Potential benefits of a virtual, home-based combined exercise and mindfulness training program for HSC transplant survivors: a single-arm pilot study.

PURPOSE: Impaired quality of life (QOL) including reduced physical fitness is a recognized late effect of hemopoietic cell transplantation (HCT). Guided exercise and mindfulness-based stress management (MBSM) programs have shown promise, mainly in the inpatient setting. We aimed to examine the feasibility of a virtual, home-based, combined exercise and MBSM program. METHODS: Patients attending post-HCT clinic were invited to participate in this single-arm pre-post study. Eligibility criteria included age 18-75 years, > 6 months post allogeneic HCT. Consented participants attended an in-person session, followed by weekly exercise and MBSM training for 6 weeks via videoconferencing. Assessments were performed pre-training, and at 3-, 6- and 12-months and compared using a linear mixed effects model. RESULTS: 21 of 24 patients consenting to the study completed the program (median age 56 years [IQR 46-62], median time post-HCT 37 months [IQR 26-46]). Six-minute walk test scores were significantly higher at 3 (mean difference 79.6, 95%CI 28-131, ES 0.55) and 12 months (mean difference 48.4, 95%CI 13-84, ES 0.33) compared to baseline. Sit-to-stand test was significantly higher at 3 (mean difference 4.4, 95%CI 1.4-7.4, ES 0.68) and 12 months (mean difference 3.9, 95%CI 0.24-7.6, ES 0.61). Dominant hand grip was significantly stronger at 3 (mean difference 0.16, 95%CI 0.04-0.28, ES 0.45), and 12 months (mean difference 0.21, 95%CI 0.08-0.24, ES 0.62). Significantly higher FACT-BMT total (mean difference 6.9, 95%CI 1.5-12.4, ES 0.49) and FACT-G scores (mean difference 5.2, 95%CI 1.4-9.1, ES 0.48) were found at 3 months. Over 80% of participants rated the virtual combined modal program highly and no adverse events were reported. CONCLUSION: A 6-week virtual, home-based exercise and MBSM program was an acceptable, and potentially effective intervention for sustained improvement of some physical capacity and QOL outcomes in HCT survivors. Virtual-based healthcare service is highly relevant particularly during pandemics. To our knowledge, this study has the longest follow-up observation period for Internet based combined modality training program reported to date and warrants additional investigation. Trial Registration Research protocol approved by St Vincent's Hospital Ethics Committee (HREC 12/SVH/175), approved 27/09/2012, trial commenced 24/05/13 and the first participant 07/06/13. Retrospectively registered with ANZCTR (ACTRN12613001054707) 23/09/2013.

Sustained immunotolerance in multiple sclerosis after stem cell transplant.

OBJECTIVE: Autologous haematopoietic stem cell transplantation (AHSCT) has the potential to induce sustained periods of disease remission in multiple sclerosis (MS), which is an inflammatory disease of the central nervous system (CNS) characterised by demyelination and axonal degeneration. However, the mechanisms associated with durable treatment responses in MS require further elucidation. METHODS: To characterise the longer term immune reconstitution effects of AHSCT at 24 and 36 months (M) post-transplant, high-dimensional immunophenotyping of peripheral blood mononuclear cells from 22 MS patients was performed using two custom-designed 18-colour flow cytometry panels. RESULTS: The higher baseline frequencies of specific pro-inflammatory immune cells (T-helper-17 (Th17) cells, mucosal-associated invariant T-cells and CNS-homing T-conventional (T-conv) cells observed in MS patients were decreased post-AHSCT by 36M. This was accompanied by a post-AHSCT increase in frequencies and absolute counts of immunoregulatory CD56hi natural killer cells at 24M and terminally differentiated CD8+ CD28- CD57+ cells until 36M. A sustained increase in the proportion of naïve B-cells, with persistent depletion of memory B-cells and plasmablasts was observed until 36M. Reconstitution of the B-cell repertoire was accompanied by a reduction in the frequency of circulating T-follicular helper cells (cTfh) expressing programmed cell death-1 (PD1+ ) at 36M. Associations between frequency dynamics and clinical outcomes indicated only responder patients to exhibit a decrease in Th17, CNS-homing T-conv and PD1+ cTfh pro-inflammatory subsets at 36M, and an increase in CD39+ T-regulatory cells at 24M. INTERPRETATION: AHSCT induces substantial recalibration of pro-inflammatory and immunoregulatory components of the immune system of MS patients for up to 36M post-transplant.

