A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Significance: Contrast‐enhanced (CE) and Fluid attenuation inversion recovery (FLAIR) MRI are current standard of care tools for delineating radiation treatment targets in high‐grade glioma (HGG) patients. However, in the setting of retreatment, tumor regrowth and non‐tumor therapy‐related inflammation, known as post‐treatment radiation effect (PTRE), have identical MRI appearances. As a result, FLAIR MRI can be an unreliable tool for treatment planning. Surgical biopsy can definitively distinguish recurrent tumors from PTRE but has many disadvantages, namely operative risk and cost. Dynamic Susceptibility‐weighted Contrast‐ Enhanced (DSC) MRI Perfusion can non‐invasively detect distinct characteristics of tumor and PTRE through measurements of relative cerebral blood volume (rCBV). PTRE exhibits decreased microvascular density, whereas tumor recurrence displays angiogenesis and microvascular proliferation. Thus, DSC‐MRI affords the opportunity to better define tumor burden within and possibly outside of these nonspecific regions. Objective: To assess the extent with which rCBV maps correlate with re‐radiation treatment plans in patients with recurrent tumor in order to identify potential differences in treatment planning. Design: This study enrolled 8 previously treated HGG patients presenting for re‐irradiation of suspected recurrent tumor at a single hospital on an IRB‐approved trial. All patients underwent DSC‐MRI and routine MRI imaging prior to re‐irradiation treatment planning, and underwent treatment as per routine clinical protocol. Following therapy, rCBV and radiation dose maps were overlaid on conventional MR to delineate differences in identified tumor burden. Results: Of the 8 patients, four rCBV images showed evidence of tumor outside of the RT planning volumes, while the other 4 showed fully treated tumor but with large volumes of uninvolved brain receiving radiation. Conclusion: DSC‐MRI better identified unique regions of potential tumor burden in recurrent HGG patients compared to conventional MRI and could be used to improve radiation treatment planning in re‐radiated patients.

In 2007, there will be an estimated 178,480 new cases of breast cancer diagnosed in women in the United States. The elucidation of the vast heterogeneity of individual tumors has led to a paradigm shift from a one-size fits all treatment strategy to more individualized treatment based on the molecular profile of the tumor. Identifying biomarkers that respond to or predict the action of drugs is important in identifying efficacious targets and drugs that will improve clinical outcome. To examine this, we first identified two breast cancer cell lines (ACC-3199 and ACC-3171) from a panel of low passage breast cells lines that were capable of growing serially as tumor xenografts. This was followed by the in vivo molecular characterization of these two cell lines. In ACC-3199 tumors, we identified a gain of pAKT expression compared to cultured cells. Based on this finding, we investigated the role of diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) as potential imaging biomarkers in identifying early response to PX-866, a PI3K inhibitor, in ACC-3199 tumors as represented by changes in tumor cellularity and hemodynamic parameters, respectively. Our results indicated that DW-MRI was able to identify an early response to PX-886 in ACC-3199 tumors as defined by an increase in the apparent diffusion coefficient (ADC) value of the tumors prior to changes in tumor volumes. Using DCE-MRI, we were able to conclude that PX-866 was not an effective anti-angiogenic agent as indicated by an increase in tumor permeability following therapy. Based on the VEGFR2 expression observed in ACC-3171 tumor xenografts, we examined the response of MDA-MB-231/GFP and ACC-3171 tumor xenografts to the anti-angiogenic agent, sunitinib, using the same imaging modalities. DW-MRI was able to detect increases in ADC values as early as 12 h post-treatment in both MDA-MB-231/GFP and ACC-3171 tumors. Thus, it appears that DW-MRI may be a useful clinical test in predicting the early response to PI3K and anti-angiogenic inhibitors. These imaging approaches, in addition to the further molecular characterization of breast tumors may lead to the improvement and development of medical therapies for breast cancer patients.

Highly metastatic cancer cells are more likely to escape and form metastases, and only minimal improvements in treatment can be achieved. Despite metas- tases being the primary cause of cancer-related mortality, they often proceed unnoticed. Current imaging modalities rely solely on the morphological fea- tures of the tumor for characterization, rather than cellular differences. Our goal is to develop an MR cellular imaging capability for characterizing the po- tential of breast cancer cells to metastasize and enable early cancer detection using manganese. Experiments on breast cell lines demonstrated that aggres- sive cancer cells significantly enhanced on T1 -weighted MR images as a result of a higher uptake and retention of manganese. These results suggest that dif- ferences in uptake of manganese can help the detection and characterization of breast cancers. The proposed technique can also be useful for other cancers, and could bring a critically needed dimension to cancer imaging.

