Fludarabine as a cost-effective adjuvant to enhance engraftment of human normal and malignant hematopoiesis in immunodeficient mice

There is still an unmet need for xenotransplantation models that efficiently recapitulate normal and malignant human hematopoiesis. Indeed, there are a number of strategies to generate humanized mice and specific protocols, including techniques to optimize the cytokine environment of recipient mice and drug alternatives or complementary to the standard conditioning regimens, that can be significantly modulated. Unfortunately, the high costs related to the use of sophisticated mouse models may limit the application of these models to studies that require an extensive experimental design. Here, using an affordable and convenient method, we demonstrate that the administration of fludarabine (FludaraTM) promotes the extensive and rapid engraftment of human normal hematopoiesis in immunodeficient mice. Quantification of human CD45+ cells in bone marrow revealed approximately a 102-fold increase in mice conditioned with irradiation plus fludarabine. Engrafted cells in the bone marrow included hematopoietic stem cells, as well as myeloid and lymphoid cells. Moreover, this model proved to be sufficient for robust reconstitution of malignant myeloid hematopoiesis, permitting primary acute myeloid leukemia cells to engraft as early as 8 weeks after the transplant. Overall, these results present a novel and affordable model for engraftment of human normal and malignant hematopoiesis in immunodeficient mice

Theoretical study of peculiarities of unstable longitudinal shear crack growth in sub-Rayleigh and supershear regimes

In the paper we present the results of the theoretical study of some fundamental aspects of mode II crack propagation in conventional sub-Rayleigh regime and transition to intersonic regime. It is shown that development of a sub-Rayleigh shear crack is determined in many respects by elastic vortex traveling ahead of the crack tip at a shear wave velocity. Formation of such a vortex helps to better understand the well-known phenomenon of acceleration of a shear crack towards the longitudinal wave velocity. Simulation results have shown that due to self-similarity of shear crack propagation the conditions of sub-Rayleigh to intersonic transition depend on dimensionless material and crack parameters. Two key dimensionless parameters are proposed

Human Monoclonal Antibodies Neutralizing Cytomegalovirus (CMV) for Prophylaxis of CMV Disease: Report of a Phase I Trial in Bone Marrow Transplant Recipients

The safety and pharmacokinetics of the two neutralizing human IgG1 monoclonal antibodies to cytomegalovirus (CMV) SDZ89-104 and 89-109 in bonemarrowtransplant (BM1)recipients was assessed in an open phase I trial. Thirteen patients, 8 seropositive and 5 seronegative for CMV, were treated with allogeneic or autologous bone marrow transplantation. SDZ 89-104 was given to 5 and SDZ 89-109 to 8 patients. Patients were divided into high-and low-dose groups. A fixed prestudy dose of 0.1 mg/kg was given 4 days before BMT. On days 3, 17, 31,45, 59, and 73, patients were treated with either 0.5 or 2 mg/kg of the respective antibody. Results indicate that doses of 2 mg/kg of SDZ 89-104 or SDZ 89-109 in alternating weeks can be safely administered to BMT patients. Serum trough levels measured by antiidiotype ELISA were ∼10 µg/ml after administration of 0.5 mg/kg and ∼50 µg/ml after treatment with 2 mg/kg of SDZ 89-104 or SDZ 89-109. High serum levels defined by antiidiotype ELISA techniques closely paralleled increased neutralizing activity. Serum half-lives calculatedfrom these data were ∼6 day

Long-term follow-up of high-dose chemotherapy with autologous stem-cell transplantation and response-adapted whole-brain radiotherapy for newly diagnosed primary CNS lymphoma: results of the multicenter Ostdeutsche Studiengruppe Hämatologie und Onkologie OSHO-53 phase II study

Background We previously reported the results of a phase II study for patients with newly diagnosed primary central nervous system lymphoma treated with autologous peripheral blood stem-cell transplantation (aPBSCT) and response-adapted whole-brain radiotherapy (WBRT). Now, we update the initial results. Patients and methods From 1999 to 2004, 23 patients received high-dose methotrexate. In case of at least partial remission, high-dose busulfan/thiotepa (HD-BuTT) followed by aPBSCT was carried out. Patients refractory to induction or without complete remission after HD-BuTT received WBRT. Eight patients still alive in 2011 were contacted and Mini-Mental State Examination (MMSE) and the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire (QLQ)-C30 were carried out. Results Of eight patients still alive, median follow-up is 116.9 months. Only one of nine irradiated patients is still alive with a severe neurologic deficit. In seven of eight patients treated with HD-BuTT, health condition and quality of life are excellent. MMSE and QLQ-C30 showed remarkably good results in patients who did not receive WBRT. All of them have a Karnofsky score of 90%-100%. Conclusions Follow-up shows an overall survival of 35%. In six of seven patients where WBRT could be avoided, no long-term neurotoxicity has been observed and all patients have an excellent quality of lif

