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Myeloablation followed by autologous stem cell transplantation normalises systemic sclerosis molecular signatures.
Assassi S, Wang X, Chen G, Goldmuntz E, Keyes-Elstein L, Ying J, Wallace PK, Turner J, Zheng WJ, Pascual V, Varga J, Hinchcliff ME, Bellocchi C, McSweeney P, Furst DE, Nash RA, Crofford LJ, Welch B, Pinckney A, Mayes MD, Sullivan KM
(2019) Ann Rheum Dis 78: 1371-1378
MeSH Terms: Adult, Cyclophosphamide, Down-Regulation, Female, Hematopoietic Stem Cell Transplantation, Humans, Interferons, Male, Middle Aged, Multilevel Analysis, Myeloablative Agonists, Neutrophils, Randomized Controlled Trials as Topic, Scleroderma, Systemic, Transcriptome, Transplantation Conditioning, Transplantation, Autologous, Treatment Outcome, Up-Regulation
Show Abstract · Added March 25, 2020
OBJECTIVE - In the randomised scleroderma: Cyclophosphamide Or Transplantation (SCOT trial) (NCT00114530), myeloablation, followed by haematopoietic stem cell transplantation (HSCT), led to improved clinical outcomes compared with monthly cyclophosphamide (CYC) treatment in systemic sclerosis (SSc). Herein, the study aimed to determine global molecular changes at the whole blood transcript and serum protein levels ensuing from HSCT in comparison to intravenous monthly CYC in 62 participants enrolled in the SCOT study.
METHODS - Global transcript studies were performed at pretreatment baseline, 8 months and 26 months postrandomisation using Illumina HT-12 arrays. Levels of 102 proteins were measured in the concomitantly collected serum samples.
RESULTS - At the baseline visit, interferon (IFN) and neutrophil transcript modules were upregulated and the cytotoxic/NK module was downregulated in SSc compared with unaffected controls. A paired comparison of the 26 months to the baseline samples revealed a significant decrease of the IFN and neutrophil modules and an increase in the cytotoxic/NK module in the HSCT arm while there was no significant change in the CYC control arm. Also, a composite score of correlating serum proteins with IFN and neutrophil transcript modules, as well as a multilevel analysis showed significant changes in SSc molecular signatures after HSCT while similar changes were not observed in the CYC arm. Lastly, a decline in the IFN and neutrophil modules was associated with an improvement in pulmonary forced vital capacity and an increase in the cytotoxic/NK module correlated with improvement in skin score.
CONCLUSION - HSCT contrary to conventional treatment leads to a significant 'correction' in disease-related molecular signatures.
© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
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19 MeSH Terms
New-Onset Post-Transplant Diabetes Mellitus after Allogeneic Hematopoietic Cell Transplant Is Initiated by Insulin Resistance, Not Immunosuppressive Medications.
