MSBI Thesis & Abstracts 2015-2016

Joshua Fisher
Advisor: Dr. Steven Hetts, MD
Thesis Title: In vitro Binding of ChemoFilter with Cisplatin
Introduction: Endovascular chemotherapy treatment allows localized delivery adjacent to the target tumor; allowing an increased dosage and decreased leakage to other areas. It also allows for the opportunity to filter chemotherapy escaping the target tumor and entering the bloodstream. The ChemoFilter - a temporarily deployable, endovascular device will do just that; reducing systemic toxicity thus reducing adverse side effects from chemotherapy treatment. This will allow further increased dosage, increased tumor suppression, and increased tolerance to treatment. ChemoFilter has successfully filtered the chemotherapeutic Doxorubicin, but had yet to be tested in other chemotherapeutics. This study evaluates binding with new chemotherapeutics: Cisplatin, Carboplatin, and a cocktail comprised of Cisplatin and Doxorubicin.

Materials and Methods: ChemoFilter prototypes based on: 1.) Genomic DNA and 2.) Dowex (ion-exchange) resin, were evaluated for their ability to bind chemotherapy in vitro in phosphate-buffered saline (PBS). ChemoFilter was tested free in solution and encapsulated in nylon or polyester mesh packets of various dimensions. Concentrations were quantified using inductively coupled plasma mass spectrometry (IPC-MS), ultraviolet-visible spectrophotometry (UV-Vis), or fluorospectrometry. 11C, 13C, and/or 14C radiolabeling Carboplatin began for in vitro and in vivo ChemoFilter quantification. In vitro quantification can include scintillation and/or gamma counting. In vivo may include Positron Emission Tomography (PET) imaging, Hyperpolarized 13C Magnetic Resonance Imaging (MRI), and/or Magnetic Resonance Spectroscopy (MRS) for real-time visualization. Reactions were verified using High Performance Liquid Chromatography (HPLC) for chemical species identification.

Results and Discussion: Results indicate significant and nearly complete, ~99% (p<0.01) clearance of Cisplatin using the DNA ChemoFilter sequestered in Nylon mesh, quantified with gold standard ICP-MS (evidenced at 214 and 265 nm). The Ion-exchange ChemoFilter has significant clearance, within seconds, of both Doxorubicin and Cisplatin mixed in a cocktail solution. However, it appears some Cisplatin is binding to the Nylon Mesh itself. Size, shape, and material of the mesh have been optimized. A potential mechanism for 11C, 13C, or 14C radiolabeling of Carboplatin has been developed and early results have been successful. ChemoFilter works much more efficiently when sequestered in nylon packets of specific geometries. Significant improvements have been made to ChemoFilter, moving the device closer to clinical trials.

Catherine Fu
Advisor: Dr. Henry Vanbrocklin, PhD
Thesis Title: Translation of Zirconium -85 labeled antibodies for human imaging

Wesley Kuo
Advisor: Dr. Steven Hetts, MD
Thesis Title: Binding Kinetics of Cisplatin with Ion-exchange Resin
Objective: Localized chemotherapy can be more effective at treating cancers than traditional chemotherapy methods. Increased dosage leads to increased systemic toxicity, a critical issue that must be addressed. The ChemoFilter - a temporarily deployable, endovascular device - aims to extract chemotherapeutic agents from the bloodstream in order to reduce adverse side effects in other areas of the body. In this study, we report the binding effectiveness of ion-exchange resins with cisplatin, a commonly administered chemotherapeutic.

Materials and Methods: All experiments were conducted in vitro using cisplatin in distilled water and phosphate buffered saline. Ion-exchange resins (Dowex 50Wx2, Amberlite FPC22, Tulsion T-66, Amberlite IRC, Purolite S930/950) were tested in solution individually and the total amount of free cisplatin in solution was quantified using ultraviolet-visible spectroscopy and inductively coupled plasma mass spectroscopy.

Results: Quantification of cisplatin using UV-visible methods demonstrated that strong acid cation exchangers perform exceptionally well in saline solutions, removing over 90% of free cisplatin within one minute. The concentration of free cisplatin did not drop when reacted with strong cation exchangers in water. Weak acid cation exchangers and chelating resins also displayed no binding of cisplatin in PBS. Assessing the performance of the strong cation exchange resin, Dowex 50Wx2, using ICP-MS showed that ion exchange filtration was comparable in both water and PBS.

