Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2007. / Includes bibliographical references (leaves 151-166). Also available in electronic version.

A research report submitted in fulfilment of the requirement for the degree Masters in Medicine in Surgery to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2019 / Background: Phyllodes tumours are rare fibroepithelial neoplasms of the breast. The dilemma with phyllodes tumours is their tendency to local recurrence. This retrospective review of phyllodes tumours in a South African population aims to describe the most common histological and clinical features, and describe the clinical and histological risk factors for local recurrence. Methods: All histological reports of patients diagnosed with a phyllodes tumour after surgery at the University of the Witwatersrand Anatomical Pathology Laboratories in Johannesburg were assessed from 1 January 2005 to 30 June 2016. Clinical and histological parameters were analysed. Results: Over the study period, 185 patients were identified. The median age of the patients was 42 years. There were 89 (48.1%) patients with a benign tumour, 34 (18.4%) with a borderline tumour and 62 (33.5%) with a malignant tumour. The size of the tumours ranged from 11 to 460mm, with a median of 85.0mm  79.6 SD. Breast conserving surgery (BCS) was performed on 64.3% of patients and 35.7% of patients had a mastectomy. There was an overall local recurrence rate of 3.78% (2.2% for benign and 8.1% for malignant tumours). No clinical or histological factors, including margin status, were found to significantly predict local recurrence. Most recurrences (71.4%, n=5) occurred within the first two years. Conclusion: Our study did not find any predictors of local recurrence, but we provide further support to the recent suggestion of revising the common practice of wide local excision with a 1cm margin, to an excision with negative margins combined with close follow-up for two years. / TL (2020)

INTRODUCTION: Despite the use of modern minimally invasive surgical techniques, post-operative complications following lung cancer resection remain common and challenging to predict. Pulmonary ventilation imaging modalities offer detailed regional assessment of airflow obstruction and are highly sensitive to subclinical airway and/or parenchymal disease. Nevertheless, ventilation imaging is seldom integrated into pre-operative lung function assessment and risk stratification procedures. Therefore, the objective of this thesis was to quantify the burden of ventilation defects observed by Technegas SPECT and 129Xe MRI before lung cancer resection and establish their association with the occurrence and clinical impact of post-operative complications. METHODS: Patients undergoing lung cancer resection at St. Joseph’s Healthcare Hamilton were recruited into a prospective, proof-of-concept, six-week observational study. Participants were evaluated prior to resection surgery to document baseline demographics and clinical characteristics, performed standard pulmonary function tests and sputum induction, and underwent Technegas SPECT and 129Xe MRI to assess ventilation. Abnormal ventilation was quantified as the ventilation defect percent (VDP) and was considered abnormal if VDP was ≥mean+2 standard deviations of a healthy population. Following surgery, participants were followed for 4 weeks to document the incidence of post-operative complications, as specified by the Ottawa TM&M categorization system, and the length of hospital stay. RESULTS: One hundred and twenty-three participants were enrolled, of whom 103 were evaluated pre-operatively and followed for post-operative outcomes. Of the 103 participants (69±8 years, 58% female), 89% (92/103) underwent minimally invasive surgery, and 74% (76/103) underwent lobectomy. Abnormal ventilation was observed pre-operatively by Technegas SPECT and 129Xe MRI for 59% (58/99) and 84% (82/98) of participants, respectively. In a subset of 69 participants in whom sputum was collected, 51% (35/69) had intraluminal inflammation. A total of 64 post-operative complications occurred; 16 (25%) were pulmonary, and 48 (75%) were pleural complications. A post-operative complication occurred in 42% (41/103) of participants. Pre-operative Technegas SPECT and 129Xe MRI VDP were higher for participants with post-operative complications compared to those without (Technegas SPECT: 26±17% vs 19±7%, p=0.02; 129Xe MRI: 13±12% vs 7±6% p=0.003) and were positively correlated with post-operative length of hospital stay (Technegas SPECT: r=0.43, p<0.0001; 129Xe MRI: r=0.49, p<0.0001). Multivariable regression models revealed that preoperative Technegas SPECT and 129Xe MRI VDP were predictors of post-operative complications (Technegas SPECT: Odds ratio=1.08, p=0.005; 129Xe MRI: Odds ratio=1.16, p=0.002) and post-operative length of hospital stay (Technegas SPECT: unstandardized β=0.13, p<0.001; 129Xe MRI: unstandardized β=0.24, p<0.001). CONCLUSIONS: Abnormal ventilation, quantified by Technegas SPECT and 129Xe MRI VDP, is prevalent prior to lung cancer resection and a predictor of post-operative complications and length of hospital stay. / Thesis / Master of Science (MSc) / Post-operative complications are frequent adverse events following lung cancer resection, resulting in substantial patient morbidity and mortality that have a significant clinical and economic impact. Despite this, post-operative complications remain inadequately predicted, and limited research has been dedicated to reducing the risk of pulmonary complications after lung cancer resection. Standard clinical screening tools, such as pulmonary function tests, are used for patient selection in lung cancer resection surgery; however, they provide a global estimate of a complex multicompartment organ and may lack the sensitivity to detect subclinical lung pathology that influences post-operative outcomes. Thus, using high-resolution medical imaging modalities such as single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI), we investigated the prevalence and clinical relevance of abnormal ventilation, a functional consequence of airway and/or parenchymal disease. One hundred and three participants were enrolled in a six-week prospective, proof-of-concept observational study. Participants performed pre-operative imaging and were followed for four weeks post-operatively to document post-operative complications and relevant clinical outcomes. Pre-operative SPECT and MRI revealed a high prevalence of abnormal ventilation. The pre-operative ventilation defect burden was greater in participants who developed one or more complications during the four-week post-operative period and was an independent predictor of both the incidence of post-operative complications and the length of hospital stay. These observations provide proof-of-concept evidence that abnormal ventilation, assessed by two ventilation imaging modalities, is prevalent and clinically relevant prior to lung cancer resection. Taken together, this thesis establishes that ventilation imaging may have implications for risk stratification and risk modification in patients scheduled to undergo lung cancer resection.

