published_or_final_version / abstract / Electrical and Electronic Engineering / Master / Master of Philosophy

Photodynamic therapy (PDT) and Magnetic resonance imaging (MRI) are two techniques used in therapeutic and diagnostic purpose respectively. PDT can selectively kill the cancer cells by utilizing light and photosensitizer, while MRI provides invasive imaging on our interior bodies. If these two techniques combine, the probe can act as both PDT and MRI agent at the same time. This theranostic agents can bring great efficiency in the cancer treatment. In this project, a porphyrin-cyclen gadolinium based dual functions bio-probe, PZnGdL, is designed for diagnostic and photodynamic therapeutic functions. PZnGdL demonstrated a great T1 signal enhancement for MRI, in which its T1 relaxivity is 15.06 mM-1s-1 (at 1.4T, 37oC). The T1 relaxivity is five-fold higher than the clinically approved MRI contrasting agent Gd-DOTA, (2.92 at 1.4T, 37oC). Furthermore, PZnGdL exhibits low dark toxicity and high photocytotoxicity. Therefore, its photodynamic therapeutic index (PDI) in HeLa cells is as high as 1348 upon 1 J/cm2 light irradiation. Results from the present study show that PZnGdL is an effective photodynamic therapy agent as well as a safe and promising MRI contrasting agent.

The management of advanced cervical and ovarian cancers remains a significant challenge as many women fail to respond to recommended therapy, resulting in disease progression and ultimately patient death. Because of tumour heterogeneity, it is rare for all cancers of a particular type to respond to a specific therapy. Many patients therefore receive treatment from which they derive little or no benefit, leading to increased morbidity and costs. A marker that could rapidly predict disease outcome would clearly be beneficial in allowing the administration of tailored therapy while reducing toxicity and cost. Novel functional imaging techniques have the ability to characterise biological tissues and non-invasively integrate physical and metabolic information. These include diffusion weighted MRI (DW-MRI), which is particularly sensitive to the microscopic motion of water molecules and changes in tissue cellularity, as well as dynamic contrast-enhanced MRI (DCE-MRI) which can assess tumour vascular characteristics during the passage of a paramagnetic contrast agent through tissues. Both imaging techniques have demonstrated potential as biomarkers of tumour response in various malignancies such as brain tumours, but have not been fully explored in gynaecological cancers.

Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer ranked as the 5th most common in Hong Kong. We aimed to study the role of dynamic contrast-enhanced MRI (DCE-MRI) and dynamic 2-deoxy-2-[fluorine-18]fluoro -D-glucose positron emission tomography (FDG-PET) for characterizing NPC tumors in newly-diagnosed patients, and to quantitatively evaluate the intratumoral heterogeneity of NPC. In Chapter 2 we employed semi-quantitative analysis of DCE-MRI to study the dynamic enhancement pattern by analyzing the time-intensity curves in 25 NPC patients. Our findings suggested that high blood flow caused a high initial intensity enhancement rate (ER), and that neovasculature due to tumor angiogenesis in tumors of larger volume or higher T-stage caused more accumulation of contrast agent which can be detected by DCE-MRI. PET and semi-quantitative DCE-MRI parameters were not correlated and may reflect different physiological/molecular processes in the microenvironment of NPC tumor. However the major limitation of semi-quantitative analysis was that the physiological correlates of these parameters were unclear. In Chapter 3 we applied quantitative analysis of DCE-MRI to study the permeability and perfusion characteristics in the same cohort as in Chapter 2. Our findings implied that the permeability may be high compared to blood flow in NPC tumor. We also observed significant correlations between iAUC (the initial area under the time-intensity curve) by semi-quantitative analysis and ve (the volume fraction of extravascular extracellular space) by quantitative analysis, and between the two rate constants (kep’s) from these two methods, which showed that semi-quantitative analysis was a feasible alternative in reflecting the physiological characteristics of NPC. However, we did not observe any significant correlation between PET and DCE-MRI quantitative parameters, also suggesting that PET and DCE-MRI reflected different physiological information in NPC. In Chapter 4 we applied dynamic PET scan to study the glucose metabolism in 18 NPC tumors (16 included in DCE-MRI cohort). Our findings showed that the overall FDG uptake was mainly composed of the FDG in tissue compartment (Ki), which was governed by the phosphorylation (k3) but not the transport of FDG (K1). This finding may further indicate a potential role of the phosphorylation rate k3 in NPC. Dynamic PET parameters did not correlate with DCE-MRI, indicating that the two modalities reflect different molecular information in NPC. In Chapter 5, intratumoral heterogeneity in NPC tumors of 40 patients was studied using 18F-FDG PET scan. Our findings showed that as tumors grew to a larger volume and higher T-stage, they showed more heterogeneous glucose metabolism. It was found that more heterogeneous tumor was associated with worse disease-free survival, indicating that tumor metabolic heterogeneity may play an important role for NPC patient prognosis. To summarize, these results showed that DCE-MRI and dynamic PET improved our understanding about the physiological/molecular process of NPC, and, these two modalities reflected different physiological information in the microenvironment of NPC tumors. This indicated that the relationship between supply of nutrients such as glucose and blood flow/permeability is complex and not directly related. Moreover, intratumoral heterogeneity by PET scan was also of importance in prognostication. / published_or_final_version / Diagnostic Radiology / Doctoral / Doctor of Philosophy