Alloreactivity: the Janus-face of hematopoietic stem cell transplantation

Differences in major and minor histocompatibility antigens between donor and recipient trigger powerful graft-versus-host reactions after allogeneic hematopoietic stem cell transplantation (HSCT). The clinical effects of alloreactivity present a Janus-face: detrimental graft-versus-host disease increases non-relapse mortality, beneficial graft-versus-malignancy may cure the recipient. The ultimate consequences on long-term outcome remain a matter of debate. We hypothesized that increasing donor-recipient antigen matching would decrease the negative effects, while preserving antitumor alloreactivity. We analyzed retrospectively a predefined cohort of 32 838 such patients and compared it to 59 692 patients with autologous HSCT as reference group. We found a significant and systematic decrease in non-relapse mortality with decreasing phenotypic and genotypic antigen disparity, paralleled by a stepwise increase in overall and relapse-free survival (Spearman correlation coefficients of cumulative excess event rates at 5 years 0.964; P<0.00; respectively 0.976; P<0.00). We observed this systematic stepwise effect in all main disease and disease-stage categories. The results suggest that detrimental effects of alloreactivity are additive with each step of mismatching; the beneficial effects remain preserved. Hence, if there is a choice, the best match should be donor of choice. The data support an intensified search for predictive genomic and environmental factors of ‘no-graft-versus-host disease’.Leukemia advance online publication, 7 April 2017; doi:10.1038/leu.2017.79

Starting from scratch: patient-reported outcome questionnaires & their role in an integrative medicine primary care minimum-dataset

Aim This research explored the use of patient questionnaires for evaluating integrative medicine (IM) clinics in the primary care setting. Background Integrative medicine (IM) combines traditional, complementary, and alternative medicine with conventional biomedicine. With more clinics in Australia offering IM, it is important to evaluate outcomes. Methods Mixed methods were used. This included a case study of an IM clinic in Sydney, Australia; interviews with 20 patients and 13 staff at the clinic; and a systematic literature review of patient questionnaires. Results Challenges for meausring IM outcomes limitations with routine clinical data collection, selecting appropriate questionnaires able to measure the wide range of IM outcomes whilst minimizing responder burden, patient recruitment and practitioner support. Electronic questionnaires have many advantages. Alternative formats such as paper are still needed. Not all interviewees were interested in cohort results or research and instead wanted to access their individual patient results. Discussion The results from the studies were synthesised and a set of recommendations are offered. Conclusions Patient questionnaires could be used to establish a minimum dataset for use in research, health service development, and informing and improving individual patient care. A bottom-up approach that adresses stakeholders’ needs for a dataset is essential

Hydronephrosis Resulting from Bilateral Ureteral Stenosis: A Late Complication of Polyoma BK Virus Cystitis?

We report here a case of acute lymphoblastic leukemia in remission presenting a late-onset bilateral hydronephrosis probably due to polyoma BK virus-induced proliferation of bladder endothelium on both ostii. The diagnosis was made virologically by BK virus Polymerase Chain Reaction (PCR) detection in the absence of any other bladder disease. Awareness of this late complication is necessary not only in patients after renal transplantation but also in patients after hematopoietic stem cell transplantation from matched unrelated donor

Essential requirements for setting up a stem cell processing laboratory

The Graft Processing subcommittee of the Worldwide Network for Blood and Marrow Transplantation wrote this guideline to assist physicians and laboratory technologists with the setting up of a cell processing laboratory (CPL) to support a hematopoietic stem cell transplant program, thereby facilitating the start-up of a transplant program in a new location and improving patient access to transplantation worldwide. This guideline describes the minimal essential features of designing such a laboratory and provides a list of equipment and supply needs and staffing recommendations. It describes the typical scope of services that a CPL is expected to perform, including product testing services, and discusses the basic principles behind the most frequent procedures. Quality management (QM) principles specific to a CPL are also discussed. References to additional guidance documents that are available worldwide to assist with QM and regulatory compliance are also provided. © 2014 Macmillan Publishers Limited All rights reserved