published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

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AIMS The aims of this thesis are to provide understanding of the psychosocial impact of recurrent cancer on patients and family members and to develop a substantive theory that explains the phenomenon of recurrence from a psychosocial perspective. BACKGROUND Cancer survival is increasing, and as people live longer, cancer recurrence is a real possibility. Recurrence has been described as one of the most stressful phases of cancer. Despite this reality, recurrence is poorly understood from a psychosocial perspective. Nurses, caring for patients and family members through their cancer trajectory, need to develop new understanding of how families experience recurrence in order to help them adapt to this phase of cancer. METHODS This grounded theory study was conducted in four cancer units of two hospitals in North of Spain. The sample consisted of 15 patients, 13 relatives, and 14 nurses. Triangulation of sources of data including family interviews, individual interviews, memos, and literature was used to provide a different but complementary view of the impact of cancer recurrence. Data collection and analysis were based on the constant comparative method of grounded theory. RESULTS A core category and three main categories have emerged from the data. The first main category, “again”- when fear of recurrence becomes reality, shows the suffering of cancer survivors and their family members after a diagnosis of recurrent cancer. The term “again” symbolises past suffering due to the fear of recurrence and new sufferings as a result of the diagnosis of recurrent cancer; it also implies a re-encounter with health services and nurses. Suffering has been found to take on a social dimension in that recurrence was not an individual experience, but also a family experience. In addition, the social construction of suffering impacted on the nurses caring for the patients and families. The second main category, identified as demoralisation as a response to the suffering of recurrence, refers to the nature of suffering after the families knew that cancer had come back. Demoralisation has been found to be an emotional reaction characterised by feelings of exhaustion, uncertainty, and a resurgence of the fear of death. Such a condition posed great challenges to the nurses who described caring for these patients as harder than caring for newly diagnosed cancer patients. The third main category, identified as rebuilding morale in the experience of recurrence, highlights families’ search for meaning in their experience of recurrence and how nurses shifted the focus of care when caring for patients with recurrent cancer. The core category of this study is demoralisation in cancer recurrence. It is the foundation of a proposed theory for family nursing which explains what the experience of cancer recurrence involves for patients and families, and proposes a psychosocial framework for the management of demoralisation in families facing recurrent cancer. CONCLUSIONS This thesis contributes to new understanding of the psychosocial impact of cancer recurrence on families and the nurses’ experiences of caring during the recurrent phase of cancer. The re-conceptualisation of demoralisation brings an original understanding of the concept, which has been unpublished and unexplored in cancer nursing so far.

<p> <i>Chromobacterium violaceum</i> (CV) produces a violet color pigment known as Violacein. It has been reported that violacein has anticancer activity. This compound is produced by CV a gram-negative facultatively anaerobic bacterium found in soil and water environmental samples. The purpose of this study was to determine the effect of purified violacein on select cancer cell lines. Violacein used in this study was purified from CV strain (14N23), a strain isolated from environmental samples collected in the Tennessee Copper Basin. The previous reports used a crude extract preparation of violacein; thus, it was of interest to determine the effect of the pure compound on cancer cell growth was similar to that of the crude extracts. The compound purified following the method of Mehta, et al. was exposed to cancer cells and cell death assessed using the Alamar Blue procedure. It was found that violacein had no effect on A549, BT549, and PC3 cancer cell growth; however, there was a significant effect on Colo-320 cancer cells. It was concluded that further studies are required to assess the effect of violacein on enzymes and proteins involved in the cancer cell apoptotic pathways. Such studies will explain why cancer cell death was observed in certain cancer cells and not others.</p>