Meeting the COVID challenge: Optimizing vCD34+ in cryopreserved HPC samples for implementation of an external QA Program.

BACKGROUND: The COVID-19 pandemic has forced a fundamental change in the global procurement of allogeneic hematopoietic progenitor cells (HPCs) for transplantation. To better meet the emergent challenges of transporting cryopreserved allogeneic HPC during pandemics, there is an urgent need for External Quality Assurance (EQA) programs to evaluate reproducibility and harmonization of viable CD34+ cell (vCD34+) HPC enumeration, as the current EQA programs are unsuitable for analysis of vCD34+. The cost-effective distribution of HPC cryopreserved reference samples (CRSs) with acceptable reproducibility and specificity is key to the success of a vCD34+ EQA program. METHODS: Cryopreserved HPC samples (n = 11) were either stored on dry ice for 1 to 4 days or for 1 day followed by liquid nitrogen (LN) storage for 1 to 3 days to assess optimal conditions for vCD34+ EQA. Flow cytometric enumeration of vCD34+ HPCs was performed using a single platform assay combined with 7-AAD viability dye exclusion. The optimum transportation condition was validated in pilot and multicenter national studies (n = 12). RESULTS: A combination of 1 day on dry ice followed by LN storage stabilized viability compared with continuous storage on dry ice. This study demonstrates that dispatch of CRSs on dry ice to recipient centers across a distance of ≤4000 km within 26 h, followed by LN storage, resulted in reproducible intercenter vCD34+ enumeration. The estimated cost of safer and more convenient dry ice delivery is >20-fold lower than that of LN. CONCLUSION: This approach can form the basis for economically and scientifically acceptable distribution of CRSs for external vCD34+ EQA.

Effect of donor age on adult unrelated donor haemopoietic cell transplant outcome: the Australian experience.

BACKGROUND: Results have been varied regarding the effect of donor age on the outcome of unrelated donor haemopoietic cell transplantation (HCT). AIMS: To determine the influence of donor age on adult unrelated donor HCT outcome in Australia. METHODS: Patients were included in the study if they were aged 16 years or above and underwent first allogeneic unrelated donor HCT in Australia for the indications of acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML), chronic myelogenous leukaemia (CML) or myelodysplastic syndromes (MDS) between the years of 2001 and 2014 inclusive. The main outcome measure was overall survival (OS), which was tested against independent variables using univariate Kaplan-Meier methods and multivariate Cox regression. RESULTS: A total of 1158 unrelated donor HCT were represented in the data. Cumulative incidences of engraftment, transplant related mortality (TRM), acute graft-versus-host disease (GvHD), chronic GvHD and relapse were not significantly affected by donor age. OS probability at 5 years post-transplant was 48.3%. In multivariate analysis of OS, year of transplant 2001-2007, recipient age 40 years or greater, poor risk disease, human leukocyte antigen (HLA) match less than 6/6 and poor performance status at transplant (Karnofsky scale) were independently significant adverse OS risk factors. Donor age was not a significant risk factor for OS in univariate or multivariate analysis. CONCLUSIONS: The conclusion from this study was that donor age (up to 59 years) did not influence post-transplant outcome among adult unrelated donor HCT performed in Australia for haematologic malignancies.

Autologous Hematopoietic Stem Cell Transplantation for Behçet's Disease: A Retrospective Survey of Patients Treated in Europe, on Behalf of the Autoimmune Diseases Working Party of the European Society for Blood and Marrow Transplantation.

