MSBI Thesis & Abstracts 2013-2014

Nabeel Al-Aziz
Advisor: Dr. Henry Vanbrocklin, PhD
Thesis Title: Synthesis of [18F]-MFBG analogs with in vitro characterization
Introduction: The human norepinephrine transporter (hNET) is involved in a number of pathological disorders and is the target of many pharmaceutical drugs. [123 I]MIBG is a clinically established radiotracer used in single photon emission computed tomography (SPECT) imaging of hNET expression in tumors and sympathetic innervation. We evaluated a new method for synthesizing the fluorine-18 analog of MIBG, i.e., [18 F]MFBG and sought to optimize its production parameters.

Materials and Methods: A two-step labeling process was developed using an iodonium benzyl guanidine salt precursor created by Ground Flour Pharmaceuticals. The labeling was analyzed with radio TLC in 100% ethyl acetate and the solution is purified using an HLB sep-pak and HPLC. The synthesized [ 18 F]MFBG was then tested for uptake in NB1691 (control) and NB1691-hNET cell lines after being incubated for 1 hour.

Results: An average labeling yield of 16.0% (±13%) was established after multiple optimization steps, showing inconsistent labeling. Roughly 12.3% (±7.7%) of the recovered 85% activity is isolated for HPLC purification. This leads to an overall radiochemical yield of 6.9% (±4.4%) at the end of the synthetic process. When performing in vitro studies hNET-overexpressing cells (NB1691-hNET) showed a 3.5 fold increase in uptake (21.4% of 1 μCi) compared to control (6.2% of 1 μCi).

Loi Do
Advisor: Dr. Maythem Saeed, PhD
Thesis Title: Quantitative MRI Measurements of Function Perfusion and Viability in Microembolized Severely Ischemic Hearts
Introduction: Multiple factors make assessment of microembolization clinically challenging. We aimed to 1) provide detailed analysis and comparison of infarct healing in ischemic myocardium with and without microemboli and 2) validate MRI measurements against histochemical/histological staining.

Methods: Animals either served as controls (group I, n=8) or were subjected to one of two percutaneous coronary interventions (PCI) (n=8/group): 1) 45 min occlusion of the left anterior descending (LAD) coronary artery followed by reperfusion (group II) and 2) the same duration of occlusion followed by microemboli delivery prior to reperfusion (group III). Cine, perfusion and delayed contrast enhanced MRI (DE-MRI) were performed on a 1.5T scanner after 3 days and 5 weeks. The left ventricles (LV) were sliced and stained with TTC (triphenyltetrazolium chloride) and Masson trichrome to visualize, delineate and compute scar tissue planemetrically in groups II and III, respectively.

Results: Both intervention groups showed on MRI an increase in end systolic volume and decrease in ejection fraction compared to controls and these changes were more pronounced in group III than II. Unlike group II, group III showed persistent perfusion deficits. Small but homogeneous MI on DE-MRI was visible in group II (1.3±0.9g) with substantially larger MI in group III (7.7±0.5g), however, the resorption was significantly smaller in group III (22%) than group II (60%, P <0.05). Postmortem TTC revealed similar extent of scar tissue to DE-MRI in groups II (1.6±1.0g) and III (group III 9.2±1.6g) at 5 weeks. Histology revealed larger infarct extent in group II (2.8±0.4g, P <0.05) and III (10.5±1.5, P <0.01) than DE-MRI.

Conclusion: MRI detected structural and functional changes in moderately ischemic myocardium with and without microemboli. In ischemic microembolized myocardium, homogeneous infarct, patchy microinfarct and compensatory hypertrophy were visible at 5 weeks. Microvascular obstruction exacerbates the development of compensatory hypertrophy. DE-MRI has the potential to monitor infarct resorption after PCI, but has limited spatial resolution for estimating true infarct extent, which should be taken into account when used to testing the efficacy of newer cardioprotective therapies and distal protective devices in improving LV function.

