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Chao, Nelson Jen An

Overview:

My research interests are in two broad areas, clinical hematopoietic stem cell and cord blood transplantation and in the laboratory studies related to graft vs. host disease and immune reconstitution. On the clinical side we are currently conducting approximately 50 different clinical protocols ranging from preparatory regimens, supportive care studies and disease specific protocols. Most of these clinical studies are centered around studies of the sources of stem cells and the methods to improve the long term outcome. There are exploratory protocols for novel therapies such as dendritic cell therapy for several malignancies, antiangiogenesis therapy, graft engineering to prevent graft-versus-host disease and antigen specific T cells or non specific NK cells to prevent relapse. Moreover a strong focus of the program is to develop cord-blood transplantation for adult patients with hematologic malignancies. The laboratory studies center on understanding the immunological events that occur with graft-vs-host disease and methods to prevent this disease. The current efforts focus on understanding murine reconstitution following transplantation, use of a peptide polymer to block MHC class II recognition of minor histocompatibility antigens, use of T cell engineering to prevent graft-versus-host disease at the same time preserving a graft-versus-malignancy effect.

For more information see http://ed-media.mc.duke.edu/BMT.nsf

Positions:

Professor of Medicine

Medicine, Cellular Therapy
School of Medicine

Donald D. and Elizabeth G. Cooke Cancer Research Professor

Medicine, Cellular Therapy
School of Medicine

ResearchProfessor of Global Health

Duke Global Health Institute
Institutes and Provost's Academic Units

Professor in Immunology

Immunology
School of Medicine

Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Chief, Division of Cell Therapy in the Department of Medicine

Medicine, Cellular Therapy
School of Medicine

Education:

M.D. 1981

M.D. — Yale University

Medical Resident, Medicine

Stanford University

Fellow In Oncology, Medicine

Stanford University

News:

Grants:

Translational Research in Surgical Oncology

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
January 01, 2002
End Date
August 31, 2021

Patient-centered home-based hematopoietic stem cell transplantation

Administered By
Medicine, Cellular Therapy
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 2016
End Date
April 30, 2021

Centers for Medical Countermeasures against Radiation Consortium

Administered By
Medicine, Cellular Therapy
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 31, 2005
End Date
July 31, 2020

Role of ErbB receptor signaling in regulating normal and leukemic stem cell fate

Administered By
Medicine, Hematological Malignancies
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 09, 2014
End Date
August 31, 2019

Dissecting mechanism(s) by which ionizing radiation promotes clonal expansion of premalignant cells in the thymus

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
September 15, 2016
End Date
August 31, 2018

Transplant Infectious Diseases Interdisciplinary Research Training Grant

Administered By
Medicine, Infectious Diseases
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 01, 2013
End Date
August 31, 2018

A novel therapeutic target for radiation-induced hematological malignancies: calcium calmodulin kinase kinase 2

Administered By
Medicine, Cellular Therapy
AwardedBy
Department of Defense
Role
Principal Investigator
Start Date
September 15, 2015
End Date
September 14, 2017

Determining the mechanism of the protective of action of STO-609, a CaMKK2 inhibitor, in acute radiation syndrome

Administered By
Medicine, Cellular Therapy
AwardedBy
Columbia University
Role
Collaborator
Start Date
April 01, 2016
End Date
July 31, 2017

2-O, 3-O desulfated heparin for the prevention of GVHD

Administered By
Medicine, Cellular Therapy
AwardedBy
Cantex Pharmaceuticals, Inc.
Role
Principal Investigator
Start Date
June 25, 2015
End Date
June 30, 2017

Duke-UNC Clinical Hematology and Transfusion Research Career Development Program

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 28, 2006
End Date
April 30, 2017

Point of Care Biodosimeter

Administered By
Medicine, Cellular Therapy
AwardedBy
Department of Health and Human Services
Role
Principal Investigator
Start Date
December 16, 2009
End Date
December 31, 2016

RITN2016

Administered By
Medicine, Cellular Therapy
AwardedBy
National Marrow Donor Program
Role
Principal Investigator
Start Date
October 01, 2015
End Date
August 31, 2016

Plerixafor for allogeneic hematopoietic stem cell transplantation

Administered By
Medicine, Hematological Malignancies
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
August 01, 2014
End Date
June 30, 2016

Validation of a microRNA signature for the prediction, diagnosis and prognosis of acute graft-versus-host disease

Administered By
Immunology
AwardedBy
Blood and Marrow Transplant Clinical Trials Network
Role
Co Investigator
Start Date
January 20, 2015
End Date
December 31, 2015

BAFF Pathology: Novel Therapeutic Targets in Chronic Graft versus Host Disease

Administered By
Medicine, Cellular Therapy
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 12, 2011
End Date
June 30, 2015

Plasma microRNAs as non-invasive biomarker for acute graft-versus-host diseases

Administered By
Immunology
AwardedBy
The Biomarker Factory
Role
Investigator
Start Date
February 01, 2014
End Date
April 30, 2015

RITN Agreement

Administered By
Medicine, Cellular Therapy
AwardedBy
National Marrow Donor Program
Role
Principal Investigator
Start Date
November 01, 2006
End Date
September 30, 2014

Novel Approaches to Stem Cell Transplantation

Administered By
Medicine, Cellular Therapy
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 2009
End Date
June 30, 2014

Endothelial Progenitor Cell Transplant to Accelerate Hematopoietic Recovery

Administered By
Medicine, Cellular Therapy
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
August 15, 2008
End Date
July 31, 2013

Skin Stem Cells in Combined Radiation Injury

Administered By
Medicine, Cellular Therapy
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 18, 2008
End Date
July 31, 2013

Graft Engineering and Immunotherapy After Unrelated Cord Blood Transplantation

Administered By
Pediatrics, Blood and Marrow Transplantation
AwardedBy
National Institutes of Health
Role
Significant Contributor
Start Date
August 13, 2007
End Date
June 30, 2011

Innate Immune Response to Environmental Endotoxin

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
February 06, 2004
End Date
January 31, 2009

Non-Myeloablative Cord Blood Transplantation

Administered By
Medicine, Cellular Therapy
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1999
End Date
December 31, 2008

Dendritic Cell Based Vaccination for Multiple Myeloma

Administered By
Medicine, Cellular Therapy
AwardedBy
National Institutes of Health
Role
Sponsor
Start Date
August 01, 2002
End Date
July 31, 2007

Cord Blood Transplantation

Administered By
Medicine, Cellular Therapy
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 2002
End Date
April 30, 2007

Bone Marrow Transplantation for Breast Cancer

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 01, 1990
End Date
June 30, 2003

Cancer Center Core Support Grant

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1976
End Date
December 31, 1998

Comprehensive Cancer Center Core Support Grant

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1976
End Date
December 31, 1998
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Publications:

Outcomes of Maintenance Therapy with Bortezomib after Autologous Stem Cell Transplantation for Patients with Multiple Myeloma.

Comprehensive recommendations for maintenance therapy after autologous stem cell transplantation (ASCT) for patients with multiple myeloma (MM) have yet to be defined. Bortezomib has been utilized as maintenance therapy after ASCT, but data attesting to the safety and efficacy of this agent compared with lenalidomide in the post-ASCT setting are limited. Therefore, we retrospectively analyzed the outcomes of 102 patients with MM who received maintenance therapy with bortezomib after ASCT at Duke University's adult bone marrow transplant clinic between 2005 and 2015. Maintenance with bortezomib was initiated between 60 and 90 days after ASCT as a single agent 1.3 mg/m2 once every 2 weeks (n = 92) or in combination with lenalidomide (10 mg/day) (n = 10). The median age at ASCT was 64 (range, 31 to 78). Of the 99 patients with molecular data available, 42% had high-risk cytogenetics (including d17p, t(4;14), +1q, and t(14;16) by fluorescein in situ hybridization). Overall, 46% of patients experienced side effects from maintenance therapy, with 31% of all patients experiencing peripheral neuropathy. In total, 2% of patients required discontinuation of bortezomib maintenance because of adverse events. No secondary malignancies were reported from the therapy. The median progression-free survival (PFS) for patients receiving maintenance therapy with bortezomib after ASCT was 36.5 months (95% confidence interval [CI], 21.3 to not available) and median overall survival was 72.7 months (95% CI, 63.9 to not available). The PFS of patients with high-risk cytogenetics was not statistically significantly different from those with standard-risk cytogenetics, suggesting that maintenance with bortezomib may help overcome the impact of high-risk cytogenetics on early progression. These results indicate that maintenance therapy with bortezomib represents a safe, well-tolerated, and efficacious option for patients with high-risk cytogenetics, renal insufficiency, an inability to tolerate lenalidomide, or a previous history of another cancer.

Authors
Sivaraj, D; Green, MM; Li, Z; Sung, AD; Sarantopoulos, S; Kang, Y; Long, GD; Horwitz, ME; Lopez, RD; Sullivan, KM; Rizzieri, DA; Chao, NJ; Gasparetto, C
MLA Citation
Sivaraj, D, Green, MM, Li, Z, Sung, AD, Sarantopoulos, S, Kang, Y, Long, GD, Horwitz, ME, Lopez, RD, Sullivan, KM, Rizzieri, DA, Chao, NJ, and Gasparetto, C. "Outcomes of Maintenance Therapy with Bortezomib after Autologous Stem Cell Transplantation for Patients with Multiple Myeloma." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 23.2 (February 2017): 262-268.
PMID
27856369
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
23
Issue
2
Publish Date
2017
Start Page
262
End Page
268
DOI
10.1016/j.bbmt.2016.11.010

Allogeneic Hematopoietic Cell Transplantation for Aggressive NK-Cell Leukemia. A CIBMTR Analysis.

Authors
Hamadani, M; Kanate, AS; DiGilio, A; Woo Ahn, K; Smith, SM; Wook Lee, J; Ayala, E; Chao, N; Hari, P; Bolaños-Meade, J; Gress, R; Smedegaard Anderson, N; Chen, Y-B; Farooq, U; Schiller, G; Yared, J; Sureda, A; Fenske, TS; Olteanu, H
MLA Citation
Hamadani, M, Kanate, AS, DiGilio, A, Woo Ahn, K, Smith, SM, Wook Lee, J, Ayala, E, Chao, N, Hari, P, Bolaños-Meade, J, Gress, R, Smedegaard Anderson, N, Chen, Y-B, Farooq, U, Schiller, G, Yared, J, Sureda, A, Fenske, TS, and Olteanu, H. "Allogeneic Hematopoietic Cell Transplantation for Aggressive NK-Cell Leukemia. A CIBMTR Analysis." Biology of Blood and Marrow Transplantation (February 2017).
Source
crossref
Published In
Biology of Blood and Marrow Transplantation
Publish Date
2017
DOI
10.1016/j.bbmt.2017.01.082

Efficacy and safety of high-dose chemotherapy with autologous stem cell transplantation in senior versus younger adults with newly diagnosed multiple myeloma.

We retrospectively studied 340 fit patients with multiple myeloma (MM) who underwent autologous stem cell transplantation (ASCT). We hypothesized that progression-free survival (PFS) of older patients was non-inferior to that of younger patients after ASCT. Our null hypothesis was that the PFS hazard ratio (HR) for a 5-year increase in age was ≥1.05; the alternative (non-inferiority) hypothesis was that the HR was ≤1. The observed HR was 0.94 (95% confidence interval [CI] 0.86-1.03); since the CI upper bound was <1.05, we reject the null hypothesis and conclude that PFS in older patients was at least as good as in younger patients. We cannot reject an analogous null hypothesis for overall survival (HR 1.06 [95% CI 0.94-1.19]), since the CI upper bound >1.05. Toxicity was similar across ages and transplant-related mortality was minimal. 28% of subjects <65 versus 45% of those ≥65 received maintenance therapy. In summary, ASCT prolongs PFS equally well in older vs. younger adults. Although we cannot exclude maintenance as a confounder, these data support ASCT for fit seniors with MM.

Authors
Huang, L-W; Bacon, W; Cirrincione, C; Peterson, B; Long, G; Rizzieri, D; Sullivan, KM; Corbet, K; Horwitz, M; Chao, N; Gasparetto, C; Tuchman, SA
MLA Citation
Huang, L-W, Bacon, W, Cirrincione, C, Peterson, B, Long, G, Rizzieri, D, Sullivan, KM, Corbet, K, Horwitz, M, Chao, N, Gasparetto, C, and Tuchman, SA. "Efficacy and safety of high-dose chemotherapy with autologous stem cell transplantation in senior versus younger adults with newly diagnosed multiple myeloma." Hematological oncology (January 19, 2017).
PMID
28105753
Source
epmc
Published In
Hematological Oncology
Publish Date
2017
DOI
10.1002/hon.2379

Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms.

The role of osteolineage cells in regulating hematopoietic stem cell (HSC) regeneration following myelosuppression is not well understood. Here we show that deletion of the pro-apoptotic genes Bak and Bax in osterix (Osx, also known as Sp7 transcription factor 7)-expressing cells in mice promotes HSC regeneration and hematopoietic radioprotection following total body irradiation. These mice showed increased bone marrow (BM) levels of the protein dickkopf-1 (Dkk1), which was produced in Osx-expressing BM cells. Treatment of irradiated HSCs with Dkk1 in vitro increased the recovery of both long-term repopulating HSCs and progenitor cells, and systemic administration of Dkk1 to irradiated mice increased hematopoietic recovery and improved survival. Conversely, inducible deletion of one allele of Dkk1 in Osx-expressing cells in adult mice inhibited the recovery of BM stem and progenitor cells and of complete blood counts following irradiation. Dkk1 promoted hematopoietic regeneration via both direct effects on HSCs, in which treatment with Dkk1 decreased the levels of mitochondrial reactive oxygen species and suppressed senescence, and indirect effects on BM endothelial cells, in which treatment with Dkk1 induced epidermal growth factor (EGF) secretion. Accordingly, blockade of the EGF receptor partially abrogated Dkk1-mediated hematopoietic recovery. These data identify Dkk1 as a regulator of hematopoietic regeneration and demonstrate paracrine cross-talk between BM osteolineage cells and endothelial cells in regulating hematopoietic reconstitution following injury.

Authors
Himburg, HA; Doan, PL; Quarmyne, M; Yan, X; Sasine, J; Zhao, L; Hancock, GV; Kan, J; Pohl, KA; Tran, E; Chao, NJ; Harris, JR; Chute, JP
MLA Citation
Himburg, HA, Doan, PL, Quarmyne, M, Yan, X, Sasine, J, Zhao, L, Hancock, GV, Kan, J, Pohl, KA, Tran, E, Chao, NJ, Harris, JR, and Chute, JP. "Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms." Nature medicine 23.1 (January 2017): 91-99.
PMID
27918563
Source
epmc
Published In
Nature Medicine
Volume
23
Issue
1
Publish Date
2017
Start Page
91
End Page
99
DOI
10.1038/nm.4251

Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration.

Imprinted genes are differentially expressed by adult stem cells, but their functions in regulating adult stem cell fate are incompletely understood. Here we show that growth factor receptor-bound protein 10 (Grb10), an imprinted gene, regulates hematopoietic stem cell (HSC) self-renewal and regeneration. Deletion of the maternal allele of Grb10 in mice (Grb10(m/+) mice) substantially increased HSC long-term repopulating capacity, as compared to that of Grb10(+/+) mice. After total body irradiation (TBI), Grb10(m/+) mice demonstrated accelerated HSC regeneration and hematopoietic reconstitution, as compared to Grb10(+/+) mice. Grb10-deficient HSCs displayed increased proliferation after competitive transplantation or TBI, commensurate with upregulation of CDK4 and Cyclin E. Furthermore, the enhanced HSC regeneration observed in Grb10-deficient mice was dependent on activation of the Akt/mTORC1 pathway. This study reveals a function for the imprinted gene Grb10 in regulating HSC self-renewal and regeneration and suggests that the inhibition of Grb10 can promote hematopoietic regeneration in vivo.

Authors
Yan, X; Himburg, HA; Pohl, K; Quarmyne, M; Tran, E; Zhang, Y; Fang, T; Kan, J; Chao, NJ; Zhao, L; Doan, PL; Chute, JP
MLA Citation
Yan, X, Himburg, HA, Pohl, K, Quarmyne, M, Tran, E, Zhang, Y, Fang, T, Kan, J, Chao, NJ, Zhao, L, Doan, PL, and Chute, JP. "Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration." Cell reports 17.6 (November 2016): 1584-1594.
PMID
27806297
Source
epmc
Published In
Cell Reports
Volume
17
Issue
6
Publish Date
2016
Start Page
1584
End Page
1594
DOI
10.1016/j.celrep.2016.10.025

Universal Mask Usage for Reduction of Respiratory Viral Infections After Stem Cell Transplant: A Prospective Trial.

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.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).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).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.

Authors
Sung, AD; Sung, JAM; Thomas, S; Hyslop, T; Gasparetto, C; Long, G; Rizzieri, D; Sullivan, KM; Corbet, K; Broadwater, G; Chao, NJ; Horwitz, ME
MLA Citation
Sung, AD, Sung, JAM, Thomas, S, Hyslop, T, Gasparetto, C, Long, G, Rizzieri, D, Sullivan, KM, Corbet, K, Broadwater, G, Chao, NJ, and Horwitz, ME. "Universal Mask Usage for Reduction of Respiratory Viral Infections After Stem Cell Transplant: A Prospective Trial." Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 63.8 (October 2016): 999-1006.
PMID
27481873
Source
epmc
Published In
Clinical Infectious Diseases
Volume
63
Issue
8
Publish Date
2016
Start Page
999
End Page
1006
DOI
10.1093/cid/ciw451

Myeloablative conditioning with total body irradiation for AML: Balancing survival and pulmonary toxicity

Authors
Stephens, SJ; Thomas, S; Rizzieri, DA; Horwitz, ME; Chao, NJ; Engemann, AM; Lassiter, M; Kelsey, CR
MLA Citation
Stephens, SJ, Thomas, S, Rizzieri, DA, Horwitz, ME, Chao, NJ, Engemann, AM, Lassiter, M, and Kelsey, CR. "Myeloablative conditioning with total body irradiation for AML: Balancing survival and pulmonary toxicity." October 2016.
Source
crossref
Published In
Advances in Radiation Oncology
Volume
1
Issue
4
Publish Date
2016
Start Page
272
End Page
280
DOI
10.1016/j.adro.2016.07.001

Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery.

The binding of CXCR4 with its ligand (stromal-derived factor-1) maintains hematopoietic stem/progenitor cells (HSPCs) in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT) promotes hematopoiesis by inducing HSC proliferation.We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 μg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/μl and platelet count >20,000/μl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis.Thirty patients received plerixafor following peripheral blood stem cell (n = 28) (PBSC) or bone marrow (n = 2) transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04) and platelet recovery >20 K (p = 0.04) compared to the controls.Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted.ClinicalTrials.gov NCT01280955.

Authors
Green, MMB; Chao, N; Chhabra, S; Corbet, K; Gasparetto, C; Horwitz, A; Li, Z; Venkata, JK; Long, G; Mims, A; Rizzieri, D; Sarantopoulos, S; Stuart, R; Sung, AD; Sullivan, KM; Costa, L; Horwitz, M; Kang, Y
MLA Citation
Green, MMB, Chao, N, Chhabra, S, Corbet, K, Gasparetto, C, Horwitz, A, Li, Z, Venkata, JK, Long, G, Mims, A, Rizzieri, D, Sarantopoulos, S, Stuart, R, Sung, AD, Sullivan, KM, Costa, L, Horwitz, M, and Kang, Y. "Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery." Journal of hematology & oncology 9.1 (August 17, 2016): 71-.
PMID
27535663
Source
epmc
Published In
Journal of Hematology and Oncology
Volume
9
Issue
1
Publish Date
2016
Start Page
71
DOI
10.1186/s13045-016-0301-2

The Diagnostic Yield of Site and Symptom-Based Biopsies for Acute Gastrointestinal Graft-Versus-Host Disease: A 5-Year Retrospective Review.

Graft-versus-host disease (GVHD) complicates half of hematopoietic stem cell transplants (HCT), and the gastrointestinal tract is commonly affected. Endoscopic biopsies have a key role in the diagnosis. The optimal procedure(s) to perform and site(s) to biopsy remain unclear.We retrospectively analyzed the charts of all adult patients who underwent allogeneic HCT at Duke University Medical Center between 1/1/05 and 1/1/11 and extracted data from those who underwent endoscopic biopsy for suspected GVHD. All histology was re-evaluated by blinded pathologists using 2006 NIH diagnostic criteria and then compared to the original clinical diagnosis of GVHD.A total of 169 adult patients underwent 250 endoscopic procedures to evaluate GVHD. The sensitivity of biopsies for clinical GVHD was 76 and 72% for upper and lower tract sites, respectively. In the presence of nausea, upper tract biopsies were positive for GVHD in 65%, 70% while lower tract biopsies were positive in 61-70%. In the presence of diarrhea, lower tract biopsies were positive in 65%, while upper tract sites were positive in 64-69%. Twenty six (40%) of the sixty-five endoscopies that simultaneously sampled upper and lower tract sites had discordant results. All were histologically positive for GVHD, yet 15% of upper tract biopsies and 25% of lower tract biopsies were negative.In this large review, the overall sensitivity of biopsies taken during EGD and Flex-Sig was 76 and 72%, respectively. A symptom-driven biopsy approach was not clearly supported as upper tract and lower tract biopsies were similarly diagnostic for GVHD regardless of symptoms.

Authors
Wild, D; Sung, AD; Cardona, D; Cirricione, C; Sullivan, K; Detweiler, C; Shealy, M; Balmadrid, B; Rowes, KL; Chao, N; Piryani, S; Karimabad, HM; Martin, P; Poleski, M
MLA Citation
Wild, D, Sung, AD, Cardona, D, Cirricione, C, Sullivan, K, Detweiler, C, Shealy, M, Balmadrid, B, Rowes, KL, Chao, N, Piryani, S, Karimabad, HM, Martin, P, and Poleski, M. "The Diagnostic Yield of Site and Symptom-Based Biopsies for Acute Gastrointestinal Graft-Versus-Host Disease: A 5-Year Retrospective Review." Digestive diseases and sciences 61.3 (March 2016): 806-813.
PMID
26537485
Source
epmc
Published In
Digestive Diseases and Sciences
Volume
61
Issue
3
Publish Date
2016
Start Page
806
End Page
813
DOI
10.1007/s10620-015-3938-8

The Role of the Transplant Program in a Nuclear Accident or Terrorism

© 2016 John Wiley & Sons, Ltd. All rights reserved.Release of radioactivity, either intended or not, is an undeniable possibility and potentially catastrophic. Reports of nuclear proliferation in nations unfriendly to the United States and the Western world, and the poisoning of a Russian dissident with polonium-210 are further reminders of the terrorist threat. Healthcare needs for displaced populations can easily overwhelm the infrastructure in regions immediately surrounding a disaster area. People exposed to high levels of radiation usually >1-2 Gy over a short period of time may develop acute radiation syndrome. Administering myeloid cytokines to appropriately selected victims offers potential benefits after a mass casualty radiation incident. Consortiums such as the Radiation Injury Treatment Network are engaged in services such as developing treatment guidelines for managing hematologic toxicity among victims of radiation exposure. Similarly, the European Group for Blood and Marrow Transplantation (EBMT) is establishing a network to offer training courses and improve cooperation between institutions.

Authors
Chao, NJ; Confer, DL
MLA Citation
Chao, NJ, and Confer, DL. "The Role of the Transplant Program in a Nuclear Accident or Terrorism." Thomas' Hematopoietic Cell Transplantation: Fifth Edition. January 1, 2016. 431-437.
Source
scopus
Volume
1-2
Publish Date
2016
Start Page
431
End Page
437
DOI
10.1002/9781118416426.ch38

Hematopoietic Stem Cell Transplantation for CD40 Ligand Deficiency: Single Institution Experience.

X-linked hyper-IgM syndrome (X-HIGM) due to mutations in the gene encoding CD40 ligand results in failure of Ig class switching and an increased propensity for recurrent sinopulmonary and other infections, and thus decreased life expectancy. Allogeneic hematopoietic stem cell transplantation (HSCT) is curative, but long-term follow-up data are limited.We conducted a retrospective analysis of seven patients who have undergone allogeneic HSCT for HIGM syndrome at Duke University Medical Center.Median age at transplant was 5.2 years (range 0.7-19.3). None of the patients had active hepatic or pulmonary disease immediately prior to transplant, but all had a history of serious infections. Five patients received myeloablative conditioning, and two patients received reduced intensity conditioning. Graft sources included bone marrow, peripheral blood, and unrelated umbilical cord blood. Post-transplantation complications included veno-occlusive disease, hemorrhagic cystitis, adenoviremia, and cryptosporidium recurrence in one patient each. Two patients developed acute GVHD grades II-IV that resolved promptly with treatment and none developed extensive chronic GVHD. All patients are intravenous IgG-independent and 6/7 have normal antibody titers. Immunoglobulin (Ig) A levels normalized in all but one patient and T and B cell numbers and function are otherwise normal in all. All patients are alive at a median follow-up of 9.7 (range 9.7-16.1) years post-transplantation with predominantly donor chimerism and no recurrent infections.Allogeneic HSCT results in excellent survival and sustained immune reconstitution in patients with CD40 ligand deficiency using both myeloablative and reduced intensity conditioning approaches and various graft sources, including bone marrow, peripheral blood, and umbilical cord blood.

Authors
Allewelt, H; Martin, PL; Szabolcs, P; Chao, N; Buckley, R; Parikh, S
MLA Citation
Allewelt, H, Martin, PL, Szabolcs, P, Chao, N, Buckley, R, and Parikh, S. "Hematopoietic Stem Cell Transplantation for CD40 Ligand Deficiency: Single Institution Experience." Pediatric blood & cancer 62.12 (December 2015): 2216-2222.
PMID
26291959
Source
epmc
Published In
Pediatric Blood & Cancer
Volume
62
Issue
12
Publish Date
2015
Start Page
2216
End Page
2222
DOI
10.1002/pbc.25711

Differential Requirements of TCR Signaling in Homeostatic Maintenance and Function of Dendritic Epidermal T Cells.

Dendritic epidermal T cells (DETCs) are generated exclusively in the fetal thymus and maintained in the skin epithelium throughout postnatal life of the mouse. DETCs have restricted antigenic specificity as a result of their exclusive usage of a canonical TCR. Although the importance of the TCR in DETC development has been well established, the exact role of TCR signaling in DETC homeostasis and function remains incompletely defined. In this study, we investigated TCR signaling in fully matured DETCs by lineage-restricted deletion of the Lat gene, an essential signaling molecule downstream of the TCR. We found that Lat deletion impaired TCR-dependent cytokine gene activation and the ability of DETCs to undergo proliferative expansion. However, linker for activation of T cells-deficient DETCs were able to maintain long-term population homeostasis, although with a reduced proliferation rate. Mice with Lat deletion in DETCs exhibited delayed wound healing accompanied by impaired clonal expansion within the wound area. Our study revealed differential requirements for TCR signaling in homeostatic maintenance of DETCs and in their effector function during wound healing.

Authors
Zhang, B; Wu, J; Jiao, Y; Bock, C; Dai, M; Chen, B; Chao, N; Zhang, W; Zhuang, Y
MLA Citation
Zhang, B, Wu, J, Jiao, Y, Bock, C, Dai, M, Chen, B, Chao, N, Zhang, W, and Zhuang, Y. "Differential Requirements of TCR Signaling in Homeostatic Maintenance and Function of Dendritic Epidermal T Cells." Journal of immunology (Baltimore, Md. : 1950) 195.9 (November 2015): 4282-4291.
PMID
26408667
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
195
Issue
9
Publish Date
2015
Start Page
4282
End Page
4291
DOI
10.4049/jimmunol.1501220

A Roadmap for a New Academic Pathway for Global Radiation Oncology.

Authors
Olson, AC; Coleman, CN; Hahn, SM; DeWeese, TL; Shulman, LN; Chabner, BA; Chao, N; Martei, YM; Mundt, AJ; Grover, S
MLA Citation
Olson, AC, Coleman, CN, Hahn, SM, DeWeese, TL, Shulman, LN, Chabner, BA, Chao, N, Martei, YM, Mundt, AJ, and Grover, S. "A Roadmap for a New Academic Pathway for Global Radiation Oncology." International journal of radiation oncology, biology, physics 93.3 (November 2015): 493-496.
PMID
26460990
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
93
Issue
3
Publish Date
2015
Start Page
493
End Page
496
DOI
10.1016/j.ijrobp.2015.06.023

Tacrolimus versus Cyclosporine after Hematopoietic Cell Transplantation for Acquired Aplastic Anemia.

Combinations of cyclosporine (CSP) with methotrexate (MTX) have been widely used for immunosuppression after allogeneic transplantation for acquired aplastic anemia. We compared outcomes with tacrolimus (TAC)+MTX versus CSP+MTX after transplantation from HLA-identical siblings (SIB) or unrelated donors (URD) in a retrospective cohort of 949 patients with severe aplastic anemia. Study endpoints included hematopoietic recovery, graft failure, acute graft-versus-host disease (GVHD), chronic GVHD, and mortality. TAC+MTX was used more frequently in older patients and, in recent years, in both SIB and URD groups. In multivariate analysis, TAC+MTX was associated with a lower risk of mortality in URD recipients and with slightly earlier absolute neutrophil count recovery in SIB recipients. Other outcomes did not differ statistically between the 2 regimens. No firm conclusions were reached regarding the relative merits of TAC+MTX versus CSP+MTX after hematopoietic cell transplantation for acquired aplastic anemia. Prospective studies would be needed to determine whether the use of TAC+MTX is associated with lower risk of mortality in URD recipients with acquired aplastic anemia.

Authors
Inamoto, Y; Flowers, MED; Wang, T; Urbano-Ispizua, A; Hemmer, MT; Cutler, CS; Couriel, DR; Alousi, AM; Antin, JH; Gale, RP; Gupta, V; Hamilton, BK; Kharfan-Dabaja, MA; Marks, DI; Ringdén, OTH; Socié, G; Solh, MM; Akpek, G; Cairo, MS; Chao, NJ; Hayashi, RJ; Nishihori, T; Reshef, R; Saad, A; Shah, A; Teshima, T; Tallman, MS; Wirk, B; Spellman, SR; Arora, M; Martin, PJ
MLA Citation
Inamoto, Y, Flowers, MED, Wang, T, Urbano-Ispizua, A, Hemmer, MT, Cutler, CS, Couriel, DR, Alousi, AM, Antin, JH, Gale, RP, Gupta, V, Hamilton, BK, Kharfan-Dabaja, MA, Marks, DI, Ringdén, OTH, Socié, G, Solh, MM, Akpek, G, Cairo, MS, Chao, NJ, Hayashi, RJ, Nishihori, T, Reshef, R, Saad, A, Shah, A, Teshima, T, Tallman, MS, Wirk, B, Spellman, SR, Arora, M, and Martin, PJ. "Tacrolimus versus Cyclosporine after Hematopoietic Cell Transplantation for Acquired Aplastic Anemia." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 21.10 (October 2015): 1776-1782.
PMID
26033280
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
21
Issue
10
Publish Date
2015
Start Page
1776
End Page
1782
DOI
10.1016/j.bbmt.2015.05.023

Are We Ready for a Radiological Terrorist Attack Yet? Report From the Centers for Medical Countermeasures Against Radiation Network.

Authors
Brenner, DJ; Chao, NJ; Greenberger, JS; Guha, C; McBride, WH; Swartz, HM; Williams, JP
MLA Citation
Brenner, DJ, Chao, NJ, Greenberger, JS, Guha, C, McBride, WH, Swartz, HM, and Williams, JP. "Are We Ready for a Radiological Terrorist Attack Yet? Report From the Centers for Medical Countermeasures Against Radiation Network." International journal of radiation oncology, biology, physics 92.3 (July 2015): 504-505.
PMID
26068482
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
92
Issue
3
Publish Date
2015
Start Page
504
End Page
505
DOI
10.1016/j.ijrobp.2015.02.042

Cyclophosphamide-based hematopoietic stem cell mobilization before autologous stem cell transplantation in newly diagnosed multiple myeloma.

High-dose cyclophosphamide (Cy) is frequently employed for peripheral blood mobilization of hematopoietic stem cells before high-dose chemotherapy with autologous stem cell transplantation (ASCT) in multiple myeloma (MM). The benefit of mobilization with Cy over filgrastim (granulocyte colony-stimulating factor; G-CSF) alone is unclear. Between 2000 and 2008, 167 patients with newly diagnosed MM underwent single ASCT after melphalan conditioning at our institution. Seventy-three patients were mobilized with G-CSF alone, and 94 patients with Cy plus G-CSF (Cy+G-CSF). We retrospectively analyzed Cy's impact on both toxicity and efficacy. Mobilization efficiency was augmented by Cy; a mean total of 12 versus 5.8 × 10(6) CD34+ cells/kg were collected from patients mobilized with Cy+G-CSF versus G-CSF, respectively, (P < 0.01), over a mean of 1.6 versus 2.2 days of peripheral blood apheresis (p = 0.001). Mobilization-related toxicity was also, however, augmented by Cy; 14% of Cy+G-CSF patients were hospitalized because of complications versus none receiving G-CSF (P < 0.0001). Toxicity, including death, related to ASCT was similar between cohorts. Regarding long-term outcomes, multivariate analysis revealed no difference for Cy+G-CSF versus G-CSF (hazard ratio 0.8 for event-free survival [95% confidence interval {CI} 0.57-1.25] and 0.96 for overall survival [95% CI 0.61-1.54]). In summary, we show that mobilization with Cy increases toxicity without positively impacting long-term outcomes in MM. Our findings place into question Cy's benefit as a routine component of stem cell mobilization regimens in MM. Randomized trials are needed to elucidate the risks and benefits of Cy more definitively.

Authors
Tuchman, SA; Bacon, WA; Huang, L-W; Long, G; Rizzieri, D; Horwitz, M; Chute, JP; Sullivan, K; Morris Engemann, A; Yopp, A; Li, Z; Corbet, K; Chao, N; Gasparetto, C
MLA Citation
Tuchman, SA, Bacon, WA, Huang, L-W, Long, G, Rizzieri, D, Horwitz, M, Chute, JP, Sullivan, K, Morris Engemann, A, Yopp, A, Li, Z, Corbet, K, Chao, N, and Gasparetto, C. "Cyclophosphamide-based hematopoietic stem cell mobilization before autologous stem cell transplantation in newly diagnosed multiple myeloma." Journal of clinical apheresis 30.3 (June 2015): 176-182.
PMID
25293363
Source
epmc
Published In
Journal of Clinical Apheresis
Volume
30
Issue
3
Publish Date
2015
Start Page
176
End Page
182
DOI
10.1002/jca.21360

Molecular and cellular profiling of acute responses to total body radiation exposure in ovariectomized female cynomolgus macaques.

