46 results on '"Nelson J"'
Search Results
2. Heparan sulfate, an endogenous TLR4 agonist, promotes acute GVHD after allogeneic stem cell transplantation.
- Author
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Brennan TV, Lin L, Huang X, Cardona DM, Li Z, Dredge K, Chao NJ, and Yang Y
- Subjects
- Animals, Cell Proliferation, Dendritic Cells, Female, Flow Cytometry, Graft vs Host Disease mortality, Hematologic Neoplasms therapy, Humans, Luciferases metabolism, Lymphocyte Depletion, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Middle Aged, Survival Rate, T-Lymphocytes immunology, Transplantation, Homologous, Graft vs Host Disease etiology, Hematologic Neoplasms complications, Heparitin Sulfate adverse effects, Stem Cell Transplantation adverse effects, T-Lymphocytes drug effects, Toll-Like Receptor 4 agonists
- Abstract
Graft-versus-host disease (GVHD) remains the most common cause of nonrelapse-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although T-cell depletion and intensive immunosuppression are effective in the control of GVHD, they are often associated with higher rates of infection and tumor recurrence. In this study, we showed that heparan sulfate (HS), an extracellular matrix component, can activate Toll-like receptor 4 on dendritic cells in vitro, leading to the enhancement of dendritic cell maturation and alloreactive T-cell responses. We further demonstrated in vivo that serum HS levels were acutely elevated at the onset of clinical GVHD in mice after allo-HSCT. Treatment with the serine protease inhibitor α1-antitrypsin decreased serum levels of HS, leading to a reduction in alloreactive T-cell responses and GVHD severity. Conversely, an HS mimetic that increased serum HS levels accelerated GVHD. In addition, in patients undergoing allo-HSCT for hematologic malignancies, serum HS levels were elevated and correlated with the severity of GVHD. These results identify a critical role for HS in promoting acute GVHD after allo-HSCT, and they suggest that modulation of HS release may have therapeutic potential for the control of clinical GVHD.
- Published
- 2012
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3. Severe pulmonary toxicity after myeloablative conditioning using total body irradiation: an assessment of risk factors.
- Author
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Kelsey CR, Horwitz ME, Chino JP, Craciunescu O, Steffey B, Folz RJ, Chao NJ, Rizzieri DA, and Marks LB
- Subjects
- Acute Disease, Adult, Analysis of Variance, Cyclophosphamide administration & dosage, Etoposide administration & dosage, Female, Graft vs Host Disease etiology, Humans, Lung drug effects, Lung radiation effects, Male, Melphalan administration & dosage, Middle Aged, Pneumonia mortality, Retrospective Studies, Risk Factors, Transplantation Conditioning methods, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Whole-Body Irradiation methods, Young Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Hematologic Neoplasms therapy, Pneumonia etiology, Stem Cell Transplantation, Transplantation Conditioning adverse effects, Whole-Body Irradiation adverse effects
- Abstract
Purpose: To assess factors associated with severe pulmonary toxicity after myeloablative conditioning using total body irradiation (TBI) followed by allogeneic stem cell transplantation., Methods and Materials: A total of 101 adult patients who underwent TBI-based myeloablative conditioning for hematologic malignancies at Duke University between 1998 and 2008 were reviewed. TBI was combined with high-dose cyclophosphamide, melphalan, fludarabine, or etoposide, depending on the underlying disease. Acute pulmonary toxicity, occurring within 90 days of transplantation, was scored using Common Terminology Criteria for Adverse Events version 3.0. Actuarial overall survival and the cumulative incidence of acute pulmonary toxicity were calculated via the Kaplan-Meier method and compared using a log-rank test. A binary logistic regression analysis was performed to assess factors independently associated with acute severe pulmonary toxicity., Results: The 90-day actuarial risk of developing severe (Grade 3-5) pulmonary toxicity was 33%. Actuarial survival at 90 days was 49% in patients with severe pulmonary toxicity vs. 94% in patients without (p < 0.001). On multivariate analysis, the number of prior chemotherapy regimens was the only factor independently associated with development of severe pulmonary toxicity (odds ratio, 2.7 per regimen)., Conclusions: Severe acute pulmonary toxicity is prevalent after TBI-based myeloablative conditioning regimens, occurring in approximately 33% of patients. The number of prior chemotherapy regimens appears to be an important risk factor., (Copyright © 2011 Elsevier Inc. All rights reserved.)
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- 2011
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4. Assessing surge capacity for radiation victims with marrow toxicity.
- Author
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Davids MS, Case C Jr, Hornung R 3rd, Chao NJ, Chute JP, Coleman CN, Weisdorf D, Confer DL, and Weinstock DM
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- Academic Medical Centers, Adult, Blood Banks, Bone Marrow Diseases etiology, Child, Fetal Blood, Hospital Bed Capacity, Humans, Interinstitutional Relations, Triage, United States, Bone Marrow Diseases surgery, Bone Marrow Transplantation, Disaster Planning organization & administration, Health Services Needs and Demand, Mass Casualty Incidents, Nuclear Weapons, Patient Simulation, Radioactive Hazard Release, Stem Cell Transplantation, Terrorism
- Abstract
Hematologists/oncologists would provide essential care for victims of a catastrophic radiation incident, such as the detonation of an improvised nuclear device (IND). The US Radiation Injury Treatment Network (RITN) is a voluntary consortium of 37 academic medical centers, 8 blood donor centers, and 7 umbilical cord banks focused on preparedness for radiation incidents. The RITN conducted 2 tabletop exercises to evaluate response capability after a hypothetical IND detonation in a U.S. city. In the 2008 exercise, medical centers voluntarily accepted 1757 victims at their institutions, a small fraction of the number in need. In the 2009 exercise, each center was required to accept 300 victims. In response, the centers outlined multiple strategies to increase bed availability, extend staff and resources, and support family and friends accompanying transferred victims. The exercises highlighted shortcomings in current planning and future steps for improving surge capacity that are applicable to various mass casualty scenarios., (Copyright © 2010 American Society for Blood and Marrow Transplantation. All rights reserved.)
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- 2010
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5. Natural killer cell-enriched donor lymphocyte infusions from A 3-6/6 HLA matched family member following nonmyeloablative allogeneic stem cell transplantation.
- Author
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Rizzieri DA, Storms R, Chen DF, Long G, Yang Y, Nikcevich DA, Gasparetto C, Horwitz M, Chute J, Sullivan K, Hennig T, Misra D, Apple C, Baker M, Morris A, Green PG, Hasselblad V, and Chao NJ
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- Adult, Hematopoietic Stem Cell Transplantation methods, Humans, Lymphocyte Transfusion methods, Lymphocytes immunology, Tissue Donors, Transplantation Conditioning methods, Transplantation, Homologous, HLA Antigens immunology, Killer Cells, Natural immunology, Killer Cells, Natural transplantation, Stem Cell Transplantation methods
- Abstract
Infusing natural killer (NK) cells following transplantation may allow less infections and relapse with little risk of acute graft-versus-host disease (aGVHD). We delivered 51 total NK cell-enriched donor lymphocyte infusions (DLIs) to 30 patients following a 3-6/6 HLA matched T cell-depleted nonmyeloablative allogeneic transplant. The primary endpoint of this study was feasibility and safety. Eight weeks following transplantation, donor NK cell-enriched DLIs were processed using a CD56(+) selecting column with up to 3 fresh infusions allowed. Toxicity, relapse, and survival were monitored. T cell phenotype, NK cell functional recovery, and KIR typing were assessed for association with outcomes. Fourteen matched and 16 mismatched transplanted patients received a total of 51 NK cell-enriched DLIs. Selection resulted in 96% (standard deviation [SD] 8%) purity and 83% (SD 21%) yield in the matched setting and 97% (SD 3%) purity and 77% (SD 24%) yield in the mismatched setting. The median number of CD3(-) CD56(+) NK cells infused was 10.6 (SD 7.91) x 10(6) cells/kg and 9.21 (SD 5.6) x 10(6) cells/kg, respectively. The median number of contaminating CD3(+)CD56(-) T cells infused was .53 (1.1) x 10(6) and .27 (.78) x 10(6) in the matched and mismatched setting, respectively. Only 1 patient each in the matched (n = 14) or mismatched (n = 16) setting experienced severe aGVHD with little other toxicity attributable to the infusions. Long-term responders with multiple NK cell-enriched infusions and improved T cell phenotypic recovery had improved duration of responses (p = .0045) and overall survival (OS) (P = .0058). A 1-step, high-yield process is feasible, and results in high doses of NK cells infused with little toxicity. NK cell-enriched DLIs result in improved immune recovery and outcomes for some. Future studies must assess whether the improved outcomes are the direct result of the high doses and improved NK cell function or other aspects of immune recovery.
- Published
- 2010
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6. Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity.
- Author
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Muramoto GG, Russell JL, Safi R, Salter AB, Himburg HA, Daher P, Meadows SK, Doan P, Storms RW, Chao NJ, McDonnell DP, and Chute JP
- Subjects
- Aldehyde Dehydrogenase genetics, Aldehyde Dehydrogenase metabolism, Aldehyde Dehydrogenase 1 Family, Animals, Antineoplastic Agents pharmacology, Cell Differentiation drug effects, Cell Differentiation physiology, Cell Division drug effects, Cell Division physiology, Cells, Cultured, Cytoprotection drug effects, Enzyme Inhibitors therapeutic use, Hematopoietic Stem Cells drug effects, Hematopoietic Stem Cells radiation effects, Humans, Mice, Mice, Congenic, Mice, Inbred C57BL, RNA, Small Interfering genetics, Radiation, Ionizing, Retinal Dehydrogenase, Signal Transduction drug effects, Signal Transduction physiology, Tretinoin metabolism, Tretinoin pharmacology, p-Aminoazobenzene analogs & derivatives, p-Aminoazobenzene pharmacology, p-Aminoazobenzene therapeutic use, Aldehyde Dehydrogenase antagonists & inhibitors, Cell Proliferation drug effects, Cytoprotection physiology, Enzyme Inhibitors pharmacology, Hematopoietic Stem Cells enzymology, Stem Cell Transplantation methods
- Abstract
Hematopoietic stem cells (HSCs) are enriched for aldehyde dehydrogenase (ALDH) activity and ALDH is a selectable marker for human HSCs. However, the function of ALDH in HSC biology is not well understood. We sought to determine the function of ALDH in regulating HSC fate. Pharmacologic inhibition of ALDH with diethylaminobenzaldehyde (DEAB) impeded the differentiation of murine CD34(-)c-kit(+)Sca-1(+)lineage(-) (34(-)KSL) HSCs in culture and facilitated a ninefold expansion of cells capable of radioprotecting lethally irradiated mice compared to input 34(-)KSL cells. Treatment of bone marrow (BM) 34(-)KSL cells with DEAB caused a fourfold increase in 4-week competitive repopulating units, verifying the amplification of short-term HSCs (ST-HSCs) in response to ALDH inhibition. Targeted siRNA of ALDH1a1 in BM HSCs caused a comparable expansion of radioprotective progenitor cells in culture compared to DEAB treatment, confirming that ALDH1a1 was the target of DEAB inhibition. The addition of all trans retinoic acid blocked DEAB-mediated expansion of ST-HSCs in culture, suggesting that ALDH1a1 regulates HSC differentiation via augmentation of retinoid signaling. Pharmacologic inhibition of ALDH has therapeutic potential as a means to amplify ST-HSCs for transplantation purposes.
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- 2010
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7. Endothelial progenitor cell infusion induces hematopoietic stem cell reconstitution in vivo.