<p>B cells and humoral immunity are critical components of an effective immune response. However, B cells are also a significant driver of a variety of autoimmune diseases and can also become malignant. Antibody-mediated B cell depletion is now regularly used in the clinic to treat both B cell-derived cancers and B-cell driven autoimmunity, and while depletion itself is effective in some patients, removal of B cells is not often curative for patients and may present additional, unforeseen risks. The overall goal of this dissertation was therefore to determine the impact of B cell depletion on T cell homeostasis and function during infection and to elucidate the genetic factors that determine the effectiveness of antibody-mediated therapy. </p><p>In Chapter 3 of this dissertation, the role of B cells in promoting T cell homeostasis was investigated by depleting mature B cells using CD20 monoclonal antibody (mAb). Acute B cell depletion in adult mice significantly reduced spleen and lymph node T cell numbers, including naïve, activated, and cytokine-producing cells, as well as Foxp3+ regulatory T cells, whereas chronic B cell depletion in aged mice resulted in a profound decrease in activated and cytokine&#61485;producing T cell numbers. To determine the significance of this finding, B cell-depleted adult mice were infected with acute lymphocytic choriomeningitis virus (LCMV). Despite their expansion, activated and cytokine-producing T cell numbers were still significantly reduced one week later. Moreover, viral peptide-specific T cell numbers and effector cell development were significantly reduced in mice lacking B cells, while LCMV titers were dramatically increased. Thus, B cells are required for optimal T cell homeostasis, activation, and effector development in vivo, particularly during acute viral infection.</p><p>In Chapter 4 of this dissertation, lymphoma genetic changes that conferred either sensitivity or resistance to CD20 mAb therapy were examined in a preclinical mouse lymphoma model. An examination of primary lymphomas and extensive lymphoma families demonstrated that sensitivity to CD20 mAb was not regulated by differences in CD20 expression, prior exposure to CD20 mAb, nor serial in vivo passage. An unbiased forward genetic screen of CD20 mAb-resistant and -sensitive lymphomas identified galectin-1 as a significant factor driving CD20 mAb therapy resistance. As lymphomas acquired therapy resistance following serial in vivo passage, galectin-1 expression also increased. Furthermore, inducing lymphoma galectin-1 expression within the tumor microenvironment ablated lymphoma sensitivity to CD20 mAb. Therefore, lymphoma acquisition of galectin-1 expression confers CD20 mAb therapy resistance.</p><p>In Chapter 5 of this dissertation, the distinct germline components that control the efficacy of host CD20 mAb-dependent B cell and lymphoma depletion were evaluated using genetically distinct lab mouse strains. Variations in B cell depletion by CD20 mAb among several lab mouse strains were observed, where 129 mice had significantly impaired mAb-dependent depletion of endogenous B cells and primary lymphomas relative to B6 mice. An unbiased forward genetic screen of mice revealed that a 1.5 Mbp region of Chromosome 12 that contains mycn significantly altered CD20 mAb-dependent lymphoma depletion. Elevated mycn expression enhanced mAb-dependent B cell depletion and lymphoma phagocytosis and correlated with higher macrophage numbers. Thus, host genetic variations in mycn expression in macrophages alter the outcome of Ab-dependent depletion of endogenous and malignant cells.</p><p>These studies collectively demonstrate that B cells are required for effective cellular immune responses during infection and identified factors that alter the effectiveness of mAb-dependent B cell depletion. This research also established and validated an unbiased forward genetics approach to identify the totality of host and tumor-intrinsic factors that influence mAb therapy in vivo. The findings of these studies ultimately urge careful consideration in the clinical application of B cell depletion therapies.</p> / Dissertation

<p> While MR-only treatment planning has shown promise, there are still several well-known challenges that are currently limiting widespread clinical implementation. Firstly, MR images are affected by both patient-induced and system-level geometric distortions that can significantly degrade treatment planning accuracy. In addition, the availability of comprehensive distortion analysis software is currently limited. Also while many groups have been working toward a synthetic CT solution, further study is needed on the implementation of synCTs as the reference datasets for linac-based image-guided radiation therapy (IGRT) to help determine their robustness in an MR-only workflow. </p><p> To determine candidate materials for phantom and software development, 1.0 T MR and CT images were acquired of twelve urethane foam samples of various densities and strengths. Samples were precision machined to accommodate 6 mm diameter paintballs used as landmarks. Final material candidates were selected by balancing strength, machinability, weight, and cost. Bore sizes and minimum aperture width resulting from couch position were tabulated from the literature. Bore geometry and couch position were simulated using MATLAB to generate machine-specific models to optimize the phantom build. Previously developed software for distortion characterization was modified for several magnet geometries, compared against previously published 1.0 T results, and integrated into the 3DSlicer application platform. </p><p> To evaluate the performance of synthetic CTs in an image guided workflow, magnetic resonance simulation and CT simulation images were acquired of an anthropomorphic skull phantom and 12 patient brain cancer cases. SynCTs were generated using fluid attenuation inversion recovery, ultrashort echo time, and Dixon data sets through a voxel-based weighted summation of 5 tissue classifications. The DRRs were generated from the phantom synCT, and geometric fidelity was assessed relative to CT-generated DRRs through bounding box and landmark analysis. An offline retrospective analysis was conducted to register cone beam CTs to synCTs and CTs using automated rigid registration in the treatment planning system. Planar MV and KV images were rigidly registered to synCT and CT DRRs using an in-house script. Planar and volumetric registration reproducibility was assessed and margin differences were characterized by the van Herk formalism. </p><p> Over the sampled FOV, non-negligible residual gradient distortions existed as close as 9.5 cm from isocenter, with a maximum distortion of 7.4mm as close as 23 cm from isocenter. Over 6 months, average gradient distortions were -0.07&plusmn;1.10 mm and 0.10&plusmn;1.10 mm in the x and y-directions for the transverse plane, 0.03&plusmn;0.64 and -0.09&plusmn;0.70 mm in the sagittal plane, and 0.4&plusmn;1.16 and 0.04&plusmn;0.40 mm in the coronal plane. After implementing 3D correction maps, distortions were reduced to &lt; 1 pixel width (1mm) for all voxels up to 25 cm from magnet isocenter. </p><p> Bounding box and landmark analysis of phantom synCT DRRs were within 1 mm of CT DRRs. Absolute planar registration shift differences ranged from 0.0 to 0.7 mm for phantom DRRs on all treatment platforms and from 0.0 to 0.4 mm for volumetric registrations. For patient planar registrations, the mean shift differences were 0.4&plusmn;0.5 mm, 0.0&plusmn;0.5 mm, and 0.1&plusmn;0.3 mm for the superior-inferior (S-I), left-right (L-R), and anterior-posterior (A-P) axes, respectively. The mean shift differences in volumetric registrations were 0.6&plusmn;0.4 mm (range, 0.2 to 1.6 mm), 0.2&plusmn;0.4 mm, and 0.2&plusmn;0.3 mm for the S-I, L-R, and A-P axes, respectively. The CT-SIM and synCT derived margins were &lt;0.3mm different. </p><p> This work has characterized the inaccuracies related to GNL distortion for a previously uncharacterized MR-SIM system at large FOVs, and established that while distortions are still non-negligible after current vendor corrections are applied, simple post-processing methods can be used to further reduce these distortions to less than 1mm for the entire field of view. Additionally, it was important to not only establish effective corrections, but to establish the previously uncharacterized temporal stability of these corrections. This work also developed methods to improve the accessibility of these distortion characterizations and corrections. We first tested the application of a more readily available 2D phantom as a surrogate for 3D distortion characterization by stepping the table with an integrated batch script file. Later we developed and constructed a large modular distortion phantom using easily obtainable materials, and showed and constructed a large modular distortion phantom using easily obtainable materials, and used it to characterize the distortion on several widely available MR systems. To accompany this phantom, open source software was also developed for easy characterization of system-dependent distortions. Finally, while the dosimetric equivalence of synCT with CT has been well established, it was necessary to characterize any differences that may exist between synCT and CT in an IGRT setting. This work has helped to establish the geometric equivalence of these two modalities, with some caveats that have been discussed at length. (Abstract shortened by ProQuest.) </p>