The threat of radiation exposure requires a mechanistic understanding of radiation-induced immune injury and recovery. The study objective was to evaluate responses to ionizing radiation in ovariectomized (surgically post-menopausal) female cynomolgus macaques.Animals received a single total-body irradiation (TBI) exposure at doses of 0, 2 or 5 Gy with scheduled necropsies at 5 days, 8 weeks and 24 weeks post-exposure. Blood and lymphoid tissues were evaluated for morphologic, cellular, and molecular responses.Irradiated animals developed symptoms of acute hematopoietic syndrome, and reductions in thymus weight, thymopoiesis, and bone marrow cellularity. Acute, transient increases in plasma monocyte chemoattractant protein 1 (MCP-1) were observed in 5 Gy animals along with dose-dependent alterations in messenger ribonucleic acid (mRNA) signatures in thymus, spleen, and lymph node. Expression of T cell markers was lower in thymus and spleen, while expression of macrophage marker CD68 (cluster of differentiation 68) was relatively elevated in lymphoid tissues from irradiated animals.Ovariectomized female macaques exposed to moderate doses of radiation experienced increased morbidity, including acute, dose-dependent alterations in systemic and tissue-specific biomarkers, and increased macrophage/T cell ratios. The effects on mortality exceeded expectations based on previous studies in males, warranting further investigation.

Authors
DeBo, RJ; Register, TC; Caudell, DL; Sempowski, GD; Dugan, G; Gray, S; Owzar, K; Jiang, C; Bourland, JD; Chao, NJ; Cline, JM
MLA Citation
DeBo, RJ, Register, TC, Caudell, DL, Sempowski, GD, Dugan, G, Gray, S, Owzar, K, Jiang, C, Bourland, JD, Chao, NJ, and Cline, JM. "Molecular and cellular profiling of acute responses to total body radiation exposure in ovariectomized female cynomolgus macaques." International journal of radiation biology 91.6 (June 2015): 510-518.
PMID
25786585
Source
epmc
Published In
International Journal of Radiation Biology (Informa)
Volume
91
Issue
6
Publish Date
2015
Start Page
510
End Page
518
DOI
10.3109/09553002.2015.1028597

Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease.

Novel therapies for chronic graft-versus-host disease (cGVHD) are needed. Aberrant B-cell activation has been demonstrated in mice and humans with cGVHD. Having previously found that human cGVHD B cells are activated and primed for survival, we sought to further evaluate the role of the spleen tyrosine kinase (Syk) in cGVHD in multiple murine models and human peripheral blood cells. In a murine model of multiorgan system, nonsclerodermatous disease with bronchiolitis obliterans where cGVHD is dependent on antibody and germinal center (GC) B cells, we found that activation of Syk was necessary in donor B cells, but not T cells, for disease progression. Bone marrow-specific Syk deletion in vivo was effective in treating established cGVHD, as was a small-molecule inhibitor of Syk, fostamatinib, which normalized GC formation and decreased activated CD80/86(+) dendritic cells. In multiple distinct models of sclerodermatous cGVHD, clinical and pathological disease manifestations were not eliminated when mice were therapeutically treated with fostamatinib, though both clinical and immunologic effects could be observed in one of these scleroderma models. We further demonstrated that Syk inhibition was effective at inducing apoptosis of human cGVHD B cells. Together, these data demonstrate a therapeutic potential of targeting B-cell Syk signaling in cGVHD.

Authors
Flynn, R; Allen, JL; Luznik, L; MacDonald, KP; Paz, K; Alexander, KA; Vulic, A; Du, J; Panoskaltsis-Mortari, A; Taylor, PA; Poe, JC; Serody, JS; Murphy, WJ; Hill, GR; Maillard, I; Koreth, J; Cutler, CS; Soiffer, RJ; Antin, JH; Ritz, J; Chao, NJ; Clynes, RA; Sarantopoulos, S; Blazar, BR
MLA Citation
Flynn, R, Allen, JL, Luznik, L, MacDonald, KP, Paz, K, Alexander, KA, Vulic, A, Du, J, Panoskaltsis-Mortari, A, Taylor, PA, Poe, JC, Serody, JS, Murphy, WJ, Hill, GR, Maillard, I, Koreth, J, Cutler, CS, Soiffer, RJ, Antin, JH, Ritz, J, Chao, NJ, Clynes, RA, Sarantopoulos, S, and Blazar, BR. "Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease." Blood 125.26 (June 2015): 4085-4094.
PMID
25852057
Source
epmc
Published In
Blood
Volume
125
Issue
26
Publish Date
2015
Start Page
4085
End Page
4094
DOI
10.1182/blood-2014-08-595470

Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research.

Although transplant practices have changed over the last decades, no information is available on trends in incidence and outcome of chronic graft-versus-host disease (cGVHD) over time. This study used the central database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to describe time trends for cGVHD incidence, nonrelapse mortality, and risk factors for cGVHD. The 12-year period was divided into 3 intervals, 1995 to 1999, 2000 to 2003, and 2004 to 2007, and included 26,563 patients with acute leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. Multivariate analysis showed an increased incidence of cGVHD in more recent years (odds ratio = 1.19, P < .0001), and this trend was still seen when adjusting for donor type, graft type, or conditioning intensity. In patients with cGVHD, nonrelapse mortality has decreased over time, but at 5 years there were no significant differences among different time periods. Risk factors for cGVHD were in line with previous studies. This is the first comprehensive characterization of the trends in cGVHD incidence and underscores the mounting need for addressing this major late complication of transplantation in future research.

Authors
Arai, S; Arora, M; Wang, T; Spellman, SR; He, W; Couriel, DR; Urbano-Ispizua, A; Cutler, CS; Bacigalupo, AA; Battiwalla, M; Flowers, ME; Juckett, MB; Lee, SJ; Loren, AW; Klumpp, TR; Prockup, SE; Ringdén, OTH; Savani, BN; Socié, G; Schultz, KR; Spitzer, T; Teshima, T; Bredeson, CN; Jacobsohn, DA; Hayashi, RJ; Drobyski, WR; Frangoul, HA; Akpek, G; Ho, VT; Lewis, VA; Gale, RP; Koreth, J; Chao, NJ; Aljurf, MD; Cooper, BW; Laughlin, MJ; Hsu, JW; Hematti, P; Verdonck, LF; Solh, MM; Norkin, M et al.
MLA Citation
Arai, S, Arora, M, Wang, T, Spellman, SR, He, W, Couriel, DR, Urbano-Ispizua, A, Cutler, CS, Bacigalupo, AA, Battiwalla, M, Flowers, ME, Juckett, MB, Lee, SJ, Loren, AW, Klumpp, TR, Prockup, SE, Ringdén, OTH, Savani, BN, Socié, G, Schultz, KR, Spitzer, T, Teshima, T, Bredeson, CN, Jacobsohn, DA, Hayashi, RJ, Drobyski, WR, Frangoul, HA, Akpek, G, Ho, VT, Lewis, VA, Gale, RP, Koreth, J, Chao, NJ, Aljurf, MD, Cooper, BW, Laughlin, MJ, Hsu, JW, Hematti, P, Verdonck, LF, Solh, MM, and Norkin, M et al. "Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 21.2 (February 2015): 266-274.
PMID
25445023
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
21
Issue
2
Publish Date
2015
Start Page
266
End Page
274
DOI
10.1016/j.bbmt.2014.10.021

Cyclophosphamide-based hematopoietic stem cell mobilization before autologous stem cell transplantation in newly diagnosed multiple myeloma

© 2014 Wiley Periodicals, Inc.High-dose cyclophosphamide (Cy) is frequently employed for peripheral blood mobilization of hematopoietic stem cells before high-dose chemotherapy with autologous stem cell transplantation (ASCT) in multiple myeloma (MM). The benefit of mobilization with Cy over filgrastim (granulocyte colony-stimulating factor; G-CSF) alone is unclear. Between 2000 and 2008, 167 patients with newly diagnosed MM underwent single ASCT after melphalan conditioning at our institution. Seventy-three patients were mobilized with G-CSF alone, and 94 patients with Cy plus G-CSF (Cy+G-CSF). We retrospectively analyzed Cy's impact on both toxicity and efficacy. Mobilization efficiency was augmented by Cy; a mean total of 12 versus 5.8 × 106 CD34+ cells/kg were collected from patients mobilized with Cy+G-CSF versus G-CSF, respectively, (P < 0.01), over a mean of 1.6 versus 2.2 days of peripheral blood apheresis (p = 0.001). Mobilization-related toxicity was also, however, augmented by Cy; 14% of Cy+G-CSF patients were hospitalized because of complications versus none receiving G-CSF (P < 0.0001). Toxicity, including death, related to ASCT was similar between cohorts. Regarding long-term outcomes, multivariate analysis revealed no difference for Cy+G-CSF versus G-CSF (hazard ratio 0.8 for event-free survival [95% confidence interval {CI} 0.57-1.25] and 0.96 for overall survival [95% CI 0.61-1.54]). In summary, we show that mobilization with Cy increases toxicity without positively impacting long-term outcomes in MM. Our findings place into question Cy's benefit as a routine component of stem cell mobilization regimens in MM. Randomized trials are needed to elucidate the risks and benefits of Cy more definitively.

Authors
Tuchman, SA; Bacon, WA; Huang, LW; Long, G; Rizzieri, D; Horwitz, M; Chute, JP; Sullivan, K; Engemann, AM; Yopp, A; Li, Z; Corbet, K; Chao, N; Gasparetto, C
MLA Citation
Tuchman, SA, Bacon, WA, Huang, LW, Long, G, Rizzieri, D, Horwitz, M, Chute, JP, Sullivan, K, Engemann, AM, Yopp, A, Li, Z, Corbet, K, Chao, N, and Gasparetto, C. "Cyclophosphamide-based hematopoietic stem cell mobilization before autologous stem cell transplantation in newly diagnosed multiple myeloma." Journal of Clinical Apheresis 30.3 (January 1, 2015): 176-182.
Source
scopus
Published In
Journal of Clinical Apheresis
Volume
30
Issue
3
Publish Date
2015
Start Page
176
End Page
182
DOI
10.1002/jca.21360

Protein tyrosine phosphatase-σ regulates hematopoietic stem cell-repopulating capacity.

Hematopoietic stem cell (HSC) function is regulated by activation of receptor tyrosine kinases (RTKs). Receptor protein tyrosine phosphatases (PTPs) counterbalance RTK signaling; however, the functions of receptor PTPs in HSCs remain incompletely understood. We found that a receptor PTP, PTPσ, was substantially overexpressed in mouse and human HSCs compared with more mature hematopoietic cells. Competitive transplantation of bone marrow cells from PTPσ-deficient mice revealed that the loss of PTPσ substantially increased long-term HSC-repopulating capacity compared with BM cells from control mice. While HSCs from PTPσ-deficient mice had no apparent alterations in cell-cycle status, apoptosis, or homing capacity, these HSCs exhibited increased levels of activated RAC1, a RhoGTPase that regulates HSC engraftment capacity. shRNA-mediated silencing of PTPσ also increased activated RAC1 levels in wild-type HSCs. Functionally, PTPσ-deficient BM cells displayed increased cobblestone area-forming cell (CAFC) capacity and augmented transendothelial migration capacity, which was abrogated by RAC inhibition. Specific selection of human cord blood CD34⁺CD38⁻CD45RA⁻lin⁻ PTPσ⁻ cells substantially increased the repopulating capacity of human HSCs compared with CD34⁺CD38⁻CD45RA⁻lin⁻ cells and CD34⁺CD38⁻CD45RA⁻lin⁻PTPσ⁺ cells. Our results demonstrate that PTPσ regulates HSC functional capacity via RAC1 inhibition and suggest that selecting for PTPσ-negative human HSCs may be an effective strategy for enriching human HSCs for transplantation.

Authors
Quarmyne, M; Doan, PL; Himburg, HA; Yan, X; Nakamura, M; Zhao, L; Chao, NJ; Chute, JP
MLA Citation
Quarmyne, M, Doan, PL, Himburg, HA, Yan, X, Nakamura, M, Zhao, L, Chao, NJ, and Chute, JP. "Protein tyrosine phosphatase-σ regulates hematopoietic stem cell-repopulating capacity." The Journal of clinical investigation 125.1 (January 2015): 177-182.
PMID
25415437
Source
epmc
Published In
Journal of Clinical Investigation
Volume
125
Issue
1
Publish Date
2015
Start Page
177
End Page
182
DOI
10.1172/jci77866

The International Cancer Expert Corps: A Unique Approach for Sustainable Cancer Care in Low and Lower-Middle Income Countries

Authors
Coleman, CN; Formenti, SC; Williams, TR; Petereit, DG; Soo, KC; Wong, J; Chao, N; Shulman, LN; Grover, S; Magrath, I; Hahn, S; Liu, F-F; DeWeese, T; Khleif, SN; Steinberg, M; Roth, L; Pistenmaa, DA; Love, RR; Mohiuddin, M; Vikram, B
MLA Citation
Coleman, CN, Formenti, SC, Williams, TR, Petereit, DG, Soo, KC, Wong, J, Chao, N, Shulman, LN, Grover, S, Magrath, I, Hahn, S, Liu, F-F, DeWeese, T, Khleif, SN, Steinberg, M, Roth, L, Pistenmaa, DA, Love, RR, Mohiuddin, M, and Vikram, B. "The International Cancer Expert Corps: A Unique Approach for Sustainable Cancer Care in Low and Lower-Middle Income Countries." Frontiers in Oncology 4 (November 19, 2014).
Source
crossref
Published In
Frontiers in Oncology
Volume
4
Publish Date
2014
DOI
10.3389/fonc.2014.00333

Pleiotrophin mediates hematopoietic regeneration via activation of RAS.

Hematopoietic stem cells (HSCs) are highly susceptible to ionizing radiation-mediated death via induction of ROS, DNA double-strand breaks, and apoptotic pathways. The development of therapeutics capable of mitigating ionizing radiation-induced hematopoietic toxicity could benefit both victims of acute radiation sickness and patients undergoing hematopoietic cell transplantation. Unfortunately, therapies capable of accelerating hematopoietic reconstitution following lethal radiation exposure have remained elusive. Here, we found that systemic administration of pleiotrophin (PTN), a protein that is secreted by BM-derived endothelial cells, substantially increased the survival of mice following radiation exposure and after myeloablative BM transplantation. In both models, PTN increased survival by accelerating the recovery of BM hematopoietic stem and progenitor cells in vivo. PTN treatment promoted HSC regeneration via activation of the RAS pathway in mice that expressed protein tyrosine phosphatase receptor-zeta (PTPRZ), whereas PTN treatment did not induce RAS signaling in PTPRZ-deficient mice, suggesting that PTN-mediated activation of RAS was dependent upon signaling through PTPRZ. PTN strongly inhibited HSC cycling following irradiation, whereas RAS inhibition abrogated PTN-mediated induction of HSC quiescence, blocked PTN-mediated recovery of hematopoietic stem and progenitor cells, and abolished PTN-mediated survival of irradiated mice. These studies demonstrate the therapeutic potential of PTN to improve survival after myeloablation and suggest that PTN-mediated hematopoietic regeneration occurs in a RAS-dependent manner.

Authors
Himburg, HA; Yan, X; Doan, PL; Quarmyne, M; Micewicz, E; McBride, W; Chao, NJ; Slamon, DJ; Chute, JP
MLA Citation
Himburg, HA, Yan, X, Doan, PL, Quarmyne, M, Micewicz, E, McBride, W, Chao, NJ, Slamon, DJ, and Chute, JP. "Pleiotrophin mediates hematopoietic regeneration via activation of RAS." The Journal of clinical investigation 124.11 (November 2014): 4753-4758.
PMID
25250571
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
11
Publish Date
2014
Start Page
4753
End Page
4758
DOI
10.1172/jci76838

Verification of a novel method for tube voltage constancy measurement of orthovoltage x-ray irradiators.

For orthovoltage x-ray irradiators, the tube voltage is one of the most fundamental system parameters as this directly relates to the dosimetry in radiation biology studies; however, to the best of our knowledge, there is no commercial portable quality assurance (QA) tool to directly test the constancy of the tube voltage greater than 160 kV. The purpose of this study is to establish the Beam Quality Index (BQI), a quantity strongly correlated to the tube voltage, as an alternative parameter for the verification of the tube voltage as part of the QA program of orthovoltage x-ray irradiators.A multipurpose QA meter and its associated data acquisition software were used to customize the measurement parameters to measure the BQI and collect its time-plot. BQI measurements were performed at 320 kV with four filtration levels on three orthovoltage x-ray irradiators of the same model, one of which had been recently energy-calibrated at the factory.For each of the four filtration levels, the measured BQI values were in good agreement (<5%) between the three irradiators. BQI showed filtration-specificity, possibly due to the difference in beam quality.The BQI has been verified as a feasible alternative for monitoring the constancy of the tube voltage for orthovoltage irradiators. The time-plot of BQI offers information on the behavior of beam energy at different phases of the irradiation time line. In addition, this would provide power supply performance characteristics from initial ramp-up to plateau, and finally, the sharp drop-off at the end of the exposure.

Authors
Wang, C; Belley, MD; Chao, NJ; Dewhirst, MW; Yoshizumi, T
MLA Citation
Wang, C, Belley, MD, Chao, NJ, Dewhirst, MW, and Yoshizumi, T. "Verification of a novel method for tube voltage constancy measurement of orthovoltage x-ray irradiators." Medical physics 41.8 (August 2014): 084101-.
PMID
25086562
Source
epmc
Published In
Medical physics
Volume
41
Issue
8
Publish Date
2014
Start Page
084101
DOI
10.1118/1.4889778

Allotransplantation for patients age ≥40 years with non-Hodgkin lymphoma: encouraging progression-free survival.

Non-Hodgkin lymphoma (NHL) disproportionately affects older patients, who do not often undergo allogeneic hematopoietic cell transplantation (HCT). We analyzed Center for International Blood and Marrow Transplant Research data on 1248 patients age ≥40 years receiving reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning HCT for aggressive (n = 668) or indolent (n = 580) NHL. Aggressive lymphoma was more frequent in the oldest cohort 49% for age 40 to 54 versus 57% for age 55 to 64 versus 67% for age ≥65; P = .0008). Fewer patients aged ≥65 had previous autografting (26% versus 24% versus 9%; P = .002). Rates of relapse, acute and chronic GVHD, and nonrelapse mortality (NRM) at 1 year post-HCT were similar in the 3 age cohorts (22% [95% confidence interval (CI), 19% to 26%] for age 40 to 54, 27% [95% CI, 23% to 31%] for age 55 to 64, and 34% [95% CI, 24% to 44%] for age ≥65. Progression-free survival (PFS) and overall survival (OS) at 3 years was slightly lower in the older cohorts (OS: 54% [95% CI, 50% to 58%] for age 40 to 54; 40% [95% CI, 36% to 44%] for age 55 to 64, and 39% [95% CI, 28% to 50%] for age ≥65; P < .0001). Multivariate analysis revealed no significant effect of age on the incidence of acute or chronic GVHD or relapse. Age ≥55 years, Karnofsky Performance Status <80, and HLA mismatch adversely affected NRM, PFS, and OS. Disease status at HCT, but not histological subtype, was associated with worse NRM, relapse, PFS, and OS. Even for patients age ≥55 years, OS still approached 40% at 3 years, suggesting that HCT affects long-term remission and remains underused in qualified older patients with NHL.

Authors
McClune, BL; Ahn, KW; Wang, H-L; Antin, JH; Artz, AS; Cahn, J-Y; Deol, A; Freytes, CO; Hamadani, M; Holmberg, LA; Jagasia, MH; Jakubowski, AA; Kharfan-Dabaja, MA; Lazarus, HM; Miller, AM; Olsson, R; Pedersen, TL; Pidala, J; Pulsipher, MA; Rowe, JM; Saber, W; van Besien, KW; Waller, EK; Aljurf, MD; Akpek, G; Bacher, U; Chao, NJ; Chen, Y-B; Cooper, BW; Dehn, J; de Lima, MJ; Hsu, JW; Lewis, ID; Marks, DI; McGuirk, J; Cairo, MS; Schouten, HC; Szer, J; Ramanathan, M; Savani, BN; Seftel, M; Socie, G et al.
MLA Citation
McClune, BL, Ahn, KW, Wang, H-L, Antin, JH, Artz, AS, Cahn, J-Y, Deol, A, Freytes, CO, Hamadani, M, Holmberg, LA, Jagasia, MH, Jakubowski, AA, Kharfan-Dabaja, MA, Lazarus, HM, Miller, AM, Olsson, R, Pedersen, TL, Pidala, J, Pulsipher, MA, Rowe, JM, Saber, W, van Besien, KW, Waller, EK, Aljurf, MD, Akpek, G, Bacher, U, Chao, NJ, Chen, Y-B, Cooper, BW, Dehn, J, de Lima, MJ, Hsu, JW, Lewis, ID, Marks, DI, McGuirk, J, Cairo, MS, Schouten, HC, Szer, J, Ramanathan, M, Savani, BN, Seftel, M, and Socie, G et al. "Allotransplantation for patients age ≥40 years with non-Hodgkin lymphoma: encouraging progression-free survival." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20.7 (July 2014): 960-968.
PMID
24641829
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
20
Issue
7
Publish Date
2014
Start Page
960
End Page
968
DOI
10.1016/j.bbmt.2014.03.013

Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment.

Delayed hematopoietic recovery is a major drawback of umbilical cord blood (UCB) transplantation. Transplantation of ex vivo-expanded UCB shortens time to hematopoietic recovery, but long-term, robust engraftment by the expanded unit has yet to be demonstrated. We tested the hypothesis that a UCB-derived cell product consisting of stem cells expanded for 21 days in the presence of nicotinamide and a noncultured T cell fraction (NiCord) can accelerate hematopoietic recovery and provide long-term engraftment.In a phase I trial, 11 adults with hematologic malignancies received myeloablative bone marrow conditioning followed by transplantation with NiCord and a second unmanipulated UCB unit. Safety, hematopoietic recovery, and donor engraftment were assessed and compared with historical controls.No adverse events were attributable to the infusion of NiCord. Complete or partial neutrophil and T cell engraftment derived from NiCord was observed in 8 patients, and NiCord engraftment remained stable in all patients, with a median follow-up of 21 months. Two patients achieved long-term engraftment with the unmanipulated unit. Patients transplanted with NiCord achieved earlier median neutrophil recovery (13 vs. 25 days, P < 0.001) compared with that seen in historical controls. The 1-year overall and progression-free survival rates were 82% and 73%, respectively.UCB-derived hematopoietic stem and progenitor cells expanded in the presence of nicotinamide and transplanted with a T cell-containing fraction contain both short-term and long-term repopulating cells. The results justify further study of NiCord transplantation as a single UCB graft. If long-term safety is confirmed, NiCord has the potential to broaden accessibility and reduce the toxicity of UCB transplantation.Clinicaltrials.gov NCT01221857.Gamida Cell Ltd.

Authors
Horwitz, ME; Chao, NJ; Rizzieri, DA; Long, GD; Sullivan, KM; Gasparetto, C; Chute, JP; Morris, A; McDonald, C; Waters-Pick, B; Stiff, P; Wease, S; Peled, A; Snyder, D; Cohen, EG; Shoham, H; Landau, E; Friend, E; Peleg, I; Aschengrau, D; Yackoubov, D; Kurtzberg, J; Peled, T
MLA Citation
Horwitz, ME, Chao, NJ, Rizzieri, DA, Long, GD, Sullivan, KM, Gasparetto, C, Chute, JP, Morris, A, McDonald, C, Waters-Pick, B, Stiff, P, Wease, S, Peled, A, Snyder, D, Cohen, EG, Shoham, H, Landau, E, Friend, E, Peleg, I, Aschengrau, D, Yackoubov, D, Kurtzberg, J, and Peled, T. "Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment." The Journal of clinical investigation 124.7 (July 2014): 3121-3128.
PMID
24911148
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
7
Publish Date
2014
Start Page
3121
End Page
3128
DOI
10.1172/jci74556

How I treat sinusoidal obstruction syndrome.

Sinusoidal obstruction syndrome (SOS), previously called veno-occlusive disease (VOD) can be a difficult problem after hematopoietic cell transplantation (HCT). The overall incidence has changed since the early days of allogeneic HCT. Prophylaxis and treatment remain important components of supportive care. As the indication and the comorbidities for HCT continue to change, especially with older and more infirm patients, SOS remains an important area for clinicians. I discuss how SOS could be addressed, from prophylaxis to diagnosis and potential therapy.

Authors
Chao, N
MLA Citation
Chao, N. "How I treat sinusoidal obstruction syndrome." Blood 123.26 (June 2014): 4023-4026.
PMID
24833355
Source
epmc
Published In
Blood
Volume
123
Issue
26
Publish Date
2014
Start Page
4023
End Page
4026
DOI
10.1182/blood-2014-03-551630

Loss of β-catenin triggers oxidative stress and impairs hematopoietic regeneration.

Accidental or deliberate ionizing radiation exposure can be fatal due to widespread hematopoietic destruction. However, little is known about either the course of injury or the molecular pathways that regulate the subsequent regenerative response. Here we show that the Wnt signaling pathway is critically important for regeneration after radiation-induced injury. Using Wnt reporter mice, we show that radiation triggers activation of Wnt signaling in hematopoietic stem and progenitor cells. β-Catenin-deficient mice, which lack the ability to activate canonical Wnt signaling, exhibited impaired hematopoietic stem cell regeneration and bone marrow recovery after radiation. We found that, as part of the mechanism, hematopoietic stem cells lacking β-catenin fail to suppress the generation of reactive oxygen species and cannot resolve DNA double-strand breaks after radiation. Consistent with the impaired response to radiation, β-catenin-deficient mice are also unable to recover effectively after chemotherapy. Collectively, these data indicate that regenerative responses to distinct hematopoietic injuries share a genetic dependence on β-catenin and raise the possibility that modulation of Wnt signaling may be a path to improving bone marrow recovery after damage.

Authors
Lento, W; Ito, T; Zhao, C; Harris, JR; Huang, W; Jiang, C; Owzar, K; Piryani, S; Racioppi, L; Chao, N; Reya, T
MLA Citation
Lento, W, Ito, T, Zhao, C, Harris, JR, Huang, W, Jiang, C, Owzar, K, Piryani, S, Racioppi, L, Chao, N, and Reya, T. "Loss of β-catenin triggers oxidative stress and impairs hematopoietic regeneration." Genes & development 28.9 (May 2014): 995-1004.
PMID
24788518
Source
epmc
Published In
Genes & development
Volume
28
Issue
9
Publish Date
2014
Start Page
995
End Page
1004
DOI
10.1101/gad.231944.113

Inhibiting glycogen synthase kinase-3 mitigates the hematopoietic acute radiation syndrome in mice.

Exposure to a nuclear accident or radiological attack can cause death from acute radiation syndrome (ARS), which results from radiation injury to vital organs such as the hematopoietic system. However, the U.S. Food and Drug Administration (FDA) has not approved any medical countermeasures for this specific purpose. With growing concern over nuclear terrorism, there is an urgent need to develop small molecule deliverables that mitigate mortality from ARS. One emerging modulator of hematopoietic stem/progenitor cell (HSPC) activity is glycogen synthase kinase-3 (GSK-3). The inhibition of GSK-3 has been shown to augment hematopoietic repopulation in mouse models of bone marrow transplantation. In this study, we performed an in vitro screen using irradiated bone marrow mononuclear cells (BM-MNCs) to test the effects of four GSK-3 inhibitors: CHIR99021; 6-Bromoindirubin-3'-oxime (BIO); SB415286; and SB216763. This screen showed that SB216763 significantly increased the frequency of c-Kit(+) Lin(-) Sca1(+) (KLS) cells and hematopoietic colony-forming cells in irradiated BM-MNCs. Importantly, administration of a single dose of SB216763 to C57BL/6J mice by subcutaneous injection 24 h after total-body irradiation significantly improved hematopoietic recovery and mitigated hematopoietic ARS. Collectively, our results demonstrate that the GSK-3 inhibitor SB216763 is an effective medical countermeasure against acute radiation injury of the hematopoietic system.

Authors
Lee, C-L; Lento, WE; Castle, KD; Chao, NJ; Kirsch, DG
MLA Citation
Lee, C-L, Lento, WE, Castle, KD, Chao, NJ, and Kirsch, DG. "Inhibiting glycogen synthase kinase-3 mitigates the hematopoietic acute radiation syndrome in mice." Radiation research 181.5 (May 2014): 445-451.
PMID
24720754
Source
epmc
Published In
Radiation Research
Volume
181
Issue
5
Publish Date
2014
Start Page
445
End Page
451
DOI
10.1667/rr13692.1

Increased BCR responsiveness in B cells from patients with chronic GVHD.

Although B cells have emerged as important contributors to chronic graft-versus-host-disease (cGVHD) pathogenesis, the mechanisms responsible for their sustained activation remain unknown. We previously showed that patients with cGVHD have significantly increased B cell-activating factor (BAFF) levels and that their B cells are activated and resistant to apoptosis. Exogenous BAFF confers a state of immediate responsiveness to antigen stimulation in normal murine B cells. To address this in cGVHD, we studied B-cell receptor (BCR) responsiveness in 48 patients who were >1 year out from allogeneic hematopoietic stem cell transplantation (HSCT). We found that B cells from cGVHD patients had significantly increased proliferative responses to BCR stimulation along with elevated basal levels of the proximal BCR signaling components B cell linker protein (BLNK) and Syk. After initiation of BCR signaling, cGVHD B cells exhibited increased BLNK and Syk phosphorylation compared with B cells from patients without cGVHD. Blocking Syk kinase activity prevented relative post-HSCT BCR hyper-responsiveness of cGVHD B cells. These data suggest that a lowered BCR signaling threshold in cGVHD associates with increased B-cell proliferation and activation in response to antigen. We reveal a mechanism underpinning aberrant B-cell activation in cGVHD and suggest that therapeutic inhibition of the involved kinases may benefit these patients.

Authors
Allen, JL; Tata, PV; Fore, MS; Wooten, J; Rudra, S; Deal, AM; Sharf, A; Hoffert, T; Roehrs, PA; Shea, TC; Serody, JS; Richards, KL; Jagasia, M; Lee, SJ; Rizzieri, D; Horwitz, ME; Chao, NJ; Sarantopoulos, S
MLA Citation
Allen, JL, Tata, PV, Fore, MS, Wooten, J, Rudra, S, Deal, AM, Sharf, A, Hoffert, T, Roehrs, PA, Shea, TC, Serody, JS, Richards, KL, Jagasia, M, Lee, SJ, Rizzieri, D, Horwitz, ME, Chao, NJ, and Sarantopoulos, S. "Increased BCR responsiveness in B cells from patients with chronic GVHD." Blood 123.13 (March 2014): 2108-2115.
PMID
24532806
Source
epmc
Published In
Blood
Volume
123
Issue
13
Publish Date
2014
Start Page
2108
End Page
2115
DOI
10.1182/blood-2013-10-533562

Toward an organ based dose prescription method for the improved accuracy of murine dose in orthovoltage x-ray irradiators.

Accurate dosimetry is essential when irradiating mice to ensure that functional and molecular endpoints are well understood for the radiation dose delivered. Conventional methods of prescribing dose in mice involve the use of a single dose rate measurement and assume a uniform average dose throughout all organs of the entire mouse. Here, the authors report the individual average organ dose values for the irradiation of a 12, 23, and 33 g mouse on a 320 kVp x-ray irradiator and calculate the resulting error from using conventional dose prescription methods.Organ doses were simulated in the Geant4 application for tomographic emission toolkit using the MOBY mouse whole-body phantom. Dosimetry was performed for three beams utilizing filters A (1.65 mm Al), B (2.0 mm Al), and C (0.1 mm Cu + 2.5 mm Al), respectively. In addition, simulated x-ray spectra were validated with physical half-value layer measurements.Average doses in soft-tissue organs were found to vary by as much as 23%-32% depending on the filter. Compared to filters A and B, filter C provided the hardest beam and had the lowest variation in soft-tissue average organ doses across all mouse sizes, with a difference of 23% for the median mouse size of 23 g.This work suggests a new dose prescription method in small animal dosimetry: it presents a departure from the conventional approach of assigninga single dose value for irradiation of mice to a more comprehensive approach of characterizing individual organ doses to minimize the error and uncertainty. In human radiation therapy, clinical treatment planning establishes the target dose as well as the dose distribution, however, this has generally not been done in small animal research. These results suggest that organ dose errors will be minimized by calibrating the dose rates for all filters, and using different dose rates for different organs.

Authors
Belley, MD; Wang, C; Nguyen, G; Gunasingha, R; Chao, NJ; Chen, BJ; Dewhirst, MW; Yoshizumi, TT
MLA Citation
Belley, MD, Wang, C, Nguyen, G, Gunasingha, R, Chao, NJ, Chen, BJ, Dewhirst, MW, and Yoshizumi, TT. "Toward an organ based dose prescription method for the improved accuracy of murine dose in orthovoltage x-ray irradiators." Medical physics 41.3 (March 2014): 034101-.
PMID
24593746
Source
epmc
Published In
Medical physics
Volume
41
Issue
3
Publish Date
2014
Start Page
034101
DOI
10.1118/1.4864237

WT1 vaccination in acute myeloid leukemia: new methods of implementing adoptive immunotherapy.