- Author
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Salter AB, Meadows SK, Muramoto GG, Himburg H, Doan P, Daher P, Russell L, Chen B, Chao NJ, and Chute JP
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- Animals, Blood Cell Count, Cell Differentiation physiology, Endothelial Cells physiology, Fetal Blood cytology, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells radiation effects, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Recovery of Function, Stem Cells physiology, Whole-Body Irradiation adverse effects, Endothelial Cells transplantation, Hematopoiesis physiology, Hematopoietic Stem Cells physiology, Stem Cell Transplantation
- Abstract
Hematopoietic stem cells (HSCs) reside in association with bone marrow (BM) sinusoidal vessels in vivo, but the function of BM endothelial cells (ECs) in regulating hematopoiesis is unclear. We hypothesized that hematopoietic regeneration following injury is regulated by BM ECs. BALB/c mice were treated with total body irradiation (TBI) and then infused with C57Bl6-derived endothelial progenitor cells (EPCs) to augment endogenous BM EC activity. TBI caused pronounced disruption of the BM vasculature, BM hypocellularity, ablation of HSCs, and pancytopenia in control mice, whereas irradiated, EPC-treated mice displayed accelerated recovery of BM sinusoidal vessels, BM cellularity, peripheral blood white blood cells (WBCs), neutrophils, and platelets, and a 4.4-fold increase in BM HSCs. Systemic administration of anti-VE-cadherin antibody significantly delayed hematologic recovery in both EPC-treated mice and irradiated, non-EPC-treated mice compared with irradiated controls. These data demonstrate that allogeneic EPC infusions can augment hematopoiesis and suggest a relationship between BM microvascular recovery and hematopoietic reconstitution in vivo.
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- 2009
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8. Production of donor-derived sperm after spermatogonial stem cell transplantation in the dog.
- Author
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Kim Y, Turner D, Nelson J, Dobrinski I, McEntee M, and Travis AJ
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- Animals, Dogs, Genotype, Male, Microsatellite Repeats, Models, Animal, Spermatogenesis radiation effects, Spermatozoa physiology, Testis radiation effects, Transplantation Conditioning methods, Transplantation, Homologous, Spermatogenesis physiology, Spermatogonia transplantation, Stem Cell Transplantation methods
- Abstract
Spermatogonial stem cell transplantation (SSCT) offers unique approaches to investigate SSC and to manipulate the male germline. We report here the first successful performance of this technique in the dog, which is an important model of human diseases. First, we investigated an irradiation protocol to deplete endogenous male germ cells in recipient testes. Histologic examination confirmed >95% depletion of endogenous spermatogenesis, but retention of normal testis architecture. Then, 5-month-old recipient dogs (n=5) were focally irradiated on their testes prior to transplantation with mixed seminiferous tubule cells (fresh (n=2) or after 2 weeks of culture (n=3)). The dogs receiving cultured cells showed an immediate allergic response, which subsided quickly with palliative treatment. No such response was seen in the dogs receiving fresh cells, for which a different injection medium was used. Twelve months post-injection recipients were castrated and sperm was collected from epididymides. We performed microsatellite analysis comparing DNA from the epididymal sperm with genomic DNA from both the recipients and the donors. We used six markers to demonstrate the presence of donor alleles in the sperm from one recipient of fresh mixed tubule cells. No evidence of donor alleles was detected in sperm from the other recipients. Using quantitative PCR based on single nucleotide polymorphisms (SNPs), about 19.5% of sperm were shown to be donor derived in the recipient. Our results demonstrate the first successful completion of SSCT in the dog, an important step toward transgenesis through the male germline in this valuable biomedical model.
- Published
- 2008
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9. Morphologic examination of sequential bone marrow biopsies after nonmyeloablative stem cell transplantation complements molecular studies of donor engraftment.
- Author
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Lagoo AS, Gong JZ, Stenzel TT, Goodman BK, Buckley PJ, Chao NJ, Gasparetto C, Long GD, and Rizzieri DA
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- Adult, Biopsy, Hematologic Neoplasms pathology, Hematologic Neoplasms surgery, Humans, Lymphoproliferative Disorders pathology, Lymphoproliferative Disorders surgery, Middle Aged, Neoplasm Recurrence, Local pathology, Neoplasms pathology, Postoperative Period, Preoperative Care, Time Factors, Tissue Donors, Bone Marrow pathology, Graft Survival genetics, Neoplasms surgery, Stem Cell Transplantation
- Abstract
Context: Nonmyeloablative stem cell transplantation (NMSCT) is a mode of immunotherapy increasingly employed in treating hematologic, lymphoid, and solid tumors. Patients are monitored principally by molecular analysis of donor engraftment., Objective: To determine the role of morphologic examination of bone marrow after NMSCT., Design: Seventy-three patients undergoing NMSCT under the Campath 1H (humanized anti-CD52 antibody) protocol were studied. Pretransplant and sequential posttransplant bone marrow specimens were evaluated and the findings were correlated with corresponding engraftment data., Results: Pretransplant bone marrow specimens from 43% of the patients were involved by disease, and these marrow specimens were significantly more cellular than those that were free of disease. Morphologically detectable disease was still present in day 14 posttransplant marrow specimens in more than one half of these patients, but there was no difference in engraftment in those with or without marrow disease. Early posttransplant marrow in nearly one half of the patients showed myeloid hyperplasia and atypical localization of immature myeloid precursors. Marrow cellularity for the first 2 months after NMSCT was significantly lower in those patients receiving stem cells mismatched at 1 to 3 loci as compared with those who received fully matched grafts (mean cellularity, 38.1% vs 54.1% at day 14). Marrow failure without recurrent disease at 3 to 6 months after transplant was detected by engraftment study in only approximately 15% of cases. Similarly, early recurrence of disease was detected first by morphologic examination in 4 of 13 cases before a decline in donor engraftment occurred., Conclusion: Morphologic examination of bone marrow provides additional information that is complementary to donor engraftment analysis for optimal management after NMSCT.
- Published
- 2006
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10. Dendritic cell recovery following nonmyeloablative allogeneic stem cell transplants.
- Author
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Morse MA, Rizzieri D, Stenzel TT, Hobeika AC, Vredenburgh JJ, Chao NJ, Clay TM, Mosca PJ, and Lyerly HK
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- Alemtuzumab, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized, Antibodies, Neoplasm therapeutic use, Antigens, CD analysis, Antineoplastic Agents therapeutic use, Flow Cytometry methods, Fluorescent Antibody Technique, Hematologic Diseases immunology, Hematopoietic Stem Cell Mobilization, Hematopoietic Stem Cells cytology, Humans, Myelodysplastic Syndromes immunology, Myelodysplastic Syndromes therapy, Neoplasms drug therapy, Neoplasms immunology, Time Factors, Transplantation Chimera immunology, Vidarabine therapeutic use, Dendritic Cells immunology, Hematologic Diseases therapy, Neoplasms therapy, Stem Cell Transplantation, Transplantation, Homologous immunology, Vidarabine analogs & derivatives
- Abstract
Nonmyeloablative allogeneic stem cell transplantation (NMSCT) may destroy some malignancies through a graft-versus-tumor (GVT) effect, but tumor relapse and viral reactivation remain challenges for which immunizations may be helpful. Dendritic cells (DC), particularly DC1 and ex vivo-cultured DC, induce antigen-specific immune responses following viral infections and anti-tumor immunizations. DC2 may be tolerogenic. We hypothesize that successful immunizations following NMSCT will require adequate numbers of functional DC1 or ex vivo-generated DC. We determined the number, phenotype, and function of blood DC1 and DC2 and ex vivo-generated DC obtained from donor-recipient pairs before and up to 90 days after NMSCT. Although the percentage and number of recipient blood Lin(-) HLA-DR(+) CD11c(+) DC1 following NMSCT (median 0.46%, IQR 0.33-0.52%) was lower than donor DC1 (median 0.94%, IQR 0.40-2.2%) this was not significant. In contrast, the percentage and absolute number of blood Lin(-) HLA-DR(+) CD11c(-) CD123(+) DC2 was significantly decreased following the transplant (median 0.01% IQR 0.01-0.01% at day 60 compared with median 0.14%, IQR 0.10-0.38% for the donor before transplantation, p < 0.05). The yield (median 6.0%, IQR 5.5-8.5%) and allostimulatory function of ex vivo-generated DC did not differ significantly at any time point. The donor chimerism of blood and cultured DC reflected that of the overall white blood cells. Ex vivo-generated, donor DC loaded with cytomegalovirus (CMV) antigens were capable of stimulating a CMV-specific immune response in vitro within peripheral blood mononuclear cells of a patient following NMSCT. We conclude that blood DC numbers may be diminished following NMSCT transplant, but that DC1 recovery exceeds DC2 and functional DC may be generated from peripheral blood progenitors at all time points suggesting a possible use in immunization strategies.
- Published
- 2002
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11. High-dose chemotherapy and hematopoietic support for patients with high-risk primary breast cancer and involvement of 4 to 9 lymph nodes.
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Stuart MJ, Peters WP, Broadwater G, Hussein A, Ross M, Marks LB, Folz RJ, Long GD, Rizzieri D, Chao NJ, and Vredenburgh JJ
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- Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Breast Neoplasms drug therapy, Breast Neoplasms mortality, Breast Neoplasms surgery, Carmustine administration & dosage, Cisplatin administration & dosage, Combined Modality Therapy, Cyclophosphamide administration & dosage, Female, Granulocyte Colony-Stimulating Factor therapeutic use, Humans, Middle Aged, Multivariate Analysis, Patient Selection, Recombinant Proteins, Regression Analysis, Survival Analysis, Transplantation, Autologous, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms pathology, Breast Neoplasms therapy, Lymphatic Metastasis, Stem Cell Transplantation
- Abstract
Despite modern chemotherapy, advanced breast cancer remains a significant cause of cancer morbidity and mortality in women. Patients with disease involvement of multiple lymph nodes represent a subgroup with a high risk of relapse. In particular, 50% of patients with 4 to 9 axillary lymph nodes involved will relapse after standard chemotherapy. In an effort to improve the survival of patients with 4 to 9 involved nodes, we performed a phase II study in which 61 patients with surgically diagnosed stage II or III breast cancer and 4 to 9 positive lymph nodes received 3 cycles of doxorubicin and 5-fluorouracil followed by high-dose chemotherapy consisting of cisplatin, cyclophosphamide, and carmustine and infusion of autologous hematopoietic progenitor cells. All patients received posttransplantation localized radiotherapy unless contraindicated, and all patients with hormone receptor-positive disease received tamoxifen. After a median patient follow-up of 6.7 years (range, 4.6-8.6 years), the 5-year overall survival rate was 79% (95% CI, 69%-90%), with relapse-free survival of 73% (95% CI, 62%-85%). Treatment-related mortality was 3%. Interstitial pneumonitis occurred in 69% of patients but did not contribute to mortality. Our study presents long-term favorable results regarding the use of consolidative HDC with autologous hematopoietic support in previously untreated patients with high-risk primary breast cancer.
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- 2002
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12. Inhibition of Aldehyde Dehydrogenase and Retinoid Signaling Induces the Expansion of Human Hematopoietic Stem Cells
- Author
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Chute, John P., Muramoto, Garrett G., Whitesides, John, Colvin, Michael, Safi, Rachid, Chao, Nelson J., and McDonnell, Donald P.
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- 2006
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13. Risk Factors for CMV Viremia and Treatment-Associated Adverse Events Among Pediatric Hematopoietic Stem Cell Transplant Recipients.