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published_or_final_version / Pathology / Master / Master of Medical Sciences

In the study of the mechanical behavior of biological tissues, many complex tissues are often modeled as poroelastic systems due to their high fluid content and mobility. Fluid content and fluid transport mechanisms in tissues are known to be highly correlated with several pathologies. Thus, imaging techniques capable of providing accurate information about these mechanisms can potentially be of great diagnostic value. Ultrasound elastography is an imaging modality that is currently used as a complement to sonographic methods to detect a variety of tissue pathologies. Poroelastography is a new elastographic technique that has been recently proposed to image the mechanical behavior of tissues that can be modeled as poroelastic media. The few poroelastographic studies retrievable focus primarily on homogeneous poroelastic media. In this study, a statistical analysis of the performance of poroelastographic techniques in a non-homogeneous poroelastic simulation model under different loading conditions was carried out. The two loading conditions simulated were stress relaxation (application of constant strain) and creep compression (application of constant stress), both of which have been commonly used in the field of poroelastography. Simulations were performed using a FE poroelastic simulation software combined with ultrasound simulation software techniques and poroelastography processing algorithms developed in our laboratory. The non-homogeneous poroelastic medium was modeled as a cube (background) containing a cylindrical inclusion (target). Different permeability, Young’s modulus and Poisson’s ratio contrasts between the underlying matrix of the background and the target were considered. Both stress relaxation and creep compression loading conditions were simulated. The performance of poroelastography techniques was quantified in terms of accuracy, elastographic contrast–to–noise ratio and contrast transfer efficiency. The results of this study show that, in general, image quality of both axial strain and effective Poisson’s ratio poroelastograms is a complex function of time, which depends on the contrast between the poroelastic material properties of the background and the poroelastic material properties of the target and the boundary conditions. The results of this study could have important implications in defining the clinical range of applications of poroelastographic techniques and in the methodologies currently deployed.

This joint PhD program is part of a collaboration between Hong Kong Baptist University (Dr. Gary K-L Wong) and Laboratoire d'Ingénierie Moléculaire Appliquée à l'Analyse (LIMAA - Dr. Loïc Charbonnière) funded by the Alsace region to synthesize new nanoprobes for sensing, imaging, and inhibiting cancer diseases. The first work was to synthesize new hybrid ultrabright nanoparticles. They have been obtained from a La0.9Tb0.1F3 core and coated by different ligands. Thanks to a mechanism of antenna effect, the brightness of the nanoparticles has been significantly improved. The second work was to synthesize a new ligand to photosensitize water-soluble La0.90Eu0.1F3 nanoparticles in order to improve the emission of europium. A second ligand and new heterometallic nanoparticles have been synthesized with the aim to promote the energy transfer from Tb(III) ions on the surface of the NPs to Eu(III) ions in the core of the nanoparticles and to get a very long excited-state lifetime and an exceptional quantum yield in aqueous solution. The last work was to functionalize water-soluble graphitic-carbon nitride (g-C3N4) nanoparticles by porphyrins. The porphyrins have been synthesized to generate singlet oxygen (1O2), to host a Ga3+ ion inside their cavity and with two different linkers to be coupled to nanoparticles. This system aims to be a pH sensor, and a PDT and PET theranostic agent.