INTRODUCTION: The Wilms tumor 1 (WT1) gene was originally identified as a tumor suppressor gene that, when mutated, would lead to the development of pediatric renal tumors. More recently, it has been determined that WT1 is overexpressed in 90% of patients with acute myeloid leukemia (AML) and is mutated in approximately 10% of AML patients. WT1 plays a role in normal hematopoiesis and, in AML specifically, it has oncogenic function and plays an important role in cellular proliferation and differentiation. The ubiquity of WT1 in leukemia has lead to the development of vaccines aimed at employing the host immune system to mount a T-cell response to a known antigen. AREAS COVERED: In this evaluation, the authors discuss the role of WT1 in normal hematopoiesis as well as in the development of hematologic malignancies. Furthermore, the authors discuss the data supporting the development of WT1 vaccines, and the clinical trials supporting their use in patients with acute leukemia. EXPERT OPINION: Several small trials have been conducted which support the safety and efficacy of this therapy, although larger trials are certainly warranted. In the authors' opinion, the WT1 vaccination has potential in terms of its application as an adjuvant therapy for patients with AML who are at high risk of relapse or who have detectable minimal residual disease after initial standard therapy.

Authors
Rein, LAM; Chao, NJ
MLA Citation
Rein, LAM, and Chao, NJ. "WT1 vaccination in acute myeloid leukemia: new methods of implementing adoptive immunotherapy." Expert opinion on investigational drugs 23.3 (March 2014): 417-426.
PMID
24521058
Source
epmc
Published In
Expert Opinion on Investigational Drugs
Volume
23
Issue
3
Publish Date
2014
Start Page
417
End Page
426
DOI
10.1517/13543784.2014.889114

Reduced-intensity allogeneic transplantation using alemtuzumab from HLA-matched related, unrelated, or haploidentical related donors for patients with hematologic malignancies.

We present a comparative study on 124 patients with hematologic malignancies who had undergone reduced-intensity conditioning and then received a transplant from an HLA-matched related (MRD), an HLA-matched unrelated (MUD), or an HLA-haploidentical related (HAPLO) donor. The conditioning regimen, which consisted of fludarabine, melphalan or busulfan, and alemtuzumab was administered to patients with lymphoid (n = 62) or myeloid disease (n = 62). Mycophenolate mofetil was used as prophylaxis for graft-versus-host disease (GVHD), and 38, 58, and 33 patients received transplants from MRD, MUD, and HAPLO donors, respectively. Only 2 patients experienced primary graft failure (GF) after melphalan-based regimen, whereas 8 of the 17 patients who received a transplant from HAPLO donors experienced a primary GF after busulfan-based regimen. The cumulative incidence of grade III to IV acute GVHD in engrafted patients who had received transplants from MRD, MUD, or HAPLO donors was 3%, 11%, and 27%, respectively, and the 2-year overall survival (OS) rates were 51%, 22%, and 23%, respectively. According to multivariate analysis, transplantation from either MUD or HAPLO donors compared with MRD were adverse factors that affected the OS (P = .006 and P = .002, respectively). In conclusion, the reduced-intensity regimen that included fludarabine, busulfan, or melphalan and alemtuzumab using only mycophenolate mofetil as the GVHD prophylaxis conferred favorable outcomes in the MRD group but lower survival rates in the MUD and HAPLO groups. The busulfan-based regimen led to a high incidence of GF in the HAPLO group, suggesting the need for modification or intensification of immunosuppression.

Authors
Kanda, J; Long, GD; Gasparetto, C; Horwitz, ME; Sullivan, KM; Chute, JP; Morris, A; Shafique, M; Li, Z; Chao, NJ; Rizzieri, DA
MLA Citation
Kanda, J, Long, GD, Gasparetto, C, Horwitz, ME, Sullivan, KM, Chute, JP, Morris, A, Shafique, M, Li, Z, Chao, NJ, and Rizzieri, DA. "Reduced-intensity allogeneic transplantation using alemtuzumab from HLA-matched related, unrelated, or haploidentical related donors for patients with hematologic malignancies." Biol Blood Marrow Transplant 20.2 (February 2014): 257-263.
PMID
24269380
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
20
Issue
2
Publish Date
2014
Start Page
257
End Page
263
DOI
10.1016/j.bbmt.2013.11.010

A translatable predictor of human radiation exposure.

Terrorism using radiological dirty bombs or improvised nuclear devices is recognized as a major threat to both public health and national security. In the event of a radiological or nuclear disaster, rapid and accurate biodosimetry of thousands of potentially affected individuals will be essential for effective medical management to occur. Currently, health care providers lack an accurate, high-throughput biodosimetric assay which is suitable for the triage of large numbers of radiation injury victims. Here, we describe the development of a biodosimetric assay based on the analysis of irradiated mice, ex vivo-irradiated human peripheral blood (PB) and humans treated with total body irradiation (TBI). Interestingly, a gene expression profile developed via analysis of murine PB radiation response alone was inaccurate in predicting human radiation injury. In contrast, generation of a gene expression profile which incorporated data from ex vivo irradiated human PB and human TBI patients yielded an 18-gene radiation classifier which was highly accurate at predicting human radiation status and discriminating medically relevant radiation dose levels in human samples. Although the patient population was relatively small, the accuracy of this classifier in discriminating radiation dose levels in human TBI patients was not substantially confounded by gender, diagnosis or prior exposure to chemotherapy. We have further incorporated genes from this human radiation signature into a rapid and high-throughput chemical ligation-dependent probe amplification assay (CLPA) which was able to discriminate radiation dose levels in a pilot study of ex vivo irradiated human blood and samples from human TBI patients. Our results illustrate the potential for translation of a human genetic signature for the diagnosis of human radiation exposure and suggest the basis for further testing of CLPA as a candidate biodosimetric assay.

Authors
Lucas, J; Dressman, HK; Suchindran, S; Nakamura, M; Chao, NJ; Himburg, H; Minor, K; Phillips, G; Ross, J; Abedi, M; Terbrueggen, R; Chute, JP
MLA Citation
Lucas, J, Dressman, HK, Suchindran, S, Nakamura, M, Chao, NJ, Himburg, H, Minor, K, Phillips, G, Ross, J, Abedi, M, Terbrueggen, R, and Chute, JP. "A translatable predictor of human radiation exposure." PloS one 9.9 (January 2014): e107897-.
Website
http://hdl.handle.net/10161/10977
PMID
25255453
Source
epmc
Published In
PloS one
Volume
9
Issue
9
Publish Date
2014
Start Page
e107897
DOI
10.1371/journal.pone.0107897

G protein-coupled receptor kinase-3-deficient mice exhibit WHIM syndrome features and attenuated inflammatory responses

Chemokine receptor interactions coordinate leukocyte migration in inflammation. Chemokine receptors are GPCRs that when activated, are phosphorylated by GRKs to turn off G protein-mediated signaling yet recruit additional signaling machinery. Recently, GRK3 was identified as a negative regulator of CXCL12/ CXCR4 signaling that is defective in human WHIM syndrome. Here, we report that GRK3-/- mice exhibit numerous features of human WHIM, such as impaired CXCL12-mediated desensitization, enhanced CXCR4 signaling to ERK activation, altered granulocyte migration, and a mild myelokathexis. Moreover, GRK3 -/-protects mice from two acute models of inflammatory arthritis (K/BxN serum transfer and CAIA). In these granulocyte-dependent disease models, protection of GRK3-/- mice is mediated by retention of cells in the marrow, fewer circulating granulocytes in the peripheral blood, and reduced granulocytes in the joints during active inflammation. In contrast to WHIM, GRK3-/- mice have minimal hypogammaglobulinemia and a peripheral leukocytosis with increased lymphocytes and absent neutropenia. Thus, we conclude that the loss of GRK3-mediated regulation of CXCL12/CXCR4 signaling contributes to some, but not all, of the complete WHIM phenotype and that GRK3 inhibition may be beneficial in the treatment of inflammatory arthritis. J. Leukoc. Biol. 94: 1243-1251; 2013. © Society for Leukocyte Biology.

Authors
Tarrant, TK; Billard, MJ; Timoshchenko, RG; McGinnis, MW; Stephen Serafin, D; Foreman, O; Esserman, DA; Chao, NJ; Lento, WE; Lee, DM; Patel, D; Siderovski, DP
MLA Citation
Tarrant, TK, Billard, MJ, Timoshchenko, RG, McGinnis, MW, Stephen Serafin, D, Foreman, O, Esserman, DA, Chao, NJ, Lento, WE, Lee, DM, Patel, D, and Siderovski, DP. "G protein-coupled receptor kinase-3-deficient mice exhibit WHIM syndrome features and attenuated inflammatory responses." Journal of Leukocyte Biology 94.6 (December 1, 2013): 1243-1251.
PMID
23935208
Source
scopus
Published In
Journal of leukocyte biology
Volume
94
Issue
6
Publish Date
2013
Start Page
1243
End Page
1251
DOI
10.1189/jlb.0213097

Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease.

Acute graft-versus-host disease (aGVHD) is the leading cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Approximately 35% to 50% of HCT recipients develop aGVHD; however, there are no validated diagnostic and predictive blood biomarkers for aGVHD in clinical use. Here, we show that plasma samples from aGVHD patients have a distinct microRNA (miRNA) expression profile. We found that 6 miRNAs (miR-423, miR-199a-3p, miR-93*, miR-377, miR-155, and miR-30a) were significantly upregulated in the plasma of aGVHD patients (n = 116) when compared with non-GVHD patients (n = 52) in training and validation phases. We have developed a model including 4 miRNAs (miR-423, miR-199a-3p, miR-93*, and miR-377) that can predict the probability of aGVHD with an area under the curve of 0.80. Moreover, these elevated miRNAs were detected before the onset of aGVHD (median = 16 days before diagnosis). In addition, the levels of these miRNAs were positively associated with aGVHD severity, and high expression of the miRNA panel was associated with poor overall survival. Furthermore, the miRNA signature for aGVHD was not detected in the plasma of lung transplant or nontransplant sepsis patients. Our results have identified a specific plasma miRNA signature that may serve as an independent biomarker for the prediction, diagnosis, and prognosis of aGVHD.

Authors
Xiao, B; Wang, Y; Li, W; Baker, M; Guo, J; Corbet, K; Tsalik, EL; Li, Q-J; Palmer, SM; Woods, CW; Li, Z; Chao, NJ; He, Y-W
MLA Citation
Xiao, B, Wang, Y, Li, W, Baker, M, Guo, J, Corbet, K, Tsalik, EL, Li, Q-J, Palmer, SM, Woods, CW, Li, Z, Chao, NJ, and He, Y-W. "Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease." Blood 122.19 (November 7, 2013): 3365-3375.
PMID
24041574
Source
pubmed
Published In
Blood
Volume
122
Issue
19
Publish Date
2013
Start Page
3365
End Page
3375
DOI
10.1182/blood-2013-06-510586

Outcomes and costs of autologous stem cell mobilization with chemotherapy plus G-CSF vs G-CSF alone

Chemotherapy plus G-CSF (C+G) and G-CSF alone are two of the most common methods used to mobilize CD34 + cells for autologous hematopoietic SCT (AHSCT). In order to compare and determine the real-world outcomes and costs of these strategies, we performed a retrospective study of 226 consecutive patients at 11 medical centers (64 lymphoma, 162 multiple myeloma), of whom 55% of lymphoma patients and 66% of myeloma patients received C+G. Patients with C+G yielded more CD34 + cells/day than those with G-CSF alone (lymphoma: average 5.51 × 10 6 cells/kg on day 1 vs 2.92 × 10 6 cells/kg, P=0.0231; myeloma: 4.16 × 10 6 vs 3.69 × 10 6 cells/kg, P<0.00001) and required fewer days of apheresis (lymphoma: average 2.11 vs 2.96 days, P=0.012; myeloma: 2.02 vs 2.83 days, P=0.0015), although nearly all patients ultimately reached the goal of 2 × 10 6 cells/kg. With the exception of higher rates of febrile neutropenia in myeloma patients with C+G (17% vs 2%, P<0.05), toxicities and other outcomes were similar. Mobilization with C+G cost significantly more (lymphoma: median $10 300 vs $7300, P<0.0001; myeloma: $8800 vs $5600, P<0.0001), although re-mobilization adds $6700 for drugs alone. Our results suggest that although both C+G and G-CSF alone are effective mobilization strategies, C+G may be more cost-effective for patients at high risk of insufficient mobilization.

Authors
Sung, AD; Grima, DT; Bernard, LM; Brown, S; Carrum, G; Holmberg, L; Horwitz, ME; Liesveld, JL; Kanda, J; McClune, B; Shaughnessy, P; Tricot, GJ; Chao, NJ
MLA Citation
Sung, AD, Grima, DT, Bernard, LM, Brown, S, Carrum, G, Holmberg, L, Horwitz, ME, Liesveld, JL, Kanda, J, McClune, B, Shaughnessy, P, Tricot, GJ, and Chao, NJ. "Outcomes and costs of autologous stem cell mobilization with chemotherapy plus G-CSF vs G-CSF alone." Bone Marrow Transplantation 48.11 (November 1, 2013): 1444-1449.
Source
scopus
Published In
Bone Marrow Transplantation
Volume
48
Issue
11
Publish Date
2013
Start Page
1444
End Page
1449
DOI
10.1038/bmt.2013.80

Outcomes and costs of autologous stem cell mobilization with chemotherapy plus G-CSF vs G-CSF alone.

Chemotherapy plus G-CSF (C+G) and G-CSF alone are two of the most common methods used to mobilize CD34(+) cells for autologous hematopoietic SCT (AHSCT). In order to compare and determine the real-world outcomes and costs of these strategies, we performed a retrospective study of 226 consecutive patients at 11 medical centers (64 lymphoma, 162 multiple myeloma), of whom 55% of lymphoma patients and 66% of myeloma patients received C+G. Patients with C+G yielded more CD34(+) cells/day than those with G-CSF alone (lymphoma: average 5.51 × 10(6) cells/kg on day 1 vs 2.92 × 10(6) cells/kg, P=0.0231; myeloma: 4.16 × 10(6) vs 3.69 × 10(6) cells/kg, P<0.00001) and required fewer days of apheresis (lymphoma: average 2.11 vs 2.96 days, P=0.012; myeloma: 2.02 vs 2.83 days, P=0.0015), although nearly all patients ultimately reached the goal of 2 × 10(6) cells/kg. With the exception of higher rates of febrile neutropenia in myeloma patients with C+G (17% vs 2%, P<0.05), toxicities and other outcomes were similar. Mobilization with C+G cost significantly more (lymphoma: median $10,300 vs $7300, P<0.0001; myeloma: $8800 vs $5600, P<0.0001), although re-mobilization adds $6700 for drugs alone. Our results suggest that although both C+G and G-CSF alone are effective mobilization strategies, C+G may be more cost-effective for patients at high risk of insufficient mobilization.

Authors
Sung, AD; Grima, DT; Bernard, LM; Brown, S; Carrum, G; Holmberg, L; Horwitz, ME; Liesveld, JL; Kanda, J; McClune, B; Shaughnessy, P; Tricot, GJ; Chao, NJ
MLA Citation
Sung, AD, Grima, DT, Bernard, LM, Brown, S, Carrum, G, Holmberg, L, Horwitz, ME, Liesveld, JL, Kanda, J, McClune, B, Shaughnessy, P, Tricot, GJ, and Chao, NJ. "Outcomes and costs of autologous stem cell mobilization with chemotherapy plus G-CSF vs G-CSF alone." Bone marrow transplantation 48.11 (November 2013): 1444-1449.
PMID
23749109
Source
epmc
Published In
Bone Marrow Transplantation
Volume
48
Issue
11
Publish Date
2013
Start Page
1444
End Page
1449
DOI
10.1038/bmt.2013.80

Acute graft-versus-host disease: are we close to bringing the bench to the bedside?

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplant (AHSCT) associated with significant morbidity and mortality. This review focuses on the pathophysiology, prevention, and treatment of acute GVHD. Specifically, we explain how new discoveries in immunology have expanded our understanding of GVHD, in which tissue damage from chemotherapy or radiation results in cytokine release, activating T cells, resulting in proliferation and differentiation, trafficking to target organs, and tissue destruction and inflammation. Insights into the mechanisms of this disease relate directly to the development of preventive strategies and therapies, such as immunosuppression, calcineurin inhibitors, T-cell depletion, CCR5 antagonists, gut decontamination, extracorporeal photopheresis, and more. Understanding the immunobiology of GVHD and developing effective preventions and treatments are critical to the continuing success of AHSCT.

Authors
Sung, AD; Chao, NJ
MLA Citation
Sung, AD, and Chao, NJ. "Acute graft-versus-host disease: are we close to bringing the bench to the bedside?." Best practice & research. Clinical haematology 26.3 (September 2013): 285-292. (Review)
PMID
24309532
Source
epmc
Published In
Best Practice & Research: Clinical Haematology
Volume
26
Issue
3
Publish Date
2013
Start Page
285
End Page
292
DOI
10.1016/j.beha.2013.10.009

Pre-engraftment syndrome after myeloablative dual umbilical cord blood transplantation: risk factors and response to treatment.

High fevers and/or rashes prior to neutrophil engraftment are frequently observed after umbilical cord blood (UCB) transplantation, and the condition is referred to as pre-engraftment syndrome (PES). Few studies have evaluated the risk factors for and treatment response to PES. Therefore, we retrospectively characterized PES in 57 consecutive engrafted patients (≥ 12 years old) who received myeloablative dual UCB transplantation. All patients received TBI (≥ 13.2 Gy)-based myeloablative conditioning. Tacrolimus (n=35) or CYA (n=22) combined with mycophenolate mofetil was used as GVHD prophylaxis. PES was defined as the presence of non-infectious fever (≥ 38.5 °C) and/or rash prior to or on the day of neutrophil engraftment. The incidence (95% confidence interval) of PES was 77% (66-88%). The incidence of PES was significantly higher in patients who received CYA as a GVHD prophylaxis than those who received tacrolimus (P<0.001), and this association was confirmed in the multivariate analysis. The occurrence of PES did not impact OS or tumor relapse, although it may have increased non-relapse mortality (P=0.071). The incidence of acute GHVD or treatment-related mortality was not influenced by the choice to use corticosteroids to treat PES. This study suggests that use of CYA for GVHD prophylaxis increases the risk of PES following dual UCB transplantation.

Authors
Kanda, J; Kaynar, L; Kanda, Y; Prasad, VK; Parikh, SH; Lan, L; Shen, T; Rizzieri, DA; Long, GD; Sullivan, KM; Gasparetto, C; Chute, JP; Morris, A; Winkel, S; McPherson, J; Kurtzberg, J; Chao, NJ; Horwitz, ME
MLA Citation
Kanda, J, Kaynar, L, Kanda, Y, Prasad, VK, Parikh, SH, Lan, L, Shen, T, Rizzieri, DA, Long, GD, Sullivan, KM, Gasparetto, C, Chute, JP, Morris, A, Winkel, S, McPherson, J, Kurtzberg, J, Chao, NJ, and Horwitz, ME. "Pre-engraftment syndrome after myeloablative dual umbilical cord blood transplantation: risk factors and response to treatment." Bone Marrow Transplant 48.7 (July 2013): 926-931.
PMID
23334274
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
48
Issue
7
Publish Date
2013
Start Page
926
End Page
931
DOI
10.1038/bmt.2012.279

Insulin-like growth factor 1 mitigates hematopoietic toxicity after lethal total body irradiation.

PURPOSE: To investigate whether and how insulin-like growth factor 1 (IGF-1) mitigates hematopoietic toxicity after total body irradiation. METHODS AND MATERIALS: BALB/c mice were irradiated with a lethal dose of radiation (7.5 Gy) and treated with IGF-1 at a dose of 100 μg/dose intravenously once a day for 5 consecutive days starting within 1 hour after exposure. Survival and hematopoietic recovery were monitored. The mechanisms by which IGF-1 promotes hematopoietic recovery were also studied by use of an in vitro culture system. RESULTS: IGF-1 protected 8 of 20 mice (40%) from lethal irradiation, whereas only 2 of 20 mice (10%) in the saline control group survived for more than 100 days after irradiation. A single dose of IGF-1 (500 μg) was as effective as daily dosing for 5 days. Positive effects were noted even when the initiation of treatment was delayed as long as 6 hours after irradiation. In comparison with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red blood cells in peripheral blood, total cell numbers, hematopoietic stem cells, and progenitor cells in the bone marrow when measured at day 14 after irradiation. IGF-1 protected both hematopoietic stem cells and progenitor cells from radiation-induced apoptosis and cell death. In addition, IGF-1 was able to facilitate the proliferation and differentiation of nonirradiated and irradiated hematopoietic progenitor cells. CONCLUSIONS: IGF-1 mitigates radiation-induced hematopoietic toxicity through protecting hematopoietic stem cells and progenitor cells from apoptosis and enhancing proliferation and differentiation of the surviving hematopoietic progenitor cells.

Authors
Zhou, D; Deoliveira, D; Kang, Y; Choi, SS; Li, Z; Chao, NJ; Chen, BJ
MLA Citation
Zhou, D, Deoliveira, D, Kang, Y, Choi, SS, Li, Z, Chao, NJ, and Chen, BJ. "Insulin-like growth factor 1 mitigates hematopoietic toxicity after lethal total body irradiation." Int J Radiat Oncol Biol Phys 85.4 (March 15, 2013): 1141-1148.
PMID
23021438
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
85
Issue
4
Publish Date
2013
Start Page
1141
End Page
1148
DOI
10.1016/j.ijrobp.2012.08.014

Epidermal growth factor regulates hematopoietic regeneration after radiation injury.

The mechanisms that regulate hematopoietic stem cell (HSC) regeneration after myelosuppressive injury are not well understood. We identified epidermal growth factor (EGF) to be highly enriched in the bone marrow serum of mice bearing deletion of Bak and Bax in TIE2-expressing cells in Tie2Cre; Bak1(-/-); Bax(flox/-) mice. These mice showed radioprotection of the HSC pool and 100% survival after a lethal dose of total-body irradiation (TBI). Bone marrow HSCs from wild-type mice expressed functional EGF receptor (EGFR), and systemic administration of EGF promoted the recovery of the HSC pool in vivo and improved the survival of mice after TBI. Conversely, administration of erlotinib, an EGFR antagonist, decreased both HSC regeneration and the survival of mice after TBI. Mice with EGFR deficiency in VAV-expressing hematopoietic cells also had delayed recovery of bone marrow stem and progenitor cells after TBI. Mechanistically, EGF reduced radiation-induced apoptosis of HSCs and mediated this effect through repression of the proapoptotic protein PUMA. Our findings show that EGFR signaling regulates HSC regeneration after myelosuppressive injury.

Authors
Doan, PL; Himburg, HA; Helms, K; Russell, JL; Fixsen, E; Quarmyne, M; Harris, JR; Deoliviera, D; Sullivan, JM; Chao, NJ; Kirsch, DG; Chute, JP
MLA Citation
Doan, PL, Himburg, HA, Helms, K, Russell, JL, Fixsen, E, Quarmyne, M, Harris, JR, Deoliviera, D, Sullivan, JM, Chao, NJ, Kirsch, DG, and Chute, JP. "Epidermal growth factor regulates hematopoietic regeneration after radiation injury." Nat Med 19.3 (March 2013): 295-304.
PMID
23377280
Source
pubmed
Published In
Nature Medicine
Volume
19
Issue
3
Publish Date
2013
Start Page
295
End Page
304
DOI
10.1038/nm.3070

A Phase I study of arsenic trioxide (Trisenox), ascorbic acid, and bortezomib (Velcade) combination therapy in patients with relapsed/refractory multiple myeloma.

PURPOSE: This Phase I study assessed the feasibility of concomitant arsenic trioxide (ATO), ascorbic acid (AA), and bortezomib (Velcade™) (AAV) for patients with relapsed/refractory multiple myeloma. EXPERIMENTAL DESIGN: ATO (0.25 mg/kg) and AA (1 g) were given with an escalating dose of bortezomib (1 mg/m(2) or 1.3 mg/m(2) IV bolus on days 1 and 8 of a 21-day cycle). RESULTS: Ten patients (median age 62 years), with a median of 3 prior regimens, were enrolled. Four (40%) patients achieved clinical benefit, with one patient achieving a durable partial response. No formal DLTs were encountered. CONCLUSION: AAV combination was feasible and demonstrated some benefits in this heavily pretreated population.

Authors
Held, LA; Rizzieri, D; Long, GD; Gockerman, JP; Diehl, LF; de Castro, CM; Moore, JO; Horwitz, ME; Chao, NJ; Gasparetto, C
MLA Citation
Held, LA, Rizzieri, D, Long, GD, Gockerman, JP, Diehl, LF, de Castro, CM, Moore, JO, Horwitz, ME, Chao, NJ, and Gasparetto, C. "A Phase I study of arsenic trioxide (Trisenox), ascorbic acid, and bortezomib (Velcade) combination therapy in patients with relapsed/refractory multiple myeloma." Cancer Invest 31.3 (March 2013): 172-176.
PMID
23406188
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
31
Issue
3
Publish Date
2013
Start Page
172
End Page
176
DOI
10.3109/07357907.2012.756109

Tie2(+) bone marrow endothelial cells regulate hematopoietic stem cell regeneration following radiation injury.

Hematopoietic stem cells (HSCs) reside in proximity to bone marrow endothelial cells (BM ECs) and maintenance of the HSC pool is dependent upon EC-mediated c-kit signaling. Here, we used genetic models to determine whether radioprotection of BM ECs could facilitate hematopoietic regeneration following radiation-induced myelosuppression. We developed mice bearing deletion of the proapoptotic proteins, BAK and BAX, in Tie2(+) ECs and HSCs (Tie2Bak/Bax(Fl/-) mice) and compared their hematopoietic recovery following total body irradiation (TBI) with mice which retained Bax in Tie2(+) cells. Mice bearing deletion of Bak and Bax in Tie2(+) cells demonstrated protection of BM HSCs, preserved BM vasculature, and 100% survival following lethal dose TBI. In contrast, mice that retained Bax expression in Tie2(+) cells demonstrated depletion of BM HSCs, disrupted BM vasculature, and 10% survival post-TBI. In a complementary study, VEcadherinBak/Bax(Fl/-) mice, which lack Bak and Bax in VEcadherin(+) ECs, also demonstrated increased recovery of BM stem/progenitor cells following TBI compared to mice which retained Bax in VEcadherin(+) ECs. Importantly, chimeric mice that lacked Bak and Bax in HSCs but retained Bak and Bax in BM ECs displayed significantly decreased HSC content and survival following TBI compared to mice lacking Bak and Bax in both HSCs and BM ECs. These data suggest that the hematopoietic response to ionizing radiation is dependent upon HSC-autonomous responses but is regulated by BM EC-mediated mechanisms. Therefore, BM ECs may be therapeutically targeted as a means to augment hematopoietic reconstitution following myelosuppression.

Authors
Doan, PL; Russell, JL; Himburg, HA; Helms, K; Harris, JR; Lucas, J; Holshausen, KC; Meadows, SK; Daher, P; Jeffords, LB; Chao, NJ; Kirsch, DG; Chute, JP
MLA Citation
Doan, PL, Russell, JL, Himburg, HA, Helms, K, Harris, JR, Lucas, J, Holshausen, KC, Meadows, SK, Daher, P, Jeffords, LB, Chao, NJ, Kirsch, DG, and Chute, JP. "Tie2(+) bone marrow endothelial cells regulate hematopoietic stem cell regeneration following radiation injury." Stem Cells 31.2 (February 2013): 327-337.
PMID
23132593
Source
pubmed
Published In
Stem Cells
Volume
31
Issue
2
Publish Date
2013
Start Page
327
End Page
337
DOI
10.1002/stem.1275

Concise review: acute graft-versus-host disease: immunobiology, prevention, and treatment.

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplant (AHSCT) associated with significant morbidity and mortality. This review focuses on the pathophysiology, clinical features, prevention, and treatment of acute GVHD. Specifically, we explain how new discoveries in immunology have expanded our understanding of GVHD, in which tissue damage from chemotherapy or radiation results in cytokine release, which activates T cells, resulting in proliferation and differentiation, trafficking to target organs, and tissue destruction and inflammation. Insights into the mechanisms of this disease relate directly to the development of preventive strategies and therapies, such as immunosuppression, T-cell depletion, calcineurin inhibitors, CCR5 antagonists, gut decontamination, extracorporeal photopheresis, and more. We also discuss how GVHD affects the gut, liver, and skin, as well as diagnosis, grading, and scoring. We end by examining future directions of treatment, including new immunomodulators and biomarkers. Understanding the immunobiology of GVHD and developing effective preventions and treatments are critical to the continuing success of AHSCT.

Authors
Sung, AD; Chao, NJ
MLA Citation
Sung, AD, and Chao, NJ. "Concise review: acute graft-versus-host disease: immunobiology, prevention, and treatment." Stem cells translational medicine 2.1 (January 2013): 25-32. (Review)
PMID
23283494
Source
epmc
Published In
Stem cells translational medicine
Volume
2
Issue
1
Publish Date
2013
Start Page
25
End Page
32
DOI
10.5966/sctm.2012-0115

Acute graft-versus-host disease: Are we close to bringing the bench to the bedside?

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplant (AHSCT) associated with significant morbidity and mortality. This review focuses on the pathophysiology, prevention, and treatment of acute GVHD. Specifically, we explain how new discoveries in immunology have expanded our understanding of GVHD, in which tissue damage from chemotherapy or radiation results in cytokine release, activating T cells, resulting in proliferation and differentiation, trafficking to target organs, and tissue destruction and inflammation. Insights into the mechanisms of this disease relate directly to the development of preventive strategies and therapies, such as immunosuppression, calcineurin inhibitors, T-cell depletion, CCR5 antagonists, gut decontamination, extracorporeal photopheresis, and more. Understanding the immunobiology of GVHD and developing effective preventions and treatments are critical to the continuing success of AHSCT. © 2013 Elsevier Ltd. All rights reserved.

Authors
Sung, AD; Chao, NJ
MLA Citation
Sung, AD, and Chao, NJ. "Acute graft-versus-host disease: Are we close to bringing the bench to the bedside?." Bailliere's Best Practice and Research in Clinical Haematology (2013).
Source
scival
Published In
Best Practice & Research: Clinical Haematology
Publish Date
2013
DOI
10.1016/j.beha.2013.10.009

Long-term in vivo imaging of multiple organs at the single cell level.

Two-photon microscopy has enabled the study of individual cell behavior in live animals. Many organs and tissues cannot be studied, especially longitudinally, because they are located too deep, behind bony structures or too close to the lung and heart. Here we report a novel mouse model that allows long-term single cell imaging of many organs. A wide variety of live tissues were successfully engrafted in the pinna of the mouse ear. Many of these engrafted tissues maintained the normal tissue histology. Using the heart and thymus as models, we further demonstrated that the engrafted tissues functioned as would be expected. Combining two-photon microscopy with fluorescent tracers, we successfully visualized the engrafted tissues at the single cell level in live mice over several months. Four dimensional (three-dimensional (3D) plus time) information of individual cells was obtained from this imaging. This model makes long-term high resolution 4D imaging of multiple organs possible.

Authors
Chen, BJ; Jiao, Y; Zhang, P; Sun, AY; Pitt, GS; Deoliveira, D; Drago, N; Ye, T; Liu, C; Chao, NJ
MLA Citation
Chen, BJ, Jiao, Y, Zhang, P, Sun, AY, Pitt, GS, Deoliveira, D, Drago, N, Ye, T, Liu, C, and Chao, NJ. "Long-term in vivo imaging of multiple organs at the single cell level." PLoS One 8.1 (2013): e52087-.
PMID
23300962
Source
pubmed
Published In
PloS one
Volume
8
Issue
1
Publish Date
2013
Start Page
e52087
DOI
10.1371/journal.pone.0052087

Insulin-like growth factor 1 mitigates hematopoietic toxicity after lethal total body irradiation

Purpose: To investigate whether and how insulin-like growth factor 1 (IGF-1) mitigates hematopoietic toxicity after total body irradiation. Methods and Materials: BALB/c mice were irradiated with a lethal dose of radiation (7.5 Gy) and treated with IGF-1 at a dose of 100 μg/dose intravenously once a day for 5 consecutive days starting within 1 hour after exposure. Survival and hematopoietic recovery were monitored. The mechanisms by which IGF-1 promotes hematopoietic recovery were also studied by use of an in vitro culture system. Results: IGF-1 protected 8 of 20 mice (40%) from lethal irradiation, whereas only 2 of 20 mice (10%) in the saline control group survived for more than 100 days after irradiation. A single dose of IGF-1 (500 μg) was as effective as daily dosing for 5 days. Positive effects were noted even when the initiation of treatment was delayed as long as 6 hours after irradiation. In comparison with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red blood cells in peripheral blood, total cell numbers, hematopoietic stem cells, and progenitor cells in the bone marrow when measured at day 14 after irradiation. IGF-1 protected both hematopoietic stem cells and progenitor cells from radiation-induced apoptosis and cell death. In addition, IGF-1 was able to facilitate the proliferation and differentiation of nonirradiated and irradiated hematopoietic progenitor cells. Conclusions: IGF-1 mitigates radiation-induced hematopoietic toxicity through protecting hematopoietic stem cells and progenitor cells from apoptosis and enhancing proliferation and differentiation of the surviving hematopoietic progenitor cells. © 2013 Elsevier Inc. All rights reserved.

Authors
Zhou, D; Deoliveira, D; Kang, Y; Choi, SS; Li, Z; Chao, NJ; Chen, BJ
MLA Citation
Zhou, D, Deoliveira, D, Kang, Y, Choi, SS, Li, Z, Chao, NJ, and Chen, BJ. "Insulin-like growth factor 1 mitigates hematopoietic toxicity after lethal total body irradiation." International Journal of Radiation Oncology Biology Physics 85.4 (2013): 1141-1148.
Source
scival
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
85
Issue
4
Publish Date
2013
Start Page
1141
End Page
1148
DOI
10.1016/j.ijrobp.2012.08.014

Double unit grafts successfully extend the application of umbilical cord blood transplantation in adults with acute leukemia

Cell dose is a major limitation for umbilical cord blood (UCB) transplantation because units containing a minimum of 2.5 × 107 total nucleated cells (TNC)/kilogram patient body weight are frequently not available. The transplantation of 2 partially HLA-matched UCB units has been adopted as a simple approach for increasing the TNC. We sought to determine whether the relative safety and efficacy of this approach was comparable with a single UCB transplantation. Included are adults with acute leukemia who received transplants with 1 (n = 106) or 2 (n = 303) UCB units. All UCB units for single UCB transplantations contained TNC ≥ 2.5 × 107/kg. For double UCB transplantations, the total TNC for units 1 and 2 were > 2.5 × 107/kg but in approximately half of these transplantations, 1 of the 2 units contained < 2.5 × 107 TNC/kg. Adjusting for factors associated with outcomes, risks of neutrophil recovery (odds ratio 0.83, P = .59), transplantation-related mortality (hazard ratio [HR] 0.91, P = .63), relapse (HR 0.90, P = .64), and overall mortality (HR 0.93, P = .62) was similar after double UCB and adequate dose single UCB transplantations. These data support double UCB unit transplantation for acute leukemia when an adequately dosed single UCB unit is not available thereby extending access to nearly all patients. © 2013 by The American Society of Hematology.