Highly metastatic cancer cells are more likely to escape and form metastases, and only minimal improvements in treatment can be achieved. Despite metas- tases being the primary cause of cancer-related mortality, they often proceed unnoticed. Current imaging modalities rely solely on the morphological fea- tures of the tumor for characterization, rather than cellular differences. Our goal is to develop an MR cellular imaging capability for characterizing the po- tential of breast cancer cells to metastasize and enable early cancer detection using manganese. Experiments on breast cell lines demonstrated that aggres- sive cancer cells significantly enhanced on T1 -weighted MR images as a result of a higher uptake and retention of manganese. These results suggest that dif- ferences in uptake of manganese can help the detection and characterization of breast cancers. The proposed technique can also be useful for other cancers, and could bring a critically needed dimension to cancer imaging.

No description available.

Acetabular labral tears are associated with hip osteoarthritis. A current surgical treatment strategy for a torn labrum, labral resection, has recently shown poor patient outcomes with radiographic signs of osteoarthritis two-years post-operation. Since mechanical factors play a role in the etiology of osteoarthritis, identifying the mechanical role of the labrum may enhance current surgical treatment strategies. In this pilot study, we assessed the relationship between mean cartilage strain, maximum cartilage strain and the three-dimensional cartilage strain distribution in six human cadaver hips with various pathologic conditions of the labrum. We developed a novel technique of mapping cartilage strain using quantitative magnetic resonance imaging (qMRl). qMRl provides a non-invasive means of quantifying the cartilage strain distribution in the hip in three dimensions. Each specimen was assessed first with an intact labrum, then after surgically simulating a longitudinal peripheral labral tear, then after arthroscopically repairing the tear, and after labral resection. We validated the precision of the technique through use of an additional specimen which served as a control. To minimize motion artifact in the high-resolution MR images, we determined that 225 minutes was required for cartilage to reach a steady-state thickness under load. We also determined 16.5 hours was required for cartilage to recover to a steady-state unloaded thickness. The difference in mean and maximum cartilage strain when the labrum was repaired and resected was assessed using a paired t-test. We found that the resected group had an increased mean and maximum cartilage strain of 4% and 6%, respectively and the 3D cartilage strain distribution was elevated throughout the region of interest. When the condition of the intact labrum was compared to the torn labrum, we found no change in mean and maximum cartilage strain, and little obvious change in the 3D pattern of cartilage strain distribution. Based on our findings of increased cartilage strain after labral resection when compared to labral repair, we hypothesize that the labrum’s contribution of additional surface area assists in load distribution, which spares cartilage from excessive loads. We therefore recommend that the longitudinal peripheral torn labrum should not be resected if it is possible to be repaired, because in vivo, labral resection may create an environment with increased articular cartilage strain, which is thought to be associated with cartilage degeneration.

A novel approach for the analysis of spinal cord deformation based on a combined technique of non-invasive imaging and medical image processing is presented. A sopposed to traditional approaches where animal spinal cords are exposed and directly subjected to mechanical impact in order to be examined, this approach can be used to quantify deformities of the spinal cord in vivo, so that deformations — specifically those of myelopathy-related sustained compression — of the spinal cord can be computed in its original physiological environment. This, then, allows for a more accurate understanding of spinal cord deformations and injuries. Images of rat spinal cord deformations, acquired using magnetic resonance imaging (MRI), were analyzed using a combination of various image processing methods, including image segmentation, a versor-based rigid registration technique, and a B-spline-based non-rigid registration technique. To verify the validity and assess the accuracy of this approach, several validation schemes were implemented to compare the deformation fields computed by the proposed algorithm against known deformation fields. First, validation was performed on a synthetically-generated spinal cord model data warped using synthetic deformations; error levels achieved were consistently below 6% with respect to cord width, even for large degrees of deformation up to half of the dorsal-ventral width of the cord (50% deflection). Then, accuracy was established using in vivo rat spinal cord images warped using those same synthetic deformations; error levels achieved were also consistently below 6% with respect to cord width, in this case for large degrees of deformation up to the entire dorsal-ventral width of the cord (100% deflection). Finally, the accuracy was assessed using data from the Visible Human Project (VHP) warped using simulated deformations obtained from finite element (FE) analysis of the spinal cord; error levels achieved were as low as 3.9% with respect to cord width. This in vivo, non-invasive semi-automated analysis tool provides a new framework through which the causes, mechanisms, and tolerance parameters of myelopathy-related sustained spinal cord compression, as well as the measures used in neuroprotection and regeneration of spinal cord tissue, can be prospectively derived in a manner that ensures the bio-fidelity of the cord.