With all the improvements in cancer treatments, multidrug resistance is still the major challenge in treating cancer. Cells can develop multidrug resistance (MDR) during or after treatment, which will render the cancer cells resistant not only to the chemotherapy drug being used but also to many other structurally- and mechanically-different chemotherapeutics. In the first project, the main focus was on development of drug resistant cell lines by selection with taxol. Gene changes in the L1T2 cell line after treatment with Taxol was studied. Treatment of L1T2 cells with taxol leads to changes in the expression of ABC transporter proteins, whereas the combination of Taxol with protease inhibitors leads to increased efficacy via inhibition of P-glycoprotein (P-gp). In the second project, we showed that our innovatively-designed Au-loaded poly(lactide-co-glycolic acid) nanoparticles (GPLGA NPs) are able to cross biological barriers and deliver inside the cells without being recognized by the ABC protein transporter. (We focus specifically on P-gp-mediated drug efflux in a model of HEK cell lines.) The concentration of gold was measured using inductively-coupled plasma/mass spectrometry (ICP-MS) after 6- and 24-hour treatment of GPLGA NPs, which did not show significant increase of gold inside the cells in presence of the P-gp inhibitor valspodar. Cancer cells were treated with the GPLGA NPs for 24 hours and then irradiated 5 minutes at 1Wcm-2 using laser settings at 680 or 808 nm. Heat generation in cancer cells, after internalizing GPLGA NPs and laser irradiation, was significant irrespective of laser wavelength. The plasmomic heating response in this in vitro model can be a step closer to overcome MDR. Finally, for the third and last project represented in this dissertation, the focus was on the design and synthesis of innovative, biodegradable PLGA NPs, encapsulated with the platinum(II)-based non-organometallic/non-cyclometalated phosphorescent complex PTA = [Pt(ptp)2], a brightly phosphorescent complex (ptp = square-planar bis[3,5-bis(2-pyridyl)-1,2,4-triazolato]). Size-tunable, emission-polarized phosphorescent PTA-loaded PLGA NPs were synthesized using a single-emulsion, solvent evaporation technique. Photoluminescence characterization shows that PTA-loaded PLGA NPs exhibit strong and stable orange emission with peak maximum ~ 580 nm. The photoluminescence quantum yield (QY) of the synthesized PTA-PLGA NPs was evaluated at ~55%, which allows recording of images with a much better contrast than that with PTA in organic solvents without the PLGA (QY ~0.5% and ~0 emission polarization) or even that with typical fluorescent organic dyes like rhodamines.

Conventional imaging techniques for cancer detection have difficulty finding small, deep tumors. Single-detector radiation probes have been developed to search for deep lesions in a patient who has been given a tumor-seeking radiopharmaceutical. These probes perform poorly, however, when the background activity in the patient varies greatly from site to site. We have developed a surgical dual-detector probe that solves the problem of background activity variation, by simultaneously monitoring counts from a region of interest and counts from adjacent normal tissue. A comparison of counts from the detectors can reveal the class of tissue, tumor or normal, in the region of interest. In this dissertation we apply methods from statistical decision theory and derive a suitable comparison of counts to help us decide whether a tumor is present in the region of interest. We use the Hotelling trace criterion with a few assumptions to find a linear discriminant function, which can be reduced to a normalized subtraction of the counts for large background count-rate variations. If area under the ROC curve is our figure of merit, the likelihood ratio is the optimum discriminant. We model likelihood functions of the data given the "tumor" and "no-tumor" hypotheses, and calculate the likelihood ratio. Using a spatial response map of the dual probe, a computer torso phantom, and estimates of activity distribution, we simulate a surgical staging procedure to test the dual probe and the discriminant functions. Results of the simulations show that the dual probe effectively solves the problem of background activity variations when used with any of the discriminant functions derived in this dissertation.

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