Authors
Scaradavou, A; Brunstein, CG; Eapen, M; Le-Rademacher, J; Barker, JN; Chao, N; Cutler, C; Delaney, C; Kan, F; Isola, L; Karanes, C; Laughlin, MJ; Wagner, JE; Shpall, EJ
MLA Citation
Scaradavou, A, Brunstein, CG, Eapen, M, Le-Rademacher, J, Barker, JN, Chao, N, Cutler, C, Delaney, C, Kan, F, Isola, L, Karanes, C, Laughlin, MJ, Wagner, JE, and Shpall, EJ. "Double unit grafts successfully extend the application of umbilical cord blood transplantation in adults with acute leukemia." Blood 121.5 (2013): 752-758.
PMID
23223509
Source
scival
Published In
Blood
Volume
121
Issue
5
Publish Date
2013
Start Page
752
End Page
758
DOI
10.1182/blood-2012-08-449108

Karl Georg Blume, MD

Authors
Forman, SJ; Negrin, R; Chao, N
MLA Citation
Forman, SJ, Negrin, R, and Chao, N. "Karl Georg Blume, MD." Biology of Blood and Marrow Transplantation 19.6 (2013): 845-846.
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
19
Issue
6
Publish Date
2013
Start Page
845
End Page
846
DOI
10.1016/j.bbmt.2013.04.003

Blazing a new TRAIL in hematopoietic cell transplantation

There is a ying/yang to most biological therapies, and the balance of efficacy versus toxicity is delicate and sometimes difficult to achieve in favor of the patients. When the therapeutic window is wide, these therapies can be used in the majority of patients, but when the therapeutic window is narrow, the decision to proceed must be carefully balanced with a thoughtful risk-benefit analysis. In this issue of the JCI, Ghosh et al. tackle one of the major obstacles in hematopoietic cell transplantation (HCT) technology: balancing the beneficial antitumor effect with the harmful anti-host effect. Copyright © 2013, American Society for Clinical Investigation.

Authors
Chao, N
MLA Citation
Chao, N. "Blazing a new TRAIL in hematopoietic cell transplantation." Journal of Clinical Investigation 123.6 (2013): 2362-2363.
PMID
23676458
Source
scival
Published In
Journal of Clinical Investigation
Volume
123
Issue
6
Publish Date
2013
Start Page
2362
End Page
2363
DOI
10.1172/JCI69909

Pre-engraftment syndrome after myeloablative dual umbilical cord blood transplantation: Risk factors and response to treatment

High fevers and/or rashes prior to neutrophil engraftment are frequently observed after umbilical cord blood (UCB) transplantation, and the condition is referred to as pre-engraftment syndrome (PES). Few studies have evaluated the risk factors for and treatment response to PES. Therefore, we retrospectively characterized PES in 57 consecutive engrafted patients (≥12 years old) who received myeloablative dual UCB transplantation. All patients received TBI (≥13.2 Gy)-based myeloablative conditioning. Tacrolimus (n=35) or CYA (n=22) combined with mycophenolate mofetil was used as GVHD prophylaxis. PES was defined as the presence of non-infectious fever (≥38.5 °C) and/or rash prior to or on the day of neutrophil engraftment. The incidence (95% confidence interval) of PES was 77% (66-88%). The incidence of PES was significantly higher in patients who received CYA as a GVHD prophylaxis than those who received tacrolimus (P<0.001), and this association was confirmed in the multivariate analysis. The occurrence of PES did not impact OS or tumor relapse, although it may have increased non-relapse mortality (P=0.071). The incidence of acute GHVD or treatment-related mortality was not influenced by the choice to use corticosteroids to treat PES. This study suggests that use of CYA for GVHD prophylaxis increases the risk of PES following dual UCB transplantation. © 2013 Macmillan Publishers Limited All rights reserved.

Authors
Kanda, J; Kaynar, L; Kanda, Y; Prasad, VK; Parikh, SH; Lan, L; Shen, T; Rizzieri, DA; Long, GD; Sullivan, KM; Gasparetto, C; Chute, JP; Morris, A; Winkel, S; McPherson, J; Kurtzberg, J; Chao, NJ; Horwitz, ME
MLA Citation
Kanda, J, Kaynar, L, Kanda, Y, Prasad, VK, Parikh, SH, Lan, L, Shen, T, Rizzieri, DA, Long, GD, Sullivan, KM, Gasparetto, C, Chute, JP, Morris, A, Winkel, S, McPherson, J, Kurtzberg, J, Chao, NJ, and Horwitz, ME. "Pre-engraftment syndrome after myeloablative dual umbilical cord blood transplantation: Risk factors and response to treatment." Bone Marrow Transplantation 48.7 (2013): 926-931.
Source
scival
Published In
Bone Marrow Transplantation
Volume
48
Issue
7
Publish Date
2013
Start Page
926
End Page
931
DOI
10.1038/bmt.2012.279

Pharmacoeconomics of hematopoietic stem cell mobilization: An overview of current evidence and gaps in the literature

Adequate hematopoietic stem cell (HSC) mobilization and collection is required prior to proceeding with high dose chemotherapy and autologous hematopoietic stem cell transplant. Cytokines such as G-CSF, GM-CSF, and peg-filgrastim, alone or in combination with plerixafor, and after chemotherapy have been used to mobilize HSCs. Studies have shown that the efficiency of HSC mobilization and collection may vary when different methods of mobilization are used. No studies have shown that survival is significantly affected by the method of mobilization, but some studies have suggested that cost and resource utilization may be different between different mobilization techniques. After the FDA approval of plerixafor with G-CSF to mobilize HSCs many transplant centers became concerned about the cost of HSC mobilization. A panel of experts was convened ant this paper reviews the current literature on the pharmacoeconomics of HSC mobilization. © 2013 American Society for Blood and Marrow Transplantation.

Authors
Shaughnessy, P; Chao, N; Shapiro, J; Walters, K; McCarty, J; Abhyankar, S; Shayani, S; Helmons, P; Leather, H; Pazzalia, A; Pickard, S
MLA Citation
Shaughnessy, P, Chao, N, Shapiro, J, Walters, K, McCarty, J, Abhyankar, S, Shayani, S, Helmons, P, Leather, H, Pazzalia, A, and Pickard, S. "Pharmacoeconomics of hematopoietic stem cell mobilization: An overview of current evidence and gaps in the literature." Biology of Blood and Marrow Transplantation 19.9 (2013): 1301-1309.
PMID
23685251
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
19
Issue
9
Publish Date
2013
Start Page
1301
End Page
1309
DOI
10.1016/j.bbmt.2013.05.008

Immune recovery in adult patients after myeloablative dual umbilical cord blood, matched sibling, and matched unrelated donor hematopoietic cell transplantation.

Immunologic reconstitution after allogeneic hematopoietic cell transplantation is a critical component of successful outcome. Umbilical cord blood (UCB) transplantation in adult recipients is associated with slow and often inadequate immune recovery. We characterized the kinetics and extent of immune recovery in 95 adult recipients after a dual UCB (n = 29) and matched sibling donor (n = 33) or matched unrelated donor (n = 33) transplantation. All patients were treated with myeloablative conditioning. There were no differences in the immune recovery profile of matched sibling donor and matched unrelated donor recipients. Significantly lower levels of CD3+, CD4+, and CD8+ T cells were observed in UCB recipients until 6 months after transplantation. Lower levels of regulatory T cells persisted until 1 year after transplantation. Thymopoiesis as measured by TCR rearrangement excision circle was comparable among all recipients by 6 months after transplantation. In a subset of patients 1 year after transplantation with similar levels of circulating T cells and TCR rearrangement excision circle, there was no difference in TCR diversity. Compared to HLA-identical matched sibling donor and matched unrelated donor adult hematopoietic cell transplantation recipients, quantitative lymphoid recovery in UCB transplantation recipients is slower in the first 3 months, but these differences disappeared by 6 to 12 months after transplantation.

Authors
Kanda, J; Chiou, L-W; Szabolcs, P; Sempowski, GD; Rizzieri, DA; Long, GD; Sullivan, KM; Gasparetto, C; Chute, JP; Morris, A; McPherson, J; Hale, J; Livingston, JA; Broadwater, G; Niedzwiecki, D; Chao, NJ; Horwitz, ME
MLA Citation
Kanda, J, Chiou, L-W, Szabolcs, P, Sempowski, GD, Rizzieri, DA, Long, GD, Sullivan, KM, Gasparetto, C, Chute, JP, Morris, A, McPherson, J, Hale, J, Livingston, JA, Broadwater, G, Niedzwiecki, D, Chao, NJ, and Horwitz, ME. "Immune recovery in adult patients after myeloablative dual umbilical cord blood, matched sibling, and matched unrelated donor hematopoietic cell transplantation." Biol Blood Marrow Transplant 18.11 (November 2012): 1664-1676.e1.
PMID
22698485
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
18
Issue
11
Publish Date
2012
Start Page
1664
End Page
1676.e1
DOI
10.1016/j.bbmt.2012.06.005

Mini test dose of intravenous busulfan (busulfex(®)) in allogeneic non-myeloablative stem cell transplantation, followed by liquid chromatography tandem-mass spectrometry.

Authors
Spasojevic, I; da Costa, LRS; Horwitz, ME; Long, GD; Sullivan, KM; Chute, JP; Gasparetto, C; Morris, A; Chao, NJ; Rizzieri, DA
MLA Citation
Spasojevic, I, da Costa, LRS, Horwitz, ME, Long, GD, Sullivan, KM, Chute, JP, Gasparetto, C, Morris, A, Chao, NJ, and Rizzieri, DA. "Mini test dose of intravenous busulfan (busulfex(®)) in allogeneic non-myeloablative stem cell transplantation, followed by liquid chromatography tandem-mass spectrometry." Cancer Invest 30.9 (November 2012): 679-682.
PMID
23020519
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
30
Issue
9
Publish Date
2012
Start Page
679
End Page
682
DOI
10.3109/07357907.2012.726386

Pleiotrophin regulates the retention and self-renewal of hematopoietic stem cells in the bone marrow vascular niche.

The mechanisms through which the bone marrow (BM) microenvironment regulates hematopoietic stem cell (HSC) fate remain incompletely understood. We examined the role of the heparin-binding growth factor pleiotrophin (PTN) in regulating HSC function in the niche. PTN(-/-) mice displayed significantly decreased BM HSC content and impaired hematopoietic regeneration following myelosuppression. Conversely, mice lacking protein tyrosine phosphatase receptor zeta, which is inactivated by PTN, displayed significantly increased BM HSC content. Transplant studies revealed that PTN action was not HSC autonomous, but rather was mediated by the BM microenvironment. Interestingly, PTN was differentially expressed and secreted by BM sinusoidal endothelial cells within the vascular niche. Furthermore, systemic administration of anti-PTN antibody in mice substantially impaired both the homing of hematopoietic progenitor cells to the niche and the retention of BM HSCs in the niche. PTN is a secreted component of the BM vascular niche that regulates HSC self-renewal and retention in vivo.

Authors
Himburg, HA; Harris, JR; Ito, T; Daher, P; Russell, JL; Quarmyne, M; Doan, PL; Helms, K; Nakamura, M; Fixsen, E; Herradon, G; Reya, T; Chao, NJ; Harroch, S; Chute, JP
MLA Citation
Himburg, HA, Harris, JR, Ito, T, Daher, P, Russell, JL, Quarmyne, M, Doan, PL, Helms, K, Nakamura, M, Fixsen, E, Herradon, G, Reya, T, Chao, NJ, Harroch, S, and Chute, JP. "Pleiotrophin regulates the retention and self-renewal of hematopoietic stem cells in the bone marrow vascular niche." Cell Rep 2.4 (October 25, 2012): 964-975.
PMID
23084748
Source
pubmed
Published In
Cell Reports
Volume
2
Issue
4
Publish Date
2012
Start Page
964
End Page
975
DOI
10.1016/j.celrep.2012.09.002

Heparan sulfate, an endogenous TLR4 agonist, promotes acute GVHD after allogeneic stem cell transplantation.

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.

Authors
Brennan, TV; Lin, L; Huang, X; Cardona, DM; Li, Z; Dredge, K; Chao, NJ; Yang, Y
MLA Citation
Brennan, TV, Lin, L, Huang, X, Cardona, DM, Li, Z, Dredge, K, Chao, NJ, and Yang, Y. "Heparan sulfate, an endogenous TLR4 agonist, promotes acute GVHD after allogeneic stem cell transplantation." Blood 120.14 (October 4, 2012): 2899-2908.
PMID
22760779
Source
pubmed
Published In
Blood
Volume
120
Issue
14
Publish Date
2012
Start Page
2899
End Page
2908
DOI
10.1182/blood-2011-07-368720

Allospecific CD4(+) effector memory T cells do not induce graft-versus-host disease in mice.

We studied whether allospecific CD4(+) effector memory T cells (T(EM)) could induce graft-versus-host disease (GVHD) using a novel GVHD model induced solely by CD4(+) T cell receptor transgenic TEa cells. Allospecific T(EM) generated in a lymphopenic host bore a typical memory phenotype. Moreover, these cells were able to elicit a faster and more effective proliferative response on challenge with alloantigen in vitro and to mediate "second-set" skin graft rejection in vivo. However, these allospecific T(EM) were unable to induce GVHD. Allospecific T(EM) recipients became tolerant to alloantigen as a result of clonal deletion. Even though allospecific T(EM) were able to respond to alloantigen initially, the expansion of these cells and inflammatory cytokine production during GVHD were dramatically decreased. The inability of allospecific T(EM) to sustain the alloresponse may be a result of enhanced activation-induced cell death. These observations provide insight into how allospecific CD4(+) T(EM) respond to alloantigen during GVHD and underscore the fundamental differences in alloresponses mediated by allospecific T(EM) in graft rejection and GVHD settings.

Authors
Zhang, P; Wu, J; Deoliveira, D; Chao, NJ; Chen, BJ
MLA Citation
Zhang, P, Wu, J, Deoliveira, D, Chao, NJ, and Chen, BJ. "Allospecific CD4(+) effector memory T cells do not induce graft-versus-host disease in mice." Biol Blood Marrow Transplant 18.10 (October 2012): 1488-1499.
PMID
22809867
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
18
Issue
10
Publish Date
2012
Start Page
1488
End Page
1499
DOI
10.1016/j.bbmt.2012.07.009

Preemptive dosing of plerixafor given to poor stem cell mobilizers on day 5 of G-CSF administration.

Plerixafor, given on day 4 of G-CSF treatment is more effective than G-CSF alone in mobilizing hematopoietic progenitor cells. We tested a strategy of preemptive plerixafor use following assessment of the peak mobilization response to 5 days of G-CSF. Patients were eligible for plerixafor if, on day 5 of G-CSF, there were <7 circulating CD34+ cells/μL or if <1.3 × 10(6) CD34+ cells/kg were collected on the first day of apheresis. Plerixafor (0.24 mg/kg s.c.) was given on day 5 of G-CSF followed by apheresis on day 6. This was repeated for up to two additional doses of plerixafor. The primary end point of the study was the percentage of patients who collected at least 2 × 10(6) CD34+ cells/kg. Twenty candidates for auto-SCT enrolled on the trial. The circulating CD34+ cell level increased a median of 3.1 fold (range 1-8 fold) after the first dose of plerixafor and a median of 1.2 fold (range 0.3-6.5 fold) after the second dose of plerixafor. In all, 15 out of 20 (75%) patients achieved the primary end point. In conclusion, the decision to administer plerixafor can be delayed until after the peak mobilization response to G-CSF has been fully assessed.

Authors
Horwitz, ME; Chute, JP; Gasparetto, C; Long, GD; McDonald, C; Morris, A; Rizzieri, DA; Sullivan, KM; Chao, NJ
MLA Citation
Horwitz, ME, Chute, JP, Gasparetto, C, Long, GD, McDonald, C, Morris, A, Rizzieri, DA, Sullivan, KM, and Chao, NJ. "Preemptive dosing of plerixafor given to poor stem cell mobilizers on day 5 of G-CSF administration." Bone Marrow Transplant 47.8 (August 2012): 1051-1055.
PMID
22080963
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
47
Issue
8
Publish Date
2012
Start Page
1051
End Page
1055
DOI
10.1038/bmt.2011.217

Differential impact of inhibitory and activating Killer Ig-Like Receptors (KIR) on high-risk patients with myeloid and lymphoid malignancies undergoing reduced intensity transplantation from haploidentical related donors.

The impact of activating KIR (aKIR) and inhibitory KIR (iKIR) on OS, relapse-related mortality (RRM) and acute GVHD (aGVHD) was prospectively studied in 84 adults with high-risk hematologic malignancies receiving reduced intensity conditioning (RIC) T-cell depleted hematopoietic SCT (HSCT) from haploidentical related donors. In this clinical model, freedom from RRM is dependent on GVL effect. Patients were divided into myeloid (n=49) and lymphoid (n=35) malignancy groups. KIR-ligand and ligand-ligand models were studied in both GVH and rejection directions and statistically correlated with outcome measures. In the myeloid group, OS was higher (P=0.009) and RRM was lower (P=0.036) in patients missing HLA-C group2 ligand to donor iKIR. OS was higher if patients had >1 missing ligand (P=0.018). In lymphoid malignancy, missing ligand to donor KIR had no impact on OS or RRM. However, OS was better with donor aKIR 2DS2 (P=0.028). There was a trend towards shorter OS in recipient with KIR 2DS1, 2DS5 and 3DS1, although sample sizes were too small to provide inferential statistics. Findings in lymphoid malignancy patients should be further studied. These results suggest that the absence of appropriate HLA ligands in the recipient to donor iKIR may induce GVL without aGVHD in myeloid malignancy patients undergoing TCD-RIC transplants.

Authors
Chen, D-F; Prasad, VK; Broadwater, G; Reinsmoen, NL; DeOliveira, A; Clark, A; Sullivan, KM; Chute, JP; Horwitz, ME; Gasparetto, C; Long, GD; Yang, Y; Chao, NJ; Rizzieri, DA
MLA Citation
Chen, D-F, Prasad, VK, Broadwater, G, Reinsmoen, NL, DeOliveira, A, Clark, A, Sullivan, KM, Chute, JP, Horwitz, ME, Gasparetto, C, Long, GD, Yang, Y, Chao, NJ, and Rizzieri, DA. "Differential impact of inhibitory and activating Killer Ig-Like Receptors (KIR) on high-risk patients with myeloid and lymphoid malignancies undergoing reduced intensity transplantation from haploidentical related donors." Bone Marrow Transplant 47.6 (June 2012): 817-823.
PMID
22139069
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
47
Issue
6
Publish Date
2012
Start Page
817
End Page
823
DOI
10.1038/bmt.2011.181

Outcomes of a 1-day nonmyeloablative salvage regimen for patients with primary graft failure after allogeneic hematopoietic cell transplantation.

Primary graft failure after allogeneic hematopoietic cell transplantation is a life-threatening complication. A shortened conditioning regimen may reduce the risk of infection and increase the chance of survival. Here, we report the outcome of 11 patients with hematologic diseases (median age, 44; range, 25-67 years, seven males) who received a 1-day reduced-intensity preparative regimen given as a re-transplantation for primary graft failure. The salvage regimen consisted of fludarabine, cyclophosphamide, alemtuzumab and TBI, all administered 1 day before re-transplantation. All patients received T-cell replete PBSCs from the same or a different haploidentical donor (n=10) or from the same matched sibling donor (n=1). Neutrophil counts promptly increased to >500/μL for 10 of the 11 patients at a median of 13 days. Of these, none developed grade III/IV acute GVHD. At present, 8 of the 11 patients are alive with a median follow-up of 11.2 months from re-transplantation and 5 of the 8 are in remission. In conclusion, this series suggests that our 1-day preparative regimen is feasible, leads to successful engraftment in a high proportion of patients, and is appropriate for patients requiring immediate re-transplantation after primary graft failure following reduced-intensity transplantation.

Authors
Kanda, J; Horwitz, ME; Long, GD; Gasparetto, C; Sullivan, KM; Chute, JP; Morris, A; Hennig, T; Li, Z; Chao, NJ; Rizzieri, DA
MLA Citation
Kanda, J, Horwitz, ME, Long, GD, Gasparetto, C, Sullivan, KM, Chute, JP, Morris, A, Hennig, T, Li, Z, Chao, NJ, and Rizzieri, DA. "Outcomes of a 1-day nonmyeloablative salvage regimen for patients with primary graft failure after allogeneic hematopoietic cell transplantation." Bone Marrow Transplant 47.5 (May 2012): 700-705.
PMID
21804612
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
47
Issue
5
Publish Date
2012
Start Page
700
End Page
705
DOI
10.1038/bmt.2011.158

Strategies to enhance hematopoietic stem cell engraftment following transplantation

© Springer Science+Business Media, LLC 2012.Following intravenous infusion of hematopoietic stem/progenitor cells (HSPCs) during hematopoietic cell transplantation (HCT), HSPCs home to and engraft in marrow niche microenvironment, which ultimately leads to reconstitution of whole immunological and hematological repertoire of the recipient. The homing and engraftment of HSPCs occur relatively early (during the initial stage of HCT), but have major impacts on the success and outcomes of transplantation. HSPC homing and engraftment require well-coordinated interplay involving various cells (endothelial cells, osteoblasts, osteoclasts, and other mesenchymal stem cells), cytokines and chemokines, soluble and membrane-bound factors, as well as extracellular matrix. Many aspects and the detailed mechanisms regulating HSPC homing and engraftment still remain to be elucidated. In this chapter, we first provide a brief overview of HSPC homing and engraftment processes and the interactions between HSPCs and various cell types and different molecules in the niche microenvironment. We then summarize several strategies to enhance HSPC homing and engraftment during HCT. In particular, we present ongoing studies in our laboratories using CXCR4 antagonists to enhance donor cell engraftment following HCT.

Authors
Kang, Y; Chao, NJ
MLA Citation
Kang, Y, and Chao, NJ. "Strategies to enhance hematopoietic stem cell engraftment following transplantation." Novel Developments in Stem Cell Mobilization: Focus on CXCR4. January 1, 2012. 439-456.
Source
scopus
Publish Date
2012
Start Page
439
End Page
456
DOI
10.1007/978-1-4614-1960-0_23

You Cannot Improve What You Do Not Measure

Authors
Chao, N
MLA Citation
Chao, N. "You Cannot Improve What You Do Not Measure." Biology of Blood and Marrow Transplantation 18.10 (2012): 1467-1468.
PMID
22771840
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
18
Issue
10
Publish Date
2012
Start Page
1467
End Page
1468
DOI
10.1016/j.bbmt.2012.07.001

Control of GVHD: It's in our DNA!

Selective depletion of the alloreactiveT cells causing graft-versus-host disease (GVHD) without loss of the graft-versus-leukemia (GVL) effect is the holy grail of hematopoietic cell transplantation (HCT). In this issue of Blood, He et al demonstrate that inhibition of histone methylation leads to selective apoptosis of the alloreactive effector cells. 1 Moreover, they demonstrate that this inhibition of histone methylation remarkably stops ongoing GVHD.

Authors
Chao, N
MLA Citation
Chao, N. "Control of GVHD: It's in our DNA!." Blood 119.5 (2012): 1102-1103.
Source
scival
Published In
Blood
Volume
119
Issue
5
Publish Date
2012
Start Page
1102
End Page
1103
DOI
10.1182/blood-2011-12-395905

Lenalidomide before and after Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma.

Although multiple myeloma remains incurable outside of allogeneic hematopoietic stem cell transplantation, novel agents made available only in the last few decades have nonetheless tremendously improved the landscape of myeloma treatment. Lenalidomide, of the immunomodulatory class of drugs, is one of those novel agents. In the non-transplant and relapsed/refractory settings, lenalidomide clearly benefits patients in terms of virtually all meaningful outcomes including overall survival. Data supporting the usage of lenalidomide as part of treatment approaches incorporating high-dose chemotherapy with autologous stem cell support (ASCT) are less mature as pertains to such long-term outcomes and toxicity, and lenalidomide is not currently approved by regulatory agencies for use in the context of ASCT in either the United States or Europe. That said, relatively preliminary efficacy data describing lenalidomide as a component of ASCT-based treatment approaches to MM are indeed promising, and consequently lenalidomide's role in ASCT-based treatment strategies is growing. In this review we summarize existing data that pertains to lenalidomide in the specific context of ASCT, and we share our thoughts on how our own group applies these data to approach this complex issue clinically.

Authors
Tuchman, SA; Chao, NJ; Gasparetto, CG
MLA Citation
Tuchman, SA, Chao, NJ, and Gasparetto, CG. "Lenalidomide before and after Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma." Adv Hematol 2012 (2012): 712613-.
PMID
22690220
Source
pubmed
Published In
Advances in Hematology
Volume
2012
Publish Date
2012
Start Page
712613
DOI
10.1155/2012/712613

Risk factors for acute GVHD and survival after hematopoietic cell transplantation

Risk factors for acute GVHD (AGVHD), overall survival, and transplant-related mortality were evaluated in adults receiving allogeneic hematopoietic cell transplants (1999-2005) from HLA-identical sibling donors (SDs; n = 3191) or unrelated donors (URDs; n = 2370) and reported to the Center for International Blood and Marrow Transplant Research, Minneapolis, MN. To understand the impact of transplant regimen onAGVHD risk, 6 treatment categories were evaluated: (1) myeloablative conditioning (MA) with total body irradiation (TBI) + PBSCs, (2) MA + TBI + BM, (3) MA + nonTBI + PB-SCs, (4) MA + nonTBI + BM, (5) reduced intensity conditioning (RIC) + PBSCs, and (6) RIC + BM. The cumulative incidences of grades B-D AGVHD were 39% (95% confidence interval [CI], 37%-41%) in the SD cohort and 59% (95% CI, 57%-61%) in the URD cohort. Patients receiving SD transplants with MA + nonTBI + BM and RIC + PBSCs had significantly lower risks of grades B-D AGVHD than patients in other treatment categories. Those receiving URD transplants with MA + TBI + BM, MA + nonTBI + BM, RIC + BM, or RIC + PB-SCs had lower risks of grades B-DAGVHD than those in other treatment categories. The 5-year probabilities of survival were 46% (95% CI, 44%-49%) with SD transplants and 33% (95% CI, 31%-35%) with URD transplants. Conditioning intensity, TBI and graft source have a combined effect on risk of AGVHD that must be considered in deciding on a treatment strategy for individual patients.

Authors
Jagasia, M; Arora, M; Flowers, MED; Chao, NJ; McCarthy, PL; Cutler, CS; Urbano-Ispizua, A; Pavletic, SZ; Haagenson, MD; Zhang, M-J; Antin, JH; Bolwell, BJ; Bredeson, C; Cahn, J-Y; Cairo, M; Gale, RP; Gupta, V; Lee, SJ; Litzow, M; Weisdorf, DJ; Horowitz, MM; Hahn, T
MLA Citation
Jagasia, M, Arora, M, Flowers, MED, Chao, NJ, McCarthy, PL, Cutler, CS, Urbano-Ispizua, A, Pavletic, SZ, Haagenson, MD, Zhang, M-J, Antin, JH, Bolwell, BJ, Bredeson, C, Cahn, J-Y, Cairo, M, Gale, RP, Gupta, V, Lee, SJ, Litzow, M, Weisdorf, DJ, Horowitz, MM, and Hahn, T. "Risk factors for acute GVHD and survival after hematopoietic cell transplantation." Blood 119.1 (2012): 296-307.
PMID
22010102
Source
scival
Published In
Blood
Volume
119
Issue
1
Publish Date
2012
Start Page
296
End Page
307
DOI
10.1182/blood-2011-06-364265

Radiation Disasters: Role of the BMT Team

Bone marrow transplant (BMT) teams do not generally consider themselves to be emergency responders. But the bone marrow is the most radiosensitive organ in the body, and early changes in peripheral blood counts remain the best indicator of major total-body radiation exposures. Following a mass casualty incident, such as that occasioned by a nuclear detonation, BMT teams should expect that they will be called upon for their expertise in managing severe myelosuppression. Numerous resources, including the Radiation Injury Treatment Network, are available to assist BMT teams in planning for such a role. © 2012.

Authors
Confer, DL; Weisdorf, D; Weinstock, D; Case, C; Chao, N
MLA Citation
Confer, DL, Weisdorf, D, Weinstock, D, Case, C, and Chao, N. "Radiation Disasters: Role of the BMT Team." Biology of Blood and Marrow Transplantation 18.1 SUPPL. (2012): S189-S192.
PMID
22226106
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
18
Issue
1 SUPPL.
Publish Date
2012
Start Page
S189
End Page
S192
DOI
10.1016/j.bbmt.2011.11.021

Increased numbers of total nucleated and CD34+ cells in blood group O cord blood: An analysis of neonatal innate factors in the Korean population

BACKGROUND: We analyzed neonatal factors that could affect hematopoietic variables of cord blood (CB) donated from Korean neonates. STUDY DESIGN AND METHODS: The numbers of total nucleated cells (TNCs), CD34+ cells, and CD34+ cells/TNCs of CB in neonates were compared according to sex, gestational age, birth weight, birth weight centile for gestational age, and ABO blood group. RESULTS: With 11,098 CB units analyzed, blood group O CB showed an increased number of TNCs, CD34+ cells, and CD34+ cells/TNCs compared with other blood groups. Although TNC counts were lower in males, no difference in the number of CD34+ cells was demonstrated because the number of CD34+ cells/TNCs was higher in males. An increase in the gestational age resulted in an increase in the number of TNCs and decreases in the number of CD34+ cells and CD34+ cells/TNCs. The numbers of TNCs, CD34+ cells, and CD34+ cells/TNCs increased according to increased birth weight centile as well as birth weight. CONCLUSION: CB with blood group O has unique hematologic variables in this large-scale analysis of Korean neonates, although the impact on the storage policies of CB banks or the clinical outcome of transplantation remains to be determined. © 2011 American Association of Blood Banks.

Authors
Lee, HR; Park, JS; Shin, S; Roh, EY; Yoon, JH; Han, KS; Kim, BJ; Storms, RW; Chao, NJ
MLA Citation
Lee, HR, Park, JS, Shin, S, Roh, EY, Yoon, JH, Han, KS, Kim, BJ, Storms, RW, and Chao, NJ. "Increased numbers of total nucleated and CD34+ cells in blood group O cord blood: An analysis of neonatal innate factors in the Korean population." Transfusion 52.1 (2012): 76-81.
PMID
21790633
Source
scival
Published In
Transfusion
Volume
52
Issue
1
Publish Date
2012
Start Page
76
End Page
81
DOI
10.1111/j.1537-2995.2011.03262.x

Pleiotrophin Regulates the Retention and Self-Renewal of Hematopoietic Stem Cells in the Bone Marrow Vascular Niche

Authors
Himburg, HA; Harris, JR; Ito, T; Daher, P; Russell, JL; Quarmyne, M; Doan, PL; Helms, K; Nakamura, M; Fixsen, E; Herradon, G; Reya, T; Chao, NJ; Harroch, S; Chute, JP
MLA Citation
Himburg, HA, Harris, JR, Ito, T, Daher, P, Russell, JL, Quarmyne, M, Doan, PL, Helms, K, Nakamura, M, Fixsen, E, Herradon, G, Reya, T, Chao, NJ, Harroch, S, and Chute, JP. "Pleiotrophin Regulates the Retention and Self-Renewal of Hematopoietic Stem Cells in the Bone Marrow Vascular Niche." Cell Reports 2.6 (2012): 1774--.
Source
scival
Published In
Cell Reports
Volume
2
Issue
6
Publish Date
2012
Start Page
1774-
DOI
10.1016/j.celrep.2012.11.005

Medical planning and response for a nuclear detonation: A practical guide

This article summarizes major points from a newly released guide published online by the Office of the Assistant Secretary for Preparedness and Response (ASPR). The article reviews basic principles about radiation and its measurement, short-term and long-term effects of radiation, and medical countermeasures as well as essential information about how to prepare for and respond to a nuclear detonation. A link is provided to the manual itself, which in turn is heavily referenced for readers who wish to have more detail. © 2012, Mary Ann Liebert, Inc.

Authors
Coleman, CN; Adams, S; Adrianopoli, C; Ansari, A; Bader, JL; Buddemeier, B; Caro, JJ; Casagrande, R; Case, C; Caspary, K; Chang, AS; Chang, HF; Chao, N; Cliffer, KD; Confer, D; Deitchman, S; Derenzo, EG; Dobbs, A; Dodgen, D; Donnelly, EH; Gorman, S; Grace, MB; Hatchett, R; Hick, JL; Hrdina, C; Jones, R; Kane, E; Knebel, A; Koerner, JF; Laffan, AM; Larson, L; Livinski, A; MacKinney, J; Maidment, BW; Manning, R; Marinissen, MJ; Martin, C; Michael, G; Murrain-Hill, P; Nemhauser, JB; Norwood, AE et al.
MLA Citation
Coleman, CN, Adams, S, Adrianopoli, C, Ansari, A, Bader, JL, Buddemeier, B, Caro, JJ, Casagrande, R, Case, C, Caspary, K, Chang, AS, Chang, HF, Chao, N, Cliffer, KD, Confer, D, Deitchman, S, Derenzo, EG, Dobbs, A, Dodgen, D, Donnelly, EH, Gorman, S, Grace, MB, Hatchett, R, Hick, JL, Hrdina, C, Jones, R, Kane, E, Knebel, A, Koerner, JF, Laffan, AM, Larson, L, Livinski, A, MacKinney, J, Maidment, BW, Manning, R, Marinissen, MJ, Martin, C, Michael, G, Murrain-Hill, P, Nemhauser, JB, and Norwood, AE et al. "Medical planning and response for a nuclear detonation: A practical guide." Biosecurity and Bioterrorism 10.4 (2012): 346-371.
PMID
23244500
Source
scival
Published In
Biosecurity and Bioterrorism: Biodefense Strategy, Practice, and Science
Volume
10
Issue
4
Publish Date
2012
Start Page
346
End Page
371
DOI
10.1089/bsp.2012.1025

Severe pulmonary toxicity after myeloablative conditioning using total body irradiation: an assessment of risk factors.