Conclusion: The current effectiveness of localized chemotherapy is limited by its corresponding increased systemic toxicity. The ChemoFilter seeks to mitigate the effects of chemotherapeutics on non-targeted areas of the body by extracting or inactivating the chemotherapy agents that pass through it. Our benchtop OPDA method of quantifying cisplatin in solution indicated that strong acid cation exchangers were exceptionally well-suited to the task. However, quantification using ICP-MS revealed that our previous UV-visible method of cisplatin quantification was not compatible with ion exchange resin studies and that these resins may not be very useful at fulfilling the ChemoFilter’s objective of removing cisplatin from solution.

Joanne Lau
Advisor: Dr. Shabnam Peyvandi, MD
Thesis Title: Fetal Brain Measurements Predict Neonatal Brain Injury in Patients with CHD

Nathan Poulin
Advisor: Dr. Steven Hetts, MD
Thesis Title: Simulations of RF Probes for ENdovascular MRI using the Finite Element Method
The positioning of surface receiver coils limits the signal-to-noise ratio (SNR) of MRI. Endovascular RF imaging coils placed at or near the region of interest can image at greatly enhanced SNR compared with surface coils. Treatment protocols for neurovascular and cardiovascular diseases and conditions would benefit from better image quality.

A series of numerical simulations using the Finite Element Method (FEM) of the electric and magnetic fields of endovascular RF probes of the looped and loopless (antenna) kinds were performed in order to assess their imaging performances and to improve their designs at the imaging strength of 3T. Safety of the probes was also considered. Emphasis is placed on simulations of a loopless coil, with and without the addition of an extremely high dielectric coating. A new design concept for actively tracking the distal end of a loopless coil is proposed, where signal dropout normally prevents its visualization and localization. This would be one of the few available multi-functional coils which could be used for imaging and tracking. The design consists of a corkscrew shaped inductive loop placed at the end of the loopless coil (maintaining an open circuit), with its axis oriented in the xy plane, allowing for signal gain in the axis of the loop. Electric and magnetic fields were mapped and preliminary SNRs and Specific Absorption Rates (SARs) are presented, showing the corkscrew's viability as a potential active tracking mechanism

Vishal Samboju
Advisor: Dr. Adam Cunha, PhD
Thesis Title: Evaluation of needle displacement errors in brachytherapy using electromagnetic (EM) tracking

Sizhe Wang
Advisor: Dr. Benjamin Yeh, MD
Thesis Title: Quantifying Bio-elimination of Oral Fumed Silica-based CT Contrast Agent

Jiajing Xu
Advisor: Dr. Srikantan Nagarajan, PhD
Thesis Title: Exploring and Evaluation Novel Algorithm for interference rejection in MEG data
Introduction: MEG recordings are prone to interferences. Lots of efforts have been made to deal with interference rejection in MEG data, but still there are some kinds of interferences could not be handled well so far, e.g. large amplitude interferences like those caused by vagus nerve stimulators (VNS) implant in epilepsy patients, and dealing with these interferences well are of clinical importance for these patients. In this study, we illustrated a novel MEG interference rejection algorithm called dual signal subspace projection (DSSP) that could potentially help deal with such interferences, and evaluated its performance through computer simulation data and clinical data

Method: Computer simulation is performed with several types of interferences varying in localization and signal type, and DSPP-processed data was compared with the true signal for performance evaluation. The performance of DSSP in the clinical data was mainly tested through a retrospective cohort study from epilepsy patients with VNS implant receiving MEG for interictal spike mapping. The evaluation was based on direct MEG recording reading for epileptic spike identification, successful spike localization using the clinical standard dipole fitting model, and spike localization and activity time-series recovery using a more reliable MEG source reconstruction algorithms called Champagne

Results: DSSP handled various kinds of interference setting in computer simulation well, but also showed preference towards periodic interference outside region of interest. Direct MEG recording reading showed that MEG recordings became more readable after DSSP processing and more epileptic spikes could be identified. More spike could be localized using the dipole fitting method with DSSP-processed data, and localization results differed from that achieved with DSSP-unprocessed data. Evaluation with Champagne algorithm showed that DSSP-processed data had a higher chance to achieve successful spike localization with reasonable location and meaningful recovered activity time-series data. The localization result achieved with Champagne algorithm also differed from the previous spike mapping result using the DSSP-unprocessed data

Conclusion: DSSP is a valuable novel interference rejection algorithm to be explored. It potentially works better with interference periodic and located outside the region of interest, and could help to recover the distorted MEG recordings from epilepsy patient with VNS impact.

