at low fields being targeted for point-of-care low-field MRI systems, have a unique combination of magnetic and structural properties that produce large T1 relaxivities.

Conformance of a 3T radiotherapy MRI scanner to the QIBA Diffusion Profile.

PURPOSE: To assess the technical performance of the apparent diffusion coefficient (ADC) on a dedicated 3T radiotherapy scanner, using a standardized phantom and sequences. Investigations into factors that could impact the technical performance of ADC in the clinic were also completed, including changing the slice-encoded imaging direction and the reference sample ADC value. METHODS: ADC acquisitions were performed monthly on an isotropic diffusion phantom over 1 year. Measurements of ADC %bias, coefficients of variation for short-/long-term repeatability and precision (CVST /CVLT and CVP ), and b-value dependency (Depb ) were calculated. The measurements were then assessed according to the Quantitative Imaging Biomarker Alliance (QIBA) Diffusion Profile specifications. RESULTS: The average of all measurements over the year was within Profile recommended ranges. This included when testing was performed in different imaging directions, and on samples that had different ADC reference values (0.4-1.1 µm2 /ms). Results in the axial plane for the central water vial included a bias of +0.05%, CVST /CVLT /CVP  = 0.1%/ 0.9%/0.4% and Depb  = 0.4%. CONCLUSIONS: The technical performance of ADC on a radiotherapy dedicated MRI scanner over the course of 12 months was considered conformant to the QIBA Profile. Quantifying these metrics and factors that may affect the performance is essential in progressing the use of ADC clinically: ensuring that the observed change of ADC in a tissue is due to a physiological response and not measurement variability.

Do Your Kids Vape?: Investigating Parent Knowledge of Adolescent e-Cigarette Use.

OBJECTIVE: This study aimed to evaluate parental knowledge of their adolescent's e-cigarette use and their awareness of negative effects. METHODS: Participants were English-speaking 12- to 18-year-old patients and their guardians presenting to a pediatric emergency department. Patients and guardians were invited to complete a survey detailing e-cigarette use, parental awareness, and the understanding of risks. Participants were given separate surveys. They were monitored by research assistants in the room to ensure that answers were kept private. χ2 Analysis was used to interpret the data. RESULTS: A total of 309 paired surveys were obtained over an 8-month period. Of adolescents surveyed, 85 (27.5%) admitted to having ever used an e-cigarette and 33 (10.7%) admitted to regular use. Regular usage was defined as use within the last 30 days. Of the adolescents who used e-cigarettes, the majority (77.8%) had never smoked a traditional cigarette before. For teens who used e-cigarettes, 71.8% of their respective guardians were aware. When the adolescent reported that they did not use e-cigarettes, 91.3% of guardians responded that they did not believe their child was using the device. Guardians were somewhat worse at knowing if their child regularly used e-cigarettes, with only 54.8% of parents reporting to think that their child regularly uses. Finally, both adolescents and guardians reported to know that e-cigarette use was harmful. On a scale of 1 to 5, with 5 being the worst, 83.5% and 88.3% of patients and guardians, respectively, rated e-cigarette usage harm at 4 or 5. CONCLUSIONS: It seems guardians are generally aware of their adolescent's e-cigarette use, and both parents and adolescents are aware of the negative side effects of e-cigarettes on health. We did not investigate whether guardians discussed their concerns on e-cigarette usage with their adolescents. It is also unclear what specific health consequences guardians and adolescents are aware of. These may be points of further investigation and intervention.

Development, validation, qualification, and dissemination of quantitative MR methods: Overview and recommendations by the ISMRM quantitative MR study group.

On behalf of the International Society for Magnetic Resonance in Medicine (ISMRM) Quantitative MR Study Group, this article provides an overview of considerations for the development, validation, qualification, and dissemination of quantitative MR (qMR) methods. This process is framed in terms of two central technical performance properties, i.e., bias and precision. Although qMR is confounded by undesired effects, methods with low bias and high precision can be iteratively developed and validated. For illustration, two distinct qMR methods are discussed throughout the manuscript: quantification of liver proton-density fat fraction, and cardiac T1 . These examples demonstrate the expansion of qMR methods from research centers toward widespread clinical dissemination. The overall goal of this article is to provide trainees, researchers, and clinicians with essential guidelines for the development and validation of qMR methods, as well as an understanding of necessary steps and potential pitfalls for the dissemination of quantitative MR in research and in the clinic.

Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia.

DNA methylation, a key epigenetic driver of transcriptional silencing, is universally dysregulated in cancer. Reversal of DNA methylation by hypomethylating agents, such as the cytidine analogs decitabine or azacytidine, has demonstrated clinical benefit in hematologic malignancies. These nucleoside analogs are incorporated into replicating DNA where they inhibit DNA cytosine methyltransferases DNMT1, DNMT3A and DNMT3B through irreversible covalent interactions. These agents induce notable toxicity to normal blood cells thus limiting their clinical doses. Herein we report the discovery of GSK3685032, a potent first-in-class DNMT1-selective inhibitor that was shown via crystallographic studies to compete with the active-site loop of DNMT1 for penetration into hemi-methylated DNA between two CpG base pairs. GSK3685032 induces robust loss of DNA methylation, transcriptional activation and cancer cell growth inhibition in vitro. Due to improved in vivo tolerability compared with decitabine, GSK3685032 yields superior tumor regression and survival mouse models of acute myeloid leukemia.