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.

Authors
Kelsey, CR; Horwitz, ME; Chino, JP; Craciunescu, O; Steffey, B; Folz, RJ; Chao, NJ; Rizzieri, DA; Marks, LB
MLA Citation
Kelsey, CR, Horwitz, ME, Chino, JP, Craciunescu, O, Steffey, B, Folz, RJ, Chao, NJ, Rizzieri, DA, and Marks, LB. "Severe pulmonary toxicity after myeloablative conditioning using total body irradiation: an assessment of risk factors." Int J Radiat Oncol Biol Phys 81.3 (November 1, 2011): 812-818.
PMID
20932682
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
81
Issue
3
Publish Date
2011
Start Page
812
End Page
818
DOI
10.1016/j.ijrobp.2010.06.058

Hematopoietic cell infusion for the treatment of nuclear disaster victims: new data from the Chernobyl accident.

PURPOSE: To present previously unavailable data on the use of stem cell administration to aid recovery of victims of the Chernobyl disaster. On 26 April 1986, an accident at Unit 4 of the Chernobyl Nuclear Power Plant took place during the planned test of one of the safety systems. The diagnosis of acute radiation syndrome (ARS) was confirmed in 134 individuals exposed to high levels of radiation. There were nine patients heretofore unreported in the scientific literature who underwent intraosseous injections of allogeneic bone marrow cells in Kyiv. CONCLUSIONS: Transplantation was associated with significantly shortened time to recovery of granulocyte and platelet counts in these patients. While current guidelines would certainly include the use of cytokines, these data provide an indication of the effectiveness of stem cell transplant to treat victims of radiation exposure.

Authors
Klymenko, SV; Belyi, DA; Ross, JR; Owzar, K; Jiang, C; Li, Z; N Minchenko, J; N Kovalenko, A; Bebeshko, VG; J Chao, N
MLA Citation
Klymenko, SV, Belyi, DA, Ross, JR, Owzar, K, Jiang, C, Li, Z, N Minchenko, J, N Kovalenko, A, Bebeshko, VG, and J Chao, N. "Hematopoietic cell infusion for the treatment of nuclear disaster victims: new data from the Chernobyl accident." Int J Radiat Biol 87.8 (August 2011): 846-850.
PMID
21406047
Source
pubmed
Published In
International Journal of Radiation Biology (Informa)
Volume
87
Issue
8
Publish Date
2011
Start Page
846
End Page
850
DOI
10.3109/09553002.2011.560995

An ear punch model for studying the effect of radiation on wound healing.

PURPOSE: Radiation and wound combined injury represents a major clinical challenge because of the synergistic interactions that lead to higher morbidity and mortality than either insult would produce singly. The purpose of this study was to develop a mouse ear punch model to study the physiological mechanisms underlying radiation effects on healing wounds. MATERIALS AND METHODS: Surgical wounds were induced by a 2 mm surgical punch in the ear pinnae of MRL/MpJ mice. Photographs of the wounds were taken and the sizes of the ear punch wounds were quantified by image analysis. Local radiation to the ear was delivered by orthovoltage X-ray irradiator using a specially constructed jig that shields the other parts of body. RESULTS: Using this model, we demonstrated that local radiation to the wound area significantly delayed the healing of ear punch wounds in a dose-dependent fashion. The addition of sublethal whole body irradiation (7 Gy) further delayed the healing of ear punch wounds. These results were replicated in C57BL/6 mice; however, wound healing in MRL/MpJ mice was accelerated. CONCLUSIONS: These data indicate that the mouse ear punch model is a valuable model to study radiation and wound combined injury.

Authors
Deoliveira, D; Jiao, Y; Ross, JR; Corbin, K; Xiao, Q; Toncheva, G; Anderson-Evans, C; Yoshizumi, TT; Chen, BJ; Chao, NJ
MLA Citation
Deoliveira, D, Jiao, Y, Ross, JR, Corbin, K, Xiao, Q, Toncheva, G, Anderson-Evans, C, Yoshizumi, TT, Chen, BJ, and Chao, NJ. "An ear punch model for studying the effect of radiation on wound healing." Int J Radiat Biol 87.8 (August 2011): 869-877.
PMID
21480768
Source
pubmed
Published In
International Journal of Radiation Biology (Informa)
Volume
87
Issue
8
Publish Date
2011
Start Page
869
End Page
877
DOI
10.3109/09553002.2011.568575

Adult dual umbilical cord blood transplantation using myeloablative total body irradiation (1350 cGy) and fludarabine conditioning.

High treatment-related mortality (TRM) and high graft failure rate are serious concerns in HLA-mismatched umbilical cord blood (UCB) transplantation with myeloablative conditioning. We conducted a prospective trial of dual UCB transplantation using modified myeloablation consisting of total-body irradiation (TBI; 1350 cGy) and fludarabine (Flu) (160 mg/m(2)). Twenty-seven patients (median age, 33 years; range: 20-58 years) with hematologic malignancies were enrolled. The median combined cryopreserved total nucleated cell (TNC) dose was 4.3 × 10(7)/kg (range: 3.2-7.7 × 10(7)/kg). The cumulative incidences of neutrophil (≥500/μL) and platelet (≥50,000/μL) engraftment were 80% (95% confidence interval [CI], 58%-91%) and 68% (95% CI, 46%-83%), respectively. Among engrafted patients, a single cord blood unit was predominant by 100 days posttransplantation. A higher cryopreserved and infused TNC dose and infused CD3(+) cell dose were significant factors associated with the predominant UCB unit (P = .032, .020, and .042, respectively). TRM and relapse rates at 2 years were 28% (95% CI, 12%-47%) and 20% (95% CI, 7%-37%), respectively. Cumulative incidences of grades II-IV and grades III-IV acute graft-versus-host disease (aGVHD) were 37% (95% CI, 20%-55%) and 11% (95% CI, 3%-26%), respectively, and that of chronic GVHD was 31% (95% CI, 15%-49%). With a median follow-up of 23 months, overall survival and disease-free survival rates at 2 years were 58% (95% CI, 34%-75%) and 52% (95% CI, 29%-70%), respectively. This study supports the use of TBI 1350 cGy/Flu as an alternative to conventional myeloablative conditioning for dual UCB transplantation.

Authors
Kanda, J; Rizzieri, DA; Gasparetto, C; Long, GD; Chute, JP; Sullivan, KM; Morris, A; Smith, CA; Hogge, DE; Nitta, J; Song, K; Niedzwiecki, D; Chao, NJ; Horwitz, ME
MLA Citation
Kanda, J, Rizzieri, DA, Gasparetto, C, Long, GD, Chute, JP, Sullivan, KM, Morris, A, Smith, CA, Hogge, DE, Nitta, J, Song, K, Niedzwiecki, D, Chao, NJ, and Horwitz, ME. "Adult dual umbilical cord blood transplantation using myeloablative total body irradiation (1350 cGy) and fludarabine conditioning." Biol Blood Marrow Transplant 17.6 (June 2011): 867-874.
PMID
20868761
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
17
Issue
6
Publish Date
2011
Start Page
867
End Page
874
DOI
10.1016/j.bbmt.2010.09.009

Prevention of GVHD without losing GVL effect: windows of opportunity.

Allogeneic hematopoietic cell transplantation has developed into a most successful form of immunotherapy for hematologic malignancies in the past 50 years. However, its effectiveness and wider applications have been greatly limited by the development of graft-versus-host disease (GVHD), a potentially lethal side effect associated with this procedure. Since the main effectors for both graft-versus-leukemia (GVL) effect and GVHD are T lymphocytes and these two processes share many similar pathways, it has not been easy to separate GVL from GVHD. Because the clinically used pan immunosuppressive therapy for GVHD prevention also results in decreased GVL effect, the success of allogeneic hematopoietic cell transplantation relies on a small and unpredictable therapeutic window at the present time. This review discusses how we may widen this therapeutic window so that we can reliably prevent GVHD without losing GVL effect.

Authors
Zhang, P; Chen, BJ; Chao, NJ
MLA Citation
Zhang, P, Chen, BJ, and Chao, NJ. "Prevention of GVHD without losing GVL effect: windows of opportunity." Immunol Res 49.1-3 (April 2011): 49-55. (Review)
PMID
21136200
Source
pubmed
Published In
Immunologic Research
Volume
49
Issue
1-3
Publish Date
2011
Start Page
49
End Page
55
DOI
10.1007/s12026-010-8193-7

Renal shielding and dosimetry for patients with severe systemic sclerosis receiving immunoablation with total body irradiation in the scleroderma: cyclophosphamide or transplantation trial.

PURPOSE: To describe renal shielding techniques and dosimetry in delivering total body irradiation (TBI) to patients with severe systemic sclerosis (SSc) enrolled in a hematopoietic stem cell transplant protocol. METHODS AND MATERIALS: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) protocol uses a lymphoablative preparative regimen including 800 cGy TBI delivered in two 200-cGy fractions twice a day before CD34(+) selected autologous hematopoietic stem cell transplantation. Lung and kidney doses are limited to 200 cGy to protect organs damaged by SSc. Kidney block proximity to the spinal cord was investigated, and guidelines were developed for acceptable lumbar area TBI dosing. Information about kidney size and the organ shifts from supine to standing positions were recorded using diagnostic ultrasound (US). Minimum distance between the kidney blocks (dkB) and the lumbar spine region dose was recorded, and in vivo dosimetry was performed at several locations to determine the radiation doses delivered. RESULTS: Eleven patients were treated at our center with an anteroposterior (AP)/posteroanterior (PA) TBI technique. A 10% to 20% dose inhomogeneity in the lumbar spine region was achieved with a minimum kidney block separation of 4 to 5 cm. The average lumbar spine dose was 179.6 ± 18.1 cGy, with an average dkB of 5.0 ± 1.0 cm. Kidney block shield design was accomplished using a combination of US and noncontrast computerized tomography (CT) or CT imaging alone. The renal US revealed a wide range of kidney displacement from upright to supine positions. Overall, the average in vivo dose for the kidney prescription point was 193.4 ± 5.1 cGy. CONCLUSIONS: The dose to the kidneys can be attenuated while maintaining a 10% to 20% dose inhomogeneity in the lumbar spine area. Kidneys were localized more accurately using both US and CT imaging. With this technique, renal function has been preserved, and the study continues to enroll patients.

Authors
Craciunescu, OI; Steffey, BA; Kelsey, CR; Larrier, NA; Paarz-Largay, CJ; Prosnitz, RG; Chao, N; Chute, J; Gasparetto, C; Horwitz, M; Long, G; Rizzieri, D; Sullivan, KM
MLA Citation
Craciunescu, OI, Steffey, BA, Kelsey, CR, Larrier, NA, Paarz-Largay, CJ, Prosnitz, RG, Chao, N, Chute, J, Gasparetto, C, Horwitz, M, Long, G, Rizzieri, D, and Sullivan, KM. "Renal shielding and dosimetry for patients with severe systemic sclerosis receiving immunoablation with total body irradiation in the scleroderma: cyclophosphamide or transplantation trial." Int J Radiat Oncol Biol Phys 79.4 (March 15, 2011): 1248-1255.
PMID
20800376
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
79
Issue
4
Publish Date
2011
Start Page
1248
End Page
1255
DOI
10.1016/j.ijrobp.2010.05.036

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.

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,

Authors
Rizzieri, DA; Crout, C; Storms, R; Golob, J; Long, GD; Gasparetto, C; Sullivan, KM; Horwitz, M; Chute, J; Lagoo, AS; Morris, A; Beaven, A; Yang, Y; Peterson, B; Li, Z; Chao, NJ
MLA Citation
Rizzieri, DA, Crout, C, Storms, R, Golob, J, Long, GD, Gasparetto, C, Sullivan, KM, Horwitz, M, Chute, J, Lagoo, AS, Morris, A, Beaven, A, Yang, Y, Peterson, B, Li, Z, and Chao, NJ. "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." Cancer Invest 29.1 (January 2011): 56-61.
PMID
21166499
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
29
Issue
1
Publish Date
2011
Start Page
56
End Page
61
DOI
10.3109/07357907.2010.535055

Early post transplant (F-18) 2-fluoro-2-deoxyglucose positron emission tomography does not predict outcome for patients undergoing auto-SCT in non-Hodgkin and Hodgkin lymphoma

Positron emission tomography (PET) in conjunction with computed tomography is a frequently used modality for staging patients with lymphoma. Utility of PET-computed tomography before or early following auto-SCT has not been as rigorously evaluated. We retrospectively analyzed patients who received auto-SCT for treatment of relapsed or refractory non-Hodgkins lymphoma or Hodgkins disease between the years of 1996 and 2007. Patients who had either a PET scan following salvage chemotherapy within 14 weeks of transplantation (pre-PET), and/or a PET scan 6-14 weeks following transplantation (post-PET) were included. A total of 90 patients were identified for analysis. The median follow-up time is 3.3 years, with a range of 0.13-12.0 years. The median PFS was 4.6 years, and median OS was 5.1 years. At the time of this analysis, 34 patients (37%) experienced disease relapse, and 25 (27%) of the patients died from disease progression. In multivariate Cox proportional hazards analysis, post-PET did not predict for outcome, pre-PET positivity predicted for decrease in PFS. In conclusion, post-PET scan did not predict for PFS or OS in multivariate analysis. Positive pre-PET scan did predict for PFS as seen in previous studies, and may help identify patients who would benefit from innovative post transplant therapies. © 2011 Macmillan Publishers Limited All rights reserved.

Authors
Palmer, J; Goggins, T; Broadwater, G; Chao, N; Horwitz, M; Beaven, A; Sullivan, K; Coleman, RE; Rizzieri, D
MLA Citation
Palmer, J, Goggins, T, Broadwater, G, Chao, N, Horwitz, M, Beaven, A, Sullivan, K, Coleman, RE, and Rizzieri, D. "Early post transplant (F-18) 2-fluoro-2-deoxyglucose positron emission tomography does not predict outcome for patients undergoing auto-SCT in non-Hodgkin and Hodgkin lymphoma." Bone Marrow Transplantation 46.6 (2011): 847-851.
PMID
20856212
Source
scival
Published In
Bone Marrow Transplantation
Volume
46
Issue
6
Publish Date
2011
Start Page
847
End Page
851
DOI
10.1038/bmt.2010.203

Literature review and global consensus on management of acute radiation syndrome affecting nonhematopoietic organ systems

Objectives: The World Health Organization convened a panel of experts to rank the evidence for medical countermeasures for management of acute radiation syndrome (ARS) in a hypothetical scenario involving the hospitalization of 100 to 200 victims. The goal of this panel was to achieve consensus on optimal management of ARS affecting nonhematopoietic organ systems based upon evidence in the published literature. Methods: English-language articles were identified in MEDLINE and PubMed. Reference lists of retrieved articles were distributed to conferees in advance of and updated during the meeting. Published case series and case reports of ARS, publications of 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 system. In cases in which data were limited or incomplete, a narrative review of the observations was made. Results: No randomized controlled trials of medical countermeasures have been completed for individuals with ARS. Reports of countermeasures were often incompletely described, making it necessary to rely on data generated in nonirradiated humans and in experimental animals. A strong recommendation is made forthe administration of a serotonin-receptor antagonist prophylactically when the suspected exposure is >2 Gy and topical steroids, antibiotics, and antihistamines for radiation burns, ulcers, or blisters; excision and grafting of radiation ulcers or necrosis with intractable pain; provision of supportive care to individuals with neurovascular syndrome; and administration of electrolyte replacement therapy and sedatives to individuals with significant burns, hypovolemia, and/ orshock.Astrong recommendation is made against the use of systemicsteroids in the absence of aspecific indication. A weak recommendation is made forthe use of fluoroquinolones, bowel decontamination, loperamide, and enteral nutrition, and forselective oropharyngeal/digestive decontamination, blood glucose maintenance, and stress ulcer prophylaxis in critically ill patients. Conclusions: High-quality studies of therapeutic interventions in humans exposed to nontherapeutic radiation are not available, and because of ethical concerns regarding the conduct of controlled studies in humans, such studies are unlikely to emerge in the near future. © 2011 American Medical Association.

Authors
Dainiak, N; Gent, RN; Carr, Z; Schneider, R; Bader, J; Buglova, E; Chao, N; Coleman, CN; Ganser, A; Gorin, C; Hauer-Jensen, M; Huff, LA; Lillis-Hearne, P; Maekawa, K; Nemhauser, J; Powles, R; Schunemann, H; Shapiro, A; Stenke, L; Valverde, N; Weinstock, D; White, D; Albanese, J; Meineke, V
MLA Citation
Dainiak, N, Gent, RN, Carr, Z, Schneider, R, Bader, J, Buglova, E, Chao, N, Coleman, CN, Ganser, A, Gorin, C, Hauer-Jensen, M, Huff, LA, Lillis-Hearne, P, Maekawa, K, Nemhauser, J, Powles, R, Schunemann, H, Shapiro, A, Stenke, L, Valverde, N, Weinstock, D, White, D, Albanese, J, and Meineke, V. "Literature review and global consensus on management of acute radiation syndrome affecting nonhematopoietic organ systems." Disaster Medicine and Public Health Preparedness 5.3 (2011): 183-201.
PMID
21986999
Source
scival
Published In
Disaster Medicine and Public Health Preparedness
Volume
5
Issue
3
Publish Date
2011
Start Page
183
End Page
201
DOI
10.1001/dmp.2011.73

First global consensus for evidence-based management of the hematopoietic syndrome resulting from exposure to ionizing radiation

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. © 2011 American Medical Association.

Authors
Dainiak, N; Gent, RN; Carr, Z; Schneider, R; Bader, J; Buglova, E; Chao, N; Coleman, CN; Ganser, A; Gorin, C; Hauer-Jensen, M; Huff, LA; Lillis-Hearne, P; Maekawa, K; Nemhauser, J; Powles, R; Schunemann, H; Shapiro, A; Stenke, L; Valverde, N; Weinstock, D; White, D; Albanese, J; Meineke, V
MLA Citation
Dainiak, N, Gent, RN, Carr, Z, Schneider, R, Bader, J, Buglova, E, Chao, N, Coleman, CN, Ganser, A, Gorin, C, Hauer-Jensen, M, Huff, LA, Lillis-Hearne, P, Maekawa, K, Nemhauser, J, Powles, R, Schunemann, H, Shapiro, A, Stenke, L, Valverde, N, Weinstock, D, White, D, Albanese, J, and Meineke, V. "First global consensus for evidence-based management of the hematopoietic syndrome resulting from exposure to ionizing radiation." Disaster Medicine and Public Health Preparedness 5.3 (2011): 202-212.
PMID
21987000
Source
scival
Published In
Disaster Medicine and Public Health Preparedness
Volume
5
Issue
3
Publish Date
2011
Start Page
202
End Page
212
DOI
10.1001/dmp.2011.68

Radiation injury treatment network (RITN): Healthcare professionals preparing for a mass casualty radiological or nuclear incident

Purpose: To describe the history, composition, and activities of the Radiation Injury Treatment Network (RITN). The Radiation Injury Treatment Network® is a cooperative effort of the National Marrow Donor Program and the American Society for Blood and Marrow Transplantation. The goals of RITN are to educate hematologists, oncologists, and stem cell transplant practitioners about their potential involvement in the response to a radiation incident and provide treatment expertise. Injuries to the marrow system readily occur when a victim is exposed to ionising radiation. This focus therefore leverages the expertise of these specialists who are accustomed to providing the intensive supportive care required by patients with a suppressed marrow function. Following a radiological incident, RITN centres may be asked to: Accept patient transfers to their institutions; provide treatment expertise to practitioners caring for victims at other centres; travel to other centres to provide medical expertise; or provide data on victims treated at their centres. Moving forward, it is crucial that we develop a coordinated interdisciplinary approach in planning for and responding to radiological and nuclear incidents. The ongoing efforts of radiation biologists, radiation oncologists, and health physicists can and should complement the efforts of RITN and government agencies. Conclusion: RITN serves as a vital partner in preparedness and response efforts for potential radiological and nuclear incidents. © 2011 Informa UK, Ltd.

Authors
Ross, JR; Case, C; Confer, D; Weisdorf, DJ; Weinstock, D; Krawisz, R; Chute, J; Wilhauk, J; Navarro, W; Hartzman, R; Coleman, CN; Hatchett, R; Chao, N
MLA Citation
Ross, JR, Case, C, Confer, D, Weisdorf, DJ, Weinstock, D, Krawisz, R, Chute, J, Wilhauk, J, Navarro, W, Hartzman, R, Coleman, CN, Hatchett, R, and Chao, N. "Radiation injury treatment network (RITN): Healthcare professionals preparing for a mass casualty radiological or nuclear incident." International Journal of Radiation Biology 87.8 (2011): 748-753.
PMID
21801106
Source
scival
Published In
International Journal of Radiation Biology (Informa)
Volume
87
Issue
8
Publish Date
2011
Start Page
748
End Page
753
DOI
10.3109/09553002.2011.556176

Planning and Response to Radiation Exposures

Authors
Weisdorf, D; Weinstock, D; Case, C; Chao, N; Confer, DL
MLA Citation
Weisdorf, D, Weinstock, D, Case, C, Chao, N, and Confer, DL. "Planning and Response to Radiation Exposures." Biology of Blood and Marrow Transplantation 17.8 (2011): 1262-1263.
PMID
21723406
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
17
Issue
8
Publish Date
2011
Start Page
1262
End Page
1263
DOI
10.1016/j.bbmt.2011.06.002

Radiation injury after a nuclear detonation: Medical consequences and the need for scarce resources allocation

A 10-kiloton (kT) nuclear detonation within a US city could expose hundreds of thousands of people to radiation. The Scarce Resources for a Nuclear Detonation Project was undertaken to guide community planning and response in the aftermath of a nuclear detonation, when demand will greatly exceed available resources. This article reviews the pertinent literature on radiation injuries from human exposures and animal models to provide a foundation for the triage and management approaches outlined in this special issue. Whole-body doses >2 Gy can produce clinically significant acute radiation syndrome (ARS), which classically involves the hematologic, gastrointestinal, cutaneous, and cardiovascular/central nervous systems. The severity and presentation of ARS are affected by several factors, including radiation dose and dose rate, interindividual variability in radiation response, type of radiation (eg, gamma alone, gamma plus neutrons), partial-body shielding, and possibly age, sex, and certain preexisting medical conditions. The combination of radiation with trauma, burns, or both (ie, combined injury) confers a worse prognosis than the same dose of radiation alone. Supportive care measures, including fluid support, antibiotics, and possibly myeloid cytokines (eg, granulocyte colony-stimulating factor), can improve the prognosis for some irradiated casualties. Finally, expert guidance and surge capacity for casualties with ARS are available from the Radiation Emergency Medical Management Web site and the Radiation Injury Treatment Network. © 2011 American Medical Association.

Authors
DiCarlo, AL; Maher, C; Hick, JL; Hanfling, D; Dainiak, N; Chao, N; Bader, JL; Coleman, CN; Weinstock, DM
MLA Citation
DiCarlo, AL, Maher, C, Hick, JL, Hanfling, D, Dainiak, N, Chao, N, Bader, JL, Coleman, CN, and Weinstock, DM. "Radiation injury after a nuclear detonation: Medical consequences and the need for scarce resources allocation." Disaster Medicine and Public Health Preparedness 5.SUPPL. 1 (2011): S32-S44.
PMID
21402810
Source
scival
Published In
Disaster Medicine and Public Health Preparedness
Volume
5
Issue
SUPPL. 1
Publish Date
2011
Start Page
S32
End Page
S44
DOI
10.1001/dmp.2011.17

Iron overload and allogeneic hematopoietic stem-cell transplantation

Iron overload is frequently observed in patients with hematologic diseases before and after allogeneic stem-cell transplantation because they usually receive multiple red blood cell transfusions. Elevated pretransplant serum ferritin levels, which are widely used as indicators of body iron status, are significantly associated with a lower overall survival rate and a higher incidence of treatment-related complications; for example, infections and hepatic veno-occlusive disease. As serum ferritin levels are affected, not only by iron loading but also by inflammation, imaging techniques to quantify tissue iron levels have been developed, for example, quantitative MRI using the transverse magnetic relaxation rate, and superconducting quantum interference devices. Iron chelators, such as deferasirox, a new oral iron-chelating agent, reduce iron load in transfusion-dependent patients. Iron-chelating therapy before and/or after transplantation is a promising strategy to improve the clinical outcomes of transplant patients with iron overload. However, further research is needed to prove the direct relationship between iron overload and adverse outcomes, as well as to determine the effects of treatment for iron overload on outcomes of allogeneic stem-cell transplantation. © 2011 Expert Reviews Ltd.

Authors
Kanda, J; Kawabata, H; Chao, NJ
MLA Citation
Kanda, J, Kawabata, H, and Chao, NJ. "Iron overload and allogeneic hematopoietic stem-cell transplantation." Expert Review of Hematology 4.1 (2011): 71-80.
PMID
21322780
Source
scival
Published In
Expert Review of Hematology
Volume
4
Issue
1
Publish Date
2011
Start Page
71
End Page
80
DOI
10.1586/ehm.10.81

Progenitor cell dose determines the pace and completeness of engraftment in a xenograft model for cord blood transplantation.

Two critical concerns in clinical cord blood transplantation are the initial time to engraftment and the subsequent restoration of immune function. These studies measured the impact of progenitor cell dose on both the pace and strength of hematopoietic reconstitution by transplanting nonobese diabetic/severe combined immunodeficiency/interleukin-2 receptor-gamma-null (NSγ) mice with lineage-depleted aldehyde dehydrogenase-bright CD34(+) human cord blood progenitors. The progress of each transplant was monitored over an extended time course by repeatedly analyzing the peripheral blood for human hematopoietic cells. In vivo human hematopoietic development was complete. After long-term transplantation assays (≥ 19 weeks), human T-cell development was documented within multiple tissues in 16 of 32 NSγ mice. Human T-cell differentiation was active within NSγ thymuses, as documented by the presence of CD4(+) CD8(+) T-cell progenitors as well as T-cell receptor excision circles. It is important to note that although myeloid and B-cell engraftment was detected as early as 4 weeks after transplantation, human T-cell development was exclusively late onset. High progenitor cell doses were associated with a robust human hematopoietic chimerism that accelerated both initial time to engraftment and subsequent T-cell development. At lower progenitor cell doses, the chimerism was weak and the human hematopoietic lineage development was frequently incomplete.

Authors
Liu, C; Chen, BJ; Deoliveira, D; Sempowski, GD; Chao, NJ; Storms, RW
MLA Citation
Liu, C, Chen, BJ, Deoliveira, D, Sempowski, GD, Chao, NJ, and Storms, RW. "Progenitor cell dose determines the pace and completeness of engraftment in a xenograft model for cord blood transplantation." Blood 116.25 (December 16, 2010): 5518-5527.
PMID
20833978
Source
pubmed
Published In
Blood
Volume
116
Issue
25
Publish Date
2010
Start Page
5518
End Page
5527
DOI
10.1182/blood-2009-12-260810

Haploidentical transplantation for leukemia.

Hematopoietic stem cell transplantation from human leukocyte antigen (HLA)-haploidentical family members offers a potential cure for patients in need of allogeneic immunotherapy who have no immediate access to an HLA-matched donor. The use of ex vivo T-cell-depleted stem cells combined with immuno-myeloablative conditioning has enabled durable donor engraftment with a low incidence of acute graft-versus-host disease despite the HLA disparity. Moreover, additional transplant techniques involving in vivo T-cell depletion and reduced-intensity conditioning have further minimized the risks. However, a major drawback is delayed immune reconstitution leading to infections and high relapse rates, prompting significant research efforts focused on improving recovery in the post-transplant period. Infusions with donor lymphocytes are common, though newer manipulations with a focus on donor natural killer cells hold great promise, as do other modified donor T-cell infusions. Success of these new procedures will make haploidentical transplants safer and more effective, further broadening its appeal.

Authors
Kanda, J; Chao, NJ; Rizzieri, DA
MLA Citation
Kanda, J, Chao, NJ, and Rizzieri, DA. "Haploidentical transplantation for leukemia." Curr Oncol Rep 12.5 (September 2010): 292-301. (Review)
PMID
20602183
Source
pubmed
Published In
Current Oncology Reports
Volume
12
Issue
5
Publish Date
2010
Start Page
292
End Page
301
DOI
10.1007/s11912-010-0113-4

Natural killer cell-enriched donor lymphocyte infusions from A 3-6/6 HLA matched family member following nonmyeloablative allogeneic stem cell transplantation.

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.

Authors
Rizzieri, DA; Storms, R; Chen, D-F; 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; Chao, NJ
MLA Citation
Rizzieri, DA, Storms, R, Chen, D-F, 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. "Natural killer cell-enriched donor lymphocyte infusions from A 3-6/6 HLA matched family member following nonmyeloablative allogeneic stem cell transplantation." Biol Blood Marrow Transplant 16.8 (August 2010): 1107-1114.
PMID
20188202
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
16
Issue
8
Publish Date
2010
Start Page
1107
End Page
1114
DOI
10.1016/j.bbmt.2010.02.018

Diagnosis of partial body radiation exposure in mice using peripheral blood gene expression profiles.

In the event of a terrorist-mediated attack in the United States using radiological or improvised nuclear weapons, it is expected that hundreds of thousands of people could be exposed to life-threatening levels of ionizing radiation. We have recently shown that genome-wide expression analysis of the peripheral blood (PB) can generate gene expression profiles that can predict radiation exposure and distinguish the dose level of exposure following total body irradiation (TBI). However, in the event a radiation-mass casualty scenario, many victims will have heterogeneous exposure due to partial shielding and it is unknown whether PB gene expression profiles would be useful in predicting the status of partially irradiated individuals. Here, we identified gene expression profiles in the PB that were characteristic of anterior hemibody-, posterior hemibody- and single limb-irradiation at 0.5 Gy, 2 Gy and 10 Gy in C57Bl6 mice. These PB signatures predicted the radiation status of partially irradiated mice with a high level of accuracy (range 79-100%) compared to non-irradiated mice. Interestingly, PB signatures of partial body irradiation were poorly predictive of radiation status by site of injury (range 16-43%), suggesting that the PB molecular response to partial body irradiation was anatomic site specific. Importantly, PB gene signatures generated from TBI-treated mice failed completely to predict the radiation status of partially irradiated animals or non-irradiated controls. These data demonstrate that partial body irradiation, even to a single limb, generates a characteristic PB signature of radiation injury and thus may necessitate the use of multiple signatures, both partial body and total body, to accurately assess the status of an individual exposed to radiation.

Authors
Meadows, SK; Dressman, HK; Daher, P; Himburg, H; Russell, JL; Doan, P; Chao, NJ; Lucas, J; Nevins, JR; Chute, JP
MLA Citation
Meadows, SK, Dressman, HK, Daher, P, Himburg, H, Russell, JL, Doan, P, Chao, NJ, Lucas, J, Nevins, JR, and Chute, JP. "Diagnosis of partial body radiation exposure in mice using peripheral blood gene expression profiles. (Published online)" PLoS One 5.7 (July 12, 2010): e11535-.
Website
http://hdl.handle.net/10161/4550
PMID
20634956
Source
pubmed
Published In
PloS one
Volume
5
Issue
7
Publish Date
2010
Start Page
e11535
DOI
10.1371/journal.pone.0011535

Overcoming drug resistance in mantle cell lymphoma using a combination of dose-dense and intense therapy.

We present a study of the prevalence of genetic polymorphisms and expression of genes encoding the drug-resistance proteins glutathione S-transferases (GSTs) in order to gain insights into the pattern of failure evident in mantle cell lymphoma. We note a high preponderance of genetic alterations conferring resistance to standard chemotherapy in this illness. Concurrent with this investigation, we present a series of patients who were provided dose-dense and intense chemotherapy to circumvent these drug-resistance mechanisms. High responses were noted, though durable remissions were few, indicating non-traditional chemotherapy options are important to investigate in this illness.

Authors
Crout, CA; Koh, L-P; Gockerman, JP; Moore, JO; Decastro, C; Long, GD; Diehl, L; Gasparetto, C; Niedzwiecki, D; Edwards, J; Prosnitz, L; Horwitz, M; Chute, J; Morris, A; Davis, P; Beaven, A; Chao, NJ; Ali-Osman, F; Rizzieri, DA
MLA Citation
Crout, CA, Koh, L-P, Gockerman, JP, Moore, JO, Decastro, C, Long, GD, Diehl, L, Gasparetto, C, Niedzwiecki, D, Edwards, J, Prosnitz, L, Horwitz, M, Chute, J, Morris, A, Davis, P, Beaven, A, Chao, NJ, Ali-Osman, F, and Rizzieri, DA. "Overcoming drug resistance in mantle cell lymphoma using a combination of dose-dense and intense therapy." Cancer Invest 28.6 (July 2010): 654-660.
PMID
20521909
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
28
Issue
6
Publish Date
2010
Start Page
654
End Page
660
DOI
10.3109/07357901003631015

Growth hormone mitigates against lethal irradiation and enhances hematologic and immune recovery in mice and nonhuman primates.

Medications that can mitigate against radiation injury are limited. In this study, we investigated the ability of recombinant human growth hormone (rhGH) to mitigate against radiation injury in mice and nonhuman primates. BALB/c mice were irradiated with 7.5 Gy and treated post-irradiation with rhGH intravenously at a once daily dose of 20 microg/dose for 35 days. rhGH protected 17 out of 28 mice (60.7%) from lethal irradiation while only 3 out of 28 mice (10.7%) survived in the saline control group. A shorter course of 5 days of rhGH post-irradiation produced similar results. Compared with the saline control group, treatment with rhGH on irradiated BALB/c mice significantly accelerated overall hematopoietic recovery. Specifically, the recovery of total white cells, CD4 and CD8 T cell subsets, B cells, NK cells and especially platelets post radiation exposure were significantly accelerated in the rhGH-treated mice. Moreover, treatment with rhGH increased the frequency of hematopoietic stem/progenitor cells as measured by flow cytometry and colony forming unit assays in bone marrow harvested at day 14 after irradiation, suggesting the effects of rhGH are at the hematopoietic stem/progenitor level. rhGH mediated the hematopoietic effects primarily through their niches. Similar data with rhGH were also observed following 2 Gy sublethal irradiation of nonhuman primates. Our data demonstrate that rhGH promotes hematopoietic engraftment and immune recovery post the exposure of ionizing radiation and mitigates against the mortality from lethal irradiation even when administered after exposure.