Engelhardt BG, Savani U, Jung DK, Powers AC, Jagasia M, Chen H, Winnick JJ, Tamboli RA, Crowe JE, Abumrad NN
(2019) Biol Blood Marrow Transplant 25: 1225-1231
MeSH Terms: Adult, Diabetes Mellitus, Female, Hematopoietic Stem Cell Transplantation, Humans, Insulin Resistance, Male, Middle Aged, Transplantation Conditioning, Transplantation, Homologous
Show Abstract · Added March 31, 2019
New-onset post-transplant diabetes mellitus (PTDM) occurs frequently after allogeneic hematopoietic cell transplant (HCT). Although calcineurin inhibitors and corticosteroids are assumed to be the cause for hyperglycemia, patients developing PTDM have elevated fasting C-peptide levels before HCT and before immunosuppressive medications. To determine if PTDM results from established insulin resistance present before transplant, we performed oral glucose tolerance tests (OGTTs) and measured whole body, peripheral, and hepatic insulin sensitivity with euglycemic hyperinsulinemic clamps before and 90 days after HLA-identical sibling donor HCT in 20 patients without pretransplant diabetes. HCT recipients were prospectively followed for the development of new-onset PTDM defined as a weekly fasting blood glucose ≥ 126 mg/dL or random blood glucose ≥ 200 mg/dL. During the first 100 days all patients received calcineurin inhibitors, and 11 individuals (55%) were prospectively diagnosed with new-onset PTDM. PTDM diagnosis preceded corticosteroid treatment. During the pretransplant OGTT, elevated fasting (87 mg/dL versus 101 mg/dL; P = .005) but not 2-hour postprandial glucose levels predicted PTDM diagnosis (P = .648). In response to insulin infusion during the euglycemic hyperinsulinemic clamp, patients developing PTDM had lower whole body glucose utilization (P = .047) and decreased peripheral/skeletal muscle uptake (P = .031) before and after transplant, respectively, when compared with non-PTDM patients. Hepatic insulin sensitivity did not differ. Survival was decreased in PTDM patients (2-year estimate, 55% versus 100%; P = .039). Insulin resistance before HCT is a risk factor for PTDM independent of immunosuppression. Fasting pretransplant glucose levels identified PTDM susceptibility, and peripheral insulin resistance could be targeted for prevention and treatment of PTDM after HCT.
Copyright © 2019 American Society for Blood and Marrow Transplantation. All rights reserved.
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10 MeSH Terms
Machine learning reveals chronic graft--host disease phenotypes and stratifies survival after stem cell transplant for hematologic malignancies.
Gandelman JS, Byrne MT, Mistry AM, Polikowsky HG, Diggins KE, Chen H, Lee SJ, Arora M, Cutler C, Flowers M, Pidala J, Irish JM, Jagasia MH
(2019) Haematologica 104: 189-196
MeSH Terms: Adult, Biomarkers, Chronic Disease, Consensus, Female, Graft vs Host Disease, Hematologic Neoplasms, Hematopoietic Stem Cell Transplantation, Humans, Machine Learning, Male, Middle Aged, National Institutes of Health (U.S.), Prospective Studies, Transplantation, Homologous, United States
Show Abstract · Added September 25, 2018
The application of machine learning in medicine has been productive in multiple fields, but has not previously been applied to analyze the complexity of organ involvement by chronic graft--host disease. Chronic graft--host disease is classified by an overall composite score as mild, moderate or severe, which may overlook clinically relevant patterns in organ involvement. Here we applied a novel computational approach to chronic graft--host disease with the goal of identifying phenotypic groups based on the subcomponents of the National Institutes of Health Consensus Criteria. Computational analysis revealed seven distinct groups of patients with contrasting clinical risks. The high-risk group had an inferior overall survival compared to the low-risk group (hazard ratio 2.24; 95% confidence interval: 1.36-3.68), an effect that was independent of graft--host disease severity as measured by the National Institutes of Health criteria. To test clinical applicability, knowledge was translated into a simplified clinical prognostic decision tree. Groups identified by the decision tree also stratified outcomes and closely matched those from the original analysis. Patients in the high- and intermediate-risk decision-tree groups had significantly shorter overall survival than those in the low-risk group (hazard ratio 2.79; 95% confidence interval: 1.58-4.91 and hazard ratio 1.78; 95% confidence interval: 1.06-3.01, respectively). Machine learning and other computational analyses may better reveal biomarkers and stratify risk than the current approach based on cumulative severity. This approach could now be explored in other disease models with complex clinical phenotypes. External validation must be completed prior to clinical application. Ultimately, this approach has the potential to reveal distinct pathophysiological mechanisms that may underlie clusters. .
Copyright© 2019 Ferrata Storti Foundation.
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16 MeSH Terms
Systemic Sclerosis as an Indication for Autologous Hematopoietic Cell Transplantation: Position Statement from the American Society for Blood and Marrow Transplantation.
