Busulfan, cyclophosphamide, and etoposide (BuCyE) is a commonly used conditioning regimen for autologous stem cell transplantation (ASCT). This multicenter, phase II study examined the safety and efficacy of BuCyE with individually adjusted busulfan based on preconditioning pharmacokinetics. The study initially enrolled Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients ages 18 to 80 years but was amended due to high early treatment-related mortality (TRM) in patients > 65 years. BuCyE outcomes were compared with contemporaneous recipients of carmustine, etoposide, cytarabine, and melphalan (BEAM) from the Center for International Blood and Marrow Transplant Research. Two hundred seven subjects with HL (n = 66) or NHL (n = 141) were enrolled from 32 centers in North America, and 203 underwent ASCT. Day 100 TRM for all subjects (n = 203), patients > 65 years (n = 17), and patients ≤ 65 years (n = 186) were 4.5%, 23.5%, and 2.7%, respectively. The estimated rates of 2-year progression-free survival (PFS) were 33% for HL and 58%, 77%, and 43% for diffuse large B cell lymphoma (DLBCL; n = 63), mantle cell lymphoma (MCL; n = 29), and follicular lymphoma (FL; n = 23), respectively. The estimated rates of 2-year overall survival (OS) were 76% for HL and 65%, 89%, and 89% for DLBCL, MCL, and FL, respectively. In the matched analysis rates of 2-year TRM were 3.3% for BuCyE and 3.9% for BEAM, and there were no differences in outcomes for NHL. Patients with HL had lower rates of 2-year PFS with BuCyE, 33% (95% CI, 21% to 46%), than with BEAM, 59% (95% CI, 52% to 66%), with no differences in TRM or OS. BuCyE provided adequate disease control and safety in B cell NHL patients ≤ 65 years but produced worse PFS in HL patients when compared with BEAM.

by Li Chi-kong. / "September 2002." / Thesis (M.D.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (p. 223-251). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2009.

Immunomodulatory drugs (IMiDs) could enhance both direct anti-tumour and graft-versus-tumour effects after allogeneic haematopoietic stem cell transplantation (AHSCT). However, clinical experience with IMiDs after AHSCT using adult peripheral blood (APB) as a stem-cell source has been limited by graft-versus-host disease. Characterization of the mechanisms by which IMIDs modulate alloresponses of T cells and identification of differential effects on T cells from different cell sources could facilitate more effective use of these drugs in the setting of AHSCT. Using in vitro modelling, multi-parameter flow cytometry and gene expression analysis, I have determined the impact of the widely used IMiD lenalidomide on alloresponses of APB and umbilical cord blood (UCB)-derived T cells. Lenalidomide-treatment potentiates net alloproliferation of APB-derived T cells by selectively enhancing proliferation of CD8+ T cells. These CD8+ T cells have enhanced effector memory differentiation, are enriched for polyfunctional effectors, have enhanced direct-cytotoxicity against heamatopoietic target-cells and have a distinct gene expression profile with altered expression of key immunoregulatory-genes and depletion of cellular ikaros. Importantly, while effects on CD8+ T cells derived from UCB are similar, lenalidomide has contrasting effects on allospecific proliferation of APB and UCB-derived CD4+ T cells. While lenalidomide-treatment has no effect on alloproliferation of APB-derived CD4+ T cells, it reduces alloproliferation of UCB-derived CD4+ T cells. The reduction in UCB-derived CD4+ T cell alloproliferation is accompanied by selective expansion of CD4+CD25+FOXP3+ regulatory T cells (Treg), resulting in an overall reduction in UCB-derived T cell alloproliferation. These findings demonstrate that lenalidomide has a differential impact on alloresponses of T cells from different cell sources; alloresponses of APB-derived T cells are increased via selective expansion of polyfunctional CD8+ effectors, while alloresponses of UCB-derived T cells are limited by expansion of tolerogenic Treg. These findings have important implications for the future use of IMiDs in the setting of AHSCT.