Authors
Chen, BJ; Deoliveira, D; Spasojevic, I; Sempowski, GD; Jiang, C; Owzar, K; Wang, X; Gesty-Palmer, D; Cline, JM; Bourland, JD; Dugan, G; Meadows, SK; Daher, P; Muramoto, G; Chute, JP; Chao, NJ
MLA Citation
Chen, BJ, Deoliveira, D, Spasojevic, I, Sempowski, GD, Jiang, C, Owzar, K, Wang, X, Gesty-Palmer, D, Cline, JM, Bourland, JD, Dugan, G, Meadows, SK, Daher, P, Muramoto, G, Chute, JP, and Chao, NJ. "Growth hormone mitigates against lethal irradiation and enhances hematologic and immune recovery in mice and nonhuman primates. (Published online)" PLoS One 5.6 (June 16, 2010): e11056-.
Website
http://hdl.handle.net/10161/4547
PMID
20585403
Source
pubmed
Published In
PloS one
Volume
5
Issue
6
Publish Date
2010
Start Page
e11056
DOI
10.1371/journal.pone.0011056

Non-myeloablative umbilical cord blood transplantation.

Allogeneic umbilical cord blood (UCB) transplantation is an established alternative to unrelated bone marrow or peripheral blood transplantation for treatment of high-risk hematologic disorders. There is growing evidence that non-myeloablative bone marrow conditioning can be used to facilitate engraftment of UCB-derived stem cells. Use of non-myeloablative conditioning reduces the risk of treatment-related mortality but increases the risk for relapse of the underlying hematologic condition. Disease status at the time of transplantation and potency of the graft versus tumor effect are important predictors of a successful outcome. It is for these reasons that non-myeloablative conditioning is best suited for patients felt to be at increased risk for treatment-related complications, and whose underlying disease is under good control. The optimal non-myeloablative conditioning regimen has yet to be determined. Further studies are needed to determine if non-myeloablative UCB transplantation can be successfully applied to pediatric patients and patients without prior exposure to cytotoxic chemotherapy.

Authors
Horwitz, ME; Chao, N
MLA Citation
Horwitz, ME, and Chao, N. "Non-myeloablative umbilical cord blood transplantation." Best Pract Res Clin Haematol 23.2 (June 2010): 231-236. (Review)
PMID
20837335
Source
pubmed
Published In
Best Practice and Research: Clinical Haematology
Volume
23
Issue
2
Publish Date
2010
Start Page
231
End Page
236
DOI
10.1016/j.beha.2010.06.001

Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells.

Hematopoietic stem cell (HSC) self-renewal is regulated by both intrinsic and extrinsic signals. Although some of the pathways that regulate HSC self-renewal have been uncovered, it remains largely unknown whether these pathways can be triggered by deliverable growth factors to induce HSC growth or regeneration. Here we show that pleiotrophin, a neurite outgrowth factor with no known function in hematopoiesis, efficiently promotes HSC expansion in vitro and HSC regeneration in vivo. Treatment of mouse bone marrow HSCs with pleiotrophin caused a marked increase in long-term repopulating HSC numbers in culture, as measured in competitive repopulating assays. Treatment of human cord blood CD34(+)CDCD38(-)Lin(-) cells with pleiotrophin also substantially increased severe combined immunodeficient (SCID)-repopulating cell counts in culture, compared to input and cytokine-treated cultures. Systemic administration of pleiotrophin to irradiated mice caused a pronounced expansion of bone marrow stem and progenitor cells in vivo, indicating that pleiotrophin is a regenerative growth factor for HSCs. Mechanistically, pleiotrophin activated phosphoinositide 3-kinase (PI3K) signaling in HSCs; antagonism of PI3K or Notch signaling inhibited pleiotrophin-mediated expansion of HSCs in culture. We identify the secreted growth factor pleiotrophin as a new regulator of both HSC expansion and regeneration.

Authors
Himburg, HA; Muramoto, GG; Daher, P; Meadows, SK; Russell, JL; Doan, P; Chi, J-T; Salter, AB; Lento, WE; Reya, T; Chao, NJ; Chute, JP
MLA Citation
Himburg, HA, Muramoto, GG, Daher, P, Meadows, SK, Russell, JL, Doan, P, Chi, J-T, Salter, AB, Lento, WE, Reya, T, Chao, NJ, and Chute, JP. "Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells." Nat Med 16.4 (April 2010): 475-482.
PMID
20305662
Source
pubmed
Published In
Nature Medicine
Volume
16
Issue
4
Publish Date
2010
Start Page
475
End Page
482
DOI
10.1038/nm.2119

Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity.

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.

Authors
Muramoto, GG; Russell, JL; Safi, R; Salter, AB; Himburg, HA; Daher, P; Meadows, SK; Doan, P; Storms, RW; Chao, NJ; McDonnell, DP; Chute, JP
MLA Citation
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. "Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity." Stem Cells 28.3 (March 31, 2010): 523-534.
PMID
20054864
Source
pubmed
Published In
Stem Cells
Volume
28
Issue
3
Publish Date
2010
Start Page
523
End Page
534
DOI
10.1002/stem.299

Hematopoietic stem cell transplantation across genetic barriers using a nonmyeloablative conditioning regimen

Authors
Koh, LP; Rizzieri, DA; Chao, NJ
MLA Citation
Koh, LP, Rizzieri, DA, and Chao, NJ. "Hematopoietic stem cell transplantation across genetic barriers using a nonmyeloablative conditioning regimen." Bone Marrow Transplantation Across Major Genetic Barriers. January 1, 2010. 1-492.
Source
scopus
Publish Date
2010
Start Page
1
End Page
492
DOI
10.1057/9789814271271_0006

"Short course" bortezomib plus melphalan and prednisone as induction prior to transplant or as frontline therapy for nontransplant candidates in patients with previously untreated multiple myeloma.

The purpose of this study was to evaluate the efficacy and safety of short-course bortezomib, melphalan, prednisone (VMP) in previously untreated multiple myeloma as frontline therapy for transplant-ineligible patients and induction prior to autologous stem cell transplantation (ASCT). Patients received up to 6 28-day cycles of bortezomib 1.3 mg/m(2), days 1, 4, 8, and 11, plus melphalan 6 mg/m(2) and prednisone 60 mg/m(2), days 1-7. After 2-6 cycles, eligible and consenting patients could proceed to ASCT. Responses were assessed by International Uniform Response Criteria. The primary endpoint was complete response (CR) rate with VMP. Forty-five patients were enrolled. Among 44 evaluable patients, response rate was 95%, including 18% >or=CR (9% stringent CR), 27% very good partial responses (VGPR), and 50% partial responses (PR). Twenty patients proceeded to ASCT. Stem cell collection was successful in all; median yield was 5.6 x 10(6) CD34(+) cells/kg. Posttransplant response rates were 30% >or=CR (10% stringent CR), 65% VGPR, and 5% PR. After median follow-up of 14.0/14.6 months, median time to progression and progression-free survival were both 19.8/27.9 months in non-ASCT/ASCT patients. Seven patients have died; 1-year survival rates were 82%/95% in non-ASCT/ASCT patients. The most common grade 3/4 toxicities were thrombocytopenia (20%), neutropenia (28%), and infection (9%). Peripheral neuropathy grade 2-4 was the most common nonhematopoietic side effect occurring 17 patients (38%), although it was typically reversible, and only 5 patients (11%) discontinued therapy as a result of it. Short-course VMP is highly effective and generally well tolerated, both as initial treatment in non-ASCT patients and induction prior to ASCT. VMP did not negatively affect stem cell collection. Longer follow-up and prospective phase III trials are required to validate these initial observations.

Authors
Gasparetto, C; Gockerman, JP; Diehl, LF; de Castro, CM; Moore, JO; Long, GD; Horwitz, ME; Keogh, G; Chute, JP; Sullivan, KM; Neuwirth, R; Davis, PH; Sutton, LM; Anderson, RD; Chao, NJ; Rizzieri, D
MLA Citation
Gasparetto, C, Gockerman, JP, Diehl, LF, de Castro, CM, Moore, JO, Long, GD, Horwitz, ME, Keogh, G, Chute, JP, Sullivan, KM, Neuwirth, R, Davis, PH, Sutton, LM, Anderson, RD, Chao, NJ, and Rizzieri, D. ""Short course" bortezomib plus melphalan and prednisone as induction prior to transplant or as frontline therapy for nontransplant candidates in patients with previously untreated multiple myeloma." Biol Blood Marrow Transplant 16.1 (January 2010): 70-77.
PMID
19733251
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
16
Issue
1
Publish Date
2010
Start Page
70
End Page
77
DOI
10.1016/j.bbmt.2009.08.017

Assessing surge capacity for radiation victims with marrow toxicity

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. © 2010 American Society for Blood and Marrow Transplantation.

Authors
Davids, MS; Case, C; Hornung, R; Chao, NJ; Chute, JP; Coleman, CN; Weisdorf, D; Confer, DL; Weinstock, DM
MLA Citation
Davids, MS, Case, C, Hornung, R, Chao, NJ, Chute, JP, Coleman, CN, Weisdorf, D, Confer, DL, and Weinstock, DM. "Assessing surge capacity for radiation victims with marrow toxicity." Biology of Blood and Marrow Transplantation 16.10 (2010): 1436-1441.
PMID
20399880
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
16
Issue
10
Publish Date
2010
Start Page
1436
End Page
1441
DOI
10.1016/j.bbmt.2010.04.007

Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: A retrospective analysis

Background: Umbilical-cord blood (UCB) is increasingly considered as an alternative to peripheral blood progenitor cells (PBPCs) or bone marrow, especially when an HLA-matched adult unrelated donor is not available. We aimed to determine the optimal role of UCB grafts in transplantation for adults with acute leukaemia, and to establish whether current graft-selection practices are appropriate. Methods: We used Cox regression to retrospectively compare leukaemia-free survival and other outcomes for UCB, PBPC, and bone marrow transplantation in patients aged 16 years or over who underwent a transplant for acute leukaemia. Data were available on 1525 patients transplanted between 2002 and 2006. 165 received UCB, 888 received PBPCs, and 472 received bone marrow. UCB units were matched at HLA-A and HLA-B at antigen level, and HLA-DRB1 at allele level (n=10), or mismatched at one (n=40) or two (n=115) antigens. PBPCs and bone-marrow grafts from unrelated adult donors were matched for allele-level HLA-A, HLA-B, HLA-C, and HLA-DRB1 (n=632 and n=332, respectively), or mismatched at one locus (n=256 and n=140, respectively). Findings: Leukaemia-free survival in patients after UCB transplantation was comparable with that after 8/8 and 7/8 allele-matched PBPC or bone-marrow transplantation. However, transplant-related mortality was higher after UCB transplantation than after 8/8 allele-matched PBPC recipients (HR 1·62, 95% CI 1·18-2·23; p=0·003) or bone-marrow transplantation (HR 1·69, 95% CI 1·19-2·39; p=0·003). Grades 2-4 acute and chronic graft-versus-host disease (GvHD) were lower in UCB recipients compared with allele-matched PBPC (HR 0·57, 95% 0·42-0·77; p=0·002 and HR 0·38, 0·27-0·53; p=0·003, respectively), while the incidence of chronic, but not acute GvHD, was lower after UCB than after 8/8 allele-matched bone-marrow transplantation (HR 0·63, 0·44-0·90; p=0·01). Interpretation: These data support the use of UCB for adults with acute leukaemia when there is no HLA-matched unrelated adult donor available, and when a transplant is needed urgently. Funding: National Cancer Institute, National Heart Lung and Blood Institute, National Institute of Allergy and Infectious Disease (U24-CA76518); Health Resources and Services Administration (HHSH234200637015C); Office of Naval Research, Department of Navy (N00014-08-1-1207); Children's Leukemia Research Association; and a Scholar in Clinical Research Award from the Leukemia and Lymphoma Society. © 2010 Elsevier Ltd.

Authors
Eapen, M; Rocha, V; Sanz, G; Scaradavou, A; Zhang, M-J; Arcese, W; Sirvent, A; Champlin, RE; Chao, N; Gee, AP; Isola, L; Laughlin, MJ; Marks, DI; Nabhan, S; Ruggeri, A; Soiffer, R; Horowitz, MM; Gluckman, E; Wagner, JE
MLA Citation
Eapen, M, Rocha, V, Sanz, G, Scaradavou, A, Zhang, M-J, Arcese, W, Sirvent, A, Champlin, RE, Chao, N, Gee, AP, Isola, L, Laughlin, MJ, Marks, DI, Nabhan, S, Ruggeri, A, Soiffer, R, Horowitz, MM, Gluckman, E, and Wagner, JE. "Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: A retrospective analysis." The Lancet Oncology 11.7 (2010): 653-660.
PMID
20558104
Source
scival
Published In
The Lancet Oncology
Volume
11
Issue
7
Publish Date
2010
Start Page
653
End Page
660
DOI
10.1016/S1470-2045(10)70127-3

Novel mechanism of rapamycin in GVHD: Increase in interstitial regulatory T cells

Rapamycin (RAPA) is an immunosuppressive drug that prevents and treats graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplant (HCT). One possible mechanism for its efficacy is induction of tolerance, through increased number or enhanced survival of regulatory T cells. In our experiments, B10.D2 BM and splenocytes were injected into lethally irradiated BALB/cJ recipients. The mice received i.p. injections of either RAPA or vehicle control on days 1-28. There was a significant survival advantage in RAPA-treated mice. Evaluation of the skin biopsies showed a dense cellular infiltrate in RAPA-treated mice. Further characterization of these cells revealed a higher percentage of regulatory T cells characterized by FoxP3-positive cells in high-dose RAPA-treated mice as compared with controls on day 30. This effect appears to be dose dependent. When peripheral blood analysis for FoxP3-positive cells was performed, there was no significant difference observed in the RAPA-treated mice as compared with control mice. These data show a novel mechanism of rapamycin in GVHD, accumulation of regulatory T cells in the GVHD target tissue: the skin. © 2010 Macmillan Publishers Limited All rights reserved.

Authors
Palmer, JM; Chen, BJ; Deoliveira, D; Le, N-D; Chao, NJ
MLA Citation
Palmer, JM, Chen, BJ, Deoliveira, D, Le, N-D, and Chao, NJ. "Novel mechanism of rapamycin in GVHD: Increase in interstitial regulatory T cells." Bone Marrow Transplantation 45.2 (2010): 379-384.
PMID
19597415
Source
scival
Published In
Bone Marrow Transplantation
Volume
45
Issue
2
Publish Date
2010
Start Page
379
End Page
384
DOI
10.1038/bmt.2009.140

Advances in cord blood transplants in adults

Umbilical cord blood is an acceptable source of hematopoietic stem cells for patients with malignant diseases but has limitations in its use. In this review, we will discuss these limitations and the recent advances in cord blood transplants that may enable cord blood to become more widely available as an alternative stem cell source for adults for the treatment of malignant diseases and for use in regenerative medicine. © 2010 Medicine Reports Ltd.

Authors
Doan, PL; Chao, NJ
MLA Citation
Doan, PL, and Chao, NJ. "Advances in cord blood transplants in adults." F1000 Medicine Reports 2.1 (2010).
PMID
20948874
Source
scival
Published In
F1000 Medicine Reports
Volume
2
Issue
1
Publish Date
2010
DOI
10.3410/M2-12

Umbilical cord blood transplantation for treatment of non-malignant disorders

As the outcomes of umbilical cord blood transplantation improve, the risk versus benefit considerations with respect to treatment of non-malignant disorders must be reassessed. Recent data would suggest that the outcome of umbilical cord blood transplantation is comparable to that of matched unrelated donor transplantation. Thus, patients felt not to be candidates for this potentially curative treatment modality due to lack of an available matched donor should be considered for matched or mismatched unrelated umbilical cord blood transplantation. This review will cover the most recent data pertaining to umbilical cord blood transplantation for the treatment of congenital immunodeficiency disorders, inborn errors of metabolism, bone marrow failure disorders, and hemoglobinopathies. © The Authors.

Authors
Horwitz, ME; Chao, N
MLA Citation
Horwitz, ME, and Chao, N. "Umbilical cord blood transplantation for treatment of non-malignant disorders." Cellular Therapy and Transplantation 2.7 (2010).
Source
scival
Published In
Cellular Therapy and Transplantation
Volume
2
Issue
7
Publish Date
2010
DOI
10.3205/ctt-2010-en-000069.01

Selective enhancement of donor hematopoietic cell engraftment by the CXCR4 antagonist AMD3100 in a mouse transplantation model

The interaction between stromal cell-derived factor-1 (SDF-1) with CXCR4 chemokine receptors plays an important role in hematopoiesis following hematopoietic stem cell transplantation. We examined the efficacy of post transplant administration of a specific CXCR4 antagonist (AMD3100) in improving animal survival and in enhancing donor hematopoietic cell engraftment using a congeneic mouse transplantation model. AMD3100 was administered subcutaneously at 5 mg/kg body weight 3 times a week beginning at day +2 post-transplant. Post-transplant administration of AMD3100 significantly improves animal survival. AMD3100 reduces pro-inflammatory cytokine/chemokine production. Furthermore, post transplant administration of AMD3100 selectively enhances donor cell engraftment and promotes recovery of all donor cell lineages (myeloid cells, T and B lymphocytes, erythrocytes and platelets). This enhancement results from a combined effect of increased marrow niche availability and greater cell division induced by AMD3100. Our studies shed new lights into the biological roles of SDF-1/CXCR4 interaction in hematopoietic stem cell engraftment following transplantation and in transplant-related mortality. Our results indicate that AMD3100 provides a novel approach for enhancing hematological recovery following transplantation, and will likely benefit patients undergoing transplantation. © 2010 Kang et al.

Authors
Kang, Y; Chen, BJ; Deoliveira, D; Mito, J; Chao, NJ
MLA Citation
Kang, Y, Chen, BJ, Deoliveira, D, Mito, J, and Chao, NJ. "Selective enhancement of donor hematopoietic cell engraftment by the CXCR4 antagonist AMD3100 in a mouse transplantation model." PLoS ONE 5.6 (2010).
Website
http://hdl.handle.net/10161/5087
PMID
20596257
Source
scival
Published In
PloS one
Volume
5
Issue
6
Publish Date
2010
DOI
10.1371/journal.pone.0011316

The role of oral beclometasone dipropionate in the treatment of gastrointestinal Graft-versus-Host Disease.

Graft-versus-host disease (GVHD) after allogeneic stem-cell transplantation causes significant morbidity and mortality. An important site of GVHD is the gastrointestinal (GI) tract because development of acute GI GVHD is prognostic of overall survival. The standard of care to treat acute GI GVHD is systemic corticosteroids and immunosuppressants; however, the use of these therapies can cause life-threatening opportunistic infections. To limit the adverse effects of systemic immunosuppression, the topically active corticosteroid beclometasone dipropionate has been investigated in case studies and in randomized placebo-controlled trials for the treatment of acute GI GVHD. In this review, we appraise these studies with beclometasone dipropionate, and discuss future randomized studies to clarify the role of beclometasone dipropionate for the treatment and prevention of acute GVHD. At present, more data are required before the addition of beclometasone dipropionate to systemic corticosteroids for the treatment of acute GVHD can be considered the standard of care.

Authors
Doan, PL; Chao, NJ
MLA Citation
Doan, PL, and Chao, NJ. "The role of oral beclometasone dipropionate in the treatment of gastrointestinal Graft-versus-Host Disease." Drugs 69.10 (July 9, 2009): 1339-1350. (Review)
PMID
19583452
Source
pubmed
Published In
Drugs
Volume
69
Issue
10
Publish Date
2009
Start Page
1339
End Page
1350
DOI
10.2165/00003495-200969100-00004

Outcomes of patients who undergo aggressive induction therapy for secondary acute myeloid leukemia.

BACKGROUND: Response and survival in 96 patients with secondary acute myeloid leukemia (sAML) who received aggressive induction chemotherapy was reviewed. METHODS: The median follow-up of survivors was 2.3 years. A total of 70 (73%) patients achieved a morphologic complete remission (CR) confirmed by absence of leukemic blasts by flow cytometry. RESULTS: For all 96 patients, the median event-free survival (EFS) was 8 months, and overall survival (OS) was 13.6 months (range, 1-119 months). Eight patients died shortly after induction therapy because of disease or side effects, and 13 are currently in continuous first remission. The median disease-free survival (DFS) for all 70 patients who achieved a morphologic CR was 9 months (range, 1-51 months), with a 64% chance of surviving 1 year. Patients with AML after previous chemotherapy or radiation therapy had a higher morphologic remission rate compared with those arising from myelodysplastic syndrome or myeloproliferative disease (82% vs 62%; P = .027). However, among the patients from the 2 groups who attained a morphologic remission, there was no difference in terms of CR rate (P = .94), DFS, EFS, or OS (P = .55, .83, and .71, respectively). This is a similar DFS to the group of 7 patients who went directly to ablative allogeneic transplant rather than having induction therapy first. In this population of patients who received aggressive chemotherapy, Charlson comorbidity index or a higher number of factors recognized as high risk in leukemia patients did not affect the chance of OS, DFS, and EFS, although having more recognized leukemia risk factors was related to a lower chance of surviving 1 year. However, it is important to note that those with higher comorbidity indexes were underrepresented in this aggressively treated cohort. CONCLUSIONS: The data from the current study demonstrate that many patients with sAML can tolerate aggressive induction therapy and attain remission, but duration of response and the chance of long-term survival remain poor.

Authors
Rizzieri, DA; O'Brien, JA; Broadwater, G; Decastro, CM; Dev, P; Diehl, L; Beaven, A; Lagoo, A; Gockerman, JP; Chao, NJ; Moore, JO
MLA Citation
Rizzieri, DA, O'Brien, JA, Broadwater, G, Decastro, CM, Dev, P, Diehl, L, Beaven, A, Lagoo, A, Gockerman, JP, Chao, NJ, and Moore, JO. "Outcomes of patients who undergo aggressive induction therapy for secondary acute myeloid leukemia." Cancer 115.13 (July 1, 2009): 2922-2929.
PMID
19452542
Source
pubmed
Published In
Cancer
Volume
115
Issue
13
Publish Date
2009
Start Page
2922
End Page
2929
DOI
10.1002/cncr.24379

Induction of type I IFN is required for overcoming tumor-specific T-cell tolerance after stem cell transplantation.

Tumor-specific T-cell tolerance represents one major mechanism of tumor-induced immune evasion. Myeloablative chemotherapy with stem cell transplantation may offer the best chance of achieving a state of minimal residual disease and, thus, minimize tumor-induced immune evasion. However, studies have shown that tumor-specific T-cell tolerance persists after transplantation. Here, we showed that CD4(+)CD25(+) regulatory T (T(Reg)) cells play a critical role in tumor-specific CD8(+) T-cell tolerance after transplantation. Removal of T(Reg) cells from the donor lymphocyte graft did not overcome this tolerance because of rapid conversion of donor CD4(+)CD25(-) T cells into CD4(+)CD25(+)Foxp3(+) T(Reg) cells in recipients after transplantation, and depletion of T(Reg) cells in recipients was necessary for the reversal of tumor-specific tolerance. These results suggest that strategies capable of overcoming T-cell tolerance in recipients are required to promote antitumor immunity after transplantation. Toward this goal, we showed that dendritic cell (DC) vaccines coadministered with the TLR9 ligand, CpG could effectively overcome tumor-specific tolerance, leading to significant prolongation of tumor-free survival after transplantation. We further showed that CpG-induced type I interferon was critical for the reversal of tumor-specific tolerance in vivo. Collectively, these results may suggest effective immunotherapeutic strategies for treating cancer after stem cell transplantation.

Authors
Horkheimer, I; Quigley, M; Zhu, J; Huang, X; Chao, NJ; Yang, Y
MLA Citation
Horkheimer, I, Quigley, M, Zhu, J, Huang, X, Chao, NJ, and Yang, Y. "Induction of type I IFN is required for overcoming tumor-specific T-cell tolerance after stem cell transplantation." Blood 113.21 (May 21, 2009): 5330-5339.
PMID
19279333
Source
pubmed
Published In
Blood
Volume
113
Issue
21
Publish Date
2009
Start Page
5330
End Page
5339
DOI
10.1182/blood-2008-05-155150

Sequential high-dose ifosfamide, carboplatin and etoposide with rituximab for relapsed Hodgkin and large B-cell non-Hodgkin lymphoma: increased toxicity without improvement in progression-free survival.

Non-cross resistant drugs given at high-dose intensity may maximise tumor cell kill leading to improved patient outcomes. We investigated the feasibility and efficacy of administering ifosfamide, carboplatin and etoposide +/- rituximab as sequential high-dose single agents. Twenty-two patients with relapsed/refractory Hodgkin lymphoma (n = 9) or non-Hodgkin (n = 13) lymphoma (NHL) were included. Therapy included: cycle 1 ifosfamide (15 g/m(2)), cycle 2 etoposide (900 mg/m(2)) and cycle 3 carboplatin (area under the curve 15). Patients with NHL received rituximab (375 mg/m(2)) with cycles 1 and 2. Blood stem cell collection was performed after etoposide. Primary endpoints were overall response (complete response (CR) + PR) and ability to mobilise stem cells after etoposide. Secondary endpoints were to assess the toxicity of the regimen and to evaluate the ability of patients to proceed to stem cell transplant (SCT). Overall response rate was 54% with CR in 4/22 (18%) subjects and PR in 8/22 (36%). Median progression-free survival was 15 months and overall survival has not been reached at 40 months. Thirteen participants proceeded to SCT. Grade 3/4 thrombocytopenia and neutropenia occurred in 58% of cycles and 91% of subjects respectively. Forty-five percent of patients required hospitalisation for toxicity and two patients died from complications of therapy. Sequential dose intense ifosfamide, etoposide, carboplatin +/- rituximab was more toxic and no more effective than the same drugs given in a conventional fashion.

Authors
Shea, TC; Beaven, AW; Moore, DT; Serody, JS; Gabriel, DA; Chao, N; Gockerman, JP; Garcia, RA; Rizzieri, DA
MLA Citation
Shea, TC, Beaven, AW, Moore, DT, Serody, JS, Gabriel, DA, Chao, N, Gockerman, JP, Garcia, RA, and Rizzieri, DA. "Sequential high-dose ifosfamide, carboplatin and etoposide with rituximab for relapsed Hodgkin and large B-cell non-Hodgkin lymphoma: increased toxicity without improvement in progression-free survival." Leuk Lymphoma 50.5 (May 2009): 741-748.
PMID
19358012
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
50
Issue
5
Publish Date
2009
Start Page
741
End Page
748
DOI
10.1080/10428190902853136

Induction of Wilms' tumor protein (WT1)-specific antitumor immunity using a truncated WT1-expressing adenovirus vaccine.

PURPOSE: Wilms' tumor protein (WT1) is overexpressed in most leukemias and many solid tumors and is a promising target for tumor immunotherapy. WT1 peptide-based cancer vaccines have been reported but have limited application due to HLA restriction of the peptides. We sought to vaccinate using adenoviral (Ad) vectors encoding tumor-associated antigens such as WT1 that can stimulate tumor-associated antigen-specific immunity across a broad array of HLA types and multiple class I and class II epitopes. EXPERIMENTAL DESIGN: We developed a novel Ad vector encoding a truncated version of WT1 (Ad-tWT1) lacking the highly conserved COOH terminus zinc finger domains and tested its ability to stimulate WT1-specific immune responses and antitumor immunity in two murine models of WT1-expressing tumors. RESULTS: Despite encoding a transcription factor, we found that Ad-tWT1-transduced murine and human dendritic cells showed cytoplasmic expression of the truncated WT1 protein. In addition, vaccination of C57BL/6 mice with Ad-tWT1 generated WT1-specific cell-mediated and humoral immune responses and conferred protection against challenge with the leukemia cell line, mWT1-C1498. Moreover, in a tumor therapy model, Ad-tWT1 vaccination of TRAMP-C2 tumor-bearing mice significantly suppressed tumor growth. CONCLUSIONS: This is the first report of a WT1-encoding Ad vector that is capable of inducing effective immunity against WT1-expressing malignancies. Based on these findings, Ad-tWT1 warrants investigation in human clinical trials to evaluate its applications as a vaccine for patients with WT1-expressing cancers.

Authors
Osada, T; Woo, CY; McKinney, M; Yang, XY; Lei, G; Labreche, HG; Hartman, ZC; Niedzwiecki, D; Chao, N; Amalfitano, A; Morse, MA; Lyerly, HK; Clay, TM
MLA Citation
Osada, T, Woo, CY, McKinney, M, Yang, XY, Lei, G, Labreche, HG, Hartman, ZC, Niedzwiecki, D, Chao, N, Amalfitano, A, Morse, MA, Lyerly, HK, and Clay, TM. "Induction of Wilms' tumor protein (WT1)-specific antitumor immunity using a truncated WT1-expressing adenovirus vaccine." Clin Cancer Res 15.8 (April 15, 2009): 2789-2796.
PMID
19351755
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
8
Publish Date
2009
Start Page
2789
End Page
2796
DOI
10.1158/1078-0432.CCR-08-2589

Umbilical cord blood: biology and transplantation.

Umbilical cord blood transplantation is becoming an acceptable alternative source of hematopoietic stem cells for patients with malignant diseases. Cord blood differs from bone marrow and peripheral blood progenitors in its immune tolerance and kinetics of engraftment. In this article, we will review the biology of cord blood stem cells and clinical studies of cord blood transplants in pediatric and adult populations. We will also discuss potential uses of cord blood stem cells in regenerative medicine and novel methods for ex vivo expansion of hematopoietic stem cells. As we learn more about cord blood transplants, there is the potential to overcome the limitations of cord blood transplants so that they can become more widely available.

Authors
Doan, PL; Chao, NJ
MLA Citation
Doan, PL, and Chao, NJ. "Umbilical cord blood: biology and transplantation." Expert Rev Hematol 2.2 (April 2009): 197-208. (Review)
PMID
21083452
Source
pubmed
Published In
Expert Review of Hematology
Volume
2
Issue
2
Publish Date
2009
Start Page
197
End Page
208
DOI
10.1586/ehm.09.9

Pharmacologic Prevention of Acute Graft-Versus-Host Disease

Authors
Chao, NJ; Sullivan, KM
MLA Citation
Chao, NJ, and Sullivan, KM. "Pharmacologic Prevention of Acute Graft-Versus-Host Disease." (March 5, 2009): 1257-1274. (Chapter)
Source
scopus
Publish Date
2009
Start Page
1257
End Page
1274
DOI
10.1002/9781444303537.ch84

Endothelial progenitor cell infusion induces hematopoietic stem cell reconstitution in vivo.

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.

Authors
Salter, AB; Meadows, SK; Muramoto, GG; Himburg, H; Doan, P; Daher, P; Russell, L; Chen, B; Chao, NJ; Chute, JP
MLA Citation
Salter, AB, Meadows, SK, Muramoto, GG, Himburg, H, Doan, P, Daher, P, Russell, L, Chen, B, Chao, NJ, and Chute, JP. "Endothelial progenitor cell infusion induces hematopoietic stem cell reconstitution in vivo." Blood 113.9 (February 26, 2009): 2104-2107.
PMID
19141867
Source
pubmed
Published In
Blood
Volume
113
Issue
9
Publish Date
2009
Start Page
2104
End Page
2107
DOI
10.1182/blood-2008-06-162941

Pharmacological manipulation of the RAR/RXR signaling pathway maintains the repopulating capacity of hematopoietic stem cells in culture.

The retinoid X receptor (RXR) contributes to the regulation of diverse biological pathways via its role as a heterodimeric partner of several nuclear receptors. However, RXR has no established role in the regulation of hematopoietic stem cell (HSC) fate. In this study, we sought to determine whether direct modulation of RXR signaling could impact human HSC self-renewal or differentiation. Treatment of human CD34(+)CD38(-)lin(-) cells with LG1506, a selective RXR modulator, inhibited the differentiation of HSCs in culture and maintained long-term repopulating HSCs in culture that were otherwise lost in response to cytokine treatment. Further studies revealed that LG1506 had a distinct mechanism of action in that it facilitated the recruitment of corepressors to the retinoic acid receptor (RAR)/RXR complex at target gene promoters, suggesting that this molecule was functioning as an inverse agonist in the context of this heterodimer. Interestingly, using combinatorial peptide phage display, we identified unique surfaces presented on RXR when occupied by LG1506 and demonstrated that other modulators that exhibited these properties functioned similarly at both a mechanistic and biological level. These data indicate that the RAR/RXR heterodimer is a critical regulator of human HSC differentiation, and pharmacological modulation of RXR signaling prevents the loss of human HSCs that otherwise occurs in short-term culture.

Authors
Safi, R; Muramoto, GG; Salter, AB; Meadows, S; Himburg, H; Russell, L; Daher, P; Doan, P; Leibowitz, MD; Chao, NJ; McDonnell, DP; Chute, JP
MLA Citation
Safi, R, Muramoto, GG, Salter, AB, Meadows, S, Himburg, H, Russell, L, Daher, P, Doan, P, Leibowitz, MD, Chao, NJ, McDonnell, DP, and Chute, JP. "Pharmacological manipulation of the RAR/RXR signaling pathway maintains the repopulating capacity of hematopoietic stem cells in culture." Mol Endocrinol 23.2 (February 2009): 188-201.
PMID
19106195
Source
pubmed
Published In
Molecular endocrinology (Baltimore, Md.)
Volume
23
Issue
2
Publish Date
2009
Start Page
188
End Page
201
DOI
10.1210/me.2008-0121

Response and toxicity of donor lymphocyte infusions following T-cell depleted non-myeloablative allogeneic hematopoietic SCT from 3-6/6 HLA matched donors.