Joy Yeh
Advisor: Dr. Duan Xu, PhD
Thesis Title: Changes in Structural Networks After Radiation Therapy in Patients with Brain Tumors
Introduction - Radiation therapy (RT) received by brain tumor patients after tumor resection can affect brain connectivity in various degrees. Structural connectivity changes in brain matter can be modeled by diffusion MRI and tractography between areas of the brain that act as nodes of the network. We hypothesize that graph theory measures, including global network descriptors and local node characteristics, may change with the application of radiation therapy and evolve over time.

Methods - Six patients with brain tumor resections were imaged either before or immediately following RT and then again six months later. Diffusion data were registered with a brain atlas (AAL), and post-gad T1- and T2-weighted FLAIR images were clinically marked for tumor-affected tissues. Networks were constructed using 90 AAL regions as nodes and connecting streamlines as edges, weighted by the average fractional anisotropy (FA) within those streamlines. Four global and four local network measures were examined. Tumor-affected node sets were defined in each patient and examined for changes, then compared against contralateral nodes and all non-affected nodes. Obtained network measures were correlated with cognitive data.

Results - Network average clustering coefficient increased significantly between scans (p=0.0313). Local clustering, local efficiency, and node strength showed increasing trends in selected node sets. Node strength increased significantly with T1 and T2 image-based definitions of tumor-affected nodes six months post-RT in a single patient. Correlation was detected between cognitive scores and betweenness centrality in select tumor-affected nodes.

Conclusions - Several connectivity measures appeared to be altered in patients after radiation therapy in a span of six months, including increases in network average clustering. Small sample size limited the level of confidence of observed changes in local measures and correlation to cognitive scores but suggests connectivity changes in tumor-affected regions and betweenness centrality in relation to cognitive scores as points of interests in future studies.

Xinheng Zhang
Advisor: Dr. David Saloner, PhD
Thesis Title: Comparison of CFD and 4D MRV in a flow model
Introduction: Information from MR blood flow quantification can be used to evaluate patient health, inform surgical decisions and provide boundary conditions for numerical simulations. Thus, it is important to determine the accuracy and precision of the flow measurement and its contributing factors. In this study, we investigated the reproducibility of the measurement by comparing flow results from 2D MRV, 4D MRV and CFD. Also, we investigated the sensitivity of the measurements at different positions in the scanner, since these could be affected by gradient field imperfections.

Methods: A phantom which was an exact replica of a patient intracranial aneurysm was set up with a flow system where flow was driven by a gravity-fed pressure head to provide constant flow. A contrast-enhanced MRA image was obtained at 0.5 mm isotropic resolution to determine the geometry. 4D MRV within the phantom was measured under 3 conditions: cine-MR at the isocenter (0 cm offset) for 5 time points, continuous measurement at the isocenter, and continuous measurement 10cm offset from the isocenter. CFD simulation was performed on commercial software COMSOL. Image post-processing was done using in-house Python tools. Qualitative comparisons were made using Paraview while quantitative comparisons were assessed by correlation and Bland-Altman plots.

Results: Imaging at 10 cm from isocenter was found to adequately visualize secondary flows such as jets in the aneurysm. Total flow through the inlets obtained from the 2D- and 4D- MRV acquisitions were 4.03 ± 0.07 mL/s and 3.65 ± 0.12 mL/s, which were significantly larger than the directly measured flow of 3.1 mL/s. The overall velocity field from the CFD results underestimate the measurements from 4D MRV, suggesting they provided inlet boundary conditions are too low. The greatest differences between the CFD and 4D MRV results appear at the vessel walls.

Conclusion: We developed a pipeline for evaluating flow measured under different conditions and modalities. A combination of noise and partial volume effects compromise velocity measurements, particularly in voxels at the vessel edge. Additionally, CFD can provide precise measurements at the wall, but the accuracy of the results depends highly on the image-derived geometric and flow boundary conditions.

Alan Zhu
Advisor: Dr. Duygu Tosun-Turgut, PhD
Thesis Title: Evaluation of structural connectome models and network diffusion in predicting cortical atrophy in Alzheimer's disease spectrum
Abstract: ​