- Author
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Heston, Sarah M, Young, Rebecca R, Tanaka, John S, Jenkins, Kirsten, Vinesett, Richard, Saccoccio, Frances M, Martin, Paul L, Chao, Nelson J, and Kelly, Matthew S
- Subjects
STEM cell transplantation ,HEMATOPOIETIC stem cells ,BK virus ,HEMATOPOIETIC stem cell transplantation ,CORD blood ,VIREMIA - Abstract
Background Cytomegalovirus (CMV) causes substantial morbidity and mortality after hematopoietic stem cell transplantation (HSCT). There are limited data on risk factors for CMV viremia and the safety of antiviral medications used to treat CMV in children. Methods We conducted a single-center retrospective study of children who underwent HSCT between 2000 and 2016. We used log-logistic regression to evaluate associations between clinical characteristics and CMV-free survival at 100 days after HSCT. We compared the incidences of laboratory-defined adverse events (AEs) during treatment with ganciclovir and foscarnet. Results Among 969 children, the median (interquartile range) age was 6.5 (3.1–11.5) years, and 80% underwent allogeneic HSCT. Two hundred forty-four (25%) children developed CMV viremia. Older age (odds ratio [OR], 0.95; 95% CI, 0.92–0.98), male sex (OR, 0.71; 95% CI, 0.51–0.99), non-Black, non-White race (OR, 0.56; 95% CI, 0.36–0.87), umbilical cord blood donor source (OR, 0.28; 95% CI, 0.08–0.97), and CMV seropositivity (R-/D+: OR, 0.17; 95% CI, 0.07–0.41; R+/D-: OR, 0.14; 95% CI, 0.09–0.21; R+/D+: OR, 0.08; 95% CI, 0.04–0.15) were associated with lower odds of 100-day CMV-free survival. Compared with foscarnet, ganciclovir was associated with lower incidences of thrombocytopenia (incidence rate ratio [IRR], 0.38; 95% CI, 0.15–0.97), electrolyte AEs (IRR, 0.42; 95% CI, 0.24–0.75), endocrine AEs (IRR, 0.52; 95% CI, 0.34–0.79), and renal AEs (IRR, 0.36; 95% CI, 0.19–0.65). Conclusions CMV viremia occurred commonly among children after HSCT, and ganciclovir and foscarnet were associated with distinct toxicity profiles among children with CMV infection. These findings should be considered when developing CMV prevention and treatment strategies for children after HSCT. [ABSTRACT FROM AUTHOR]
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- 2022
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14. House calls for stem cell transplant patients during the COVID-19 pandemic
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Nelson J. Chao, Krista Rowe Nichols, and Anthony D. Sung
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medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,medicine.medical_treatment ,Pneumonia, Viral ,Immunology ,MEDLINE ,Hematopoietic stem cell transplantation ,Biochemistry ,Betacoronavirus ,Pandemic ,House call ,Humans ,Medicine ,Letter to Blood ,Pandemics ,SARS-CoV-2 ,business.industry ,COVID-19 ,Cell Biology ,Hematology ,Telemedicine ,House Calls ,Emergency medicine ,Transplant patient ,Stem cell ,Coronavirus Infections ,business ,Stem Cell Transplantation - Published
- 2020
15. Heparan sulfate, an endogenous TLR4 agonist, promotes acute GVHD after allogeneic stem cell transplantation
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Liwen Lin, Todd V. Brennan, Zhiguo Li, Xiaopei Huang, Keith Dredge, Nelson J. Chao, Yiping Yang, and Diana M. Cardona
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Male ,T-Lymphocytes ,medicine.medical_treatment ,Immunology ,Extracellular matrix component ,Graft vs Host Disease ,chemical and pharmacologic phenomena ,Hematopoietic stem cell transplantation ,Biology ,Biochemistry ,Lymphocyte Depletion ,Mice ,chemistry.chemical_compound ,immune system diseases ,medicine ,Animals ,Humans ,Transplantation, Homologous ,Luciferases ,Receptor ,Cell Proliferation ,Mice, Inbred BALB C ,Immunosuppression ,Dendritic Cells ,Cell Biology ,Hematology ,Heparan sulfate ,Dendritic cell ,Middle Aged ,Flow Cytometry ,Mice, Inbred C57BL ,Survival Rate ,Toll-Like Receptor 4 ,Transplantation ,surgical procedures, operative ,chemistry ,Hematologic Neoplasms ,Female ,Heparitin Sulfate ,Stem cell ,Stem Cell Transplantation - Abstract
Graft-versus-host disease (GVHD) remains the most common cause of nonrelapse-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although T-cell depletion and intensive immunosuppression are effective in the control of GVHD, they are often associated with higher rates of infection and tumor recurrence. In this study, we showed that heparan sulfate (HS), an extracellular matrix component, can activate Toll-like receptor 4 on dendritic cells in vitro, leading to the enhancement of dendritic cell maturation and alloreactive T-cell responses. We further demonstrated in vivo that serum HS levels were acutely elevated at the onset of clinical GVHD in mice after allo-HSCT. Treatment with the serine protease inhibitor α1-antitrypsin decreased serum levels of HS, leading to a reduction in alloreactive T-cell responses and GVHD severity. Conversely, an HS mimetic that increased serum HS levels accelerated GVHD. In addition, in patients undergoing allo-HSCT for hematologic malignancies, serum HS levels were elevated and correlated with the severity of GVHD. These results identify a critical role for HS in promoting acute GVHD after allo-HSCT, and they suggest that modulation of HS release may have therapeutic potential for the control of clinical GVHD.
- Published
- 2012
16. Severe Pulmonary Toxicity After Myeloablative Conditioning Using Total Body Irradiation: An Assessment of Risk Factors
- Author
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Lawrence B. Marks, Junzo Chino, Oana Craciunescu, Nelson J. Chao, Chris R. Kelsey, Mitchell E. Horwitz, Rodney J. Folz, David A. Rizzieri, and B. Steffey
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Transplantation Conditioning ,Cyclophosphamide ,Pulmonary toxicity ,Graft vs Host Disease ,Young Adult ,Risk Factors ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Cumulative incidence ,Lung ,Melphalan ,Etoposide ,Retrospective Studies ,Analysis of Variance ,Radiation ,business.industry ,Common Terminology Criteria for Adverse Events ,Pneumonia ,Middle Aged ,Total body irradiation ,Surgery ,Fludarabine ,Transplantation ,Oncology ,Hematologic Neoplasms ,Acute Disease ,Toxicity ,Female ,business ,Vidarabine ,Whole-Body Irradiation ,Stem Cell Transplantation ,medicine.drug - Abstract
To assess factors associated with severe pulmonary toxicity after myeloablative conditioning using total body irradiation (TBI) followed by allogeneic stem cell transplantation.A total of 101 adult patients who underwent TBI-based myeloablative conditioning for hematologic malignancies at Duke University between 1998 and 2008 were reviewed. TBI was combined with high-dose cyclophosphamide, melphalan, fludarabine, or etoposide, depending on the underlying disease. Acute pulmonary toxicity, occurring within 90 days of transplantation, was scored using Common Terminology Criteria for Adverse Events version 3.0. Actuarial overall survival and the cumulative incidence of acute pulmonary toxicity were calculated via the Kaplan-Meier method and compared using a log-rank test. A binary logistic regression analysis was performed to assess factors independently associated with acute severe pulmonary toxicity.The 90-day actuarial risk of developing severe (Grade 3-5) pulmonary toxicity was 33%. Actuarial survival at 90 days was 49% in patients with severe pulmonary toxicity vs. 94% in patients without (p0.001). On multivariate analysis, the number of prior chemotherapy regimens was the only factor independently associated with development of severe pulmonary toxicity (odds ratio, 2.7 per regimen).Severe acute pulmonary toxicity is prevalent after TBI-based myeloablative conditioning regimens, occurring in approximately 33% of patients. The number of prior chemotherapy regimens appears to be an important risk factor.
- Published
- 2011
17. First Global Consensus for Evidence-Based Management of the Hematopoietic Syndrome Resulting From Exposure to Ionizing Radiation
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Jeffrey Nemhauser, Rita Schneider, Leif Stenke, Nelson Valverde, C. Norman Coleman, Alla Shapiro, Ray Powles, Judith L. Bader, Nicholas Dainiak, Douglas B. White, Martin Hauer-Jensen, Zhanat Carr, Patricia K. Lillis-Hearne, Robert Nicolas Gent, Joseph Albanese, Arnold Ganser, Holger J. Schünemann, David M. Weinstock, Nelson J. Chao, E. Buglova, Claude Gorin, Viktor Meineke, Kazuhiko Maekawa, and L. Andrew Huff
- Subjects
medicine.medical_specialty ,Consensus ,medicine.medical_treatment ,MEDLINE ,Psychological intervention ,Hematopoietic stem cell transplantation ,Article ,law.invention ,Randomized controlled trial ,law ,Radiation, Ionizing ,Granulocyte Colony-Stimulating Factor ,medicine ,Humans ,Intensive care medicine ,Evidence-Based Medicine ,business.industry ,Public Health, Environmental and Occupational Health ,Evidence-based management ,Acute Radiation Syndrome ,Evidence-based medicine ,Granulocyte colony-stimulating factor ,Immunology ,Cytokines ,business ,Stem Cell Transplantation - Abstract
Objective:Hematopoietic syndrome (HS) is a clinical diagnosis assigned to people who present with ≥1 new-onset cytopenias in the setting of acute radiation exposure. The World Health Organization convened a panel of experts to evaluate the evidence and develop recommendations for medical countermeasures for the management of HS in a hypothetical scenario involving the hospitalization of 100 to 200 individuals exposed to radiation. The objective of this consultancy was to develop recommendations for treatment of the HS based upon the quality of evidence.Methods:English-language articles were identified in MEDLINE and PubMed. Reference lists of retrieved articles were distributed to panel members before the meeting and updated during the meeting. Published case series and case reports of individuals with HS, published randomized controlled trials of relevant interventions used to treat nonirradiated individuals, reports of studies in irradiated animals, and prior recommendations of subject matter experts were selected. Studies were extracted using the Grading of Recommendations Assessment Development and Evaluation (GRADE) system. In cases in which data were limited or incomplete, a narrative review of the observations was made. No randomized controlled trials of medical countermeasures have been completed for individuals with radiation-associated HS. The use of GRADE analysis of countermeasures for injury to hematopoietic tissue was restricted by the lack of comparator groups in humans. Reliance on data generated in nonirradiated humans and experimental animals was necessary.Results:Based upon GRADE analysis and narrative review, a strong recommendation was made for the administration of granulocyte colony-stimulating factor or granulocyte macrophage colony-stimulating factor and a weak recommendation was made for the use of erythropoiesis-stimulating agents or hematopoietic stem cell transplantation.Conclusions:Assessment of therapeutic interventions for HS in humans exposed to nontherapeutic radiation is difficult because of the limits of the evidence.(Disaster Med Public Health Preparedness. 2011;5:202-212)
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- 2011
18. Endothelial progenitor cell infusion induces hematopoietic stem cell reconstitution in vivo
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Benny J. Chen, Phuong L. Doan, Heather A. Himburg, Lauren Russell, Pamela Daher, John P. Chute, Alice B. Salter, Sarah K. Meadows, Garrett G. Muramoto, and Nelson J. Chao
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Pathology ,medicine.medical_specialty ,Immunology ,Biology ,Biochemistry ,Endothelial progenitor cell ,Mice ,medicine ,Animals ,Progenitor cell ,Mice, Inbred BALB C ,Transplantation ,Stem Cells ,Endothelial Cells ,Hematopoietic stem cell ,Cell Differentiation ,Recovery of Function ,Cell Biology ,Hematology ,Fetal Blood ,Hematopoietic Stem Cells ,Blood Cell Count ,Hematopoiesis ,Mice, Inbred C57BL ,Endothelial stem cell ,Haematopoiesis ,medicine.anatomical_structure ,Hypocellularity ,cardiovascular system ,Bone marrow ,Stem cell ,Whole-Body Irradiation ,Stem Cell Transplantation - Abstract
Hematopoietic stem cells (HSCs) reside in association with bone marrow (BM) sinusoidal vessels in vivo, but the function of BM endothelial cells (ECs) in regulating hematopoiesis is unclear. We hypothesized that hematopoietic regeneration following injury is regulated by BM ECs. BALB/c mice were treated with total body irradiation (TBI) and then infused with C57Bl6-derived endothelial progenitor cells (EPCs) to augment endogenous BM EC activity. TBI caused pronounced disruption of the BM vasculature, BM hypocellularity, ablation of HSCs, and pancytopenia in control mice, whereas irradiated, EPC-treated mice displayed accelerated recovery of BM sinusoidal vessels, BM cellularity, peripheral blood white blood cells (WBCs), neutrophils, and platelets, and a 4.4-fold increase in BM HSCs. Systemic administration of anti–VE-cadherin antibody significantly delayed hematologic recovery in both EPC-treated mice and irradiated, non–EPC-treated mice compared with irradiated controls. These data demonstrate that allogeneic EPC infusions can augment hematopoiesis and suggest a relationship between BM microvascular recovery and hematopoietic reconstitution in vivo.