Khaled Dostzada
Advisor: Dr. Henry Vanbrocklin, PhD
Thesis Title: Radioiodination of MIBG for Neuroendocrine Tumor Imaging
The aims of this project are to develop a new general method of nucleophilic radioiodination for aromatic tracers and to apply this method for the synthesis of radiolabeled metaiodobenzylguanidine (MIBG). MIBG is a radiolabeled pharmaceutical similar in structure to noradrenaline. The compound localizes to adrenergic tissues and can be used to image and treat neuroendocrine tumors overexpressing the human norepinephrine transporter (hNET). When labeled with I-131, MIBG can be used therapeutically to eradicate tumor cells that take up and metabolize norepinephrine. Preliminary studies with stable I-127 have shown that asymmetrical diaryliodonium salts can be iodinated with high yields. With this approach, it is possible to produce radiolabeled MIBG by using a protected diaryliodonium precursor. The effects of reaction pH, labeling solution, deprotection time, and HPLC solvent were examined for this reaction. It was found that acidic conditions gave the best labeling yields. Reaction for 7 minutes was found to be sufficient to fully deprotect the product and a labeling solution containing both CH3CN and toluene was determined to give the best total yield. HPLC was used for separation of MIBG from side-products iodoanisole and metachlorobenzylguaniine (MCBG). Removal of precursor before deprotection was also found to increase specific activity 8-fold. These results show that iodonium chemistry is a novel and effective method for radioiodinating aromatic tracers and that this method may be applied to label other radioiodine compounds

Natalie Korn
Advisor: Dr. Susan Norowoloski, PhD
Thesis Title: Semi-Automatic Prostate Segmentation on an MR Fat Fraction Map
The purpose of this study was to create a semi-automatic segmentation of the prostate for an accurate estimation of prostate volume and modeling of longitudinal changes in patient data. Segmentation algorithms are available based on axial T2-weighted imaging, but decrease in accuracy in abnormal or treated data, and can be expensive. In this work, we segment based on a fat fraction map (FF map), due to the smaller change in image intensities after treatment and large contrast between the prostate and surrounding fatty tissue. The algorithm consists of five parts: a global filtering of the image; region growth from a predetermined seed point; spline interpolation of the region-enclosing polygon; a comparison of distances between boundary points on adjacent slices; and backward mapping to an upsampled plane with a final volume extrusion. Image artifact is removed by morphological opening after the initial region growth, and by removing boundary points with a shortest distance to an adjacent slice boundary greater than a predetermined threshold. FF maps emphasizing low resolution in favor of high contrast (FF_hc maps), and FF maps emphasizing low contrast in favor of high resolution (FF_hr maps) using different acquisition parameters were tested for accuracy against a manual segmentation drawn on a T2-weighted image in fourteen patients receiving a multiparametric MR exam for confirmed or suspected prostate cancer. There was no significant difference in the volumes recorded from the trial data for the semi-automatic segmentation of the FF_hr map and manual segmentation of the axial T2-weighted image (n=14, p<0.84, paired students t-test), but FF_hr map segmentation had a trend to underestimate the size of the prostate gland. The FF_hc map segmentation volumes were significantly different from those of the axial T2-weighted images (n=14, p<0.03, paired student's t-test). The segmentations of FF_hc maps showed psoas muscle invasion into the prostate region as the most common artifact due to the anatomic proximity and signal similarity, and both FF map types showed ambiguity as the prostate base abuts the bladder, leading to both over- and underestimation. This quick segmentation using FF_hr maps creates accurate prostate volume estimations and should be pursued.

Sonam Machingal
Advisor: Dr. Peder Larson, PhD
Thesis Title: Sampling Strategies for Hyperpolarized Carbon-13 Imaging
Introduction:  In hyperpolarized C-13 imaging, the magnetization obtained is in a non-equilibrium state and decays exponentially towards thermal equilibrium based on the T1 relaxation and metabolic turnover rate. During imaging, RF excitation and T1 relaxation contributes to the irreversible decay of the hyperpolarized magnetization. Various RF excitation schemes have been designed to efficiently utilize magnetization for hyperpolarized metabolic imaging. In this work, we present optimal techniques for C-13 imaging by designing flip angles taking into consideration the total imaging acquisition time, repetition time, metabolism and the T1 relaxation to maximize the lactate signal acquisition from the available magnetization.