Introduction Peritoneal metastasis is advanced disease and is usually widely disseminated at the time of discovery. It is crucial to detect peritoneal metastasis at an early stage and to allow precise patient selection for the right treatments. Both fluorodeoxyglucose positron emission tomography/computed tomography (FDGPET/CT) and magnetic resonance imaging (MRI) are used in peritoneal metastasis detection. Standardized uptake value (SUV), derived from FDGPET/ CT can evaluate glucose metabolism in cells, whilst apparent diffusion coefficient (ADC) derived from diffusion-weighted MRI (DWI) is used for quantitative analysis of tumour cellularity. Amide proton transfer (APT) MRI is a novel imaging technique based on exchangeable amide protons as endogenous contrast agent and can measure the increased amide proton signal in malignant tissues indirectly through bulk water proton signals. This thesis aims to: 1) compare the diagnostic performance of FDG-PET/CT and MRI in peritoneal metastasis evaluation; 2) study the relationship between SUV and ADC in peritoneal metastasis; 3) investigate the feasibility of APT in peritoneal metastasis evaluation. Materials and Methods Patients with peritoneal metastasis detected on FDG-PET/CT were prospectively recruited for MRI. FDG-PET/CT and MRI images were reviewed independently by two radiologists in separate sessions. Diagnostic characteristics were calculated for both imaging techniques. SUVmax and SUVmean were obtained by placing ROIs on PET, while ADCmin and ADCmean were calculated by contouring lesions on DWI. APT MRI was performed using a single-slice turbo spin echo sequence, with a block of presaturation pulses at 33 frequency offsets. ROIs were placed on peritoneal metastasis and muscle on APT. Mean of integrated asymmetrical magnetic transfer ratio (MTRasym) over 3-4 ppm with respect to water resonance was calculated for peritoneal metastasis and muscle. Results Eight patients were recruited in this study with 128 anatomical sites evaluated. DWI/MRI had good diagnostic performance (sensitivity = 92%, specificity = 99%, accuracy = 98%) compared to that of FDG-PET/CT (sensitivity = 90%, specificity= 100%, accuracy = 98%). Thirty-four peritoneal metastases were selected for quantitative analysis. Significant inverse correlation was found between ADCmean and SUVmax (r = -0.528, p = 0.001) and between ADCmean and SUVmean (r = -0.548, p = 0.001). ADCmin was significantly and negatively correlated with SUVmax (r = -0.508, p = 0.002) and SUVmean (r = -0.513, p = 0.002). In the above study cohort, 6 patients underwent APT imaging with 8 peritoneal metastases evaluated. Seven lesions showed positive APT signal and one had negative APT signal. The mean APT signal for peritoneal metastasis was 2.28%±1.76%, significantly different from that of muscle (-2.79%±0.95%, p < 0.001). Conclusions In conclusion, both DWI/MRI and FDG-PET/CT had good diagnostic performance in peritoneal metastasis evaluation. The negative correlation between SUV and ADC suggested an inverse relationship between tissue metabolism and cellularity. APT MRI is feasible to generate sufficient contrast signal for peritoneal metastasis and has potential to discriminate peritoneal tumours from its surrounding soft tissue using integrated MTRasym as a quantitative marker. These functional indices allow understanding of the biological behaviours of peritoneal tumours and could act as adjuncts in peritoneal metastasis imaging. / published_or_final_version / Diagnostic Radiology / Master / Master of Philosophy