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- 2009
19. Radiation Emergencies: Evaluation, Management, and Transplantation
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Nelson J. Chao, Jane F. Apperley, Patrick Courmelon, Norbert Claude Gorin, John R. Wingard, and Daniel J. Weisdorf
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Transplantation ,medicine.medical_specialty ,Contingency plan ,Radiation ,Hematology ,business.industry ,medicine.medical_treatment ,Stem cell transplantation ,Contingency planning ,Multiorgan injury ,Hematopoietic stem cell transplantation ,medicine.disease ,Pancytopenia ,Internal medicine ,Preparedness ,medicine ,Preparedness planning ,Intensive care medicine ,business - Abstract
Radiation or marrow toxic emergencies can lead to severe pancytopenia along with other multiorgan injury. Experience in managing severe myelosuppression suggests that hematology, oncology and transplantation physicians should participate in preparedness planning for such events. Evaluation and management of marrow injured patients requires their expertise. Understanding of the biology of radiation injury, clinical dosimetry to estimate exposure and defined elements of supportive care are essential for appropriate emergency and follow-up treatment. Some patients with expected radiation exposure >4Gy may have extended myelosuppression and be candidates for consideration of allogeneic hematopoietic stem cell transplantation (HSCT). Issues related to patient screening, supportive care, and planning for transplantation are best addressed ahead of time to enable readily available information and guidelines for patient management. National and international contingency planning for such urgencies is underway as effective emergency mobilization requires forethought, education, and pre-established protocols for treatment. Radiation and marrow toxic emergencies may seem unlikely, but the best approach to appropriate medical support is preparedness, contingency planning, and planned research to improve guidelines for the future.
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- 2007
20. Inability of memory T cells to induce graft-versus-host disease is a result of an abortive alloresponse
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Jessica Son, John F. Whitesides, Divino Deoliveira, Benny J. Chen, NgocDiep Le, Xiuyu Cui, and Nelson J. Chao
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CD4-Positive T-Lymphocytes ,Male ,Isoantigens ,Immunology ,Graft vs Host Disease ,chemical and pharmacologic phenomena ,In Vitro Techniques ,Biology ,Biochemistry ,Mice ,Interleukin 21 ,Immune system ,Animals, Congenic ,T-Lymphocyte Subsets ,medicine ,Animals ,Cytotoxic T cell ,Mice, Inbred BALB C ,Mice, Inbred C3H ,Transplantation ,ELISPOT ,CD28 ,Cell Biology ,Hematology ,T lymphocyte ,medicine.disease ,Mice, Inbred C57BL ,surgical procedures, operative ,Graft-versus-host disease ,Hemocyanins ,Female ,Lymphocyte Culture Test, Mixed ,Stem cell ,Immunologic Memory ,Stem Cell Transplantation - Abstract
Several groups, including our own, have independently demonstrated that effector memory T cells from non–alloantigen-primed donors do not cause graft-versus-host disease (GVHD). In the current study, we further investigated whether this approach could be extended to all memory T cells, and we studied the underlying mechanisms. Neither total memory T cells nor purified central memory T cells were able to induce GVHD. Memory T cells were at least 3-log less potent than bulk T cells in mediating GVHD. As expected, memory T cells failed to elicit cytotoxicity and proliferated poorly against alloantigens in standard 5-day mixed-lymphocyte cultures. However, the proliferative responses of memory T cells were more comparable with those of bulk and naive T cells when the culture time was shortened. Moreover, the frequencies of IL-2–secreting cells measured by 42-hour enzyme-linked immunosorbent spot (ELISPOT) assay were similar among naive, memory, and bulk T cells. These data indicated that memory T cells are able to respond to alloantigens initially but fail to develop to full potential. The abortive immune response, which was mediated by non–alloantigen-specific memory T cells in response to alloantigens, may explain why memory T cells from unprimed and non–alloantigen-primed donors could not induce GVHD.
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- 2006
21. Morphologic Examination of Sequential Bone Marrow Biopsies after Nonmyeloablative Stem Cell Transplantation Complements Molecular Studies of Donor Engraftment
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Anand S, Lagoo, Jerald Z, Gong, Timothy T, Stenzel, Barbara K, Goodman, Patrick J, Buckley, Nelson J, Chao, Cristina, Gasparetto, Gwynn D, Long, and David A, Rizzieri
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Adult ,Time Factors ,Biopsy ,Graft Survival ,General Medicine ,Middle Aged ,Lymphoproliferative Disorders ,Tissue Donors ,Pathology and Forensic Medicine ,Medical Laboratory Technology ,Bone Marrow ,Hematologic Neoplasms ,Neoplasms ,Preoperative Care ,Humans ,Postoperative Period ,Neoplasm Recurrence, Local ,Stem Cell Transplantation - Abstract
Context.—Nonmyeloablative stem cell transplantation (NMSCT) is a mode of immunotherapy increasingly employed in treating hematologic, lymphoid, and solid tumors. Patients are monitored principally by molecular analysis of donor engraftment. Objective.—To determine the role of morphologic examination of bone marrow after NMSCT. Design.—Seventy-three patients undergoing NMSCT under the Campath 1H (humanized anti-CD52 antibody) protocol were studied. Pretransplant and sequential posttransplant bone marrow specimens were evaluated and the findings were correlated with corresponding engraftment data. Results.—Pretransplant bone marrow specimens from 43% of the patients were involved by disease, and these marrow specimens were significantly more cellular than those that were free of disease. Morphologically detectable disease was still present in day 14 posttransplant marrow specimens in more than one half of these patients, but there was no difference in engraftment in those with or without marrow disease. Early posttransplant marrow in nearly one half of the patients showed myeloid hyperplasia and atypical localization of immature myeloid precursors. Marrow cellularity for the first 2 months after NMSCT was significantly lower in those patients receiving stem cells mismatched at 1 to 3 loci as compared with those who received fully matched grafts (mean cellularity, 38.1% vs 54.1% at day 14). Marrow failure without recurrent disease at 3 to 6 months after transplant was detected by engraftment study in only approximately 15% of cases. Similarly, early recurrence of disease was detected first by morphologic examination in 4 of 13 cases before a decline in donor engraftment occurred. Conclusion.—Morphologic examination of bone marrow provides additional information that is complementary to donor engraftment analysis for optimal management after NMSCT.
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- 2006
22. Depletion of Host Reactive T Cells by Photodynamic Cell Purging and Prevention of Graft Versus Host Disease
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Nelson J. Chao and Timothy F. Goggins
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Cancer Research ,Graft-vs-Leukemia Effect ,T-Lymphocytes ,Cell ,Lymphocyte depletion ,Graft vs Host Disease ,Graft vs Leukemia Effect ,Lymphocyte Depletion ,Transplantation Immunology ,medicine ,Animals ,Humans ,Transplantation, Homologous ,In patient ,Photosensitizing Agents ,Rhodamines ,Host (biology) ,business.industry ,T-cell depletion ,Hematology ,medicine.disease ,surgical procedures, operative ,Graft-versus-host disease ,medicine.anatomical_structure ,Photochemotherapy ,Oncology ,Immunology ,Stem cell ,business ,Stem Cell Transplantation - Abstract
Graft versus Host Disease (GVHD) is the principal cause of morbidity and mortality in patients undergoing allogeneic stem cell transplant. T cell depletion has been recognized as a method of reducing the incidence of GVHD in allogeneic transplants. Until recently, most T cell depletion methods were non-selective in reducing lymphocytes. Rhodamine purging is one method, which selectively reduces alloreactive T cells preventing GVHD. We review here the methods of non-selective and selective T cell depletion, particularly the newer method of photodynamic purging utilizing rhodamine.
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- 2003
23. Dendritic Cell Recovery Following Nonmyeloablative Allogeneic Stem Cell Transplants
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H. Kim Lyerly, Nelson J. Chao, Paul J. Mosca, Michael A. Morse, James J. Vredenburgh, Amy Hobeika, David A. Rizzieri, Timothy T. Stenzel, and Timothy M. Clay
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Time Factors ,Antibodies, Neoplasm ,Immunology ,Fluorescent Antibody Technique ,CD11c ,Antineoplastic Agents ,Biology ,Antibodies, Monoclonal, Humanized ,Immune system ,Antigens, CD ,Neoplasms ,Humans ,Transplantation, Homologous ,Alemtuzumab ,Transplantation Chimera ,Viral reactivation ,Absolute number ,Antibodies, Monoclonal ,Dendritic Cells ,Hematology ,Dendritic cell ,Flow Cytometry ,Hematopoietic Stem Cells ,Hematologic Diseases ,Hematopoietic Stem Cell Mobilization ,Transplantation ,Myelodysplastic Syndromes ,Interleukin-3 receptor ,Stem cell ,Vidarabine ,Stem Cell Transplantation - Abstract
Nonmyeloablative allogeneic stem cell transplantation (NMSCT) may destroy some malignancies through a graft-versus-tumor (GVT) effect, but tumor relapse and viral reactivation remain challenges for which immunizations may be helpful. Dendritic cells (DC), particularly DC1 and ex vivo-cultured DC, induce antigen-specific immune responses following viral infections and anti-tumor immunizations. DC2 may be tolerogenic. We hypothesize that successful immunizations following NMSCT will require adequate numbers of functional DC1 or ex vivo-generated DC. We determined the number, phenotype, and function of blood DC1 and DC2 and ex vivo-generated DC obtained from donor-recipient pairs before and up to 90 days after NMSCT. Although the percentage and number of recipient blood Lin(-) HLA-DR(+) CD11c(+) DC1 following NMSCT (median 0.46%, IQR 0.33-0.52%) was lower than donor DC1 (median 0.94%, IQR 0.40-2.2%) this was not significant. In contrast, the percentage and absolute number of blood Lin(-) HLA-DR(+) CD11c(-) CD123(+) DC2 was significantly decreased following the transplant (median 0.01% IQR 0.01-0.01% at day 60 compared with median 0.14%, IQR 0.10-0.38% for the donor before transplantation, p0.05). The yield (median 6.0%, IQR 5.5-8.5%) and allostimulatory function of ex vivo-generated DC did not differ significantly at any time point. The donor chimerism of blood and cultured DC reflected that of the overall white blood cells. Ex vivo-generated, donor DC loaded with cytomegalovirus (CMV) antigens were capable of stimulating a CMV-specific immune response in vitro within peripheral blood mononuclear cells of a patient following NMSCT. We conclude that blood DC numbers may be diminished following NMSCT transplant, but that DC1 recovery exceeds DC2 and functional DC may be generated from peripheral blood progenitors at all time points suggesting a possible use in immunization strategies.
