Malignancy within the pancreatic head can arise from pancreatic duct, distal bile duct, ampulla or duodenum. Since September 2000, surgery for all pancreatic head malignancy (PHM) has been centralised into regional pancreatic centres where assessment of preoperative imaging and subsequent surgery is undertaken. As part of this guidance, surgery must be performed within 62-days of referral. This project will assess four aspects of the pre-operative pathway in PHM: 1) Potential variation in outcome of patients referred from different sites within a Cancer Network 2) Potential variation in outcome associated with different intervals to surgery within the 62 day guideline 3) The ability of interpretation of heterogeneous pre-operative CT scans from different hospitals to determine the resectability of PHM 4) The ability of CT scan to distinguish the different tumour types of PHM Images of a consecutive series of patients were re-reported and compared with final pathology reports. Good agreement was noted in determining the tumour origin of PHM (observed agreement = 0.758, Kappa= 0.6 (0.51-0.68)). In the assessment surgical outcomes, geographical isolation from the regional centre was not associated with delay to surgery. Variation in outcome between referral centres was however noted but this was not associated with travel distance. Although little association was noted between delay to surgery and outcome overall, a paradoxical improvement in survival was noted however for the small group of patients with ampullary tumours who waited longer than the median interval to surgery.

As a validation study, this study addressed an under-researched area of bronchopulmonary cancer mortality and incidence. The association between altitude and bronchopulmonary cancer mortality and incidence was investigated using data from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research. The theoretical framework for my study was Bronfenbrenner's ecological model. This model emphasizes the relevance of social and physical environments that influence patterns of disease and injury and shape responses to these patterns of disease and injury. The age-adjusted bronchopulmonary cancer mortality and incidence rates per 100,000 people in the highest elevation and lowest elevation states were investigated. The data used in this study spans from 2006 to 2014. In this study, bivariate statistics were used to analyze the data. The relevant technique of performing an unpaired t-test was used. After performing age, gender, and race-stratified analysis, no significant difference in cancer mortality and incidence was found within the following three groups: Black or African American, Asian or Pacific Islander, and American Indian or Alaska Native. This was a new finding, as previous studies did not stratify for race. Cancer mortality and incidence were found to be lower in both the male and female groups for the highest elevation states. Cancer mortality and incidence were also found to be lower in all age categories for the highest elevation states. A positive social change impact of this study is that this research provides the groundwork for future studies to probe what in the environment is lowering the bronchopulmonary cancer mortality and incidence for the White population.

Older people represent an increasing proportion of new cancer diagnoses yet little is known about their experiences with cancer or their knowledge about risk factors, benefits of lifestyle modification to decrease risk or participation in early detection programs. Two studies were conducted, the first to document a lived experience with a new cancer diagnosis and the second to test for relationships between knowledge and attitude to cancer and self-reported participation in screening for breast, prostate and colorectal cancers. / http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1297244 / Thesis (D.Nurs.) -- School of Population Health and Clinical Practice, 2007

The purpose of this study was to investigate the influence of gender, time since diagnosis, and the family environment on the psychosocial adaptation of cancer patients. This study was important because there is a deficit in the literature investigating the effects of the family environment on psychosocial adaptation in male and female cancer patients with diverse diagnoses. This study measured psychosocial adaptation by the patient's ability to adjust to cancer-related stressors in the areas of social relationships, involvement in health care, psychological well-being, household and work related duties, and family relationships. The family environment was measured by the patient's perceived level of cohesion, expressiveness, and conflict in the family.The study's sample consisted of 149 stage I or II cancer patients over the age of 50 with no prior cancer diagnosis, recurrence, or metastases. Participants completed a set of questionnaires, including the Psychosocial Adjustment to Illness Scale and the Family Relationship Index. The combination of gender, time since diagnosis, and the family environment, with demographic variables held constant, was significant and accounted for nearly one-third (27 %) of the variance in cancer patients' psychosocial adaptation. Results showed that the family environment is a significant predictor of psychosocial adaptation in cancer patients. Gender and time since diagnosis were not significantly related to psychosocial adaptation. Implications from this study are offered. / Department of Counseling Psychology and Guidance Services