Background: Behçet's Disease (BD) is an autoimmune disease mostly presenting with recurrent oral and genital aphthosis, and uveitis. Patients are rarely refractory to immunosuppressive treatments. Autologous hematopoietic stem cell transplantation (aHSCT) is a standard of care in other autoimmune diseases. Some patients with BD have been treated with aHSCT based on compassionate use. Objectives: Evaluate the outcome of aHSCT in adult patients with BD treated in member centers of the European Society for Blood and Marrow Transplantation (EBMT). Methods: Adults who received aHSCT primarily for BD were identified retrospectively in the EBMT registry and/or in published literature. Data were extracted from either medical records of the patient or from publications. Results: Eight out of 9 cases reported to the registry and extracted data of 2 further patients from literature were analyzed. Four were female, median age at onset of BD was 24y (range 9-50). Median age at aHSCT was 32y (27-51). Patients had received median 4 (2-11) previous lines of therapy (89% corticosteroids, 50% methotrexate, anti-TNFα therapy or cyclophosphamide). All patients had active disease before mobilization. Conditioning regimen was heterogeneous. Median follow-up was 48 months (range 6-240). No treatment-related mortality was reported. This procedure induced complete remission (CR) in 80%, partial remission in 10% and lack of response in 10% of the patients. Relapse rate was 30% (2 relapses in patients in CR and 1 relapse in the patient in PR) with panuveitis (n=1), aphthosis (n=2) and arthralgia (n=1). Six patients were in CR. No late complications were reported. Conclusion: aHSCT has an acceptable safety profile and represents a feasible and relatively effective procedure in severe and conventional treatment-resistant cases of BD and has the potential to stabilize BD in patients with life-threatening involvements.

Induction of muscle-regenerative multipotent stem cells from human adipocytes by PDGF-AB and 5-azacytidine.

Terminally differentiated murine osteocytes and adipocytes can be reprogrammed using platelet-derived growth factor-AB and 5-azacytidine into multipotent stem cells with stromal cell characteristics. We have now optimized culture conditions to reprogram human adipocytes into induced multipotent stem (iMS) cells and characterized their molecular and functional properties. Although the basal transcriptomes of adipocyte-derived iMS cells and adipose tissue-derived mesenchymal stem cells were similar, there were changes in histone modifications and CpG methylation at cis-regulatory regions consistent with an epigenetic landscape that was primed for tissue development and differentiation. In a non-specific tissue injury xenograft model, iMS cells contributed directly to muscle, bone, cartilage, and blood vessels, with no evidence of teratogenic potential. In a cardiotoxin muscle injury model, iMS cells contributed specifically to satellite cells and myofibers without ectopic tissue formation. Together, human adipocyte-derived iMS cells regenerate tissues in a context-dependent manner without ectopic or neoplastic growth.

Long-Term Suppression of Circulating Proinflammatory Cytokines in Multiple Sclerosis Patients Following Autologous Haematopoietic Stem Cell Transplantation.

Autologous haematopoietic stem cell transplantation (AHSCT) is a therapeutic option for haematological malignancies, such as non-Hodgkin's lymphoma (NHL), and more recently, for autoimmune diseases, such as treatment-refractory multiple sclerosis (MS). The immunological mechanisms underlying remission in MS patients following AHSCT likely involve an anti-inflammatory shift in the milieu of circulating cytokines. We hypothesised that immunological tolerance in MS patients post-AHSCT is reflected by an increase in anti-inflammatory cytokines and a suppression of proinflammatory cytokines in the patient blood. We investigated this hypothesis using a multiplex-ELISA assay to compare the concentrations of secreted cytokine in the peripheral blood of MS patients and NHL patients undergoing AHSCT. In MS patients, we detected significant reductions in proinflammatory T helper (Th)17 cytokines interleukin (IL)-17, IL-23, IL-1ß, and IL-21, and Th1 cytokines interferon (IFN)γ and IL-12p70 in MS patients from day 8 to 24 months post-AHSCT. These changes were not observed in the NHL patients despite similar pre-conditioning treatment for AHSCT. Some proinflammatory cytokines show similar trends in both cohorts, such as IL-8 and tumour necrosis factor (TNF)-α, indicating a probable treatment-related AHSCT response. Anti-inflammatory cytokines (IL-10, IL-4, and IL-2) were only transiently reduced post-AHSCT, with only IL-10 exhibiting a significant surge at day 14 post-AHSCT. MS patients that relapsed post-AHSCT exhibited significantly elevated levels of IL-17 at 12 months post-AHSCT, unlike non-relapse patients which displayed sustained suppression of Th17 cytokines at all post-AHSCT timepoints up to 24 months. These findings suggest that suppression of Th17 cytokines is essential for the induction of long-term remission in MS patients following AHSCT.