Determining the longitudinal accuracy and reproducibility of T1 and T2 in a 3T MRI scanner.

PURPOSE: To determine baseline accuracy and reproducibility of T1 and T2 relaxation times over 12 months on a dedicated radiotherapy MRI scanner. METHODS: An International Society of Magnetic Resonance in Medicine/National Institute of Standards and Technology (ISMRM/NIST) System Phantom was scanned monthly on a 3T MRI scanner for 1 year. T1 was measured using inversion recovery (T1 -IR) and variable flip angle (T1 -VFA) sequences and T2 was measured using a multi-echo spin echo (T2 -SE) sequence. For each vial in the phantom, accuracy errors (%bias) were determined by the relative differences in measured T1 and T2 times compared to reference values. Reproducibility was measured by the coefficient of variation (CV) of T1 and T2 measurements across monthly scans. Accuracy and reproducibility were mainly assessed on vials with relaxation times expected to be in physiological ranges at 3T. RESULTS: A strong linear correlation between measured and reference relaxation times was found for all sequences tested (R2  > 0.997). Baseline bias (and CV[%]) for T1 -IR, T1 -VFA and T2 -SE sequences were +2.0% (2.1), +6.5% (4.2), and +8.5% (1.9), respectively. CONCLUSIONS: The accuracy and reproducibility of T1 and T2 on the scanner were considered sufficient for the sequences tested. No longitudinal trends of variation were deduced, suggesting less frequent measurements are required following the establishment of baselines.

A Chemical Acetylation-Based Mass Spectrometry Platform for Histone Methylation Profiling.

Histones are highly posttranslationally modified proteins that regulate gene expression by modulating chromatin structure and function. Acetylation and methylation are the most abundant histone modifications, with methylation occurring on lysine (mono-, di-, and trimethylation) and arginine (mono- and dimethylation) predominately on histones H3 and H4. In addition, arginine dimethylation can occur either symmetrically (SDMA) or asymmetrically (ADMA) conferring different biological functions. Despite the importance of histone methylation on gene regulation, characterization and quantitation of this modification have proven to be quite challenging. Great advances have been made in the analysis of histone modification using both bottom-up and top-down mass spectrometry (MS). However, MS-based analysis of histone posttranslational modifications (PTMs) is still problematic, due both to the basic nature of the histone N-terminal tails and to the combinatorial complexity of the histone PTMs. In this report, we describe a simplified MS-based platform for histone methylation analysis. The strategy uses chemical acetylation with d0-acetic anhydride to collapse all the differently acetylated histone forms into one form, greatly reducing the complexity of the peptide mixture and improving sensitivity for the detection of methylation via summation of all the differently acetylated forms. We have used this strategy for the robust identification and relative quantitation of H4R3 methylation, for which stoichiometry and symmetry status were determined, providing an antibody-independent evidence that H4R3 is a substrate for both Type I and Type II PRMTs. Additionally, this approach permitted the robust detection of H4K5 monomethylation, a very low stoichiometry methylation event (0.02% methylation). In an independent example, we developed an in vitro assay to profile H3K27 methylation and applied it to an EZH2 mutant xenograft model following small-molecule inhibition of the EZH2 methyltransferase. These specific examples highlight the utility of this simplified MS-based approach to quantify histone methylation profiles.

MEK inhibitors overcome resistance to BET inhibition across a number of solid and hematologic cancers.

BET inhibitors exhibit broad activity in cancer models, making predictive biomarkers challenging to define. Here we investigate the biomarkers of activity of the clinical BET inhibitor GSK525762 (I-BET; I-BET762) across cancer cell lines and demonstrate that KRAS mutations are novel resistance biomarkers. This finding led us to combine BET with RAS pathway inhibition using MEK inhibitors to overcome resistance, which resulted in synergistic effects on growth and survival in RAS pathway mutant models as well as a subset of cell lines lacking RAS pathway mutations. GSK525762 treatment up-regulated p-ERK1/2 levels in both RAS pathway wild-type and mutant cell lines, suggesting that MEK/ERK pathway activation may also be a mechanism of adaptive BET inhibitor resistance. Importantly, gene expression studies demonstrated that the BET/MEK combination uniquely sustains down-regulation of genes associated with mitosis, leading to prolonged growth arrest that is not observed with either single agent therapy. These studies highlight a potential to enhance the clinical benefit of BET and MEK inhibitors and provide a strong rationale for clinical evaluation of BET/MEK combination therapies in cancer.