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- 2002
24. Randomized, placebo-controlled, double-blind study of a cytomegalovirus-specific monoclonal antibody (MSL-109) for prevention of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation
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Ghislaine Gallez-Hawkins, Daniel Levitt, Karl G. Blume, Terri Cunningham, Nelson J. Chao, Ricardo Spielberger, Raleigh A. Bowden, Barry E. Storer, John A. Zaia, Michael Boeckh, and D. Kathryn Tierney
- Subjects
Ganciclovir ,Adult ,Male ,medicine.medical_specialty ,Platelet Engraftment ,medicine.medical_treatment ,pp65 antigenemia ,Congenital cytomegalovirus infection ,Cytomegalovirus ,Viremia ,Hematopoietic stem cell transplantation ,Placebo ,Antibodies, Viral ,Gastroenterology ,Antiviral Agents ,Serology ,Placebos ,MSL-109 ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Prospective Studies ,Transplantation ,Dose-Response Relationship, Drug ,business.industry ,Stem cell transplantation ,Hematopoietic Stem Cell Transplantation ,virus diseases ,Antibodies, Monoclonal ,Hematology ,medicine.disease ,Survival Rate ,surgical procedures, operative ,Treatment Outcome ,Immunology ,Cytomegalovirus Infections ,Female ,business ,medicine.drug - Abstract
MSL-109 is a monoclonal antibody specific to the cytomegalovirus (CMV) glycoprotein H with high neutralizing capacity. In a prospective, randomized, double-blind study, allogeneic hematopoietic stem cell transplantation (HSCT) recipients with positive donor and/or recipient serology for CMV before transplantation received either 60 mg/kg MSL-109 (n = 59), 15 mg/kg MSL-109 (n = 60), or placebo (n = 60) intravenously every 2 weeks from day -1 until day 84 after transplantation. CMV pp65 antigenemia, CMV-DNA load in plasma, and viremia by culture were tested weekly. Primary end points were development of pp65 antigenemia at any level and/or viremia for which ganciclovir was given. There was no statistically significant difference in CMV pp65 antigenemia or viremia among patients in the 60-mg group (pp65 antigenemia, 47%; viremia, 15%), the 15-mg group (52%; 23%), and the placebo group (45%; 17%). There was also no difference in maximum levels of pp65 antigenemia, time to clearance of pp65 antigenemia after start of ganciclovir, CMV disease, invasive bacterial and fungal infections, time to neutrophil and platelet engraftment, acute graft-versus-host disease, days of hospitalization, and overall survival rate among the 3 groups. However, a subgroup analysis of CMV-seronegative recipients with a seropositive donor (D+/R-) showed a transiently improved survival rate by day 100 in MSL-109 recipients (mortality: 60-mg group, 1/13; 15-mg group, 1/12; placebo group, 6/10 [P = .02 for 60-mg versus placebo groups; P = .08 for 15-mg versus placebo groups]); by the end of follow-up, the difference was no longer statistically significant. The improved survival rate in D+/R- patients could not be attributed to a reduction in CMV disease; however, MSL-109 was associated with improved platelet engraftment and less grade III to IV acute graft-versus-host disease in this subgroup. In a subgroup analysis of CMV-seropositive recipients of MSL-109 (D+/R+ and D-/R+), overall mortality was increased compared to that of the placebo group (P = .12 for the 60-mg versus placebo groups, P = .05 for the 15-mg versus placebo groups, and P = .04 for the dose levels combined versus placebo). MSL-109 was well tolerated and no immune response to the drug was observed. Thus, MSL-109 was safe but did not reduce CMV infection in allogeneic HSCT recipients. The transient survival advantage seen early after transplantation in CMV D+/R- patients and the negative effect on survival in seropositive patients remain unexplained. Thus, there is no evidence that MSL-109 is beneficial in CMV-seropositive HSCT recipients.
- Published
- 2001
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25. NATURAL KILLER CELL ENRICHED DONOR LYMPHOCYTE INFUSIONS FROM A 3-6/6 HLA MATCHED FAMILY MEMBER FOLLOWING NON-MYELOABLATIVE ALLOGENEIC STEM CELL TRANSPLANTATION
- Author
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Vic Hasselblad, Dong-Feng Chen, John P. Chute, Gwynn D. Long, Patrick G. Green, Yiping Yang, Nelson J. Chao, Megan Baker, Keith M. Sullivan, Ashley Morris, Debashish Misra, Daniel A. Nikcevich, Mitchell E. Horwitz, Therese Hennig, Christine Apple, Cristina Gasparetto, Robert W. Storms, and David A. Rizzieri
- Subjects
Adult ,medicine.medical_specialty ,Lymphocyte Transfusion ,Transplantation Conditioning ,medicine.medical_treatment ,Lymphocyte ,T cell ,NK cells ,Hematopoietic stem cell transplantation ,Human leukocyte antigen ,Gastroenterology ,Article ,Natural killer cell ,HLA Antigens ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Lymphocytes ,Transplantation ,business.industry ,T cell-depleted transplantation ,Hematopoietic Stem Cell Transplantation ,Hematology ,Tissue Donors ,Killer Cells, Natural ,medicine.anatomical_structure ,Immunology ,Toxicity ,business ,Stem Cell Transplantation - Abstract
Infusing natural killer (NK) cells following transplantation may allow less infections and relapse with little risk of acute graft-versus-host disease (aGVHD). We delivered 51 total NK cell-enriched donor lymphocyte infusions (DLIs) to 30 patients following a 3-6/6 HLA matched T cell-depleted nonmyeloablative allogeneic transplant. The primary endpoint of this study was feasibility and safety. Eight weeks following transplantation, donor NK cell-enriched DLIs were processed using a CD56 + selecting column with up to 3 fresh infusions allowed. Toxicity, relapse, and survival were monitored. T cell phenotype, NK cell functional recovery, and KIR typing were assessed for association with outcomes. Fourteen matched and 16 mismatched transplanted patients received a total of 51 NK cell-enriched DLIs. Selection resulted in 96% (standard deviation [SD] 8%) purity and 83% (SD 21%) yield in the matched setting and 97% (SD 3%) purity and 77% (SD 24%) yield in the mismatched setting. The median number of CD3 − CD56 + NK cells infused was 10.6 (SD 7.91) × 10 6 cells/kg and 9.21 (SD 5.6) × 10 6 cells/kg, respectively. The median number of contaminating CD3 + CD56 − T cells infused was .53 (1.1) × 10 6 and .27 (.78) × 10 6 in the matched and mismatched setting, respectively. Only 1 patient each in the matched (n = 14) or mismatched (n = 16) setting experienced severe aGVHD with little other toxicity attributable to the infusions. Long-term responders with multiple NK cell-enriched infusions and improved T cell phenotypic recovery had improved duration of responses ( p = .0045) and overall survival (OS) ( P = .0058). A 1-step, high-yield process is feasible, and results in high doses of NK cells infused with little toxicity. NK cell-enriched DLIs result in improved immune recovery and outcomes for some. Future studies must assess whether the improved outcomes are the direct result of the high doses and improved NK cell function or other aspects of immune recovery.
- Published
- 2010
26. Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity
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Sarah K. Meadows, J. Lauren Russell, Heather A. Himburg, Alice B. Salter, Pamela Daher, Donald P. McDonnell, Phuong L. Doan, Rachid Safi, Garrett G. Muramoto, John P. Chute, Nelson J. Chao, and Robert W. Storms
- Subjects
Cellular differentiation ,Aldehyde dehydrogenase ,Antineoplastic Agents ,Tretinoin ,Biology ,Aldehyde Dehydrogenase 1 Family ,Article ,Mice ,Mice, Congenic ,Radiation, Ionizing ,Animals ,Humans ,Progenitor cell ,Enzyme Inhibitors ,RNA, Small Interfering ,Cells, Cultured ,Cell Proliferation ,Retinal Dehydrogenase ,hemic and immune systems ,Cell Differentiation ,Cell Biology ,Aldehyde Dehydrogenase ,Hematopoietic Stem Cells ,Cell biology ,Transplantation ,ALDH1A1 ,Mice, Inbred C57BL ,Haematopoiesis ,Biochemistry ,P-Aminoazobenzene ,Cytoprotection ,p-Aminoazobenzene ,biology.protein ,Molecular Medicine ,Stem cell ,Cell Division ,Developmental Biology ,Signal Transduction ,Stem Cell Transplantation - Abstract
Hematopoietic stem cells (HSCs) are enriched for aldehyde dehydrogenase (ALDH) activity and ALDH is a selectable marker for human HSCs. However, the function of ALDH in HSC biology is not well understood. We sought to determine the function of ALDH in regulating HSC fate. Pharmacologic inhibition of ALDH with diethylaminobenzaldehyde (DEAB) impeded the differentiation of murine CD34−c-kit+Sca-1+lineage− (34−KSL) HSCs in culture and facilitated a ninefold expansion of cells capable of radioprotecting lethally irradiated mice compared to input 34−KSL cells. Treatment of bone marrow (BM) 34−KSL cells with DEAB caused a fourfold increase in 4-week competitive repopulating units, verifying the amplification of short-term HSCs (ST-HSCs) in response to ALDH inhibition. Targeted siRNA of ALDH1a1 in BM HSCs caused a comparable expansion of radioprotective progenitor cells in culture compared to DEAB treatment, confirming that ALDH1a1 was the target of DEAB inhibition. The addition of all trans retinoic acid blocked DEAB-mediated expansion of ST-HSCs in culture, suggesting that ALDH1a1 regulates HSC differentiation via augmentation of retinoid signaling. Pharmacologic inhibition of ALDH has therapeutic potential as a means to amplify ST-HSCs for transplantation purposes.
- Published
- 2010
27. Detailed analysis of cytomegalovirus (CMV)-specific T cells expanded for adoptive immunotherapy of CMV infection following allogeneic stem cell transplantation for malignant disease
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Amy Hobeika, Herbert Kim Lyerly, Kimberly E. Hanson, Donna Niedzwiecki, Delila Serra, Nelson J. Chao, Timothy M. Clay, Michael A. Morse, Sharon Peplinski, Y. Tanaka, David A. Rizzieri, and Takuya Osada
- Subjects
Cancer Research ,medicine.medical_treatment ,T cell ,Receptors, Antigen, T-Cell, alpha-beta ,T-Lymphocytes ,Immunology ,Cytomegalovirus ,Hematopoietic stem cell transplantation ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Immunotherapy, Adoptive ,Epitopes ,Antigen ,Neoplasms ,medicine ,Immunology and Allergy ,Humans ,Transplantation, Homologous ,Genetics (clinical) ,Cells, Cultured ,Cell Proliferation ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,virus diseases ,Cell Biology ,Immunotherapy ,medicine.disease ,Virology ,Clone Cells ,Kinetics ,surgical procedures, operative ,Graft-versus-host disease ,medicine.anatomical_structure ,Phenotype ,Oncology ,Cytomegalovirus Infections ,Cytokines ,Stem cell ,business ,Peptides ,CD8 ,Stem Cell Transplantation - Abstract
Cytomegalovirus (CMV) infection and its treatment causes significant morbidity following allogeneic stem cell transplantation (SCT) for malignancies. We studied the phenotype, function and growth kinetics of CMV pp65 antigen (Ag)-specific T cells expanded in a short-term culture for adoptive therapy.Peripheral blood mononuclear cells (PBMC) from CMV-seropositive donors were cultured in various conditions with CMV pp65((495-503)) peptide to determine the most effective method for generating CMV-specific T cells. CMV-expanded cultures were tested for frequency, phenotype and functionality using peptide-MHC tetramer analysis, cytokine flow cytometry and cytolytic assays. A patient undergoing allogeneic SCT was administered CMV pp65-specific T cells generated from the donor based on these data, and recipient PBMC were analyzed following T-cell infusion.CMV pp65-specific T cells were consistently generated from CMV-seropositive donors at high frequencies (20-40% of CD8+ T cells), secreted interferon-gamma (IFN-gamma) in response to CMV peptide and had lytic activity against CMV peptide-expressing targets. Cultured CMV-specific T cells were infused into a SCT recipient without toxicity.Stimulating donor PBMC to generate functional, Ag-specific T cells for infusion into SCT recipients was accomplished consistently using readily available technology. We observed no toxicity in one patient receiving T cells and were able to monitor infused cells. These findings support further study of this approach as a prophylaxis against the risk of infection in patients receiving allogeneic transplantation from CMV-seropositive donors.