Standardization and Accreditation in Haemopoietic Stem Cell Transplantation - an Asia Pacific Perspective.

Standardization and formal accreditation of practices related to hematopoietic stem cell transplantation (HSCT) and therapies using hematopoietic-derived cellular products aim to promote quality in clinical and laboratory practice and provide knowledge to all stakeholders of centers. This article refers to three aspects of these processes starting with the importance of accurate viable CD 34 enumeration in HSCT. A highly accurate method of enumeration and a robust EQAS program is required, especially during the current COVID-19 pandemic. The second section shares experiences with FACT-JACIE accreditation at the Singapore General Hospital demonstrating how accreditation is part of continuous improvement and not only a destination. This journey can be difficult in many HSCT centers of low- and middle-income countries (LMICs) because of the intensive and rigorous requirements of the internationally accredited models. Hence, in LMICs, a staged movement toward establishing such standards must be considered. This approach is presented in the third section of the article with data on the current situation in countries reporting to the APBMT registry.

miR-10a as a therapeutic target and predictive biomarker for MDM2 inhibition in acute myeloid leukemia.

Pharmacological inhibition of MDM2/4, which activates the critical tumor suppressor p53, has been gaining increasing interest as a strategy for the treatment of acute myeloid leukemia (AML). While clinical trials of MDM2 inhibitors have shown promise, responses have been confined to largely molecularly undefined patients, indicating that new biomarkers and optimized treatment strategies are needed. We previously reported that the microRNA miR-10a is strongly overexpressed in some AML, and demonstrate here that it modulates several key members of the p53/Rb network, including p53 regulator MDM4, Rb regulator RB1CC1, p21 regulator TFAP2C, and p53 itself. The expression of both miR-10a and its downstream targets were strongly predictive of MDM2 inhibitor sensitivity in cell lines, primary AML specimens, and correlated to response in patients treated with both MDM2 inhibitors and cytarabine. Furthermore, miR-10a inhibition induced synergy between MDM2 inhibitor Nutlin-3a and cytarabine in both in vitro and in vivo AML models. Mechanistically this synergism primarily occurs via the p53-mediated activation of cytotoxic apoptosis at the expense of cytoprotective autophagy. Together these findings demonstrate that miR-10a may be useful as both a biomarker to identify patients most likely to respond to cytarabine+MDM2 inhibition and also a druggable target to increase their efficacy.

Direct Comparison of Four Hematopoietic Differentiation Methods from Human Induced Pluripotent Stem Cells.

Induced pluripotent stem cells (iPSCs) are an invaluable resource for the study of human disease. However, there are no standardized methods for differentiation into hematopoietic cells, and there is a lack of robust, direct comparisons of different methodologies. In the current study we improved a feeder-free, serum-free method for generation of hematopoietic cells from iPSCs, and directly compared this with three other commonly used strategies with respect to efficiency, repeatability, hands-on time, and cost. We also investigated their capability and sensitivity to model genetic hematopoietic disorders in cells derived from Down syndrome and ß-thalassemia patients. Of these methods, a multistep monolayer-based method incorporating aryl hydrocarbon receptor hyperactivation ("2D-multistep") was the most efficient, generating significantly higher numbers of CD34+ progenitor cells and functional hematopoietic progenitors, while being the most time- and cost-effective and most accurately recapitulating phenotypes of Down syndrome and ß-thalassemia.

Tolerance regeneration by T regulatory cells in autologous haematopoietic stem cell transplantation for autoimmune diseases.

Autologous haematopoietic stem cell transplantation shows increasing promise as a therapeutic option for patients with treatment-refractory autoimmune disease, particularly systemic sclerosis and multiple sclerosis. However, this intensive chemotherapy-based procedure is not always possible due to potential treatment toxicities and comorbidities. The biological mechanisms of how this procedure induces long-term remission in autoimmune disease are increasingly understood. The focus of this review is on recent research findings on the role of CD4+ T regulatory cells (Tregs) in resetting the immune system leading to the eradication of the autoimmune disease after transplantation. Discovery of the precise mechanisms of this process will allow development of novel Treg-based therapies and thus avoid the need for intensive chemotherapy-based treatment for these autoimmune diseases in the future.