<p> Introduction: Analyzing trends in breast cancer mortality can ensure a precise characterization of changes over time and can be important in public health decision making. Most reported trends are limited to incidence and mortality rates among Whites and Blacks, without categorization regarding tumor clinical characteristics. This study analyzed breast cancer mortality trends among different race-ethnic groups using various approaches such as partitioning rates by factors associated at the time of diagnosis; taking into consideration age, cohort and period effects; and by evaluating geographical variations.</p><p> Methods: Incidence and mortality data from 1990 to 2012 of female invasive breast cancer among women aged 18-84 years in United States (U.S.) was provided by the National Cancer Institute. The following analyses were conducted: (1) calculation of incidence based mortality (IBM) rates by estrogen receptor (ER) status according to race-ethnicity; (2) examination of temporal trends using age-period-cohort (APC) analysis on incidence and mortality rates; and, (3) spatiotemporal analysis of the county level age-standardized breast cancer mortality rates to identify significant geographical areas with higher risk. </p><p> Results: IBM rates for ER+ tumors increased while those of ER- tumors decreased among all race-ethnic groups. APC analysis showed that race-ethnic disparities were largely among the ER- tumors and temporal trends of the ER+ tumors were similar across the race-ethnic groups, with identical effects across the various birth cohorts. Geographical variation in the breast cancer county-level mortality rate was mostly explained by age-standardization and county level risk factors, although the effect of these factors was greater in rural areas of western U.S.</p><p> Conclusion: Temporal trends in the IBM rates were more reflective of the recent changes in the incidence trends of female invasive breast cancer. Trends of ER+ tumors were similar across all race-ethnic groups suggesting a common risk factor for the persistent increase in the incidence and mortality of these tumors. Spatial analysis shows that the higher mortality risk in certain rural counties of western U.S. might be due to poor survival than an elevated incidence and the need for better health care access in these medically underserved areas. These results might explain the observed ethnic and geographic variations in breast cancer mortality, and in turn, could support a stronger theoretical basis for public health policy.</p>

Abnormal epigenetic control is a common early event in tumour progression, and aberrant acetylation in particular has been implicated in tumourigenesis. Histone deacetylases (HDACs) are enzymes that regulate acetylation of chromatin and a variety of other non-histone substrates. Significantly, HDAC inhibitors are potent anti-proliferative agents and exhibit clinical activity in lymphoproliferative and haematological maligancy. However, the mechanistic details by which HDAC inhibitors affect proliferation remain to be elucidated. I have explored the cellular processes affected by HDAC inhibitors, and begun to illuminate a new pathway, regulated by HDAC, which impinges on the cellular effect of HDAC inhibitors. My results suggest that the proteins HR23B and Myd88 are important sensitivity determinants for HDAC inhibitor treatment, and that their interplay with HDAC6 dictates cell fate choice between survival by autophagy or apoptosis.