Methods:  All simulations were done on Matlab. Verification of simulation results for the effect of total scan time and repetition time (TR) on the SNR was done with an excitation scheme defined by the optimal flip angle scheme. Images were acquired with a symmetric, ramp-sampled EPI readout. All scan parameters, other than the variable being verified (TR or total scan time) were kept constant (96 × 96 mm FOV, 32 × 32 matrix).

Results:  Optimal flip angle design is independent of the kinetic forward rate constant (kpl). Experimental data gives qualitatively similar images with varying TR and agree with total scan time simulations. An optimal study design is dictated by a total scan time window which is ~ 10s more than the relaxation time and a good T1 estimation.

Conclusions:  Designing a flip angle scheme as a solution to maximize the substrate signal results in images with increased SNR images. The kpl value of tumors need not be considered when designing flip angles. Also, TR does not have a significant effect on the SNR. These results provide certain freedom to use various pulse sequences and acquisition schemes that require a range of TRs. A good approximation of the T1 relaxation time of the metabolite at the region of interest is important to define the total scan time and to ensure that maximum signal is obtained.

Yuxin Sun
Advisor: Dr. Benjamin Yeh, MD
Thesis Title: Homogenization and Stabilization of Novel Enteric Dual Energy CT Contrast Material
Computed tomography (CT) is a one of the essential imaging modalities widely used in clinical diagnosis. To further increase the diagnostic value of CT, contrast agents, based on iodine or barium, are routinely administered to patients for enhancement blood vessels and organ parenchyma for various clinical indications. Over the course of the last four decades, there have been dramatic improvements in CT technology, including the more recent introduction of dual-energy CT (DECT) technology that enables the simultaneous image acquisition at two different x-ray tube potentials (ie. 80 kVp and 140 kVp), such that materials can be differentiated based on characteristic x-ray attenuation properties. However, a major limitation with the currently available contrast agents is that the elements iodine and barium cannot be readily distinguished due to their near-identical 80:140 kVp CT number ratios.

The objective of my thesis work is to explore viable formulations of a novel CT contrast material, based on silica microparticles. Four common excipients were tested to formulate a suspension of silica microparticles such that the solution is 1) stable, 2) homogenous, and 3) sufficiently nonviscous for translation towards potential clinical applications as an oral enteric contrast agent. Formulations were evaluated for stability at 30°C and 4°C over a period of 10 days; homogeneity was assessed by CT scanning and analysis of attenuation; viscosity measurements were obtained via a falling-ball viscometer method. One of the four excipients achieved all three criteria as stated above, and allows for further in-depth development towards pre-clinical testing and future clinical use.

Nicholas Tran
Advisor: Dr. Youngho Seo, PhD
Thesis Title: Quantitative Analysis of Hypertrophic Myocardium using Diffusion Tensor Magnetic Resonance Imaging
Systemic hypertension is a causative factor in left ventricular hypertrophy which has a range of co-morbidities. Pathologic hypertrophy may negatively impact essential cardiac function. Understanding the physical and biomechanical changes in the heart associated with hypertensive left ventricular hypertrophy is motivated by the potential to reverse or manage the dysfunction associated with structural remodeling of the myocardium in this pathology. Diffusion tensor imaging is a nondestructive magnetic resonance imaging technique that can be used to image myocardial tissue microstructure and determine the orientation of myocardial muscle fibers. In this study, we present an analysis of myocardial fiber and laminar sheet orientation using the covariance of the diffusion tensor to quantify changes in orientation associated with myocardial tissue remodeling. We performed an ex vivo evaluation of hypertrophic and normal rat hearts (N=11) using diffusion tensor magnetic resonance imaging. We observed that the hypertrophic myocardium exhibited significantly increased myocardial fiber derangement (p=0.033), having a mean dispersion of 40 degrees. In comparison, normotensive myocardium had a mean of 36 degrees of dispersion. The calculated dispersion of the laminar sheet normal in the wild-type population was 52 degrees, compared to 55 degrees in the hypertrophic population (p=0.056). The fiber orientation distribution and dispersion data we obtained could be used to further evaluate the biomechanics of myocardial hypertrophy.