Sullivan KM, Majhail NS, Bredeson C, Carpenter PA, Chatterjee S, Crofford LJ, Georges GE, Nash RA, Pasquini MC, Sarantopoulos S, Storek J, Savani B, St Clair EW
(2018) Biol Blood Marrow Transplant 24: 1961-1964
MeSH Terms: Autografts, Bone Marrow Transplantation, Cyclophosphamide, Hematopoietic Stem Cell Transplantation, Humans, Randomized Controlled Trials as Topic, Scleroderma, Systemic, Societies, Medical, United States
Show Abstract · Added March 25, 2020
Systemic sclerosis is a progressive inflammatory disease that is frequently fatal and has limited treatment options. High-dose chemotherapy with autologous hematopoietic cell transplantation (AHCT) has been evaluated as treatment for this disease in observational studies, multicenter randomized controlled clinical trials, and meta-analyses. On behalf of the American Society for Blood and Marrow Transplantation (ASBMT), a panel of experts in transplantation and rheumatology was convened to review available evidence and make a recommendation on AHCT as an indication for systemic sclerosis. Three randomized trials have compared the efficacy of AHCT with cyclophosphamide only, and all demonstrated benefit for the AHCT arm for their primary endpoint (improvement in the American Scleroderma Stem Cell versus Immune Suppression Trial, event-free survival in Autologous Stem Cell Transplantation International Scleroderma trial, and change in global rank composite score in Scleroderma: Cyclophosphamide or Transplantation trial). AHCT recipients also had better overall survival and a lower rate of disease progression. These findings have been confirmed in subsequent meta-analyses. Based on this high-quality evidence, the ASBMT recommends systemic sclerosis should be considered as a "standard of care" indication for AHCT. Close collaboration between rheumatologists and transplant clinicians is critical for optimizing patient selection and patient outcomes. Transplant centers in the United States are strongly encouraged to report patient and outcomes data to the Center for International Blood and Marrow Transplant Research on their patients receiving AHCT for this indication.
Copyright © 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma.
Sullivan KM, Goldmuntz EA, Keyes-Elstein L, McSweeney PA, Pinckney A, Welch B, Mayes MD, Nash RA, Crofford LJ, Eggleston B, Castina S, Griffith LM, Goldstein JS, Wallace D, Craciunescu O, Khanna D, Folz RJ, Goldin J, St Clair EW, Seibold JR, Phillips K, Mineishi S, Simms RW, Ballen K, Wener MH, Georges GE, Heimfeld S, Hosing C, Forman S, Kafaja S, Silver RM, Griffing L, Storek J, LeClercq S, Brasington R, Csuka ME, Bredeson C, Keever-Taylor C, Domsic RT, Kahaleh MB, Medsger T, Furst DE, SCOT Study Investigators
(2018) N Engl J Med 378: 35-47
MeSH Terms: Adolescent, Adult, Aged, Cyclophosphamide, Disease-Free Survival, Female, Follow-Up Studies, Hematopoietic Stem Cell Transplantation, Humans, Immunosuppressive Agents, Infections, Intention to Treat Analysis, Kaplan-Meier Estimate, Male, Middle Aged, Scleroderma, Systemic, Transplantation Conditioning, Transplantation, Autologous, Young Adult
Show Abstract · Added March 25, 2020
BACKGROUND - Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma.
METHODS - We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score.
RESULTS - In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group.
CONCLUSIONS - Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).
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Fertility challenges for women with sickle cell disease.
