No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

Human cancers have developed a number of mechanisms to evade detection from the immune system or to modify it to their survival advantage. In addition to the production of directly immuno-suppressive cytokines it has also been demonstrated that regulatory cell subsets, in particular regulatory T cells. are increased in many solid tumours as well as haematological malignancies. Multiple myeloma (MM) is a mature B cell malignancy with many defects of the host immune system including humoral and cell- mediated. Prior to application of immunotherapy it is important to understand the mechanisms employed by the malignant myeloma cells to be able to influence these with more targeted therapy. I hypothesised that regulatory T cells would play an important role in the biology and progression of MM. The data presented in this thesis demonstrate that patients with MM as well as monoclonal gammopathy of uncertain significance (MGUS), the precursor of MM, have increased numbers of CD4+CD2S+FoxP3 regulatory T cells compared to healthy controls and the increase correlates with the burden of disease. The number increases further in patients treated with the immune-modulatory drug thalidomide. Regulatory T cells isolated from patient samples maintain their immune-suppressive properties. Other T cells subsets such as double negative T cells (DN T cells), Tr1 cells and T H 17 cells are also examined. In a co-culture model of human myeloma cell lines (HMCL) with peripheral blood mononuclear cells (PBMNCs) from healthy donors, it was established that the malignant plasma cells are able to expand pre-existing naturally occurring regulatory T cells (nT Reg cells) but also de novo generate tumour-induced regulatory T cells (tT Reg cells) from CD4+CD25" T cells. The generation is more effective with increasing purification of the starting population, i.e. by abolishing the influence of other cellular components such as antigen-presenting cells. The phenotypic properties of the tT Reg cells generated in this model are examined and compared to nT Reg cells. Important phenotypical differences are demonstrated. It is further established that tT Reg cells are functionally suppressive and maintain their plasticity and capability to convert into T H 17 cells, The co-culture model is further employed to examine the mechanisms behind the generation of regulatory T cells, It is established that cell-contact is the most important factor but the cytokine profile in the co-culture model is also examined. Blocking experiments reveal the partial involvement of the ICOS/ICOS~L pathway. The influence of the immuno-modulatory drug thalidomide and lenalidomide as well as a HDAC inhibitor on the generation of tTReg cells is examined. The data presented in this thesis examined the interaction of malignant myeloma cells with regulatory T cells. The data suggest that regulatory T cells in multiple myeloma could be influenced by immuno-targeted therapies such as HDAC inhibitors and directions for future research studies are suggested.

TITLE: Randomised controlled trial of the efficacy of a patient educational booklet for the management of peripheral neuropathy in multiple myeloma patients. BACKGROUND: As survival improves in multiple myeloma (MM) patients, quality of life and symptom management are becoming paramount. Peripheral neuropathy (PN) is a debilitating side effect of MM and its treatment but can be managed by monitoring symptoms and modifying medication. AIMS: The primary aim of the project was to assess the impact of an educational booklet on knowledge of PN in MM patients. The secondary aim was to assess whether improved knowledge increased the reporting of PN with their HCP leading to better management of PN. METHODS: MM patients diagnosed for at least 1-year were randomised to three treatment groups; group 1 received no information on PN, group 2 & 3 received a PN educational booklet. Questionnaires were completed at 0, 4, 8 and 12-months. Group 1 and 2 completed the questionnaires by themselves whilst group 3 complete their questionnaires via a telephone interview. As group 3 had a high dropout rate during the study period, results from group 2 and 3 participants were combined for the purpose of the study analyses. No significant differences were observed in baseline data between study groups 2 and 3, which enabled the combining of these groups for analysis. RESULTS: Fifty-eight participants were enrolled (19 group 1, 39 group 2 & 3). 63% of participants were male, 67% aged >60 years and 51 % received ~3 prior lines of therapy with at least a third on active treatment at any time point throughout the study. During the course of the study, only 11 % of participants had a resolution of their PN. However, the percentage of participants discussing their PN symptoms at hospital visits significantly declined (p=0.006) over the course of the study, with 96% discussing at baseline vs. 61 % at 12 months. During the course of the study, a significantly higher proportion of participants in group 1 consistently found it a lot more or somewhat more difficult to be optimistic or hopeful about their prognosis and survival when they had PN compared to groups 2 & 3. At baseline, 35% of participants had nothing done to their MM treatment to manage their PN, which increased to 75% at 12-months despite a high number of participants experiencing PN symptoms. In addition, 46% of participants did not receive any treatment recommendations for supplementary medications to manage their PN. The educational booklet was reported as good/very good, easy to understand by virtually all the participants. The most useful section was treatment of PN. Sixty percent of participants think a booklet on PN should be available at diagnosis or at the beginning of their MM treatment with 93% of participants stating that it should be provided by their doctor or nurse. Level of knowledge of PN symptoms, management and reversibility did not significantly change in either of the treatment groups. However, participants in groups 2 & 3 demonstrated a positive change in their beliefs of the management of PN indicating that the booklet provided may have had a positive (if small) impact on knowledge. Conversely, group 1 participants reported a small decline in their beliefs on the management of PN over the course of the study. SUMMARY/CONCLUSIONS: The educational booklet had no significant impact on knowledge however; there was a positive change in beliefs of the management and reversibility of PN in the participants who received the booklet. The study results indicate that overall, PN in MM patients is not currently being adequately managed through modification of the MM therapy and/or additional treatment recommendations. Future work needs to be conducted to evaluate methods to improve the communication between healthcare professionals and MM patients to ensure consistently high levels of discussion on PN take place pre, during and post MM treatment to help drive an improvement in the management of PN.

No description available.