Thesis (M.Sc. (Biochemistry)) -- University of Limpopo, 2020 / Despite major advancements in the development of various chemotherapuetic agents, treatment for lung cancer remains costly, ineffective, toxic to neighbouring normal noncancerous cells and still hampered by high level of remissions (Wistuba et al., 2018; Tana et al., 2016; Schiller et al., 2002). Synthesis of novel quinoxalines with a wide spectrum of biological activities has recently received considerable attention with promising anticancer drug activity since most of them do not affect non-cancerous cells and are derived from readily available less costly raw materials (Srivastava et al., 2014). Since combination treatment has been shown to augment and improve single drug treatment, trace elements were employed in this study in combination with quinoxalines derivatives (Gomez et al., 2016; Kocdor et al., 2015; Ku et al., 2012; John et al., 2010; Killile and Killilea, 2007). Zinc is an essential element that is integral to many proteins and transcription factors which regulate key cellular functions such as the response to oxidative stress, DNA replication, DNA damage repair, cell cycle progression, and apoptosis (Dhawan and Chadha, 2010). Owing to the importance of these two approaches, the aim of this study was to provide in vitro preliminary anticancer activity data on A549 lung cancer cells using combination of zinc and quinoxaline derivatives. An assessment of the quinoxaline derivatives ferric reducing power and DPPH free radical scavenging activity was performed. The cytotoxic and anti-proliferation activity of these derivatives and zinc on cancer cell lines was determined using the MTT assay. The ability of the quinoxaline derivatives and zinc to modulate oxidative stress was evaluated using the H2DCFDA fluorescence assay. Cell cycle arrest stages were analysed by flow cytometry through propidium iodide cell cycle analyses. The ability of the quinoxaline derivatives to induce apoptosis in cancer cells was assessed using DAPI/PI, Acridine Orange/Ethidium Bromide (AO/EB) and Annexin V-FITC/Dead Cell assays. Western blot was used to investigate the Bcl/Bax expression ratios in A549 lung cancer cells after treatment with quinoxaline derivatives, zinc and in combination. Of the four quinoxaline derivatives tested, 3-(quinoxaline-3-yl) prop-2-ynyl methanosulphate (LA-39B) and 3-(quinoxaline-3-yl) prop-2-yn-1-ol (LA-55) produced significant anticancer properties against A549 lung cancer cells at minimal concentrations of 25μM. Both quinoxaline derivatives displayed antioxidant properties and did not induce cell death in non-cancerous Raw 267.4 macrophage cells. Cytotoxicity was observed in A549 lung cancer, HeLa cervical cancer and MCF-7 breast cancer cells albeit inhibition was more pronounced in A549 lung cancer cells. Treatment of cancer cells with zinc also resulted in pronounced cytotoxicity at a minimal concentration of 25μM. Although reduced oxidative stress was observed in Raw 264.7 macrophages, in A549 lung cancer cells both compounds were able to increase ROS production which was accompanied by high levels of apoptosis when treated with derivatives and zinc alone but when in combination an improved higher level of apoptosis is observed. The improved anti-cancer activity of this drug combination treatment was further accompanied by lower Bcl/Bax expression ratios with upregulation of Bax in A549 lung cancer cells. The results of the study suggest that 3-(quinoxaline-3-yl) prop-2-ynyl methanosulphate and 3-(quinoxaline-3-yl) prop- 2-yn-1-ol are potential candidates drug for treatment of lung cancer. The use of these quinoxaline derivatives in combination with zinc can offer alternative treatment options for lung cancer. / National Research Foundation (NRF)

The purpose of this thesis was to characterize cancer metabolism in vitro using epithelial ovarian cancer as a model on an untargeted, systems-level, basis with particular attention paid to the difference between cancer stem cell metabolism and cancer cell metabolism. Two-dimensional gas chromatography coupled to mass spectrometry was used to measure the metabolite profiles of the ovarian cancer and cancer stem cell lines under normal baseline conditions and also under chemotherapeutic and environmental perturbations. These two cell lines exhibited significant metabolic differences under normal baseline conditions and results demonstrated that metabolism in the ovarian cancer stem cell line was distinct from that of more differentiated isogenic cancer cells, showing similarities to stem cell metabolism that suggest the potential importance of metabolism for the cancer stem cell phenotype. Glucose deprivation, hypoxia, and ischemia all perturbed ovarian cancer and cancer stem cell metabolism, but not in the same ways between the cell types. Chemotherapeutic treatment with docetaxel caused metabolic changes mostly in amino acid and carbohydrate metabolism in ovarian cancer cells, while ovarian cancer stem cell metabolism was not affected by docetaxel. Overall, these metabolic differences between the two cell types will deepen our understanding of the metabolic changes occurring within the in vivo tumor and will help drive development of cancer stem cell targeted therapeutics.

published_or_final_version / abstract / Clinical Oncology / Doctoral / Doctor of Philosophy