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- 2008
28. Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study
- Author
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Stephen Villano, Jared Klein, Genovefa A. Papanicolaou, Jo Anne H. Young, George Alangaden, Michael Boeckh, Finn Bo Petersen, E.A. Vance, Kellie Sprague, Nelson J. Chao, Drew J. Winston, Vinod Pullarkat, Roy R. Chemaly, and Ravi Vij
- Subjects
Ganciclovir ,Adult ,Male ,medicine.medical_specialty ,Nausea ,Vomiting ,Immunology ,Placebo ,Biochemistry ,Gastroenterology ,Antiviral Agents ,Taste Disorders ,Double-Blind Method ,Internal medicine ,Medicine ,Humans ,Transplantation, Homologous ,Adverse effect ,Dose-Response Relationship, Drug ,business.industry ,virus diseases ,Maribavir ,Cell Biology ,Hematology ,Middle Aged ,Dose-ranging study ,Surgery ,Transplantation ,Chemoprophylaxis ,Cytomegalovirus Infections ,Benzimidazoles ,Female ,Ribonucleosides ,medicine.symptom ,business ,medicine.drug ,Stem Cell Transplantation - Abstract
The anti-cytomegalovirus (CMV) activity and safety of oral maribavir in CMV-seropositive allogeneic stem-cell transplant recipients were evaluated in a randomized, double-blind, placebo-controlled, dose-ranging study. After engraftment, 111 patients were randomized to receive CMV prophylaxis with maribavir (100 mg twice daily, 400 mg once daily, or 400 mg twice daily) or placebo. Within the first 100 days after transplantation, the incidence of CMV infection based on CMV pp65 antigenemia was lower in each of the respective maribavir groups (15%, P = .046; 19%, P = .116; 15%, P = .053) compared with placebo (39%). Similarly, the incidence of CMV infection based on plasma CMV DNA was lower in each of the respective maribavir groups (7%, P = .001; 11%, P = .007; 19%, P = .038) compared with placebo (46%). Anti-CMV therapy was also used less often in patients receiving each respective dose of maribavir (15%, P = .001; 30%, P = .051; 15%, P = .002) compared with placebo (57%). There were 3 cases of CMV disease in placebo patients but none in the maribavir patients. Adverse events, mostly taste disturbance, nausea, and vomiting, were more frequent with maribavir. Maribavir had no adverse effect on neutrophil or platelet counts. These results show that maribavir can reduce the incidence of CMV infection and, unlike ganciclovir, does not cause myelosuppression. This trial is registered at [www.ClinicalTrials.gov][1] as #[NCT00223925][2]. [1]: http://www.ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00223925&atom=%2Fbloodjournal%2F111%2F11%2F5403.atom
- Published
- 2008
29. Selective elimination of alloreactivity from immunotherapeutic T cells by photodynamic cell purging and memory T-cell sorting
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Benny J. Chen, NgocDiep Le, and Nelson J. Chao
- Subjects
Cancer Research ,T-Lymphocytes ,Immunology ,Cell ,Graft vs Host Disease ,Graft vs Leukemia Effect ,Cell Separation ,Biology ,Lymphocyte Depletion ,Immune system ,Homologous chromosome ,medicine ,Immunology and Allergy ,Humans ,Transplantation, Homologous ,Genetics (clinical) ,Transplantation ,Graft vs Tumor Effect ,Cell Biology ,Recovery of Function ,surgical procedures, operative ,medicine.anatomical_structure ,Oncology ,Photochemotherapy ,Stem cell ,Memory T cell ,DISEASE RELAPSE ,Immunologic Memory ,Stem Cell Transplantation - Abstract
Allogeneic stem cell transplantation (alloSCT), especially in the mismatched setting, carries a high risk of life-threatening GvHD because of activation of donor T cells by Ag present on host cells. Removal of mature donor T cells can prevent GvHD but leads to delayed immune reconstitution, and an increased incidence of opportunistic infections and disease relapse. These findings demonstrate the vital role of donor T cells in providing graft-versus-tumor (GvT) and anti-pathogen effects as well as facilitating immune reconstitution. It has been well documented that GvHD can be separated from GvT effects, making it possible potentially to eliminate GvHD while preserving the immunotherapeutic benefits of donor T cells. Over the past decade, major attempts have been made to reduce GvHD incidence without loss of GvT effect, especially in the haplo-identical setting. Novel techniques to deplete host-reactive donor T cells selectively have been explored. This review focuses on the use of the photodynamic cell purging (PDP) process and of sorting memory T cells for the selective elimination of alloreactivity. Minimizing the threat of GvHD while maximizing the beneficial GvT effect would broaden the scope and effectiveness of alloSCT.
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- 2005
30. Pharmacokinetic and Maximum Tolerated Dose Study of Micafungin in Combination with Fluconazole versus Fluconazole Alone for Prophylaxis of Fungal Infections in Adult Patients Undergoing a Bone Marrow or Peripheral Stem Cell Transplant
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John W. Hiemenz, D. Facklam, Donald N. Buell, James Keirns, W. Lau, D. Simpson, S. Devine, Nelson J. Chao, and Pablo J. Cagnoni
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Adult ,Male ,medicine.medical_specialty ,Antifungal Agents ,Adolescent ,Lipoproteins ,Pharmacology ,Gastroenterology ,Chemoprevention ,Peptides, Cyclic ,Echinocandins ,Lipopeptides ,Pharmacokinetics ,Double-Blind Method ,Internal medicine ,Neoplasms ,Maculopapular rash ,medicine ,Humans ,Pharmacology (medical) ,Fluconazole ,Mycosis ,Bone Marrow Transplantation ,business.industry ,Micafungin ,Area under the curve ,Middle Aged ,medicine.disease ,bacterial infections and mycoses ,Rash ,Infectious Diseases ,Mycoses ,Area Under Curve ,Chemoprophylaxis ,lipids (amino acids, peptides, and proteins) ,Drug Therapy, Combination ,Female ,medicine.symptom ,business ,medicine.drug ,Stem Cell Transplantation - Abstract
In this dose escalation study, 74 adult cancer patients undergoing bone marrow or peripheral blood stem cell transplantation received fluconazole (400 mg/day) and either normal saline (control) (12 subjects) or micafungin (12.5 to 200 mg/day) (62 subjects) for up to 4 weeks. The maximum tolerated dose (MTD) of micafungin was not reached, based on the development of Southwest Oncology Group criteria for grade 3 toxicity; drug-related toxicities were rare. Commonly occurring adverse events considered related to micafungin were headache (6.8%), arthralgia (6.8%), hypophosphatemia (4.1%), insomnia (4.1%), maculopapular rash (4.1%), and rash (4.1%). Pharmacokinetic profiles for micafungin on days 1 and 7 were similar. The mean half-life was approximately 13 h, with little variance after repeated or increasing doses. Mean maximum concentrations of the drug in serum and areas under the concentration-time curve from 0 to 24 h were approximately proportional to dose. There was no clinical or kinetic evidence of interaction between micafungin and fluconazole. Five of 12 patients (42%) in the control group and 14 of 62 (23%) in the micafungin-plus-fluconazole groups had a suspected fungal infection during treatment which resulted in empirical treatment with amphotericin B. The combination of micafungin and fluconazole was found to be safe in this high-risk patient population. The MTD of micafungin was not reached even at doses up to 200 mg/day for 4 weeks. The pharmacokinetic profile of micafungin in adult cancer patients with blood or marrow transplants is consistent with the profile in healthy volunteers, and the area under the curve is proportional to dose.
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- 2005
31. A phase III, randomized, double-blind, placebo-controlled, study of iseganan for the reduction of stomatitis in patients receiving stomatotoxic chemotherapy
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Henry J. Fuchs, Mark M. Brunvand, Patricia Devitt-Risse, Thomas C. Shea, Roberto Rodriguez, Stuart L. Goldberg, William P. Vaughan, Paul J. Martin, Thomas R. Fleming, Mark M. Schubert, Richard T. Maziarz, Daniel J. Weisdorf, John R. Wingard, Finn Bo Petersen, Elias Anaissie, Nelson J. Chao, David D. Hurd, Janis G. Pulliam, Brian J. Bolwell, Margarida Silverman, Roy A. Beveridge, Hillard M. Lazarus, Rebecca Redman, and Francis J. Giles
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Placebo-controlled study ,Antineoplastic Agents ,Placebo ,law.invention ,Cohort Studies ,Placebos ,Randomized controlled trial ,Double-Blind Method ,law ,Internal medicine ,Neoplasms ,Surveys and Questionnaires ,medicine ,Mucositis ,Humans ,Transplantation, Homologous ,Adverse effect ,Stomatitis ,Bone Marrow Transplantation ,business.industry ,Mouth Mucosa ,Proteins ,Hematology ,Middle Aged ,medicine.disease ,Surgery ,Clinical trial ,Transplantation ,Treatment Outcome ,Oncology ,Female ,business ,Peptides ,Antimicrobial Cationic Peptides ,Stem Cell Transplantation - Abstract
The invasion and colonization of oral cavity mucosal tissues by microflora may contribute to the pathophysiology of ulcerative oral mucositis (UOM). Iseganan is an analog of protegrin-1, a naturally occurring peptide with broad-spectrum microbicidal activity. A randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of iseganan in preventing UOM after stomatotoxic therapy. Patients received an oral rinse, consisting of iseganan 9mg or placebo, to be swished/swallowed six times daily, starting with stomatotoxic therapy and continuing up to 21 days. Patients were assessed for stomatitis and UOM, and administered a questionnaire evaluating mouth pain and difficulty swallowing thrice weekly. The primary study efficacy endpoint was the proportion of patients who did not have peak stomatitis NCI-CTC grade >or=2. Between November 2001 and June 2002, 502 patients were randomized to receive iseganan (251) or placebo (251). Equivalent numbers of patients in both cohorts received bone marrow or peripheral blood allogeneic or autologous stem cell transplantation (SCT). Forty-three percent and 37% of iseganan and placebo patients, respectively, did not have peak stomatitis grade =2 (P = 0.182). There was no significant difference between the cohorts in stomatitis severity, incidence of UOM, peak mouth pain, peak difficulty swallowing, amount of opiate analgesics used, or adverse event type or incidence. A major impact of Iseganan on reducing stomatitis, UOM, or its clinical sequelae in patients receiving stomatotoxic therapy was not detected on this study.
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- 2003
32. Universal Mask Usage for Reduction of Respiratory Viral Infections After Stem Cell Transplant: A Prospective Trial.
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Sung, Anthony D., Sung, Julia A. M., Thomas, Samantha, Hyslop, Terry, Gasparetto, Cristina, Long, Gwynn, Rizzieri, David, Sullivan, Keith M., Corbet, Kelly, Broadwater, Gloria, Chao, Nelson J., and Horwitz, Mitchell E.
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RESPIRATORY infections ,VIRUS diseases ,STEM cell transplantation ,NOSOCOMIAL infections ,PARAINFLUENZA viruses ,INFECTION prevention ,PREVENTION - Abstract
Background. Respiratory viral infections (RVIs) are frequent complications of hematopoietic stem cell transplant (HSCT). Surgical masks are a simple and inexpensive intervention that may reduce nosocomial spread. Methods. In this prospective single-center study, we instituted a universal surgical mask policy requiring all individuals with direct contact with HSCT patients to wear a surgical mask, regardless of symptoms or season. The primary endpoint was the incidence of RVIs in the mask period (2010-2014) compared with the premask period (2003-2009). Results. RVIs decreased from 10.3% (95/920 patients) in the premask period to 4.4% (40/911) in the mask period (P < .001). Significant decreases occurred after both allogeneic (64/378 [16.9%] to 24/289 [8.3%], P = .001) and autologous (31/542 [5.7%] to 16/622 [2.6%], P = .007) transplants. After adjusting for multiple covariates including season and year in a segmented longitudinal analysis, the decrease in RVIs remained significant, with risk of RVI of 0.4 in patients in the mask group compared with the premask group (0.19-0.85, P = .02). In contrast, no decrease was observed during this same period in an adjacent hematologic malignancy unit, which followed the same infection control practices except for the mask policy. The majority of this decrease was in parainfluenza virus 3 (PIV3) (8.3% to 2.2%, P < .001). Conclusions. Requiring all individuals with direct patient contact to wear a surgical mask is associated with a reduction in RVIs, particularly PIV3, during the most vulnerable period following HSCT. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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33. Feasibility of Low-Dose Interleukin-2 Therapy Following T-Cell-Depleted Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation From HLA-Matched or -Mismatched Family Member Donors.