Cellular Cardiomyoplasty (cell therapy for myocardial regeneration) targets the basic pathophysiology of heart failure and represents a novel technique for augmenting the function of the failing heart. Previous studies have demonstrated massive mechanical losses in the first few minutes. Thus, efforts to reduce mechanical losses may prove more beneficial than those directed against biological losses alone. We believe that "Wash-out" into the disrupted blood vessels is responsible for these early losses. / In the first part of this study we hypothesized that by increasing the size of the injectate, the amount of immediate losses can be reduced achieving better retention. Using Alginate-poly-L-lysine-Alginate (APA) miscrocapsules of two different sizes (200mum&400mum) and comparing retention with bare microspheres (10mum) of similar size to MSCs, we demonstrated that immediate retention rate increased by four folds. The retention rate for group 1 (microspheres only) was 4.28+/-3.46% which was significantly lower than that for groups 2 (microspheres in 200mum microcapsules) at 16.45+/-12.66% and group 3 (microspheres in 400mum microcapsules) at 12.93+/-6.28% for Group (p<0.05). There was no difference between group 2 and 3. / In the second part, we investigated the potential of gradually increasing the cell load on functional improvement and engraftment using conventional intramuscular delivery. Five groups of rats received escalating doses of MSCs after surgically induced ischemia (gp1 no cells, gp2 0.5x 10 6, gp3 1.5x106, gp4 3x106,gp5 5x106 MSCs). At 7 weeks, we observed significant improvement in cardiac function in groups 3 to 5 compared to post-infarction baseline. This was not observed in groups 1 & 2. However, in groups 3 to 5, we observed no functional advantage for increasing the cell load beyond a minimal therapeutic dose. This is consistent with our hypothesis that small cells are washed out into the circulation. / We also showed the ability of Alginate-Poly-l-lysine-Alginate (APA) microcapsules to sustain the viability of encapsulated MSCs in-vitro. Finally, the ability of encapsulated MSCs to improve the function of the heart in-vivo was tested.

A qualitative phenomenological study using van Manen’s human science method was conducted to gain insight into the lived experience of patients and their family members transitioning through one hundred days post haematopoietic stem cell transplantation (HSCT). Three families between zero and five years post HSCT were recruited from a bone marrow transplant unit in central Canada. Multiple in-depth open-ended interviews and field notes were employed to arrive at a detailed description of the lived experience of patients and family members. Awakening from the cocoon emerged as the main essence of patient’s and family members’ experiences, supported by three themes: the disruptions, the chrysalis, and new beginnings. The results from this study provide evidence that the families viewed the HSCT in a positive perspective and highlight the importance of supporting families throughout the acute phase of transplantation.

Severe injury may result in disconnection between the peripheral and central nervous system. Regeneration of the central portion of sensory neurons into the spinal cord is notoriously poor in adult mammals, with low regenerative drive and an unpermissive central environment, most likely resulting in persistent loss of sensory function. A variety of strategies have been addressedto augment regeneration, including application of growth promoting factors, counteraction of inhibitory molecules, and provision of growth permissive substrates. Stem cells have been investigated in these contexts, as well as for the possibility of providing new neurons to act as a relay between the periphery and spinal cord. Here we have investigated different sources of neural stem cells for their ability to form neurons and glia after transplantation to the periphery; to project axons into the spinal cord; and to assist regeneration of surviving sensory neurons. These have been performed at two locations: the "dorsal root ganglion cavity", and the transitional zone following dorsal root avulsion. Neurons and glia were generated form mouse boundary cap neural crest stem cells and embryonic stem cell derived ventral spinal cord progenitors, and in addition to this, regeneration of sensory fibers was observed after transplantation of human fetal spinal cord derived progenitors and human embryonic stem cell derived ventral spinal cord progenitors. Further, delivery of neurotrophic factor mimetics via mesoporous silica nanoparticles proved a valuable tool for stem cell survival and differentiation. While technological advances make in vivo differentiation a realistic goal, our findings indicate that so far assisting regeneration of host sensory fibers to reconnect with the spinal cord by transplantation of stem cells is a more reliable strategy.

A qualitative phenomenological study using van Manen’s human science method was conducted to gain insight into the lived experience of patients and their family members transitioning through one hundred days post haematopoietic stem cell transplantation (HSCT). Three families between zero and five years post HSCT were recruited from a bone marrow transplant unit in central Canada. Multiple in-depth open-ended interviews and field notes were employed to arrive at a detailed description of the lived experience of patients and family members. Awakening from the cocoon emerged as the main essence of patient’s and family members’ experiences, supported by three themes: the disruptions, the chrysalis, and new beginnings. The results from this study provide evidence that the families viewed the HSCT in a positive perspective and highlight the importance of supporting families throughout the acute phase of transplantation.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 4 uppsatser.