published_or_final_version / Medicine / Master / Doctor of Medicine

Diagnosis of head and neck squamous cell carcinoma (HNSCC) presents a multifarious problem. Late stage diagnosis, uncertainty regarding appropriate clinical treatment, as well as the high potential for disfigurement and functional loss resulting in diminished quality of life, contributes to anxiety, stress, fear, and uncertainty throughout the cancer treatment experience. This qualitative study sought to explore the cancer treatment experience of adults with newly diagnosed HNSCC, including laryngeal, esophageal, and oral cancers. Study participants were recruited from the University of Kentucky Ear Nose and Throat Clinic in Lexington KY. Participants agreed to be interviewed after receipt of their cancer diagnosis and again after completion of their cancer treatment. Socio-emotional Selectivity Theory, and Leventhal’s Self-Regulation Model provided the theoretical foundation for exploring the ongoing emotional, psychological, and physical aspects of the cancer experience while also recognizing the role of age and time perception. Forty-one patients completed two in depth semi- structured interviews. Transcripts were coded for key themes. Findings indicated that HNSCC in older patients is often preceded by lifelong alcohol, tobacco, and substance use. Despite frequent interaction with health and substance abuse treatment professionals, very few patients had prior knowledge of HNSCC risk or had been screened for these cancers. Experience with addiction treatment programs and perceptions of time seem to influence cancer treatment experience. The following themes were identified: (1) dynamic time perspectives including taking time, making time, junk time and time out; (2) recovery vs. cure from disease; (3) the role of reconciliation, hope, self-inventory, reflection, and spirituality in navigating the cancer experience; (4) the role of healing vs. cure; and (5) patient's moving forward to a life after cancer. Findings from this investigation suggest that patients with a history of lifelong substance use could benefit from earlier detection and improved awareness and knowledge of HNSCC risk. Findings can be applied to improve access to cancer screening through addiction and cessation programs, reduce lags in diagnosis, improve prognosis and contribute to the development of clinical tools. Additionally, the intersection of advancing chronological age, comorbidity, and perception of time warrants further investigation.

Retinoblastoma binding protein 6 (RBBP6) is a nuclear protein, previously implicated in the regulation of cell cycle and apoptosis. It is a multi-domain protein containing a Zinc finger, a RING finger, an Rb binding domain, a p53 binding domain and a novel N-terminal protein domain, the so called, Domain With No Name or DWNN. The RBBP6 gene encodes three isoforms of this particular protein. A common feature of all three isoforms of RBBP6 is the presence of the N-terminal DWNN domain. RBBP6 isoform 3 is comprised of the DWNN domain only. The DWNN itself has a ubiquitin-like fold, sharing 22% similarity with ubiquitin. It is likely that DWNN regulates intracellular levels of the two tumour suppressors, Rb and p53 through the ubiquitin-proteasome pathway and as such, DWNN may therefore play a role in the deregulation of cell cycle control in cancer cells. A mouse homologue, P2P-R of the gene has been implicated in mitotic apoptosis. The expression of DWNN, RBBP6 and their roles in the cell cycle, apoptosis and human cancer were investigated. RT-PCR and real-time PCR were used to determine the gene expression of DWNN and RBBP6 variants in human cancer cells. An anti-human DWNN antibody was characterized using both Western Blotting analysis and MALDI-TOF mass spectroscopy to determine whether the antibody specifically recognizes DWNN and RBBP6 isoforms, or if it recognizes other proteins. Western blotting was also used to determine the nature of the DWNN in human cell lines. A DWNN probe and the characterized anti-human antibody were used to localize DWNN and RBBP6 gene products at the mRNA and protein levels using ISH/FISH and Immunohistochemistry respectively. Cell labelling was also performed using this antibody to localize RBBP6 products in human cell lines. RNA interference and over-expression of DWNN and RBBP6 gene products was carried out to further investigate the role of RBBP6 products in the cell cycle, apoptosis and carcinogenesis. Cloned RT-PCR products of RBBP6 binding domains, the RING finger domain, pRb-binding and p53-binding domains in human cancers cell lines (Hek 293T, MCF7, HeLa and HepG2 cells) showed no mutations, but MCF-7 cells showed the lowest expression of the RBBP6. Real-time PCR and Western blotting analysis confirmed that MCF-7 cells express very little DWNN (RBBP6 isoform 3) and RBBP6 gene products when compared to Hek 293T, HeLa and HepG2 cells. It was also shown that the anti-human DWNN antibody recognizes the DWNN domain (RBBP6 isoform 3) and the larger RBBP6 isoforms. Using 2D gel electrophoresis and MALDI-TOF spectrometry, it was also found that DWNN is associated with other proteins namely, Recoverin and a hypothetical protein XP_002342450. This result suggested that DWNN may be a ubiquitin-like protein, which may be specific to these proteins in human cells. FISH and IHC demonstrated that the DWNN domain and its relatives are down-regulated in human cancers at both mRNA and protein levels, respectively. In contrast, however, cell staining showed that the expression of the DWNN gene products was high during the G2/Mitosis transition. Knocking-down the DWNN domain or over-expressing it did not sensitise the Hek 293T cells to Camptothecin (CPT)-induced apoptosis but rather slowed down cell growth. These results strongly suggest that the DWNN gene is likely to be involved in cell cycle control. Up-regulation in mitotic cells and down-regulation in cancers also implies that RBBP6 gene products may additionally be involved in cell cycle arrest. Moreover, down-regulation in human cancers particularly indicates that the loss of its function which correlates with loss of cell cycle control in this disease may be involved in the pathogenesis of cancer. This was confirmed by up-regulation of the DWNN in arsenic trioxide induced cell cycle arrested cells specifically at G2/M phase where a p53-dependent cell cycle arrest ensued. It is thus proposed that the DWNN may be implicated both as a p53 stabilizer and additionally as a G2/M progression regulator.