Alex Yeh
Advisor: Dr. Sarah Nelson, PhD
Thesis Title: Serial MRI/MRSI of Patients With Gliomas Being Treated With Novel Therapies
Background: Glioblastoma multiforme (GBM) is a primary brain tumor that typically results in poor outcomes. A number of combination therapies are being considered for improving the prognosis for such patients. In this study serial MRI data were evaluated from patients with newly diagnosed GBM who were participating in a single-arm, Phase II clinical trial for an autologous heat-shock protein peptide complex-96 (HSPPC-96) vaccine.

Methods: Patients underwent surgical resection, radiation with temozolomide, and concurrent administrations of heat-shock protein peptide complex-96 (HSPPC-96) vaccine and temozolomide. Anatomical, diffusion-weighted, and perfusion-weighted imaging parameters were examined starting after radiation therapy/temozolomide and before the first vaccine administration. Patients were imaged at regular time points thereafter. Imaging parameters were assessed for changes from baseline and for their association with overall survival (OS) and progression-free survival (PFS) using a Cox proportional hazards model.

Results: Starting at 200 days after the completion of radiotherapy, significant increases from baseline were consistently seen in both 10 th percentile of the normalized apparent diffusion coefficient (nADC) and the median nADC values in the T2 hyperintense lesion. At 250-350 days from baseline, significant associations were seen for nADC values with both PFS and OS.

Conclusion: Multiparametric MR imaging provides a non-invasive method to elucidate more information about how the tumor is responding to combination therapies that include adding a novel immunotherapy vaccine to standard of care radiation and temozolomide.

Jeffrey Hu
Advisor: Dr. Steven Hetts, MD
Thesis Title: Integrating Resonators to Catheters for MR-Guided Interventional Radiology
Stroke and cardiovascular disease are major health threats in the United States. Treatment is typically done under X-ray fluoroscopy but MR imaging could provide physiological information and does not have ionizing radiation. An issue with MR is that tools have to be compatible in a magnetic field environment. Hence, the aim is to build an RC with satisfactory tip visualization at various orientations. It will be utilized in a stroke model involving swine where the catheter will be inserted in the femoral artery up to the carotid. There will also be testing the accuracy of the electromagnetic simulation software XFdtd.

A unique material, pyralux (by Dupont), was processed with photolithography to etch the design. The resonators were wrapped around catheters and tuning was done to achieve the proper resonant frequency for 3.0 T and 1.5 T MR scanners. Scans were made with vascular phantoms and mainly MRA (TOF GRE) protocols. Catheters were oriented perpendicular or parallel to the B0 magnetic field. OsiriX and MS excel were used to calculate the SNR of the catheter relative to the background.

Increasing flip angle, starting from 5 degrees and ending at 90 degrees, decreases the SNR and stronger signal is achieved at 1.5T than 3.0T with these parameters. There is not a significant different between SNR with the perpendicular and parallel orientations in the 3.0T. XFdtd successfully demonstrated the relationship between frequency, capacitance, and inductance with a single coil model but not with the double helix. A clot was successfully induced in the femoral artery of a pig and temperature mapping shows insignificant heating hazards. The goal of the resonator is to visualize the tip, so wider bandwidth would be useful to account for frequency shifts caused by magnetic field disturbances. While choosing the ROI for analysis, selection was based off covering the catheter width and choosing the background such that any artifacts can be accounted for. Although the same TOF GRE sequence in previous successful cases were used, the new sequences tested this year were variable so they were not included in analysis.

From this study, it is shown that the resonator has similar SNR regardless of orientation in the GE 3.0 T scanner. It would be most beneficial to use low flip angles and currently the 1.5 T scanner.