Lung cancer is the leading cause of cancer deaths worldwide. More than 40% of lung cancers are classified as lung adenocarcinoma (LUAD), which is defined by pathological characteristics. Oncogenic mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain (TKD) are found in a significant portion of LUAD. Such mutations, which present most commonly as small in-frame deletions in exon 19 (ex19del) or as point mutations in exon 21 (L858R), allow for EGFR activation, sensitivity to EGFR tyrosine kinase inhibitors (TKIs), and molecularly targeted therapy in this malignancy. By analyzing the tumors of patients with LUAD, we identified two EGFR alterations that had not previously been reported in lung cancer: the EGFR kinase domain duplication (EGFR-KDD) and the EGFR-RAD51 fusion. While knowledge about common EGFR mutations (L858R or ex19del) has allowed for rational treatment of specific cohorts of LUAD, nothing was known about the EGFR-KDD and EGFR-RAD51 in LUAD. These mutationsâwhich we call EGFR rearrangementsâmaintain the wild type sequence of the EGFR TKD and could have mediated either sensitivity or primary resistance to EGFR-TKI therapy. The goal of these studies was to fill in this knowledge gap: to characterize a new type of EGFR alteration in LUAD, to determine the sensitivity of these rearrangements to therapy, and, along the way, to uncover more about the biology of EGFR. Collectively, the research in this dissertation used in vitro and in silico models, as well as patient-derived data, to address a previously unrecognized potential mechanism of oncogenesis in lung cancer: EGFR rearrangements. These studies established EGFR-KDD and EGFR-RAD51 as bona fide recurrent oncogenes and therapeutic targets in LUAD. The work is already proving clinically relevant as these alterations have been identified in additional lung cancer patientsâwho may now have more targeted treatment options.

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Introduction As a result of the growing and ageing population in developed countries, improved cancer detection and advances in cancer treatments, there are more people living with cancer for longer. The rising number of cancer survivors and increasing demand for oncology services, has sparked interest in alternative ways of delivering cancer follow-up care. Although a number of alternative cancer follow-up strategies have been developed, information about the relative importance of different characteristics of follow-up and how people trade between these characteristics is still limited. Aims and objectives The overall aim of the thesis was to understand what characteristics (called attributes and levels) of cancer follow-up services are important to survivors of cutaneous melanoma, breast, prostate and colorectal cancer; whether people make trade-offs between these characteristics; and whether survivors of different cancers with different personal characteristics express different preferences for cancer follow-up care. The aim was met by a number of objectives: •To conduct a review of the literature to gather information about characteristics of follow-up that are important to people. • To conduct semi-structured qualitative interviews with cancer survivors living in North East Scotland, to determine their views of current care and preferences for future cancer follow-up. • Based on the findings from the literature and semi-structured interviews, to determine characteristics (attributes and levels) of cancer follow-up services for inclusion in a discrete choice experiment. • To develop and carry out a discrete choice experiment to establish the relative importance of a number of attributes of cancer follow-up amongst cancer survivors treated and followed up for cutaneous melanoma, breast, prostate and colorectal cancer.

Metastasis is a complex, multistep process requiring alterations in many aspects of tumour cell behaviour, including changes in invasive potential, motility and adhesive interactions. Alterations in these parameters are achieved by changes in extracellular matrix degrading protease production, extracellular matrix modulation (i.e. 1 integrins, CD44) and cell adhesion molecule production, to name a few. In this series of studies, the effects of several cytokine/growth factors which are present in the complex microenvironment of a solid tumour are investigated in primary and secondary renal and ovarian cell lines. The effects which were investigated in in vitro models examined the invasion potential, motility, adhesion, matrix metalloproteinase production, 1 integrin expression, CD44 expression, fibronectin production and fibronectin splicing. Major findings were that EGF (40ng/ml) in the primary renal carcinoma cell line, A704, increased the tumour cells invasion potential, motility, altered its adhesion to several extracellular matrix components, increased the production of matrix metalloproteinase production, altered the expression of several 1 integrins and increased the expression of CD44 and its variants. In a similar manner, stimulation of a primary ovarian carcinoma cell line, CaOv3 with TGF1 (5ng/ml) resulted in changes which paralleled those of the primary renal carcinoma cell line when stimulated with EGF. Other findings in the study included demonstration of the effect of other cytokine/growth factors (PDGF and HGF) on the aforementioned parameters, however, these were not as comprehensive as EGF and TGF1 on the primary renal and ovarian carcinoma cell lines. Therefore, it is postulated that cytokine/growth factors have an important role in modulating parameters which contribute to the metastatic propensity of tumour cells. In particular EGF and TGF1 may have important respective roles in the dissemination of renal and ovarian tumours.