Ghafuri DL, Stimpson SJ, Day ME, James A, DeBaun MR, Sharma D
(2017) Expert Rev Hematol 10: 891-901
MeSH Terms: Anemia, Sickle Cell, Blood Transfusion, Chronic Pain, Female, Fertility, Fertility Preservation, Genetic Therapy, Hematopoietic Stem Cell Transplantation, Humans, Hydroxyurea, Infertility, Pregnancy, Primary Ovarian Insufficiency, Reproductive Health, Transplantation Conditioning
Show Abstract · Added November 9, 2018
INTRODUCTION - Sickle cell disease (SCD) represents one of the most common monogenic blood disorders worldwide, with an incidence of over 300,000 newborns affected per year. Reproductive challenges for men and women with SCD have been previously reviewed; however, evidence-based strategies to prevent and manage infertility and increase fecundity are lacking in women with SCD, which is one of the most important factors for quality of life. Areas covered: This review article summarizes the known risk factors for infertility, low fecundity, and premature menopause related to SCD. Expert commentary: Women with SCD have unique risk factors that may impact their ability to conceive, including chronic inflammation, oxidative stress, transfusion-related hemochromatosis, and ovarian sickling, causing ischemia and reperfusion injury to the ovary. Contraception is strongly recommended while on hydroxyurea therapy during reproductive years and discontinuing hydroxyurea for family planning and during pregnancy based on teratogenicity in animal studies. Hematopoietic stem cell transplantation (HSCT), the only curative therapy, sometimes involves conditioning regimens containing alkylating agents and total body irradiation that contribute to infertility and premature ovarian failure. Prior to HSCT or gene therapy, we strongly recommend referral to a reproductive endocrinologist to discuss fertility preservation and surrogacy options for all women with SCD.
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Reactive Oxygen Species Shielding Hydrogel for the Delivery of Adherent and Nonadherent Therapeutic Cell Types.
Dollinger BR, Gupta MK, Martin JR, Duvall CL
(2017) Tissue Eng Part A 23: 1120-1131
MeSH Terms: Animals, Cell Adhesion, Cell Count, Cell Death, Cytoprotection, Humans, Hydrogels, Hydrogen Peroxide, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells, Mice, Polymers, Reactive Oxygen Species, Rheology
Show Abstract · Added March 14, 2018
Cell therapies suffer from poor survival post-transplant due to placement into hostile implant sites characterized by host immune response and innate production of high levels of reactive oxygen species (ROS). We hypothesized that cellular encapsulation within an injectable, antioxidant hydrogel would improve viability of cells exposed to high oxidative stress. To test this hypothesis, we applied a dual thermo- and ROS-responsive hydrogel comprising the ABC triblock polymer poly[(propylene sulfide)-block-(N,N-dimethyl acrylamide)-block-(N-isopropylacrylamide)] (PPS-b-PDMA-b-PNIPAAM, PDN). The PPS chemistry reacts irreversibly with ROS such as hydrogen peroxide (HO), imparting inherent antioxidant properties to the system. Here, PDN hydrogels were successfully integrated with type 1 collagen to form ROS-protective, composite hydrogels amenable to spreading and growth of adherent cell types such as mesenchymal stem cells (MSCs). It was also shown that, using a control hydrogel substituting nonreactive polycaprolactone in place of PPS, the ROS-reactive PPS chemistry is directly responsible for PDN hydrogel cytoprotection of both MSCs and insulin-producing β-cell pseudo-islets against HO toxicity. In sum, these results establish the potential of cytoprotective, thermogelling PDN biomaterials for injectable delivery of cell therapies.
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14 MeSH Terms
Cardiac repair in a mouse model of acute myocardial infarction with trophoblast stem cells.
Li G, Chen J, Zhang X, He G, Tan W, Wu H, Li R, Chen Y, Gu R, Xie J, Xu B
(2017) Sci Rep 7: 44376
MeSH Terms: Animals, Cardiac Surgical Procedures, Cell Differentiation, Disease Models, Animal, Humans, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells, Mice, Myocardial Infarction, Myocardium, Myocytes, Cardiac, Trophoblasts
Show Abstract · Added September 11, 2017
Various stem cells have been explored for the purpose of cardiac repair. However, any individual stem cell population has not been considered as the ideal source. Recently, trophoblast stem cells (TSCs), a newly described stem cell type, have demonstrated extensive plasticity. The present study evaluated the therapeutic effect of TSCs transplantation for heart regeneration in a mouse model of myocardial infarction (MI) and made a direct comparison with the most commonly used mesenchymal stem cells (MSCs). Transplantation of TSCs and MSCs led to a remarkably improved cardiac function in contrast with the PBS control, but only the TSCs exhibited the potential of differentiation into cardiomyocytes in vivo. In addition, a significantly high proliferation level of both transplanted stem cells and resident cardiomyocytes was observed in the TSCs group. These findings primary revealed the therapeutic potential of TSCs in transplantation therapy for MI.