Favorable Outcome of Lung Transplantation for Severe Pulmonary Graft Versus Host Disease: An Australian Multicenter Case Series.

BACKGROUND: Severe pulmonary chronic graft versus host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation. Few treatments influence outcome, with 5-year overall survival as low as 13%. Lung transplantation (LTx) has been reported in small numbers of patients worldwide. METHODS: We investigated the outcomes of LTx performed for this indication at 2 large Australian LTx centers. RESULTS: Eighteen patients (aged 10-64 y; median, 29.6 y) received bilateral deceased lung transplants for pulmonary chronic GVHD between 2002 and 2017. LTx was performed at a median of 8.6 years after allogeneic stem cell transplantation (range, 2-23 y) with a median interval of 16 months from the time of transplant unit review to LTx. There were 2 early infective deaths and 3 further deaths from pulmonary infection and lung allograft rejection. There were no primary disease relapses. At a median follow-up of 5 years, the 5-year overall survival post-LTx is 80% and comparable to the Australia and New Zealand registry data of 64% for LTx performed for all indications. CONCLUSIONS: From one of the largest series of deceased LTx for this indication, we conclude that it is a feasible option for selected patients with severe pulmonary GVHD. The outcomes appear superior to that of non-LTx-based therapies and similar to the survival of the general LTx population. Establishing guidance on referral triggers, patient eligibility, organ selection, prophylaxis of allograft rejection, and supportive care would assist hematopoietic and lung transplant units in optimizing resource allocation and patient outcomes.

Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study.

BACKGROUND: Preclinical studies have shown synergistic antitumour effects between ibrutinib and immune-checkpoint blockade. The aim of this study was to assess the safety and activity of ibrutinib in combination with nivolumab in patients with relapsed or refractory B-cell malignant diseases. METHODS: We did a two-part, open-label, phase 1/2a study at 21 hospitals in Australia, Israel, Poland, Spain, Turkey, and the USA. The primary objective of part A (dose escalation) was to assess the safety of daily oral ibrutinib (420 mg or 560 mg) in combination with intravenous nivolumab (3 mg/kg every 2 weeks) to ascertain a recommended phase 2 dose in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, or diffuse large B-cell lymphoma. Dose optimisation was investigated using a modified toxicity probability interval design. The primary objective of the part B expansion phase was to establish the preliminary activity (the proportion of patients who achieved an overall response) of the combination of ibrutinib and nivolumab in four cohorts: relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, diffuse large B-cell lymphoma, and Richter's transformation. All participants who received at least one dose of treatment were included in the primary analysis and analyses were done by disease cohort. This trial is registered with ClinicalTrials.gov, number NCT02329847. The trial is ongoing. FINDINGS: Between March 12, 2015, and April 11, 2017, 144 patients were enrolled in the study. Three patients died before receiving study treatment; thus, 141 patients were included in the analysis, 14 in part A and 127 in part B. One dose-limiting toxicity (grade 3 hyperbilirubinaemia) was reported at the 420 mg dose in the diffuse large B-cell lymphoma cohort, which resolved after 5 days. The combination of ibrutinib and nivolumab led to overall responses in 22 (61%) of 36 patients with high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma, 13 (33%) of 40 patients with follicular lymphoma, 16 (36%) of 45 patients with diffuse large B-cell lymphoma, and 13 (65%) of 20 patients with Richter's transformation. The most common all-grade adverse events were diarrhoea (47 [33%] of 141 patients), neutropenia (44 [31%]), and fatigue (37 [26%]). 11 (8%) of 141 patients had adverse events leading to death; none were reported as drug-related. The most common grade 3-4 adverse events were neutropenia (40 [28%] of 141 patients) and anaemia (32 [23%]). The incidence of grade 3-4 neutropenia ranged from eight (18%) of 45 patients with diffuse large B-cell lymphoma to 19 (53%) of 36 patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma; incidence of grade 3-4 anaemia ranged from five (13%) of 40 patients with follicular lymphoma to seven (35%) of 20 patients with Richter's transformation. The most common serious adverse events included anaemia (six [4%] of 141 patients) and pneumonia (five [4%]). The most common grade 3-4 immune-related adverse events were rash (11 [8%] of 141 patients) and increased alanine aminotransferase (three [2%]). INTERPRETATION: The combination of ibrutinib and nivolumab had an acceptable safety profile and preliminary activity was similar to that reported with single-agent ibrutinib in chronic lymphocytic leukaemia or small lymphocytic lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. The clinical response in patients with Richter's transformation was promising and supports further clinical assessment. FUNDING: Janssen R&D.

Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) has been explored as a therapeutic intervention in multiple sclerosis (MS) over the last two decades; however, prospective clinical trials of the most common myeloablative conditioning regimen, BEAM, are limited. Furthermore, patient selection, optimal chemotherapeutic regimen and immunological changes associated with disease response require ongoing exploration. We present the outcomes, safety and immune reconstitution (IR) of patients with active, treatment refractory MS. METHODS: This study was a single-centre, phase II clinical trial of AHSCT for patients with active relapsing remitting (RRMS) and secondary progressive MS (SPMS). Patients underwent AHSCT using BEAM (carmustine, etoposide, cytarabine, melphalan)+antithymocyte globulin chemotherapeutic regimen. OUTCOMES: The primary outcome was event-free survival (EFS); defined as no clinical or radiological relapses and no disability progression. Multiparameter flow cytometry was performed for evaluation of post-transplant IR in both MS and lymphoma patients receiving the same chemotherapy regimen. RESULTS: Thirty-five patients (20 RRMS, 15 SPMS) completed AHSCT, with a median follow-up of 36 months (range 12-66). The median Expanded Disability Status Scores (EDSS) was 6 (2-7) and patients had failed a median of 4 (2-7) disease modifying therapies. 66% failed treatment with natalizumab. EFS at 3 years was 60%, (70% RRMS). Sustained improvement in EDSS was seen in 15 (44%) of patients. There was no treatment-related mortality. A sustained rise in CD39+ T regulatory cells, immunosuppressive CD56hi natural killer cells and ablation of proinflammatory mucosal-associated invariant T cells was seen for 12 months following AHSCT in patients with MS. These changes did not occur in patients with lymphoma receiving the same chemotherapy for AHSCT. CONCLUSIONS: The EFS in our MS cohort is significantly greater than other high-efficacy immunosuppressive therapies and similar to other AHSCT studies despite a more heavily pretreated cohort. TRIAL REGISTRATION NUMBER: ACTRN12613000339752.

Autologous hematopoietic stem cell transplant for autoimmune diseases: evolution,evidence of efficacy, and real-world economics.

Despite an increase in the development of biological therapies for autoimmune disease (AID), a proportion of patients remain treatment refractory, resulting in long term morbidity and increased rates of mortality. Furthermore, maintenance biologic therapies are associated with treatment-related side effects, significant financial cost,and restricted access, which is of particular relevance in the developing world. Although it carries a significant 'front loaded' cost both financially and regarding adverse events, autologous hematopoietic stem cell transplantation (AHSCT) represents a potential single therapeutic intervention, which in the appropriate patient, condition, and transplant center, may offer sustained disease remission resulting in improved overall survival, disease relapse-free survival, improved quality of life, and decreased financial burden. Emerging Phase II and III trial and registry data, to which our center has been a significant contributor over the past two decades, are providing invaluable evidence as to which AIDs are most likely to receive a sustained benefit from AHSCT and which conditioning regimens are preferable. Similar to trends for the treatment of malignant disease, AHSCT for AID may find a place in both developed and developing countries as nations become more familiar with the transplantation process. If this occurs, benchmarking by key regulatory bodies, collaboration between medical specialties, and the development of experienced 'centers of excellence' will be key to enhance safety and benefit to patients and society at large.

Regenerating Immunotolerance in Multiple Sclerosis with Autologous Hematopoietic Stem Cell Transplant.

Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system where evidence implicates an aberrant adaptive immune response in the accrual of neurological disability. The inflammatory phase of the disease responds to immunomodulation to varying degrees of efficacy; however, no therapy has been proven to arrest progression of disability. Recently, more intensive therapies, including immunoablation with autologous hematopoietic stem cell transplantation (AHSCT), have been offered as a treatment option to retard inflammatory disease, prior to patients becoming irreversibly disabled. Empirical clinical observations support the notion that the immune reconstitution (IR) that occurs following AHSCT is associated with a sustained therapeutic benefit; however, neither the pathogenesis of MS nor the mechanism by which AHSCT results in a therapeutic benefit has been clearly delineated. Although the antigenic target of the aberrant immune response in MS is not defined, accumulated data suggest that IR following AHSCT results in an immunotolerant state through deletion of pathogenic clones by a combination of direct ablation and induction of a lymphopenic state driving replicative senescence and clonal attrition. Restoration of immunoregulation is evidenced by changes in regulatory T cell populations following AHSCT and normalization of genetic signatures of immune homeostasis. Furthermore, some evidence exists that AHSCT may induce a rebooting of thymic function and regeneration of a diversified naïve T cell repertoire equipped to appropriately modulate the immune system in response to future antigenic challenge. In this review, we discuss the immunological mechanisms of IR therapies, focusing on AHSCT, as a means of recalibrating the dysfunctional immune response observed in MS.

Activity and Capacity Profile of Transplant Physicians and Centers in Australia and New Zealand.

We conducted a study to analyze and report on indicators of hematopoietic cell transplant (HCT) physician time use and HCT center output measures. HCT centers in Australia and New Zealand (A&NZ) were invited to provide demographic and time use details for physicians participating in HCT patient care (HCT physicians). Resource details for adult and pediatric centers were included. From a total of 46 centers that were invited to participate, completed data were received from 37 centers (80%) representing 185 HCT physicians, with a median age of 48 (range, 33 to 72), of whom 31% were women. Just over half of HCT physicians cited prior work experience in large overseas HCT centers (97, 52%) and over one-third (79, 43%) possessed postgraduate qualifications other than specialist training. Total annual mean HCTs per HCT physician full-time equivalent (FTE) were 14.2 for centers performing both allogeneic and autologous HCT, 6.6 for autologous only centers, and 10.6 for all centers. For all HCT physicians surveyed the mean proportion of time spent on HCT related tasks was 31.7%. In A&NZ, for centers that perform both allografts and autografts, there was a mean of 4.0 allogeneic HCT annually per HCT bed, compared with 2.6 for the United States and 7.1 allogeneic HCT annually per HCT physician FTE (United States, 6.3). Projections of the A&NZ HCT physician workforce indicated that the numbers of HCT physicians are likely to stay within the region of 170 to 190 for the next 10 years, whereas HCT activity will likely continue to climb steadily. Healthcare and government authorities should be prepared to enable and support greater HCT activity in A&NZ in the future.

Dealing with the spiralling price of medicines: issues and solutions.

Escalating cost of medicines is rapidly becoming a serious threat to patients and health systems. This trend has been documented to impact patient outcomes adversely. As clinicians and tax payers, it is our responsibility to be aware of the potential detrimental effects spiralling costs have on our patients, our community and our health system and to mitigate these effects by exposing this issue to our respective professional societies, representatives of the pharmaceutical companies that we interact with, government regulatory bodies and to patients who we are caring for. Only through understanding and constructive actions will we be able to provide the best quality of care to our patients and continue to enjoy universal healthcare in our country.

Pro-survival role of protein kinase C epsilon in Philadelphia chromosome positive acute leukemia.

Durable responses to imatinib monotherapy are rarely seen in aggressive forms of Philadelphia chromosome positive (Ph+) leukemias. To investigate the possible cause of treatment failure we examined the role of protein kinase C epsilon (PKCE), an oncogene highly implicated in the development of solid tumors and resistance to chemotherapy. We found high levels of PKCE transcripts in Ph+ acute lymphoblastic leukemia (ALL) cells from patients and cell lines, and imatinib resistant chronic myeloid leukemia, which were also less responsive to imatinib-induced apoptosis than Ph+ cells with lower PKCE expression. Furthermore, the siRNA-mediated knockdown or peptide inhibition of PKCE in Ph+ cells increased imatinib-induced apoptosis while overexpression of PKCE reduced imatinib-induced apoptosis, with concomitant increase in the pro-survival factor AKT. Our results suggest PKCE plays a protective role against apoptosis induced by BCR-ABL inhibition in Ph+ leukemias with high PKCE expression, such as Ph+ ALL.