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Rizzieri, David A., Crout, Christopher, Storms, Robert, Golob, Jared, Long, Gwynn D., Gasparetto, Cristina, Sullivan, Keith M., Horwitz, Mitchell, Chute, John, Lagoo, Anand S., Morris, Ashley, Beaven, Anne, Yang, Yiping, Peterson, Bercedis, Li, Zhiguo, and Chao, Nelson J.
- Subjects
CANCER chemotherapy ,LEUKEMIA ,INTERLEUKIN-2 ,T cells ,HLA histocompatibility antigens ,CANCER relapse ,FOLLOW-up studies (Medicine) ,HEMATOPOIETIC stem cells ,STEM cell transplantation - Abstract
Introduction: High relapse rates and infections remain primary causes of failure in nonmyeloablative transplantation. Interleukin-2 (IL-2) may stimulate the immune system and improve outcomes. The primary objective of this pilot study was to evaluate the feasibility of administering IL-2 following a T-cell-depleted nonmyeloablative hematopoietic stem cell transplant. Methods: Patients received T-cell-depleted nonmyeloablative transplant from a matched or mismatched related donor. Those with allogeneic engraftment < grade 2 acute GVHD at time of study entry, and no severe end organ damage were eligible and received IL-2 starting 6 weeks after the first day of stem cell infusion. Patients received 1 mu/m2 daily for 5 days each week for 4 weeks followed by a 2-week rest period for a 6-week cycle to continue for up to 1 year. Results: Eight patients aged 28–69 years were treated. Significant toxicities were limited to GVHD of the skin ≤grade 2 in 3 patients and severe fatigue in 4 patients, limiting the duration of therapy. Two of the 8 patients died of relapsed disease and 1 from CMV. With a median overall duration of follow-up of survivors of 48 months, 5 patients (63%) remain alive and in continuous complete remission. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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34. Stem Cells, Multiorgan Failure in Radiation Emergency Medical Preparedness: A U.S./European Consultation Workshop.
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Fliedner, Theodor M., Chao, Nelson J., Bader, Judith L., Boettger, Axel, Case Jr., Cullen, Chute, John, Confer, Dennis L., Ganser, Arnold, Gorin, Norbert-Claude, Gourmelon, Patrick, Graessle, Dieter H., Krawisz, Robert, Meineke, Viktor, Niederwieser, Dietger, Port, Matthias, Powles, Ray, Sirohi, Bhawna, Weinstock, David M., Wiley, Albert, and Coleman, C. Norman
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EMERGENCY management ,RADIATION injuries ,HEMATOPOIETIC stem cells ,ADULT education workshops - Abstract
The concern of the public regarding terrorist actions involving nuclear emergencies resulted in the reopening of the discussion regarding the best ways to cope with the inevitable health impairments. Medical experts from the US and from Europe considered it of importance to harmonize at an international level the diagnostic and therapeutic approaches regarding the radiation-induced health impairments. The present contribution is the result of the first U.S./European Consultation Workshop addressing approaches to radiation emergency preparedness and assistance, which was held recently at Ulm University, Ulm, Germany. Discussions dealt with the assessment of the extent of damage after total body exposure and, in particular, the quantity and quality of the damage to the hematopoietic stem cell pool. Secondly, the pathogenesis of the multiorgan failure was considered because of the organ-to-organ interactions. Thirdly, approaches were considered to harmonize the ''triage-methods'' used on an international level using the ''Response Category'' approach as developed for the European Communities. These discussions lead to the conclusion that there is a strong need for continuing education of physicians, nurses, and support personnel to address the issues posed by the management of patients suffering from radiation syndromes. Finally, the discussions expressed the need for more international cooperation in research and development of more refined methods to treat patients with any type of radiation syndromes. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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35. Minors come of age: minor histocompatibility antigens and graft-versus-host disease
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Chao, Nelson J.
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- *
HISTOCOMPATIBILITY antigens , *IMMUNOGLOBULINS , *STEM cell transplantation , *GRAFT versus host disease - Abstract
Minor histocompatibility antigens (miHA) are responsible for the occurrence of graft-versus-host disease in the setting of a major histocompatibility complex matched sibling allogeneic stem cell transplantation. These miHA are peptide fragments that are associated with major histocompatibility complex class I or class II antigens. Elegant experiments have led to the molecular characterization of these antigens. Efforts to prevent graft-versus-host disease could be targeted through this pathway by matching for these miHA or by preventing antigen recognition. Alternatively, these miHA could be exploited as targets for a more potent graft-versus-malignancy effect. This area of miHA promises to continue to be an exciting area of continued research. [Copyright &y& Elsevier]
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- 2004
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36. Microchimerism: An Investigative Frontier in Autoimmunity and Transplantation.
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Adams, Kristina M. and Nelson, J. Lee
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MOSAICISM , *GENETICS , *MATERNAL-fetal exchange , *MOTHER-child relationship , *CELL transplantation , *AUTOIMMUNITY , *MEDICAL research , *PSYCHOLOGY - Abstract
Recent studies indicate cells transfer between fetus and mother during pregnancy and can persist in both decades later. The presence within one individual of a small population of cells from another genetically distinct individual is referred to as microchimerism. Naturally acquired microchimerism has recently been investigated in autoimmune diseases, including scleroderma, thyroiditis, primary biliary cirrhosis, Sjögren syndrome, systemic lupus, dermatomyositis, and neonatal lupus. Iatrogenic chimerism has been investigated in transplantation and following blood transfusion. Considering findings of naturally acquired microchimerism along with iatrogenic microchimerism suggests microchimerism can have detrimental and/or beneficial effects in both settings. Recent identification of tissue-specific microchimerism either from naturally acquired or iatrogenic microchimerism (eg, cardiac myocytes) raises the possibility that microchimerism can be a target of autoimmunity or alternatively contribute to tissue repair. Advances in this new frontier of research with varied and numerous implications for human health are summarized. [ABSTRACT FROM AUTHOR]
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- 2004
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37. Autoimmune disease and the long-term persistence of fetal and maternal microchimerism.
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Lee Nelson, J
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- *
FETAL cells from maternal blood , *STEM cell transplantation , *AUTOIMMUNE diseases - Abstract
Editorial. Discusses the persistence of fetal cells in maternal peripheral blood several years after childbirth. Percentage of cord blood samples where maternal cells are found; Occurrence of chimerism in patients who undergo stem cell transplantation; Hypothesis on the involvement of microchimerism in the pathogenesis of some autoimmune diseases.
- Published
- 1999
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38. Acute Radiation Injury: Contingency Planning for Triage, Supportive Care, and Transplantation
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Daniel J. Weisdorf, James Olen Armitage, Nelson J. Chao, Jamie K. Waselenko, Nicholas Dainiak, Ian McNiece, and Dennis L. Confer
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Radioactive Fallout ,medicine.medical_specialty ,Contingency planning ,Models, Biological ,medicine ,Humans ,Radiation injury ,Growth Substances ,Radiation Injuries ,Intensive care medicine ,Nuclear Warfare ,Contingency plan ,Myelosuppressive Chemotherapy ,Transplantation ,business.industry ,Myelodysplastic syndromes ,Anemia, Aplastic ,Environmental Exposure ,Hematology ,Environmental exposure ,medicine.disease ,Bioterrorism ,Pancytopenia ,Triage ,Blood Cell Count ,Myelodysplastic Syndromes ,Radiation sickness ,Emergencies ,business ,Stem Cell Transplantation - Abstract
Evaluation and management of victims of exposure to myelosuppressive radiation in a military, terrorist, or accidental event is challenging. The hematopoietic syndrome with marrow suppression and pancytopenia follows intermediate intensity radiation exposure and as such produces a clinical syndrome similar to that after myelosuppressive chemotherapy or stem cell transplantation. Therefore, hematologists, oncologists, and transplantation physicians have the opportunity and challenge to plan for care of irradiation victims. Management of the hematopoietic syndrome, as a component of acute radiation sickness, requires understanding its manifestations and implementation of clinical biodosimetry to provide appropriate therapeutic support. Hematopoietic growth factors may be of value if administered early as a component of supportive care. Planning for urgent stem cell transplantation for those with intermediate- to high-dose radiation (4-10 Gy) may be required. Establishing contingency plans for triage, assessment, supportive care, and treatment resembles the development of phase II trials, with defined eligibilities, treatment plans, and incorporated data collection to assess results and plan further improvements in care. The hematology/oncology community is most suited to participate in such contingency planning, and the necessary elements for its success are reviewed.
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39. High-dose chemotherapy and hematopoietic support for patients with high-risk primary breast cancer and involvement of 4 to 9 lymph nodes
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A. Hussein, Monic J. Stuart, Nelson J. Chao, James J. Vredenburgh, Lawrence B Marks, Gwynn D. Long, Maureen Ross, Rodney J Folz, Gloria Broadwater, William P. Peters, and David A. Rizzieri
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Oncology ,Adult ,medicine.medical_specialty ,Cyclophosphamide ,Axillary lymph nodes ,medicine.medical_treatment ,Breast Neoplasms ,Transplantation, Autologous ,Breast cancer ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Granulocyte Colony-Stimulating Factor ,medicine ,Humans ,Chemotherapy ,Transplantation ,business.industry ,Patient Selection ,Cancer ,Hematology ,Middle Aged ,medicine.disease ,Carmustine ,Combined Modality Therapy ,Survival Analysis ,Recombinant Proteins ,Radiation therapy ,medicine.anatomical_structure ,Lymphatic Metastasis ,Multivariate Analysis ,Regression Analysis ,Female ,Lymph ,Cisplatin ,business ,Tamoxifen ,medicine.drug ,Stem Cell Transplantation - Abstract
Despite modern chemotherapy, advanced breast cancer remains a significant cause of cancer morbidity and mortality in women. Patients with disease involvement of multiple lymph nodes represent a subgroup with a high risk of relapse. In particular, 50% of patients with 4 to 9 axillary lymph nodes involved will relapse after standard chemotherapy. In an effort to improve the survival of patients with 4 to 9 involved nodes, we performed a phase II study in which 61 patients with surgically diagnosed stage II or III breast cancer and 4 to 9 positive lymph nodes received 3 cycles of doxorubicin and 5-fluorouracil followed by high-dose chemotherapy consisting of cisplatin, cyclophosphamide, and carmustine and infusion of autologous hematopoietic progenitor cells. All patients received posttransplantation localized radiotherapy unless contraindicated, and all patients with hormone receptor-positive disease received tamoxifen. After a median patient follow-up of 6.7 years (range, 4.6-8.6 years), the 5-year overall survival rate was 79% (95% CI, 69%-90%), with relapse-free survival of 73% (95% CI, 62%-85%). Treatment-related mortality was 3%. Interstitial pneumonitis occurred in 69% of patients but did not contribute to mortality. Our study presents long-term favorable results regarding the use of consolidative HDC with autologous hematopoietic support in previously untreated patients with high-risk primary breast cancer. Biol Blood Marrow Transplant 2002;8(12):666-73.
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40. Assessing Surge Capacity for Radiation Victims with Marrow Toxicity
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John P. Chute, Daniel J. Weisdorf, Cullen Case, Matthew S. Davids, Nelson J. Chao, Raymond A. Hornung, David M. Weinstock, C. Norman Coleman, and Dennis L. Confer
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Adult ,Neutropenia ,Disaster Planning ,medicine ,Humans ,Mass Casualty Incidents ,Nuclear ,Child ,Tabletop ,Radiation injury ,Bone Marrow Diseases ,Bone Marrow Transplantation ,Academic Medical Centers ,Health Services Needs and Demand ,Nuclear Weapons ,Transplantation ,Surge Capacity ,business.industry ,Response ,Mass Casualty ,Hematology ,medicine.disease ,Fetal Blood ,Support family ,United States ,Patient Simulation ,Blood donor ,Interinstitutional Relations ,Hospital Bed Capacity ,Preparedness ,Blood Banks ,Terrorism ,Medical emergency ,Triage ,business ,Radioactive Hazard Release ,Stem Cell Transplantation - Abstract
Hematologists/oncologists would provide essential care for victims of a catastrophic radiation incident, such as the detonation of an improvised nuclear device (IND). The US Radiation Injury Treatment Network (RITN) is a voluntary consortium of 37 academic medical centers, 8 blood donor centers, and 7 umbilical cord banks focused on preparedness for radiation incidents. The RITN conducted 2 tabletop exercises to evaluate response capability after a hypothetical IND detonation in a U.S. city. In the 2008 exercise, medical centers voluntarily accepted 1757 victims at their institutions, a small fraction of the number in need. In the 2009 exercise, each center was required to accept 300 victims. In response, the centers outlined multiple strategies to increase bed availability, extend staff and resources, and support family and friends accompanying transferred victims. The exercises highlighted shortcomings in current planning and future steps for improving surge capacity that are applicable to various mass casualty scenarios.