Accuracy, repeatability, and interplatform reproducibility of T1 quantification methods used for DCE-MRI: Results from a multicenter phantom study.

PURPOSE: To determine the in vitro accuracy, test-retest repeatability, and interplatform reproducibility of T1 quantification protocols used for dynamic contrast-enhanced MRI at 1.5 and 3 T. METHODS: A T1 phantom with 14 samples was imaged at eight centers with a common inversion-recovery spin-echo (IR-SE) protocol and a variable flip angle (VFA) protocol using seven flip angles, as well as site-specific protocols (VFA with different flip angles, variable repetition time, proton density, and Look-Locker inversion recovery). Factors influencing the accuracy (deviation from reference NMR T1 measurements) and repeatability were assessed using general linear mixed models. Interplatform reproducibility was assessed using coefficients of variation. RESULTS: For the common IR-SE protocol, accuracy (median error across platforms = 1.4-5.5%) was influenced predominantly by T1 sample (P < 10-6 ), whereas test-retest repeatability (median error = 0.2-8.3%) was influenced by the scanner (P < 10-6 ). For the common VFA protocol, accuracy (median error = 5.7-32.2%) was influenced by field strength (P = 0.006), whereas repeatability (median error = 0.7-25.8%) was influenced by the scanner (P < 0.0001). Interplatform reproducibility with the common VFA was lower at 3 T than 1.5 T (P = 0.004), and lower than that of the common IR-SE protocol (coefficient of variation 1.5T: VFA/IR-SE = 11.13%/8.21%, P = 0.028; 3 T: VFA/IR-SE = 22.87%/5.46%, P = 0.001). Among the site-specific protocols, Look-Locker inversion recovery and VFA (2-3 flip angles) protocols showed the best accuracy and repeatability (errors < 15%). CONCLUSIONS: The VFA protocols with 2 to 3 flip angles optimized for different applications achieved acceptable balance of extensive spatial coverage, accuracy, and repeatability in T1 quantification (errors < 15%). Further optimization in terms of flip-angle choice for each tissue application, and the use of B1 correction, are needed to improve the robustness of VFA protocols for T1 mapping. Magn Reson Med 79:2564-2575, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

The age-related neuroinflammatory environment promotes macrophage activation, which negatively impacts synaptic function.

The impact of infiltration of macrophages into the brain is debatable with evidence of both beneficial and detrimental effects. Recent work suggests that inflammatory macrophages, with an inflammatory phenotype that resembles the M1 activation state, may be detrimental, whereas anti-inflammatory M2-like macrophages may be beneficial. We set up a model to examine the response of bone marrow-derived macrophages to the inflammatory milieu that occurs in the aged brain. Expression of MHCII and CD40 was increased in macrophages incubated with soluble brain extract prepared from aged, compared with young, mice and this was accompanied by increased production of tumor necrosis factor-α and interleukin-6. Analysis of soluble brain extract indicated that it contained increased concentrations of several inflammatory mediators and, importantly, when bone marrow-derived macrophages were incubated in the inflammatory cytokines that were increased and applied to hippocampal slices, long-term potentiation was inhibited. The data suggest that infiltrating macrophages respond to local conditions and, in the case of aging, adopt an inflammatory phenotype that ultimately has a neurodetrimental effect.

Design of a breast phantom for quantitative MRI.

PURPOSE: We present a breast phantom designed to enable quantitative assessment of measurements of T1 relaxation time, apparent diffusion coefficient (ADC), and other attributes of breast tissue, with long-term support from a national metrology institute. MATERIALS AND METHODS: A breast phantom was created with two independent, interchangeable units for diffusion and T1 /T2 relaxation, each with flexible outer shells. The T1 unit was filled with corn syrup solution and grapeseed oil to mimic the relaxation behavior of fibroglandular and fatty tissues, respectively. The diffusion unit contains plastic tubes filled with aqueous solutions of polyvinylpyrrolidone (PVP) to modulate the ADC. The phantom was imaged at 1.5T and 3.0T using magnetic resonance imaging (MRI) scanners and common breast coils from multiple manufacturers to assess T1 and T2 relaxation time and ADC values. RESULTS: The fibroglandular mimic exhibited target T1 values on 1.5T and 3.0T clinical systems (25-75 percentile range: 1289 to 1400 msec and 1533 to 1845 msec, respectively) across all bore temperatures. PVP solutions mimicked the range of ADC values from malignant tumors to normal breast tissue (40% PVP median: 633 × 10(-6) mm(2) /s to 0% PVP median: 2231 × 10(-6) mm(2) /s) at temperatures of 17-24°C. The interchangeable phantom units allowed both the diffusion and T1 /T2 units to be tested on the left and right sides of the coil to assess any variation. CONCLUSION: This phantom enables T1 and ADC measurements, fits in a variety of clinical breast coils, and can serve as a quality control tool to facilitate the standardization of quantitative measurements for breast MRI. J. Magn. Reson. Imaging 2016;44:610-619.