Lee, Kar Ho Francis. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 148-163). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Magnetic resonance imaging plays an important yet underutilized role in determining the natural history and prognosis of oral carcinoma. Depth of tumour invasion is an emergent factor in the oral cancer literature. However, problems exist with the definition of cut-points suitable for inclusion in TNM staging criteria. Statistical methodology represents a possible explanation but is underexplored. In this work, a review of the depth of invasion literature is conducted with emphasis on statistical technique. As well, statistical simulation is used to explore the implications of the of the minimum p-value method. The results demonstrate that the use of continuous variable categorization and multiple testing is widespread, and contributes to cut-point variability and false-positive tests. Depth, as a predictor of OCLNM and survival, must be questioned. The volume of tumour invasion is a promising prognostic factor that has not been fully investigated in the oral carcinoma literature. In this work, the volume of tumour invasion is measured on MRI and compared to thickness and maximum diameter in its capacity to predict 2-year all-cause, disease-related and disease-free survival, as well as occult cervical lymph node metastasis prediction. As part of a comprehensive approach, morphometric factors are incorporated into multifactor predictive models using regression, artificial neural networks and recursive partitioning. It is evident that MRI-based volume is superior all other linear measurements for both occult cervical lymph node metastasis and survival prediction. Artificial neural networks wee superior to all other techniques for survival prediction. There is a case for a unified artificial neural networks model for survival prediction that uses volume, midline invasion and N-stage to determine prognosis. This model can be used to determine individualized probabilities of 2-year survival. The lateral extrinsic muscles of the tongue lie just beneath the surface of the lateral tongue, yet their invasion is a criterion for T4 classification using the TNM staging system. In this work, the Visible Human Female is used to conduct an anatomic study of the extrinsic muscles of the tongue. Linear measurement is used to quantify the distance from the surface mucosa to the most superficial muscle fibres of the styloglossus and genioglossus. Further, the lateral extrinsic muscles are poorly demonstrated on MRI. An anatomic atlas of the tongue is fused with MRI images of oral carcinoma to demonstrate lateral muscle invasion. The results demonstrate that the styloglossus and hyoglossus lie very close to the surface of the lateral tongue, in some cases passing within 1 mm of the surface mucosa. These extrinsic muscles are readily invaded by even small tumours of the lateral tongue. Strict application of the TNM T4a criteria leads to unnecessary upstaging as these carcinomas do not warrant the prognosis and aggressive treatment of Stage IV disease. Extrinsic muscle invasion should be removed as a T4a criterion for the oral cavity. A separate category, T4a (oral tongue) specifying invasion of the genioglossus is also recommended. This work presented in this thesis is an original contribution to the field of oral cavity cancer research and has determined that there is capacity for improvement in current efforts to determine the natural history and prognosis of oral cavity squamous cell carcinoma. This thesis is the first to examine the role of statistical methodology in oral carcinoma depth of invasion cut-point variability. Further, this work presents an original approach to the prediction of regional metastasis and survival using advanced multivariate modeling techniques. No other work explored MRI-measured volume using the substantial sample size gathered in this thesis. Finally, this work is the first to demonstrate that lateral extrinsic muscle invasion is an unnecessary component of the T4a (oral cavity) classification criteria and should be reconsidered.

published_or_final_version / Diagnostic Radiology / Doctoral / Doctor of Philosophy

Background: Parametrial tumor involvement is an important prognostic factor in cervical cancer and is used to guide management. Here, we investigate the diagnostic value of clinical examination under general anesthesia (EUA) and magnetic resonance imaging (MRI) in determining parametrial tumor spread. Methods: Post-operative pathological findings of 400 patients with primary cervical cancer were compared to the respective MRI data and the results from EUA. The gynecological oncologist had access to the MR images during clinical assessment (augmented EUA, aEUA). Results: Pathologically proven parametrial tumor invasion was present in 165 (41%) patients. aEUA exhibited a higher accuracy than MRI alone (83% vs. 76%; McNemar’s odds ratio [OR] = 2.0, 95%CI 1.25–3.27, p = 0.003). Although accuracy was not affected by tumor size in aEUA, MRI was associated with a lower accuracy in tumors ≥2.5 cm (OR for a correct diagnosis compared to smaller tumors 0.22, p < 0.001). There was also a decrease in specificity when evaluating parametrial invasion by MRI in tumors ≥2.5 cm in diameter (p < 0.0001) compared to smaller tumors (< 2.5 cm). Body mass index had no influence on performance of either method. Conclusions: aEUA has the potential to increase the diagnostic accuracy of MRI in determining parametrial tumor involvement in cervical cancer patients.