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12 MeSH Terms
Current Management of Refractory Germ Cell Tumors and Future Directions.
Allen JC, Kirschner A, Scarpato KR, Morgans AK
(2017) Curr Oncol Rep 19: 8
MeSH Terms: Antineoplastic Combined Chemotherapy Protocols, Cisplatin, Disease Management, Hematopoietic Stem Cell Transplantation, Humans, Male, Neoplasms, Germ Cell and Embryonal
Show Abstract · Added April 2, 2019
PURPOSE OF REVIEW - We review current management strategies for patients with relapsed and refractory germ cell tumors (GCTs), defined as relapsed or persistent disease following at least one line of cisplatin-based chemotherapy. Additionally, we discuss future directions in the management of these patients.
RECENT FINDINGS - Recent studies involving targeted therapies have been disappointing. Nevertheless, studies of the management of refractory germ cell cancer are ongoing, with a focus on optimal utilization of high-dose chemotherapy and autologous stem cell transplant, as well as the role of immune checkpoint inhibitors in refractory germ cell tumors. Studies aiming to identify those patients who may benefit from more intensive treatment up front to prevent the development of refractory disease are also in progress. Testicular germ cell tumors are among the most curable of all solid tumor malignancies, with cure being possible even in the refractory, metastatic setting. Treatment of refractory disease remains a challenging clinical scenario, but potentially practice changing studies are ongoing.
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Hematopoietic Stem Cell Mobilization Is Necessary but Not Sufficient for Tolerance in Islet Transplantation.
Stocks BT, Thomas AB, Elizer SK, Zhu Y, Marshall AF, Wilson CS, Moore DJ
(2017) Diabetes 66: 127-133
MeSH Terms: Allografts, Animals, Female, Flow Cytometry, Hematopoietic Stem Cell Mobilization, Hematopoietic Stem Cell Transplantation, Islets of Langerhans Transplantation, Leukocyte Common Antigens, Mice, Mice, Inbred NOD, Osteoblasts
Show Abstract · Added November 1, 2016
Overcoming the immune response to establish durable immune tolerance in type 1 diabetes remains a substantial challenge. The ongoing effector immune response involves numerous immune cell types but is ultimately orchestrated and sustained by the hematopoietic stem cell (HSC) niche. We therefore hypothesized that tolerance induction also requires these pluripotent precursors. In this study, we determined that the tolerance-inducing agent anti-CD45RB induces HSC mobilization in nonautoimmune B6 mice but not in diabetes-prone NOD mice. Ablation of HSCs impaired tolerance to allogeneic islet transplants in B6 recipients. Mobilization of HSCs resulted in part from decreasing osteoblast expression of HSC retention factors. Furthermore, HSC mobilization required a functioning sympathetic nervous system; sympathectomy prevented HSC mobilization and completely abrogated tolerance induction. NOD HSCs were held in their niche by excess expression of CXCR4, which, when blocked, led to HSC mobilization and prolonged islet allograft survival. Overall, these findings indicate that the HSC compartment plays an underrecognized role in the establishment and maintenance of immune tolerance, and this role is disrupted in diabetes-prone NOD mice. Understanding the stem cell response to immune therapies in ongoing human clinical studies may help identify and maximize the effect of immune interventions for type 1 diabetes.
© 2017 by the American Diabetes Association.
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11 MeSH Terms