This thesis contains two studies. The first study consisted of a prospective, randomized, clinical trial involving twenty-five client-owned dogs with intracranial disease. Each dog was randomly assigned to receive propofol or isoflurane for maintenance of anesthesia, without premedication. All dogs received propofol IV to effect, were intubated and mechanically ventilated (end-tidal carbon dioxide [ETCO2] 30-35 mmHg). Temperature and cardiac output were measured pre- and post-magnetic resonance imaging (MRI). Scores for mentation, neurological status, maintenance, and recovery were obtained. Pulse oximetry, end tidal gases, arterial blood pressure (AP), heart rate (HR) and requirements for dopamine administration to maintain mean AP > 60 mmHg were recorded throughout anesthesia. Cardiac index was higher, while HR was lower, with propofol in dogs younger than 5 years. Dogs receiving isoflurane were 14.7 times more likely to require dopamine. Sedation and maintenance scores and temperature were not different. Mean and diastolic AP were higher in the propofol group. Recovery scores were better with propofol. Change in neurological score from pre- to post-anesthesia was not different between treatments. In the second study, blood and CSF were collected from 11 dogs with intracranial disease after MRI (Group ID-MRI), in 10 healthy dogs post-MRI (Group H-MRI), and in 39 healthy dogs after induction of anesthesia (Group H-Anesth). Groups ID-MRI and H-MRI were induced to anesthesia with propofol, IV to effect, and maintained on isoflurane or propofol. Dogs in H-Anesth were premedicated with acepromazine and hydromorphone, induced with propofol or thiopental, IV to effect, and maintained on isoflurane. Neurologic scores (NS) and sedation scores (SS) were assessed pre-anesthesia in ID-MRI dogs. There was a tendency for higher cerebrospinal fluid lactate (CSFL) in ID-MRI than H-MRI or H-Anesth (p = 0.12). There was agreement between CSFL and plasma lactate (PL) in ID-MRI dogs (p = 0.007), but not in H-MRI (p = 0.45) or H-Anesth (p = 0.15). Of the ID-MRI dogs, those with worse NS had higher CSFL (r2 = 0.44). Propofol showed some advantages to isoflurane in this patient population for maintenance of blood pressure and recovery. The results of the second study warrant further investigation. / OVC Pet Trust

No description available.

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of invariably fatal neurodegenerative diseases of both humans and animals, thought to be caused by the abnormally folded prion protein PrPSc. Prion disease research continues to be faced by a number of difficult challenges. First, the unequivocal diagnosis of most prion diseases currently requires the post-mortem collection of central nervous system tissue, either for histological examination or Western blot analysis; second, a viable treatment for clinical stage disease has not yet been identified; third, the exact details of disease pathogenesis have not been elucidated; and fourth, the normal function of PrPC is not definitively known. The primary objective of the studies presented here was to diagnose prion disease in live animals, using Magnetic Resonance Imaging (MRI). Increases in T2 relaxation time and apparent diffusion coefficient (ADC) were observed very early following the infection of Syrian golden hamsters with the 263K strain of scrapie. These changes were evident well before the appearance of either clinical symptoms or the typical histological changes characteristic of prion disease, suggesting that they are the result of the progressive accumulation of fluid, and that this may constitute a novel early marker of prion disease pathogenesis. Following the establishment of this model system, a secondary objective was composed: to test the viability of a potential treatment (pentosan polysulphate) using a number of different treatment regimens. It was determined that pentosan polysulphate (PPS) was ineffective as a treatment unless it was administered intra-cerebrally very early in infection, although it was shown to slow the appearance of the histological hallmarks of prion disease. In response to the results of these studies, a potential model was proposed, relating PrP, aquaporin-4 (AQP4) regulation, and oedema. Although speculative, this model may have implications for both normal PrPC function and disease pathogenesis.