We report the outcome of early donor lymphocyte infusions (DLIs) after T-cell depleted non-myeloablative transplantation using stem cells from HLA-matched or mismatched donors. Sixty-nine patients with high-risk hematologic malignancies received DLI following fludarabine, CY and alemtuzumab with infusion of stem cells from a matched sibling (52) or partially matched family member donor (17). Patients received the first infusion at a median of 50 days after transplant, and doses ranged from 1 x 10(4) CD3+ cells/kg to 3.27 x 10(8) CD3+ cells/kg, depending on clinical status and the physician's discretion. A median cell dose of 1 x 10(5) CD3+ cells/kg in the mismatched setting and 1 x 10(6) CD3+ cells/kg in the matched sibling setting appears safe with only 1 of 7 (14%) and 4 of 31 patients (13%), respectively, experiencing severe acute GVHD at these doses. Importantly, 38% of patients with persistent disease before DLI attained a remission after infusion. Nine of the 69 patients remain alive and disease-free 32-71 months after the first DLI. In conclusion, low doses of DLI can be safely provided soon after T-cell depleted non-myeloablative therapy and provide a chance of remission. However, long-term survival still remains poor, primarily because of relapse in these patients.

Authors
Rizzieri, DA; Dev, P; Long, GD; Gasparetto, C; Sullivan, KM; Horwitz, M; Chute, J; Chao, NJ
MLA Citation
Rizzieri, DA, Dev, P, Long, GD, Gasparetto, C, Sullivan, KM, Horwitz, M, Chute, J, and Chao, NJ. "Response and toxicity of donor lymphocyte infusions following T-cell depleted non-myeloablative allogeneic hematopoietic SCT from 3-6/6 HLA matched donors." Bone Marrow Transplant 43.4 (February 2009): 327-333.
PMID
18850014
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
43
Issue
4
Publish Date
2009
Start Page
327
End Page
333
DOI
10.1038/bmt.2008.321

Prevention of chronic graft versus host disease

© Cambridge University Press 2009.INTRODUCTION. Chronic graft versus host disease (GVHD) is the major complication in long-term survivors of an allogeneic hematopoietic stem cell transplant (HSCT): its detrimental effect on quality of life, especially when extensive or severe, together with its protective role on leukemia relapse are well documented. This chapter will outline programs designed to prevent GVHD, including the use of agents capable of modulating T-cell function. Recent developments in our understanding of the sclerodermatous form of chronic GVHD (cGVHD) and its clinical implications will also be discussed. TIMING OF CHRONIC GVHD. This division on day 100 between acute and cGVHD is currently considered artificial. With the advent of nonmyeloablative hematopoietic cell transplantation (HCT) regimens and the use of unrelated donor stem cells, there is a need to drop this arbitrary time point from the definition of these disease entities. Current studies are more likely to utilize the clinical manifestations of these diseases rather than the arbitrary cutoff of a particular date post transplantation. This has been the conclusion of an international group of experts. A continuum of clinical findings (i.e., “overlap syndrome”) may be observed in patients with acute and cGVHD, as both disorders commonly affect similar organs, principally the skin, liver, and gastrointestinal tract. However, the target organs affected by and the clinical and histologic features associated with cGVHD may differ from those observed with acute disease. As an example, autoimmune phenomena, such as autoantibody formation, are more common with chronic disease.

Authors
Bacigalupo, A; Chao, NJ
MLA Citation
Bacigalupo, A, and Chao, NJ. "Prevention of chronic graft versus host disease." (January 1, 2009): 117-123. (Chapter)
Source
scopus
Publish Date
2009
Start Page
117
End Page
123
DOI
10.1017/CBO9780511576751.012

Endpoints for Clinical Trials Testing Treatment of Acute Graft-versus-Host Disease: A Joint Statement

Currently, no agents are approved by the United States Food and Drug Administration (FDA) for either prevention or treatment of acute graft-versus-host disease (aGVHD). Formal precedents establishing a comparative basis for assessing the efficacy and safety of new investigational agents are still lacking. As a step toward addressing this problem, a panel of experts met on 2 occasions to reach consensus on recommendations for terminology describing a clinically meaningful primary endpoint in studies assessing treatment for aGVHD. The panel recommended terminology for "very good partial response" (VGPR) that includes both diagnostic and functional criteria. The central hypothesis leading to this proposal is that the potential harm of giving more treatment than needed to produce or maintain complete response exceeds the harm of slight undertreatment that may be associated with less than complete response. VGPR clearly cannot be used as the sole outcome measure in GVHD treatment trials, and must be considered in the context of survival and safety. The proposed use of VGPR as the primary endpoint in GVHD treatment trials will remain provisional until its use has been validated through experience. © 2009 American Society for Blood and Marrow Transplantation.

Authors
Martin, PJ; Bachier, CR; Klingemann, H-G; McCarthy, PL; Szabolcs, P; Uberti, JP; Schuster, MW; Weisdorf, D; Chao, NJ; Kebriaei, P; Shpall, EJ; MacMillan, ML; Soiffer, RJ
MLA Citation
Martin, PJ, Bachier, CR, Klingemann, H-G, McCarthy, PL, Szabolcs, P, Uberti, JP, Schuster, MW, Weisdorf, D, Chao, NJ, Kebriaei, P, Shpall, EJ, MacMillan, ML, and Soiffer, RJ. "Endpoints for Clinical Trials Testing Treatment of Acute Graft-versus-Host Disease: A Joint Statement." Biology of Blood and Marrow Transplantation 15.7 (2009): 777-784.
PMID
19539208
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
15
Issue
7
Publish Date
2009
Start Page
777
End Page
784
DOI
10.1016/j.bbmt.2009.03.012

Stem cells, multiorgan failure in radiation emergency medical preparedness: A U.S./European Consultation Workshop

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. © AlphaMed Press.

Authors
Fliedner, TM; Chao, NJ; Bader, JL; Boettger, A; Jr, CC; Chute, J; Confer, DL; Ganser, A; Gorin, N-C; Gourmelon, P; Graessle, DH; Krawisz, R; Meineke, V; Niederwieser, D; Port, M; Powles, R; Sirohi, B; Weinstock, DM; Wiley, A; Coleman, CN
MLA Citation
Fliedner, TM, Chao, NJ, Bader, JL, Boettger, A, Jr, CC, Chute, J, Confer, DL, Ganser, A, Gorin, N-C, Gourmelon, P, Graessle, DH, Krawisz, R, Meineke, V, Niederwieser, D, Port, M, Powles, R, Sirohi, B, Weinstock, DM, Wiley, A, and Coleman, CN. "Stem cells, multiorgan failure in radiation emergency medical preparedness: A U.S./European Consultation Workshop." Stem Cells 27.5 (2009): 1205-1211.
PMID
19418462
Source
scival
Published In
Stem Cells
Volume
27
Issue
5
Publish Date
2009
Start Page
1205
End Page
1211
DOI
10.1002/stem.16

Myeloablative intravenous busulfan/fludarabine conditioning does not facilitate reliable engraftment of dual umbilical cord blood grafts in adult recipients.

The efficacy of once-daily intravenous busulfan with fludarabine as a preparative regimen for partially matched umbilical cord blood transplantation has not been formally studied. We randomized 10 adult patients with myeloid malignancies to receive either concurrent or sequential administration of intravenous busulfan 130 mg/m(2) once daily x 4 days and fludarabine 40 mg/m(2) daily x 4 days, followed by dual umbilical cord blood transplantation. The median combined cryopreserved total nucleated cell dose was 3.6 x 10(7)/kg recipient body weight (range: 2.8-4.5 x 10(7)/kg). Graft-versus-host disease (GVHD) prophylaxis was provided by tacrolimus and mycophenolate mofetil (MMF). Donor-derived neutrophil recovery was observed in only 2 of 10 patients, resulting in premature closure of the study as per graft failure stopping rules. We conclude that the myeloablative conditioning regimen of once-daily intravenous busulfan with fludarabine provides insufficient immunosuppression to allow for engraftment of partially matched, dual umbilical cord blood grafts.

Authors
Horwitz, ME; Morris, A; Gasparetto, C; Sullivan, K; Long, G; Chute, J; Rizzieri, D; McPherson, J; Chao, N
MLA Citation
Horwitz, ME, Morris, A, Gasparetto, C, Sullivan, K, Long, G, Chute, J, Rizzieri, D, McPherson, J, and Chao, N. "Myeloablative intravenous busulfan/fludarabine conditioning does not facilitate reliable engraftment of dual umbilical cord blood grafts in adult recipients." Biol Blood Marrow Transplant 14.5 (May 2008): 591-594.
PMID
18410902
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
14
Issue
5
Publish Date
2008
Start Page
591
End Page
594
DOI
10.1016/j.bbmt.2008.02.016

Gene expression signatures of radiation response are specific, durable and accurate in mice and humans.

BACKGROUND: Previous work has demonstrated the potential for peripheral blood (PB) gene expression profiling for the detection of disease or environmental exposures. METHODS AND FINDINGS: We have sought to determine the impact of several variables on the PB gene expression profile of an environmental exposure, ionizing radiation, and to determine the specificity of the PB signature of radiation versus other genotoxic stresses. Neither genotype differences nor the time of PB sampling caused any lessening of the accuracy of PB signatures to predict radiation exposure, but sex difference did influence the accuracy of the prediction of radiation exposure at the lowest level (50 cGy). A PB signature of sepsis was also generated and both the PB signature of radiation and the PB signature of sepsis were found to be 100% specific at distinguishing irradiated from septic animals. We also identified human PB signatures of radiation exposure and chemotherapy treatment which distinguished irradiated patients and chemotherapy-treated individuals within a heterogeneous population with accuracies of 90% and 81%, respectively. CONCLUSIONS: We conclude that PB gene expression profiles can be identified in mice and humans that are accurate in predicting medical conditions, are specific to each condition and remain highly accurate over time.

Authors
Meadows, SK; Dressman, HK; Muramoto, GG; Himburg, H; Salter, A; Wei, Z; Ginsburg, GS; Chao, NJ; Nevins, JR; Chute, JP
MLA Citation
Meadows, SK, Dressman, HK, Muramoto, GG, Himburg, H, Salter, A, Wei, Z, Ginsburg, GS, Chao, NJ, Nevins, JR, and Chute, JP. "Gene expression signatures of radiation response are specific, durable and accurate in mice and humans. (Published online)" PLoS One 3.4 (April 2, 2008): e1912-.
Website
http://hdl.handle.net/10161/13546
PMID
18382685
Source
pubmed
Published In
PloS one
Volume
3
Issue
4
Publish Date
2008
Start Page
e1912
DOI
10.1371/journal.pone.0001912

Outcomes of a second non-myeloablative allogeneic stem cell transplantation following graft rejection.

Following initial graft rejection, a second attempt at allogeneic immunotherapy is often contemplated, but data on the success is limited. We therefore report on 11 patients with hematologic malignancies, renal cell cancer or marrow failure who underwent a second reduced-intensity regimen for primary or secondary graft failure. Nine of the 11 patients initially engrafted with the second attempt including two of four who used the same donor. One of the patients engrafted after the third attempt using a different donor and conditioning regimen. There were two treatment-related deaths. Four patients died from progressive disease 1-9 months after the second transplant. Two patients are still in recovery phase less than 1 year from the second transplant. Long-term remission is possible and three patients are alive in complete remission.

Authors
Byrne, BJ; Horwitz, M; Long, GD; Gasparetto, C; Sullivan, KM; Chute, J; Chao, NJ; Rizzieri, DA
MLA Citation
Byrne, BJ, Horwitz, M, Long, GD, Gasparetto, C, Sullivan, KM, Chute, J, Chao, NJ, and Rizzieri, DA. "Outcomes of a second non-myeloablative allogeneic stem cell transplantation following graft rejection." Bone Marrow Transplant 41.1 (January 2008): 39-43.
PMID
17982503
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
41
Issue
1
Publish Date
2008
Start Page
39
End Page
43
DOI
10.1038/sj.bmt.1705882

Unmanipulated or CD34 selected haplotype mismatched transplants

Mismatched/haploidentical transplant provides an alternative approach for patients with high-risk hematological malignancies or marrow failure syndromes. Overall survival and clinical outcome continue to improve. Future challenges lie in determining the safest preparative conditioning regimen, minimizing graft-versus-host disease while preserving effective graft-versus-malignancy and promoting rapid immune reconstitution. © 2008 Wolters Kluwer Health|Lippincott Williams & Wilkins.

Authors
Kang, Y; Chao, NJ; Aversa, F
MLA Citation
Kang, Y, Chao, NJ, and Aversa, F. "Unmanipulated or CD34 selected haplotype mismatched transplants." Current Opinion in Hematology 15.6 (2008): 561-567.
PMID
18832926
Source
scival
Published In
Current Opinion in Hematology
Volume
15
Issue
6
Publish Date
2008
Start Page
561
End Page
567
DOI
10.1097/MOH.0b013e32831366eb

Radiologic and nuclear events: Contingency planning for hematologists/oncologists

Untoward events involving radioactive material, either accidental or intentional, are potentially devastating. Hematologists and oncologists are uniquely suited to help manage radiation victims, as myelosuppression is a frequent complication of radiation exposure. In the aftermath of a large event, such as a nuclear detonation, there may be a national call for surge capacity that involves hematologists/oncologists across the country in the disaster response. In preparation, the National Marrow Donor Program and American Society for Blood and Marrow Transplantation have established the Radiation Injury Treatment Network (RITN), a voluntary consortium of transplant centers, donor centers, and umbilical cord blood banks. RITN is partnered with the Office of the Assistant Secretary for Preparedness and Response in the United States Department of Health and Human Services to develop treatment guidelines, educate healthcare professionals, coordinate situation response, and provide comprehensive evaluation and care for radiation injury victims. We outline the current plans for event response and describe scenarios, including catastrophic events that would require extensive support from hematologists/oncologists across the country. In addition, we highlight important reference resources and discuss current efforts to develop medical counter-measures against radiation toxicity. Practitioners and institutions across the country are encouraged to become involved and participate in the planning.

Authors
Weinstock, DM; Jr, CC; Bader, JL; Chao, NJ; Coleman, CN; Hatchett, RJ; Weisdorf, DJ; Confer, DL
MLA Citation
Weinstock, DM, Jr, CC, Bader, JL, Chao, NJ, Coleman, CN, Hatchett, RJ, Weisdorf, DJ, and Confer, DL. "Radiologic and nuclear events: Contingency planning for hematologists/oncologists." Blood 111.12 (2008): 5440-5445.
PMID
18287516
Source
scival
Published In
Blood
Volume
111
Issue
12
Publish Date
2008
Start Page
5440
End Page
5445
DOI
10.1182/blood-2008-01-134817

Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study

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 en-graftment, 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 myelosup-pression. This trial is registered at www. ClinicalTrials.gov as #NCT00223925. © 2008 by The American Society of Hematology.

Authors
Winston, DJ; Young, J-AH; Pullarkat, V; Papanicolaou, GA; Vij, R; Vance, E; Alangaden, GJ; Chemaly, RR; Petersen, F; Chao, N; Klein, J; Sprague, K; Villano, SA; Boeckh, M
MLA Citation
Winston, DJ, Young, J-AH, Pullarkat, V, Papanicolaou, GA, Vij, R, Vance, E, Alangaden, GJ, Chemaly, RR, Petersen, F, Chao, N, Klein, J, Sprague, K, Villano, SA, and Boeckh, M. "Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study." Blood 111.11 (2008): 5403-5410.
PMID
18285548
Source
scival
Published In
Blood
Volume
111
Issue
11
Publish Date
2008
Start Page
5403
End Page
5410
DOI
10.1182/blood-2007-11-121558

Are there effective new strategies for the treatment of acute and chronic GvHD?

The molecular biology and pathophysiology underlying graft-versus-host disease (GvHD) remains an area of intensive research. Understanding normal and abnormal developments of both the innate and adaptive immune systems are beginning to provide understanding of the details of relevant pathways. Recent work in gene-expression profiling suggests a critical next step in identifying broader patterns that will stand up to examination in independent data sets and provide a sturdy basis for targeted therapy and preventive measures against GvHD. © 2007 Elsevier Ltd. All rights reserved.

Authors
Chao, NJ
MLA Citation
Chao, NJ. "Are there effective new strategies for the treatment of acute and chronic GvHD?." Best Practice and Research: Clinical Haematology 21.1 (2008): 93-98.
PMID
18342817
Source
scival
Published In
Best Practice & Research: Clinical Haematology
Volume
21
Issue
1
Publish Date
2008
Start Page
93
End Page
98
DOI
10.1016/j.beha.2007.11.012

Haploidentical hematopoietic cell transplantation

Haploidentical hematopoietic stem cell transplantation (HSCT) provides an opportunity for nearly all patients to benefit from HCT when a HLA genotypically matched sibling is not available. Initial results with the use of mismatched allografts led to limited enthusiasm due to GVHD and infectious complications resulting in unacceptable treatment-related morbidity and mortality. Recent advances with effective T-cell depletion, the use of 'megadoses' of stem cells, better antimicrobial therapy and reduced intensity conditioning has significantly decreased the early transplant-related mortality and GVHD. These modifications also enabled robust and prompt engraftment and led to enhancing the therapeutic benefits of haploidentical transplantation. However, the cardinal problems related to delayed immune reconstitution causing post-transplant infectious complications and relapse remain, limiting the efficacy of haploidentical transplant. Preliminary data have demonstrated the great potential in the use of adoptive cellular immunity and selective allodepletion in rapidly reconstituting immunity without GVHD. The encouraging reports from haploidentical transplant using noninherited maternal antigen (NIMA)-mismatched donors or natural killer (NK) alloreactive donors may greatly increase the donor availability and open a way to more appropriate donor selection in HLA-haploidentical HSCT. Future challenges remain in determining the safest approach for haploidentical transplant with minimal risk of GVHD, while preserving effective GVL activity and promoting prompt immune reconstitution.

Authors
Koh, L-P; Chao, N
MLA Citation
Koh, L-P, and Chao, N. "Haploidentical hematopoietic cell transplantation." Bone Marrow Transplantation 42.SUPPL.1 (2008): S60-S63.
PMID
18724305
Source
scival
Published In
Bone Marrow Transplantation
Volume
42
Issue
SUPPL.1
Publish Date
2008
Start Page
S60
End Page
S63
DOI
10.1038/bmt.2008.117

What do you do with the "pink sheets?".

Applying for a grant seems like an enormous challenge, sometimes akin to Sisyphus' task of rolling the boulder up the hill. In many ways, obtaining funding can be challenging, yet year after year, new investigators do obtain funding, even though there are times when the funding percentage can be low. This review offers some suggestions of what to do after the first or second round of critiques are back. There are some relatively straightforward steps one can take to improve one's chances of success. The joy of funding is worth it!

Authors
Chao, N
MLA Citation
Chao, N. "What do you do with the "pink sheets?"." Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program (2008): 23-25.
PMID
19074049
Source
scival
Published In
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program
Publish Date
2008
Start Page
23
End Page
25
DOI
10.1182/asheducation-2008.1.23

Detailed analysis of cytomegalovirus (CMV)-specific T cells expanded for adoptive immunotherapy of CMV infection following allogeneic stem cell transplantation for malignant disease.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.

Authors
Hobeika, A; Osada, T; Serra, D; Peplinski, S; Hanson, K; Tanaka, Y; Niedzwiecki, D; Chao, N; Rizzieri, D; Lyerly, H; Clay, T; Morse, M
MLA Citation
Hobeika, A, Osada, T, Serra, D, Peplinski, S, Hanson, K, Tanaka, Y, Niedzwiecki, D, Chao, N, Rizzieri, D, Lyerly, H, Clay, T, and Morse, M. "Detailed analysis of cytomegalovirus (CMV)-specific T cells expanded for adoptive immunotherapy of CMV infection following allogeneic stem cell transplantation for malignant disease." Cytotherapy 10.3 (2008): 289-302.
PMID
18418774
Source
pubmed
Published In
Cytotherapy (Informa)
Volume
10
Issue
3
Publish Date
2008
Start Page
289
End Page
302
DOI
10.1080/14653240801927040

Memory T Cells

Authors
Chao, N
MLA Citation
Chao, N. "Memory T Cells." Biology of Blood and Marrow Transplantation 14.1 SUPPL. (2008): 17-22.
PMID
18162217
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
14
Issue
1 SUPPL.
Publish Date
2008
Start Page
17
End Page
22
DOI
10.1016/j.bbmt.2007.10.013

Nonmyeloablative allogeneic hematopoietic stem cell transplant using mismatched/haploidentical donors: A review

Haploidentical hematopoietic stem cell transplantation (HSCT) provides an opportunity for patients to benefit from HCT when a human leukocyte antigen (HLA) genotypically matched sibling is not available. Initial results with the use of mismatched allograft has been disappointing due to the high incidence of graft-versus-host disease (GVHD) and infectious complications resulting in an unacceptable treatment-related morbidity and mortality. Recent advances with effective T-cell depletion, the use of 'megadose' of stem cells and reduced intensity conditioning has significantly decreased the early transplant related mortality and GvHD, while enabling robust and prompt engraftment, and hence enhancing the therapeutic benefits of haploidentical transplantation. However, the cardinal problems related to delayed immune reconstitution causing posttransplant infectious complications and relapse remain, limiting the efficacy of haploidentical transplant. Preliminary data have demonstrated the great potential in the use of adoptive cellular immunity and selective allodepletion in rapidly reconstituting immunity without GvHD. The encouraging reports from haploidentical transplant using noninherited maternal antigen (NIMA)-mismatched donors or natural killer alloreactive donors may greatly increase the donor availability and open a way to more appropriate donor selection in HLA-haploidentical HSCT. Future challenges remain in determining the safest approach for haploidentical transplant to be performed with minimal risk of GvHD, while preserving effective graft-versus-leukemia activity and promoting prompt immune reconstitution. © 2007 Elsevier Inc. All rights reserved.

Authors
Koh, L-P; Chao, NJ
MLA Citation
Koh, L-P, and Chao, NJ. "Nonmyeloablative allogeneic hematopoietic stem cell transplant using mismatched/haploidentical donors: A review." Blood Cells, Molecules, and Diseases 40.1 (2008): 20-24.
PMID
17884641
Source
scival
Published In
Blood Cells, Molecules and Diseases
Volume
40
Issue
1
Publish Date
2008
Start Page
20
End Page
24
DOI
10.1016/j.bcmd.2007.06.017

Fludarabine-based nonmyeloablative stem cell transplantation for sickle cell disease with and without renal failure: clinical outcome and pharmacokinetics.

End-organ damage is common in patients with sickle cell disease (SCD) thereby limiting the use of allogeneic stem cell transplantation (SCT). We report the outcome of 2 adult SCD patients, 1 with end-stage renal disease (ESRD), who underwent fludarabine-based nonmyeloablative SCT from HLA-identical matched siblings. To prevent fludarabine toxicity, the patient with ESRD underwent aggressive dialysis following adjusted fludarabine dosing. Pharmacokinetics of the fludarabine metabolite F-Ara-A was studied on the patient with ESRD and 2 additional patients with normal renal function. Both patients with SCD achieved full donor erythroid chimerism, have normal blood counts, and are on no immunosuppressive medications. With a 20% dose reduction followed by daily dialysis, we achieved fludarabine drug exposure that is nearly identical to that achieved in patients with normal renal function. We conclude that fludarabine-based nonmyeloablative allogeneic SCT for adult patients with SCD is feasible, even in the setting of ESRD.

Authors
Horwitz, ME; Spasojevic, I; Morris, A; Telen, M; Essell, J; Gasparetto, C; Sullivan, K; Long, G; Chute, J; Chao, N; Rizzieri, D
MLA Citation
Horwitz, ME, Spasojevic, I, Morris, A, Telen, M, Essell, J, Gasparetto, C, Sullivan, K, Long, G, Chute, J, Chao, N, and Rizzieri, D. "Fludarabine-based nonmyeloablative stem cell transplantation for sickle cell disease with and without renal failure: clinical outcome and pharmacokinetics." Biol Blood Marrow Transplant 13.12 (December 2007): 1422-1426.
PMID
18022571
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
13
Issue
12
Publish Date
2007
Start Page
1422
End Page
1426
DOI
10.1016/j.bbmt.2007.08.050

Allogeneic hematopoietic stem cell transplant using mismatched/haploidentical donors.

Haploidentical hematopoietic stem cell transplantation (HSCT) provides an opportunity for nearly all patients to benefit from HSCT when a human leukocyte antigen (HLA) genotypically matched sibling is not available. Initial results with the use of mismatched allografts led to limited enthusiasm because of graft-versus-host disease (GVHD) and infectious complications, resulting in an unacceptable treatment-related morbidity and mortality. Recent advances with effective T cell depletion, the use of a "megadose" of stem cells, earlier detection of severe infections, combined with better antimicrobial therapy and reduced-intensity conditioning (RIC) has significantly decreased the early transplant-related mortality and GVHD, whereas enabling prompt engraftment, hence advancing the therapeutic benefit of haploidentical transplantation. However, the cardinal problems related to delayed immune reconstitution allowing posttransplant infectious complications and relapse remain, limiting the efficacy of haploidentical HSCT. Preliminary data has demonstrated the potential for use of adoptive cellular immunity and selective allodepletion in rapidly reconstituting immunity without GVHD. The encouraging reports from haploidentical transplant using noninherited maternal antigen (NIMA)-mismatched or natural killer (NK) alloreactive donors may greatly increase the donor availability and open the way to more appropriate donor selection in HLA-haploidentical HSCT. Future challenges remain in determining the safest approach for haploidentical transplant to be performed with minimal risk of GVHD, whereas preserving effective graft-versus-leukemia activity and promoting prompt immune reconstitution.

Authors
Koh, L-P; Rizzieri, DA; Chao, NJ
MLA Citation
Koh, L-P, Rizzieri, DA, and Chao, NJ. "Allogeneic hematopoietic stem cell transplant using mismatched/haploidentical donors." Biol Blood Marrow Transplant 13.11 (November 2007): 1249-1267. (Review)
PMID
17950913
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
13
Issue
11
Publish Date
2007
Start Page
1249
End Page
1267
DOI
10.1016/j.bbmt.2007.08.003

Inability of memory T cells to induce graft-versus-host disease is a result of an abortive alloresponse.

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.

Authors
Chen, BJ; Deoliveira, D; Cui, X; Le, NT; Son, J; Whitesides, JF; Chao, NJ
MLA Citation
Chen, BJ, Deoliveira, D, Cui, X, Le, NT, Son, J, Whitesides, JF, and Chao, NJ. "Inability of memory T cells to induce graft-versus-host disease is a result of an abortive alloresponse." Blood 109.7 (April 1, 2007): 3115-3123.
PMID
17148592
Source
pubmed
Published In
Blood
Volume
109
Issue
7
Publish Date
2007
Start Page
3115
End Page
3123
DOI
10.1182/blood-2006-04-016410

Gene expression signatures that predict radiation exposure in mice and humans.

BACKGROUND: The capacity to assess environmental inputs to biological phenotypes is limited by methods that can accurately and quantitatively measure these contributions. One such example can be seen in the context of exposure to ionizing radiation. METHODS AND FINDINGS: We have made use of gene expression analysis of peripheral blood (PB) mononuclear cells to develop expression profiles that accurately reflect prior radiation exposure. We demonstrate that expression profiles can be developed that not only predict radiation exposure in mice but also distinguish the level of radiation exposure, ranging from 50 cGy to 1,000 cGy. Likewise, a molecular signature of radiation response developed solely from irradiated human patient samples can predict and distinguish irradiated human PB samples from nonirradiated samples with an accuracy of 90%, sensitivity of 85%, and specificity of 94%. We further demonstrate that a radiation profile developed in the mouse can correctly distinguish PB samples from irradiated and nonirradiated human patients with an accuracy of 77%, sensitivity of 82%, and specificity of 75%. Taken together, these data demonstrate that molecular profiles can be generated that are highly predictive of different levels of radiation exposure in mice and humans. CONCLUSIONS: We suggest that this approach, with additional refinement, could provide a method to assess the effects of various environmental inputs into biological phenotypes as well as providing a more practical application of a rapid molecular screening test for the diagnosis of radiation exposure.

Authors
Dressman, HK; Muramoto, GG; Chao, NJ; Meadows, S; Marshall, D; Ginsburg, GS; Nevins, JR; Chute, JP
MLA Citation
Dressman, HK, Muramoto, GG, Chao, NJ, Meadows, S, Marshall, D, Ginsburg, GS, Nevins, JR, and Chute, JP. "Gene expression signatures that predict radiation exposure in mice and humans." PLoS Med 4.4 (April 2007): e106-.
Website
http://hdl.handle.net/10161/11574
PMID
17407386
Source
pubmed
Published In
PLoS medicine
Volume
4
Issue
4
Publish Date
2007
Start Page
e106
DOI
10.1371/journal.pmed.0040106

Transplantation of vascular endothelial cells mediates the hematopoietic recovery and survival of lethally irradiated mice.

Flk-1(+) endothelial progenitors contribute critically to the definitive onset of hematopoiesis during embryogenesis. Recent studies have suggested that adult sources of endothelial cells also possess hematopoietic activity. In this study, we sought to determine whether transplantation of primary vascular endothelial cells (ECs) could enhance the hematopoietic recovery and survival of irradiated mice. C57Bl6 mice were exposed to sublethal and lethal doses of irradiation and were subsequently given transplants of either primary murine brain-derived ECs (MBECs) or fetal blood-derived ECs (FBECs). Mice that received a transplant with MBECs alone demonstrated accelerated BM cellular recovery, radioprotection of BM c-kit(+)sca-1(-)lin(-) progenitors and enhanced regeneration of c-kit(+)sca-1(+)lin(-) (KSL) stem/progenitor cells following irradiation compared with controls. MBEC transplantation also facilitated the recovery of circulating white blood cell and platelet counts following radiation exposure. Remarkably, 57% of mice that received a transplant with MBECs alone survived long term following 1050 cGy exposure, which was 100% lethal in control mice. FBEC transplantation was also associated with increased survival compared with controls, although these mice did not survive in the long term. These data suggest that reestablishment of endothelial cell activity can improve the hematopoietic recovery and survival of irradiated mice.

Authors
Chute, JP; Muramoto, GG; Salter, AB; Meadows, SK; Rickman, DW; Chen, B; Himburg, HA; Chao, NJ
MLA Citation
Chute, JP, Muramoto, GG, Salter, AB, Meadows, SK, Rickman, DW, Chen, B, Himburg, HA, and Chao, NJ. "Transplantation of vascular endothelial cells mediates the hematopoietic recovery and survival of lethally irradiated mice." Blood 109.6 (March 15, 2007): 2365-2372.
PMID
17095624
Source
pubmed
Published In
Blood
Volume
109
Issue
6
Publish Date
2007
Start Page
2365
End Page
2372
DOI
10.1182/blood-2006-05-022640

Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution.

PURPOSE: Allogeneic transplantation is typically limited to younger patients having a matched donor. To allow a donor to be found for nearly all patients, we have used a nonmyeloablative conditioning regimen in conjunction with stem cells from a related donor with one fully mismatched HLA haplotype. PATIENTS AND METHODS: Fludarabine, cyclophosphamide, and alemtuzumab were used as the preparatory regimen. Additional graft-versus-host disease (GVHD) prophylaxis included mycophenolate with or without cyclosporine. Patients with persistence of disease had a donor lymphocyte boost planned. Toxicities, engraftment, response, survival, and immune recovery are reported. RESULTS: Forty-nine patients with hematologic malignancies or marrow failure and no other available donors were enrolled. Ninety-four percent of patients had successful engraftment, and 8% had secondary graft failure. The treatment-related mortality rate was 10.2%, and 8% of patients had severe GVHD. Encouraging evidence of quantitative lymphocyte recovery through expansion of transplanted T cells was noted by 3 to 6 months. Seventy-five percent of patients attained a complete remission, and 1-year survival rate was 31% (95% CI, 18% to 44%). A standard-risk group of 19 patients with aplasia or in remission at transplantation demonstrated a 63% 1-year survival rate (95% CI, 38% to 80%) and 2.9-year median overall survival time (95% CI, 6.2 to 48 months). CONCLUSION: Nonmyeloablative therapy using haploidentical family member donors is feasible because the main obstacles of GVHD and graft rejection are manageable, allowing readily available stem-cell donors to be found for nearly all patients. Further qualitative and quantitative improvement in immune recovery is needed to address the high rate of relapse and risk of severe infections.

Authors
Rizzieri, DA; Koh, LP; Long, GD; Gasparetto, C; Sullivan, KM; Horwitz, M; Chute, J; Smith, C; Gong, JZ; Lagoo, A; Niedzwiecki, D; Dowell, JM; Waters-Pick, B; Liu, C; Marshall, D; Vredenburgh, JJ; Gockerman, J; Decastro, C; Moore, J; Chao, NJ
MLA Citation
Rizzieri, DA, Koh, LP, Long, GD, Gasparetto, C, Sullivan, KM, Horwitz, M, Chute, J, Smith, C, Gong, JZ, Lagoo, A, Niedzwiecki, D, Dowell, JM, Waters-Pick, B, Liu, C, Marshall, D, Vredenburgh, JJ, Gockerman, J, Decastro, C, Moore, J, and Chao, NJ. "Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution." J Clin Oncol 25.6 (February 20, 2007): 690-697.
PMID
17228020
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
6
Publish Date
2007
Start Page
690
End Page
697
DOI
10.1200/JCO.2006.07.0953

Editorial introductions

Authors
Chao, NJ; Sandler, SG
MLA Citation
Chao, NJ, and Sandler, SG. "Editorial introductions." Current Opinion in Hematology 14.6 (2007): vii-.
Source
scival
Published In
Current Opinion in Hematology
Volume
14
Issue
6
Publish Date
2007
Start Page
vii
DOI
10.1097/MOH.0b013e3282f1183d

Accidental or intentional exposure to ionizing radiation: Biodosimetry and treatment options

The potential risk of accidental and especially intentional radiation exposure in the form of a terrorist attack is growing. The dangers are potentially devastating. There is an urgent need for building a greater infrastructure for teaching and research in this area. Medical contingency planning and preparedness is also essential. Such planning should include an examination of our current resources, projected medical needs, management guidelines, and personnel training. Exposure to whole-body irradiation can induce acute radiation syndrome, with the resultant damage to hematopoiesis and immune suppression. In addition, acute toxicity to the skin, gut, and central nervous system are also prevalent. Complex injuries such as burns, multi-organ injury, and trauma will increase the morbidity and mortality from acute radiation syndrome. Our ability to understand and rapidly obtain data on the absorbed dose and have access to radiation mitigators are of critical importance if we are to have a beneficial impact in the exposed population. © 2007 International Society for Experimental Hematology.