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41. Pulmonary Sarcoidosis Following Stem Cell Transplantation.
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Bhagat, Rajesh, Rizzieri, David A., Vredenburgh, James J., Chao, Nelson J., and Folz, Rodney J.
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LYMPHOPROLIFERATIVE disorders ,SARCOIDOSIS ,STEM cell transplantation ,TUMORS ,LUNG diseases - Abstract
Noninfectious pulmonary complications are one of the major side effects of hematopoetic stem cell transplant (HSCT); however, the development of pulmonary sarcoidosis post-HSCT is uncommon, with only three cases previously reported. In each of those cases, sarcoidosis was also diagnosed in the stem cell donor. We now report four cases of de novo pulmonary sarcoidosis occurring post-HSCT (3 autologous HSCT and 1 allogeneic HSCT). We suggest that pulmonary sarcoidosis may develop following either autologous or allogeneic HSCT, and the prevalence may be 10-fold higher than that of the normal population. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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42. Pulse Cyclophosphamide for Steroid-Refractory Chronic Graft-Versus-Host Disease.
- Author
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Chao, Nelson J., Foster, Yevgeniya Gora, Rowe, Krista, Shah, Ankoor, and Cardones, Adela Rambi
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- *
GRAFT versus host disease , *CYCLOPHOSPHAMIDE , *STEROIDS , *STEM cell transplantation , *COMPLICATIONS from organ transplantation , *HEMATOLOGIC malignancies , *THERAPEUTICS - Published
- 2016
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43. Clinical and Neuroimaging Correlates of Post-Transplant Delirium.
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Smith, Patrick, Thompson, Jillian C., Perea, Elena, Wasserman, Brian, Bohannon, Lauren, Racioppi, Alessandro, Choi, Taewoong, Gasparetto, Cristina, Horwitz, Mitchell E., Long, Gwynn, Lopez, Richard, Rizzieri, David A., Sarantopoulos, Stefanie, Sullivan, Keith M., Chao, Nelson J., and Sung, Anthony D.
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- *
HEMATOPOIETIC stem cell transplantation , *DELIRIUM , *WHITE matter (Nerve tissue) , *CEREBRAL atrophy , *BRAIN imaging - Abstract
• Delirium is common following hematopoietic stem cell transplantation. • In this select sample, greater age, treatment regimen intensity, and greater white matter burden were all associated with greater delirium incidence. Delirium is common among adults undergoing hematopoietic stem cell transplantation (HCT), although the clinical and neuroimaging correlates of post-HCT delirium have not been adequately delineated. We therefore examined the frequency of delirium and neuroimaging correlates of post-transplant delirium in a retrospective cohort of 115 adults undergoing neuroimaging after allogeneic HCT. Delirium was established using previously validated methods for retrospective identification of chart-assessed postprocedural delirium. Chart reviews were independently conducted by a multidisciplinary team with expertise in HCT, psychiatry, and psychology on consecutive allogeneic HCT patients who underwent neuroimaging assessments and transplantation at a single center between January 2009 and December 2016. Neuroimaging markers of white matter damage and brain volume loss were also recorded. In total, 115 patients were included, ranging in age from 20 to 74 years (mean [SD] age, 49 [13]). Fifty-three patients (46%) developed post-HCT delirium. In an adjusted model, delirium incidence was associated with older age (odds ratio [OR], 1.92 [1.28, 2.87] per decade, P =.002), greater severity of white matter hyperintensities (OR, 1.95 [1.06, 3.57], P =.031), and conditioning intensity (OR, 6.37 [2.20, 18.45], P <.001) but was unrelated to cortical atrophy (P =.777). Delirium was associated with fewer hospital-free days (P =.023) but was not associated with overall survival (hazard ratio, 0.95 [0.56, 1.61], P =.844). Greater incidence of delirium following HCT was associated with greater age, microvascular burden, and conditioning intensity. Pre-HCT consideration of microvascular burden and other neuroimaging biomarkers of risk may be warranted. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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44. Longitudinal Analysis of T-Cell Receptor Variable β Chain Repertoire in Patients with Acute Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation
- Author
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Liu, Congxiao, He, Min, Rooney, Barbara, Kepler, Thomas B., and Chao, Nelson J.
- Subjects
- *
T-cell receptor genes , *STEM cell transplantation , *GRAFT versus host disease , *TRANSPLANTATION of organs, tissues, etc. - Abstract
Abstract: T-cell receptor variable β chain (TCRBV) repertoire spectratyping involves the estimation of CDR3 length distributions for monitoring T-cell receptor diversity and has proven useful for analyses of immune reconstitution and T-cell clonal expansions in graft-versus-host disease (GVHD) and graft-versus-leukemia after allogeneic stem cell transplantation. We performed a longitudinal spectratype analysis of 23 TCRBV families in 28 patients who underwent allogeneic T cell–depleted peripheral blood stem cell transplantation. Sixteen patients subsequently developed acute GVHD. We recently developed statistical methods that bring increased power and flexibility to spectratype analysis and allow us to analyze TCRBV repertoire development under appropriately complex statistical models. Applying these methods, we found that patients with acute GVHD demonstrated TCRBV repertoire development statistically distinct from that repertoire development in patients without GVHD. Specifically, GVHD patients showed spectratypes indicative of lower diversity and greater deviation from the spectratypes expected in healthy individuals at intermediate times. Most individual TCRBV subfamilies had spectratypes statistically distinguishable between GVHD and non-GVHD patients at 6 months after transplantation. These results suggest that the T-cell receptor repertoire perturbations associated with acute GVHD are widely spread throughout the TCRBV families. [Copyright &y& Elsevier]
- Published
- 2006
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45. Phase I, Dose Escalation Study of Naïve T-Cell Depleted Donor Lymphocyte Infusion Following Allogeneic Stem Cell Transplantation.
- Author
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Maung, Ko Ko, Chen, Benny J, Rizzieri, David A, Gasparetto, Cristina, Sullivan, Keith, Long, Gwynn D, Engemann, Ashley Morris, Waters-Pick, Barbara, Nichols, Krista Rowe, Lopez, Richard, Kang, Yubin, Sarantopoulos, Stefanie, Sung, Anthony D., Chao, Nelson J., and Horwitz, Mitchell E.
- Subjects
- *
STEM cell transplantation , *T cells , *LYMPHOCYTES , *CANCER relapse , *HLA histocompatibility antigens - Abstract
Introduction Prophylactic, donor lymphocyte infusion (DLI) is used to augment immune recovery and graft vs. tumor effect following a T-cell depleted alloSCT. However, it carries the risk of inducing severe GvHD. Our pre-clinical murine studies have implicated the naive T-cell, defined by CD62L marker, as the primary driver of alloreactivity. We hypothesize that transferring selected memory T-cells without naive-T cells would endow the patient with cells that do not cause GvHD while augmenting host defense against infection and tumor recurrence. Objectives The goal of the study was to determine the maximum tolerated dose of a prophylactic, delayed DLI that has been depleted of naive T-cells. Methods We enrolled 16 adult patients, median age 54 who met following criteria; a. underwent an alemtuzumab or thymoglobulin-containing non-myeloablative allogeneic transplant from an HLA-identical family donor or an 8/8 HLA-matched unrelated donor (MUD), b. at least 60 days from day of transplantation, c. no active acute GvHD grade II or higher. Primary diseases were CLL; n=1, MM; n=2, MF; n=1, NHL; n=5, MDS; n=1, AML; n=6. A dedicated, non-mobilized donor apheresis procedure was performed following enrollment. Naive, CD45RA+ T-cells were depleted from the collection under an IND using the Miltenyi clinimacs system. A standard phase I, 3+3 dose escalation schema was employed. The dose-limiting toxicity of the DLI was defined as development of grade III/IV acute GvHD within 90 days of the DLI. Results The DLI was infused on median 112.5 days (76 to 280 days) following transplant. 8 patients received matched sibling grafts and 8 received MUD grafts. 3 patients each received naive T-cell depleted CD3+ dose of 1 × 105/kg, 1 × 106/kg, and 5 × 106/kg. The top dose of 1 × 107/kg was expanded to 7 patients. No dose limiting toxicity or adverse event attributable to the DLI was observed at any dose level. 1 patient developed grade 2 acute GvHD and 1 developed moderate chronic GvHD attributable to the DLI. 4 patients had relapsed disease; 2 in the lowest dose and 2 in the highest dose levels. With a median follow-up of 2.75 years, 2-year relapse free and overall survivals are 56.25% and 68.75%, respectively (Fig 1 and 2). NK cells, CD3+T lymphocytes, CD4+ T lymphocytes and CD8+ T lymphocytes show positive correlations of 0.24, 0.40, 0.42 and 0.38 respectively with time following the DLI (Fig 3). Conclusion A prophylactic, naive T-cell depleted DLI can be provided safely, without significant risk of acute GvHD at a dose of 1 × 10e7 CD3/kg. Larger studies in a more homogeneous patient population will be needed to confirm the impact on immune recovery and relapse prevention. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
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46. Clinical and Neuroimaging Predictors of Post-Transplant Delirium.
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Smith, Patrick J., Perea, Elena, Thompson, Jillian, Wasserman, Brian, Bohannon, Lauren, Choi, Taewoong, Gasparetto, Cristina, Horwitz, Mitchell E., Long, Gwynn D., Lopez, Richard, Rizzieri, David A., Sarantopoulos, Stefanie, Chao, Nelson J., and Sung, Anthony D.
- Subjects
- *
DELIRIUM , *HEMATOPOIETIC stem cells , *STEM cell transplantation , *CEREBRAL atrophy , *TRANSPLANTING (Plant culture) , *BRAIN imaging , *VOXEL-based morphometry - Abstract
Delirium is common among adults undergoing hematopoietic stem cell transplant (HCT), although the clinical predictors and neuroimaging correlates of postoperative delirium have not been adequately delineated. We therefore examined the frequency of delirium and neuroimaging correlates of post-HCT delirium in a retrospective cohort of 115 adults undergoing BMT. Delirium was established using previously validated methods for retrospective identification of chart-assessed postoperative delirium. Chart reviews were independently conducted by a team including a HCT physician, a transplant psychiatrist, a transplant psychologist, and a psychiatry resident on consecutive allogeneic HCT patients who underwent neuroimaging assessments, transplanted between January, 2009 December, 2016Y. Neuroimaging markers of cortical volume loss and white matter hyperintensities were also recorded. One hundred fifteen patients were included, ranging in age from 20 to 74 (mean age = 49 [SD = 13]). Fifty-three patients (46%) developed post-HCT delirium. In an adjusted model, delirium incidence was associated with older age (OR = 1.92 [1.28, 2.87] per decade, P =.002), greater severity of white matter hyperintensities (OR = 1.95 [1.06, 3.57], P =.031), and treatment regimen intensity (OR = 6.37 [2.20, 18.45], P <.001) but was unrelated to cortical atrophy (P =.777). Greater incidence of delirium following BMT was associated with greater age, microvascular burden, and more severe treatment regimen. Pre-HCT consideration of microvascular burden and other neuroimaging biomarkers of risk may be warranted. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
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