B-cell chronic lymphocytic leukaemia (B-CLL) is characterized by an accumulation of clonal malignant B cells within lymphoid tissue, the bone marrow and the peripheral blood. Whilst abnormalities of these B cells are the essential cause of this disease, the aim of this research project was to investigate whether the T cell compartment may play a role in the aetiology of this disease by evaluating the expression of key surface antigens involved in both activation of and interaction with B cells and other antigen presenting cells of the immune system. There were marked abnormalities in the expression of certain key activation and interaction antigens on the peripheral blood T cells of patients with BCLL, in particular, compared to normal controls, there was a significant reduction in the number of circulating T cells expressing CD25, CD28, CD152, CD4, CD5 and CDI Ia. There was no difference in expression of TCRccp, CD8, CD54 and CD154. Significantly more T cells from CLL patients expressed HLA-DR. Removal of the malignant clone of cells prior to short-term T cell culture did not affect expression of these markers. Numbers of T cells expressing intracellular CD25 and CD152 were not decreased after activation and a significantly greater number of resting T cells expressed both antigens intracellularly. There was also evidence of a soluble factor present in CLL AB serum which caused increased numbers of normal and CLL T cells to express CD25 and CD 152 after culture. Initial results suggest that this may be IFN-y, levels of which were significantly higher, as measured by ELISA, from resting CLL T cells compared to normals. By studying the expression of these antigens using cell culture, flow cytometric and ELISA techniques, the results suggest a functional state of anergy in these T cells. This anergic state may contribute to the pathogenesis of B-CLL and its related phenomena of immunosuppression and autoirnmunity. This was further reflected in the results of the T cell functional studies and reduced IL-2 expression in the mixed lymphocyte reaction (MLR).

MBBCh Department of Surgery University of the Witwatersrand 08 March 2017 / Background: Breast cancer recurrence is a major clinical event and represents a principal cause of breast cancer related death. A discordance rate between receptor status of primary and matched recurrence tumours has been reported in the literature but the extent of this in our population is unknown. Repeating Immuno-histochemistry (IHC) and fluorescent in-situ hybridization (FISH) studies have financial and workforce implications in a resource-constrained environment. However, the results of these receptor studies have prognostic implications. Therefore it is important to determine the extent of change in receptors in the recurrence. Aim: To compare the hormone receptor profile between breast cancer primary and matched loco-regional recurrence and to ascertain the extent of receptor discordance. Methods: All patients who presented to the respective breast care facilities for breast cancer recurrences between 2006 and 2014 were identified using the mammography department records. The specimens for each patient were scrutinized. Oestrogen receptor (ER) and progesterone receptor (PgR) status as well as the Human Epidermal growth factor type 2 receptor (HER2) receptor statuses were noted for each patient and a comparison was made between primary and matching recurrence, with loss and gain being noted. Results: In the analysis, significant discordance was found for matching hormone receptor status. Discordance in oestrogen receptor status occurred in 14.3% of cases: change occurred both from ER-positive to -negative and vice versa. For progesterone receptor status this occurred in 25.7% of cases. A discordance of 14.8% was noted for HER2 receptor status. These results are not dissimilar to what has been previously reported in the literature. Of note, adverse receptor discordance: positive to negative was noted in a total of 19 receptors (ER 4; PgR 11; HER2 4) Conclusion: These results confirm the phenomenon of receptor discordance between breast cancer primary and recurrence. The results support the necessity of confirming receptor status on all loco-regional recurrent disease. This reinforces the importance of obtaining a confirmatory biopsy in patients where recurrence is suspected and therefore allowing the appropriate targeted therapy to be selected. / MT2017

Thesis advisor: André Brouillette / Thesis advisor: Margaret Eletta Guider / Thesis (STL) — Boston College, 2016. / Submitted to: Boston College. School of Theology and Ministry. / Discipline: Sacred Theology.

University of Macau / Faculty of Health Sciences

University of Macau / Faculty of Health Sciences