Authors
Chao, NJ
MLA Citation
Chao, NJ. "Accidental or intentional exposure to ionizing radiation: Biodosimetry and treatment options." Experimental Hematology 35.4 SUPPL. (2007): 24-27.
PMID
17379083
Source
scival
Published In
Experimental Hematology
Volume
35
Issue
4 SUPPL.
Publish Date
2007
Start Page
24
End Page
27
DOI
10.1016/j.exphem.2007.01.008

Regulatory T Cells: Historical Perspective

Authors
Chao, N
MLA Citation
Chao, N. "Regulatory T Cells: Historical Perspective." Biology of Blood and Marrow Transplantation 13.SUPPL. 1 (2007): 11--.
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
13
Issue
SUPPL. 1
Publish Date
2007
Start Page
11-
DOI
10.1016/j.bbmt.2006.10.009

Radiation Emergencies: Evaluation, Management, and Transplantation

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. © 2007 American Society for Blood and Marrow Transplantation.

Authors
Weisdorf, D; Apperley, J; Courmelon, P; Gorin, N-C; Wingard, J; Chao, N
MLA Citation
Weisdorf, D, Apperley, J, Courmelon, P, Gorin, N-C, Wingard, J, and Chao, N. "Radiation Emergencies: Evaluation, Management, and Transplantation." Biology of Blood and Marrow Transplantation 13.SUPPL. 1 (2007): 103-106.
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
13
Issue
SUPPL. 1
Publish Date
2007
Start Page
103
End Page
106
DOI
10.1016/j.bbmt.2006.10.002

Regulating regulatory T cells

Regulatory T cells (Tregs) are a specialized subpopulation of T cells that act to suppress activation of other immune cells and thereby maintain immune system homeostasis, self-tolerance as well as control excessive response to foreign antigens. The mere concept of Tregs was the subject of significant controversy among immunologists for many years owing to the paucity of reliable markers for defining these cells and the ambiguity of the nature and molecular basis of suppressive phenomena. However, recent advances in the molecular characterization of this cell population have firmly established their existence and their vital role in the vertebrate immune system. Of interest, accumulating evidence from both humans and experimental animal models has implicated the involvement of Tregs in the development of graft-versus-host disease (GVHD). The demonstration that Tregs could separate GVHD from graft-versus-tumor (GVT) activity suggests that their immunosuppressive potential could be manipulated to reduce GVHD without detrimental consequence on GVT effect. Although a variety of T lymphocytes with suppressive capabilities have been reported, the two best-characterized subsets are the naturally arising, intrathymic-generated Tregs (natural Tregs) and the peripherally generated, inducible Tregs (inducible Tregs). This review summarizes our current knowledge of the generation, function and regulation of these two populations of Tregs during an immune response. Their role in the development of GVHD and their therapeutic potential for the prevention and treatment of GVHD will also be described.

Authors
Le, NT; Chao, N
MLA Citation
Le, NT, and Chao, N. "Regulating regulatory T cells." Bone Marrow Transplantation 39.1 (2007): 1-9.
PMID
17057725
Source
scival
Published In
Bone Marrow Transplantation
Volume
39
Issue
1
Publish Date
2007
Start Page
1
End Page
9
DOI
10.1038/sj.bmt.1705529

Morphologic examination of sequential bone marrow biopsies after nonmyeloablative stem cell transplantation complements molecular studies of donor engraftment.

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.

Authors
Lagoo, AS; Gong, JZ; Stenzel, TT; Goodman, BK; Buckley, PJ; Chao, NJ; Gasparetto, C; Long, GD; Rizzieri, DA
MLA Citation
Lagoo, AS, Gong, JZ, Stenzel, TT, Goodman, BK, Buckley, PJ, Chao, NJ, Gasparetto, C, Long, GD, and Rizzieri, DA. "Morphologic examination of sequential bone marrow biopsies after nonmyeloablative stem cell transplantation complements molecular studies of donor engraftment." Arch Pathol Lab Med 130.10 (October 2006): 1479-1488.
PMID
17090189
Source
pubmed
Published In
Archives of Pathology and Laboratory Medicine
Volume
130
Issue
10
Publish Date
2006
Start Page
1479
End Page
1488
DOI
10.1043/1543-2165(2006)130[1479:MEOSBM]2.0.CO;2

Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells.

Aldehyde dehydrogenase (ALDH) is an enzyme that is expressed in the liver and is required for the conversion of retinol (vitamin A) to retinoic acids. ALDH is also highly enriched in hematopoietic stem cells (HSCs) and is considered a selectable marker of human HSCs, although its contribution to stem cell fate remains unknown. In this study, we demonstrate that ALDH is a key regulator of HSC differentiation. Inhibition of ALDH with diethylaminobenzaldehyde (DEAB) delayed the differentiation of human HSCs that otherwise occurred in response to cytokines. Moreover, short-term culture with DEAB caused a 3.4-fold expansion in the most primitive assayable human cells, the nonobese diabetic/severe combined immunodeficiency mouse repopulating cells, compared with day 0 CD34(+)CD38(-)lin(-) cells. The effects of DEAB on HSC differentiation could be reversed by the coadministration of the retinoic acid receptor agonist, all-trans-retinoic acid, suggesting that the ability of ALDH to generate retinoic acids is important in determining HSC fate. DEAB treatment also caused a decrease in retinoic acid receptor-mediated signaling within human HSCs, suggesting directly that inhibition of ALDH promotes HSC self-renewal via reduction of retinoic acid activity. Modulation of ALDH activity and retinoid signaling is a previously unrecognized and effective strategy to amplify human HSCs.

Authors
Chute, JP; Muramoto, GG; Whitesides, J; Colvin, M; Safi, R; Chao, NJ; McDonnell, DP
MLA Citation
Chute, JP, Muramoto, GG, Whitesides, J, Colvin, M, Safi, R, Chao, NJ, and McDonnell, DP. "Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells." Proc Natl Acad Sci U S A 103.31 (August 1, 2006): 11707-11712.
PMID
16857736
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
103
Issue
31
Publish Date
2006
Start Page
11707
End Page
11712
DOI
10.1073/pnas.0603806103

Molecular profile and partial functional analysis of novel endothelial cell-derived growth factors that regulate hematopoiesis.

Recent progress has been made in the identification of the osteoblastic cellular niche for hematopoietic stem cells (HSCs) within the bone marrow (BM). Attempts to identify the soluble factors that regulate HSC self-renewal have been less successful. We have demonstrated that primary human brain endothelial cells (HUBECs) support the ex vivo amplification of primitive human BM and cord blood cells capable of repopulating non-obese diabetic/severe combined immunodeficient repopulating (SCID) mice (SCID repopulating cells [SRCs]). In this study, we sought to characterize the soluble hematopoietic activity produced by HUBECs and to identify the growth factors secreted by HUBECs that contribute to this HSC-supportive effect. Extended noncontact HUBEC cultures supported an eight-fold increase in SRCs when combined with thrombopoietin, stem cell factor, and Flt-3 ligand compared with input CD34(+) cells or cytokines alone. Gene expression analysis of HUBEC biological replicates identified 65 differentially expressed, nonredundant transcripts without annotated hematopoietic activity. Gene ontology studies of the HUBEC transcriptome revealed a high concentration of genes encoding extracellular proteins with cell-cell signaling function. Functional analyses demonstrated that adrenomedullin, a vasodilatory hormone, synergized with stem cell factor and Flt-3 ligand to induce the proliferation of primitive human CD34(+)CD38(-)lin(-) cells and promoted the expansion of CD34(+) progenitors in culture. These data demonstrate the potential of primary HUBECs as a reservoir for the discovery of novel secreted proteins that regulate human hematopoiesis.

Authors
Chute, JP; Muramoto, GG; Dressman, HK; Wolfe, G; Chao, NJ; Lin, S
MLA Citation
Chute, JP, Muramoto, GG, Dressman, HK, Wolfe, G, Chao, NJ, and Lin, S. "Molecular profile and partial functional analysis of novel endothelial cell-derived growth factors that regulate hematopoiesis." Stem Cells 24.5 (May 2006): 1315-1327.
PMID
16373696
Source
pubmed
Published In
Stem Cells
Volume
24
Issue
5
Publish Date
2006
Start Page
1315
End Page
1327
DOI
10.1634/stemcells.2005-0029

Vascular endothelial cells produce soluble factors that mediate the recovery of human hematopoietic stem cells after radiation injury.

The risk of terrorism with nuclear or radiologic weapons is considered to be high over the coming decade. Ionizing radiation can cause a spectrum of hematologic toxicities, from mild myelosuppression to myeloablation and death. However, the potential regenerative capacity of human hematopoietic stem cells (HSCs) after radiation injury has not been well characterized. In this study, we sought to characterize the effects of ionizing radiation on human HSCs and to determine whether signals from vascular endothelial cells could promote the repair of irradiated HSCs. Exposure of human bone marrow CD34+ cells to 400 cGy caused a precipitous decline in hematopoietic progenitor cell content and primitive cells capable of repopulating nonobese diabetic/severe combined immunodeficient mice (SCID-repopulating cells), which was not retrievable via treatment with cytokines. Conversely, culture of 400 cGy-irradiated bone marrow CD34+ cells with endothelial cells under noncontact conditions supported the differential recovery of both viable progenitor cells and primitive SCID-repopulating cells. These data illustrate that vascular endothelial cells produce soluble factors that promote the repair and functional recovery of HSCs after radiation injury and suggest that novel factors with radiotherapeutic potential can be identified within this milieu.

Authors
Muramoto, GG; Chen, B; Cui, X; Chao, NJ; Chute, JP
MLA Citation
Muramoto, GG, Chen, B, Cui, X, Chao, NJ, and Chute, JP. "Vascular endothelial cells produce soluble factors that mediate the recovery of human hematopoietic stem cells after radiation injury." Biol Blood Marrow Transplant 12.5 (May 2006): 530-540.
PMID
16635788
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
12
Issue
5
Publish Date
2006
Start Page
530
End Page
540
DOI
10.1016/j.bbmt.2005.12.039

Longitudinal analysis of T-cell receptor variable beta chain repertoire in patients with acute graft-versus-host disease after allogeneic stem cell transplantation.

T-cell receptor variable beta 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.

Authors
Liu, C; He, M; Rooney, B; Kepler, TB; Chao, NJ
MLA Citation
Liu, C, He, M, Rooney, B, Kepler, TB, and Chao, NJ. "Longitudinal analysis of T-cell receptor variable beta chain repertoire in patients with acute graft-versus-host disease after allogeneic stem cell transplantation." Biol Blood Marrow Transplant 12.3 (March 2006): 335-345.
PMID
16503503
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
12
Issue
3
Publish Date
2006
Start Page
335
End Page
345
DOI
10.1016/j.bbmt.2005.09.019

Non-comparative evaluation of the safety of aerosolized amphotericin B lipid complex in patients undergoing allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplant (HSCT) recipients are at increased risk for invasive fungal infections (IFIs) over prolonged periods of time. Aerosolized amphotericin B lipid complex (ABLC) has shown promise in lung transplant recipients as a convenient means of delivering protective drug to the upper airways avoiding systemic toxicities. The safety and tolerability of aerosolized ABLC in 40 subjects undergoing allogeneic HSCT was prospectively investigated in an open-labeled, non-comparative study. Subjects received aerosolized ABLC treatment once daily for 4 days, then once weekly for 13 weeks; fluconazole was administered daily as standard of care through post-transplant day 100. Pulmonary mechanics were measured before and after each dose of inhaled ABLC; adverse events (AEs) and the development of IFI were also monitored. Cough, nausea, taste disturbance, or vomiting followed 2.2% of 458 total inhaled ABLC administrations; 5.2% of inhaled ABLC administrations were associated with >or=20% decrease in pulmonary function measurements (forced expiratory volume in 1 second or forced vital capacity) and none required treatment with bronchodilators or withdrawal from study. Four mild AEs were considered possibly or probably related to study treatment; no deaths or withdrawals from treatment were attributed to study drug. Of 3 proven IFIs occurring during the study period, only 1, a catheter-related case of disseminated fusariosis, occurred while the subject was receiving study medication. Aerosolized ABLC was well tolerated in allogeneic HSCT recipients. With only 1 of 40 subjects developing IFI while receiving treatment, the combination of fluconazole and inhaled ABLC warrants further study as antifungal prophylaxis following allogeneic HSCT.

Authors
Alexander, BD; Dodds Ashley, ES; Addison, RM; Alspaugh, JA; Chao, NJ; Perfect, JR
MLA Citation
Alexander, BD, Dodds Ashley, ES, Addison, RM, Alspaugh, JA, Chao, NJ, and Perfect, JR. "Non-comparative evaluation of the safety of aerosolized amphotericin B lipid complex in patients undergoing allogeneic hematopoietic stem cell transplantation." Transpl Infect Dis 8.1 (March 2006): 13-20.
PMID
16623816
Source
pubmed
Published In
Transplant Infectious Disease
Volume
8
Issue
1
Publish Date
2006
Start Page
13
End Page
20
DOI
10.1111/j.1399-3062.2006.00125.x

Prophylaxis and treatment of acute graft-versus-host disease.

Acute graft-versus-host disease (GVHD) remains a major obstacle to successful allogeneic hematopoietic stem cell transplantation (HSCT). The ability to prevent GVHD--the application of successful prophylaxis--is crucial as treatment when prophylaxis fails or remains suboptimal. A calcineurin inhibitor in combination with methotrexate is still the mainstream regimen for prophylaxis of GVHD. Despite a steady increase in the repertoire of available drugs, corticosteroids remain the first-line therapy for patients who fail prevention and develop GVHD. Pan T-cell depletion studies suggest that success in prophylaxis and treatment of GVHD will depend on whether GVHD can be prevented without losing anti-malignancy and anti-infectious effects. Better understanding of the allogeneic response that is responsible for GVHD will facilitate the development of such an approach.

Authors
Chao, NJ; Chen, BJ
MLA Citation
Chao, NJ, and Chen, BJ. "Prophylaxis and treatment of acute graft-versus-host disease." Semin Hematol 43.1 (January 2006): 32-41. (Review)
PMID
16412787
Source
pubmed
Published In
Seminars in Hematology
Volume
43
Issue
1
Publish Date
2006
Start Page
32
End Page
41
DOI
10.1053/j.seminhematol.2005.09.007

Editorial introductions

Authors
Chao, NJ; Sandler, SG
MLA Citation
Chao, NJ, and Sandler, SG. "Editorial introductions." Current Opinion in Hematology 13.6 (2006): vii-.
Source
scival
Published In
Current Opinion in Hematology
Volume
13
Issue
6
Publish Date
2006
Start Page
vii
DOI
10.1097/01.moh.0000247509.39522.18

Diffuse Alveolar Hemorrhage: Retrospective Review of Clinical Outcome in Allogeneic Transplant Recipients Treated With Aminocaproic Acid

Diffuse alveolar hemorrhage (DAH) after allogeneic hematopoietic stem cell transplantation (HSCT) is often fatal. Standard therapy with high-dose corticosteroid is not always effective. There is paucity of data in the literature about other potentially useful agents, such as aminocaproic acid (Amicar) in the post-transplantation setting. We retrospectively reviewed our data on 115 consecutive patients who underwent HSCT and had pulmonary complications, with the aim of determining the overall clinical outcome in recipients of allogeneic transplants and in the subgroup of these patients who were treated with concomitant Solu-Medrol and aminocaproic acid. Aminocaproic acid was added at the discretion of the attending physician. We identified 14 allogeneic transplant recipients (median age, 41 years) with 15 episodes of DAH who were treated with Solu-Medrol (250 mg to 1 g intravenously per day). Of these, 8 patients also received concomitant aminocaproic acid at 1000 mg intravenously every 6 hours. Failure to improve was the most common reason for adding aminocaproic acid. The incidence of DAH was 12.2% (10.3% in myeloablative versus 1.9% in nonmyeloablative recipients). The overall 100-day DAH mortality and median transplantation survival were 60% and 99 days, respectively. Among the subset of patients treated with the combination of Solu-Medrol and aminocaproic acid, we observed a 100-day DAH mortality and median transplantation survival of 44% and 167 days, respectively, compared with 83% and 96.5 days in those treated with Solu-Medrol alone. The median time to DAH was 40.5 days, and the median time to death was 53 days in the combined treatment group compared with 29.5 days in those treated with steroid alone. There were no significant differences in coagulation parameters between subsets. Infections (yeast, respiratory syncytial virus, herpes simplex virus, and parainfluenza) were isolated and treated from 6 diagnostic bronchial alveolar lavage samples and were more common in the subgroup treated with Solu-Medrol only. Respiratory failure was the documented cause of death in 89% of patients. There were no clinically significant side effects from aminocaproic acid. Although these historically lower DAH outcomes are intriguing, prospective studies are needed to confirm the role of aminocaproic acid in DAH occurring in the allogeneic transplantation setting. © 2006 American Society for Blood and Marrow Transplantation.

Authors
Wanko, SO; Broadwater, G; Folz, RJ; Chao, NJ
MLA Citation
Wanko, SO, Broadwater, G, Folz, RJ, and Chao, NJ. "Diffuse Alveolar Hemorrhage: Retrospective Review of Clinical Outcome in Allogeneic Transplant Recipients Treated With Aminocaproic Acid." Biology of Blood and Marrow Transplantation 12.9 (2006): 949-953.
PMID
16920561
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
12
Issue
9
Publish Date
2006
Start Page
949
End Page
953
DOI
10.1016/j.bbmt.2006.05.012

Acute Radiation Injury: Contingency Planning for Triage, Supportive Care, and Transplantation

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. © 2006 American Society for Blood and Marrow Transplantation.

Authors
Weisdorf, D; Chao, N; Waselenko, JK; Dainiak, N; Armitage, JO; McNiece, I; Confer, D
MLA Citation
Weisdorf, D, Chao, N, Waselenko, JK, Dainiak, N, Armitage, JO, McNiece, I, and Confer, D. "Acute Radiation Injury: Contingency Planning for Triage, Supportive Care, and Transplantation." Biology of Blood and Marrow Transplantation 12.6 (2006): 672-682.
PMID
16737941
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
12
Issue
6
Publish Date
2006
Start Page
672
End Page
682
DOI
10.1016/j.bbmt.2006.02.006

Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells.

In this study, we investigated whether elimination of CD4+/CD25+ Tregs using the recombinant IL-2 diphtheria toxin conjugate DAB(389)IL-2 (also known as denileukin diftitox and ONTAK) is capable of enhancing the immunostimulatory efficacy of tumor RNA-transfected DC vaccines. We show that DAB(389)IL-2 is capable of selectively eliminating CD25-expressing Tregs from the PBMCs of cancer patients without inducing toxicity on other cellular subsets with intermediate or low expression of CD25. DAB(389)IL-2-mediated Treg depletion resulted in enhanced stimulation of proliferative and cytotoxic T cell responses in vitro but only when DAB(389)IL-2 was omitted during T cell priming. DAB(389)IL-2 significantly reduced the number of Tregs present in the peripheral blood of metastatic renal cell carcinoma (RCC) patients and abrogated Treg-mediated immunosuppressive activity in vivo. Moreover, DAB(389)IL-2-mediated elimination of Tregs followed by vaccination with RNA-transfected DCs significantly improved the stimulation of tumor-specific T cell responses in RCC patients when compared with vaccination alone. Our findings may have implications in the design of immune-based strategies that may incorporate the Treg depletion strategy to achieve potent antitumor immunity with therapeutic impact.

Authors
Dannull, J; Su, Z; Rizzieri, D; Yang, BK; Coleman, D; Yancey, D; Zhang, A; Dahm, P; Chao, N; Gilboa, E; Vieweg, J
MLA Citation
Dannull, J, Su, Z, Rizzieri, D, Yang, BK, Coleman, D, Yancey, D, Zhang, A, Dahm, P, Chao, N, Gilboa, E, and Vieweg, J. "Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells." J Clin Invest 115.12 (December 2005): 3623-3633.
PMID
16308572
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
115
Issue
12
Publish Date
2005
Start Page
3623
End Page
3633
DOI
10.1172/JCI25947

Distinct hematopoietic progenitor compartments are delineated by the expression of aldehyde dehydrogenase and CD34.

A broad range of hematopoietic stem cells and progenitors reside within a fraction of umbilical cord blood (UCB) that exhibits low light scatter properties (SSC(lo)) and high expression of aldehyde dehydrogenase (ALDH(br)). Many SSC(lo) ALDH(br) cells coexpress CD34; however, other cells express either ALDH or CD34. To investigate the developmental potential of these cell subsets, purified ALDH(br) CD34+, ALDH(neg) CD34+, and ALDH(br) CD34(neg) UCB cells were characterized within a variety of in vivo and in vitro assays. Primitive progenitors capable of multilineage development were monitored in long- and short-term repopulation assays performed on nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice, and in primary and secondary long-term culture assays. These progenitors were highly enriched within the ALDH(br) CD34+ fraction. This cell fraction also enriched short-term myeloid progenitors that were detected in vitro. By comparison, ALDH(neg) CD34+ cells contained few primitive progenitors and had diminished short-term myeloid potential but exhibited enhanced short-term natural killer (NK) cell development in vitro. The ALDH(br) CD34(neg) cells were not efficiently supported by any of the assays used. These studies suggested that in particular the expression of ALDH delineated distinct CD34+ stem cell and progenitor compartments. The differential expression of ALDH may provide a means to explore normal and malignant processes associated with myeloid and lymphoid development.

Authors
Storms, RW; Green, PD; Safford, KM; Niedzwiecki, D; Cogle, CR; Colvin, OM; Chao, NJ; Rice, HE; Smith, CA
MLA Citation
Storms, RW, Green, PD, Safford, KM, Niedzwiecki, D, Cogle, CR, Colvin, OM, Chao, NJ, Rice, HE, and Smith, CA. "Distinct hematopoietic progenitor compartments are delineated by the expression of aldehyde dehydrogenase and CD34." Blood 106.1 (July 1, 2005): 95-102.
PMID
15790790
Source
pubmed
Published In
Blood
Volume
106
Issue
1
Publish Date
2005
Start Page
95
End Page
102
DOI
10.1182/blood-2004-09-3652

T-cell-mediated pure red-cell aplasia in systemic lupus erythematosus: response to cyclosporin A and mycophenolate mofetil.

Authors
Arcasoy, MO; Chao, NJ
MLA Citation
Arcasoy, MO, and Chao, NJ. "T-cell-mediated pure red-cell aplasia in systemic lupus erythematosus: response to cyclosporin A and mycophenolate mofetil." Am J Hematol 78.2 (February 2005): 161-163. (Letter)
PMID
15682416
Source
pubmed
Published In
American Journal of Hematology
Volume
78
Issue
2
Publish Date
2005
Start Page
161
End Page
163
DOI
10.1002/ajh.20237

Selective elimination of alloreactivity from immunotherapeutic T cells by photodynamic cell purging and memory T-cell sorting.

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.

Authors
Le, NT; Chen, BJ; Chao, NJ
MLA Citation
Le, NT, Chen, BJ, and Chao, NJ. "Selective elimination of alloreactivity from immunotherapeutic T cells by photodynamic cell purging and memory T-cell sorting." Cytotherapy 7.2 (2005): 126-133. (Review)
PMID
16040391
Source
pubmed
Published In
Cytotherapy (Informa)
Volume
7
Issue
2
Publish Date
2005
Start Page
126
End Page
133
DOI
10.1080/14653240510018163

Non-pharmacologic approaches to graft-versus-host prevention

Allogeneic transplant offers a curative option for selected hematological malignancies and improved disease free survival in those where cure is not possible. For patients in these categories, Graft-versus-host disease (GVHD) occurs often and is a significant cause of morbidity and mortality following transplantation. Pharmacological immunosuppression has considerable toxicity and controls GVHD in about 75% of transplant recipients when used in combination and continually. Thus, there is the need for viable and non-toxic alternatives for GVHD prevention and this is the impetus for seeking novel non-pharmacological strategies. Most techniques directed to this end are based on various permutations of T-cell depletion. Total T-cell depletion was the first graft engineering strategy employed but while beneficial, it was associated with delay in engraftment and early relapses. Modern depletion and adoptive immunotherapy techniques are directed toward specific subsets of T-cells which include alloreactive, naïve, NK cells, T-helper and cytotoxic T-cells. While large bodies of preclinical evidence attest to the efficacy of currently available non-pharmacological prevention techniques, such is not the case with vigorous clinical trials. Where available, the proven non-pharmacological prevention techniques are yet to be fully interwoven into the patient care arena. Integration of available strategies and continuing research are therefore acutely needed to improve the chronic morbidity and mortality seen with both allogeneic transplant-associated GVHD and the use of pharmaceutical immunosuppressants.

Authors
Wanko, SO; Chao, NJ
MLA Citation
Wanko, SO, and Chao, NJ. "Non-pharmacologic approaches to graft-versus-host prevention." Blood Reviews 19.4 (2005): 203-211.
PMID
15784298
Source
scival
Published In
Blood Reviews
Volume
19
Issue
4
Publish Date
2005
Start Page
203
End Page
211
DOI
10.1016/j.blre.2004.11.001

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

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. Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Authors
Hiemenz, J; Cagnoni, P; Simpson, D; Devine, S; Chao, N; Keirns, J; Lau, W; Facklam, D; Buell, D
MLA Citation
Hiemenz, J, Cagnoni, P, Simpson, D, Devine, S, Chao, N, Keirns, J, Lau, W, Facklam, D, and Buell, D. "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." Antimicrobial Agents and Chemotherapy 49.4 (2005): 1331-1336.
PMID
15793107
Source
scival
Published In
Antimicrobial agents and chemotherapy
Volume
49
Issue
4
Publish Date
2005
Start Page
1331
End Page
1336
DOI
10.1128/AAC.49.4.1331-1336.2005

Umbilical cord blood transplantation in adults: Results of the prospective cord blood transplantation (COBLT)

The Cord Blood Transplantation study group conducted a prospective study of unrelated cord blood transplantation (CBT) to better define the role of this stem cell source for subjects requiring unrelated allogeneic transplantation. We report on 1 stratum of the study designated for adult subjects. The primary end point of the study was survival at 180 days. Secondary end points included engraftment, graft-versus-host disease, relapse, and long-term survival. Eligibility criteria for malignant and nonmalignant diseases were specified. Subjects with active central nervous system disease, Karnofsky performance status <70%, grade 3 or 4 or primary myelofibrosis, or suitable related donors were excluded. Enrollment required a single cord blood unit containing >107 nucleated cells per kilogram of recipient weight and matched at ≥4 HLA-A and -B (low or intermediate resolution) and -DRB1 (high resolution) types. Thirty-four subjects were entered, with a median age of 34.5 years (range, 18.2-55 years). Most subjects (n = 23) had a 4 of 6 match, 10 subjects had a 5 of 6 match, and 1 subject had a 6 of 6 match. Diagnoses at transplantation included acute myelogenous leukemia (n = 19), acute lymphoblastic leukemia (n = 9), chronic myelogenous leukemia (n = 3), myelodysplastic syndrome (n = 1), paroxysmal nocturnal hemoglobinuria (PNH) (n = 1), and non-Hodgkin lymphoma (n = 1); 94% were classified as poor risk according to National Marrow Donor Program criteria. Subjects received total body irradiation/cyclophosphamide (n = 27) or busulfan/melphalan (n = 7) conditioning regimens. Four subjects died before CBT and are described here but are not included in the main analysis. The cumulative incidence rates and median times to neutrophil (500/μL) and platelet (>20 000/μL) engraftment were 0.66 by day 42 (median, 31 days) and 0.35 by day 180 (median, 117 days). The cumulative incidence rate for grade II-IV GVHD was 0.34 by day 100. For the primary end point, survival at 180 days, Kaplan-Meier survival estimates were 0.30 (95% confidence interval, 0.14-0.46) by day 180 after transplantation. To date there are 2 survivors, and both are >36 months from enrollment. A retrospective analysis was performed by using high-resolution HLA-A and -B typing, which revealed that approximately one third of subjects had 1 or more additional HLA mismatches compared with results of low- or intermediate-resolution HLA typing. The findings of high treatment-related mortality and slow engraftment kinetics indicate that CBT should continue to be performed in specialized centers with a research focus on cord blood cells. © 2005 American Society for Blood and Marrow Transplantation.

Authors
Cornetta, K; Laughlin, M; Carter, S; Wall, D; Weinthal, J; Delaney, C; Wagner, J; Sweetman, R; McCarthy, P; Chao, N
MLA Citation
Cornetta, K, Laughlin, M, Carter, S, Wall, D, Weinthal, J, Delaney, C, Wagner, J, Sweetman, R, McCarthy, P, and Chao, N. "Umbilical cord blood transplantation in adults: Results of the prospective cord blood transplantation (COBLT)." Biology of Blood and Marrow Transplantation 11.2 (2005): 149-160.
PMID
15682076
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
11
Issue
2
Publish Date
2005
Start Page
149
End Page
160
DOI
10.1016/j.bbmt.2004.11.020

Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease

We conducted a phase II trial in 19 chronic graft-versus-host disease (cGVHD) patients with rapamycin, calcineurin inhibitors, and prednisone with the goals of controlling cGVHD, reducing prednisone use, and defining the safety of this regimen. Rapamycin was begun as second-line (n = 9) or more than second-line (n = 10) therapy. With a median follow-up of 42 months, 16 patients were evaluable for response. Nine patients discontinued rapamycin because of poor compliance/patient request (n = 2) or an adverse event (n = 7), 3 of whom were not evaluable because of withdrawal at ≤1 month or noncompliance. The adverse events included serum creatinine ≥2.4 mg/dL (n = 4), hemolytic uremic syndrome (n = 2), and relapse of malignancy (n = 1). Fifteen of 16 evaluable patients had a clinical response. Five of the 16 discontinued the drug, and 1 died of relapsed leukemia. Of the 10 patients who continued rapamycin, 2 discontinued and 1 successfully tapered all systemic immunosuppression. Three of the 10 developed progressive cGVHD with tapering immunosuppression; all responded to resumption of prior medications. Four of the 10 patients required alternate therapy for persistent or progressive cGVHD while receiving rapamycin; prednisone was discontinued (n = 2) or tapered at the time of progressive disease (n = 2). Seventeen of 19 original patients were alive. One death was due to relapsed malignancy, and 1 was due to congestive heart failure. In this report of rapamycin as cGVHD therapy, there is evidence of rapamycin's efficacy. Given the significant toxicities described, investigation of altered administration of rapamycin and calcineurin inhibitors should be pursued in future cGVHD trials. © 2005 American Society for Blood and Marrow Transplantation.

Authors
Johnston, LJ; Brown, J; Shizuru, JA; Stockerl-Goldstein, KE; Stuart, MJ; Blume, KG; Negrin, RS; Chao, NJ
MLA Citation
Johnston, LJ, Brown, J, Shizuru, JA, Stockerl-Goldstein, KE, Stuart, MJ, Blume, KG, Negrin, RS, and Chao, NJ. "Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease." Biology of Blood and Marrow Transplantation 11.1 (2005): 47-55.
PMID
15625544
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
11
Issue
1
Publish Date
2005
Start Page
47
End Page
55
DOI
10.1016/j.bbmt.2004.10.004

Phase II feasibility and pharmacokinetic study of concurrent administration of trastuzumab and high-dose chemotherapy in advanced HER2+ breast cancer.

PURPOSE: To evaluate the safety of concurrent treatment with trastuzumab and high-dose chemotherapy (HDC), using cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), with autologous hematopoietic progenitor cells support, in patients with HER2+ advanced breast cancer. EXPERIMENTAL DESIGN: Patients with HER2-overexpressing high-risk primary breast cancer (HRPBC; defined as > or =4 involved nodes or inflammatory disease), or metastatic breast cancer (MBC) were eligible. Treatment consisted of a loading dose of trastuzumab at 4 mg/kg (day -5), HDC (days -5 to -2), autologous hematopoietic progenitor cells infusion on day 0, and weekly maintenance trastuzumab (2 mg/kg) from day +1 (minimum of 9 doses). Cardiac monitoring included serial left ventricular ejection fraction measurements before treatment and on days +20 and +65. RESULTS: Thirty-three patients were prospectively enrolled (13 HRPBC, 20 MBC). Toxicity seemed similar to that expected with this HDC regimen alone. Neutrophils and platelets engrafted promptly. There were no cases of grade 4 or 5 toxicity. One patient experienced symptomatic grade 3 acute cardiac failure on day -4, responsive to treatment. Trastuzumab did not alter the pharmacokinetics of HDC. Eleven of twelve MBC patients with measurable disease (nine of them refractory to previous chemotherapy) experienced an objective response (9 complete and 2 partial responses). At median follow-up of 34 (13-58) months, all HRPBC patients remain alive and free of disease; the MBC group has event-free survival and overall survival rates of 45 and 70%, respectively. CONCLUSIONS: Incorporation of trastuzumab into HDC (cyclophosphamide, cisplatin, and BCNU) is feasible, with no apparent increased toxicity or pharmacokinetic interactions.

Authors
Nieto, Y; Vredenburgh, JJ; Shpall, EJ; Bearman, SI; McSweeney, PA; Chao, N; Rizzieri, D; Gasparetto, C; Matthes, S; Barón, AE; Jones, RB
MLA Citation
Nieto, Y, Vredenburgh, JJ, Shpall, EJ, Bearman, SI, McSweeney, PA, Chao, N, Rizzieri, D, Gasparetto, C, Matthes, S, Barón, AE, and Jones, RB. "Phase II feasibility and pharmacokinetic study of concurrent administration of trastuzumab and high-dose chemotherapy in advanced HER2+ breast cancer." Clin Cancer Res 10.21 (November 1, 2004): 7136-7143.
PMID
15534084
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
10
Issue
21
Publish Date
2004
Start Page
7136
End Page
7143
DOI
10.1158/1078-0432.CCR-04-0891

Phase 1 trial study of 131I-labeled chimeric 81C6 monoclonal antibody for the treatment of patients with non-Hodgkin lymphoma.

We report a phase 1 study of pharmacokinetics, dosimetry, toxicity, and response of (131)I anti-tenascin chimeric 81C6 for the treatment of lymphoma. Nine patients received a dosimetric dose of 370 MBq (10 mCi). Three patients received an administered activity of 1480 MBq (40 mCi), and 2 developed hematologic toxicity that required stem cell infusion. Six patients received an administered activity of 1110 MBq (30 mCi), and 2 developed toxicity that required stem cell infusion. The clearance of whole-body activity was monoexponential with a mean effective half-life of 110 hours (range, 90-136 hours) and a mean effective whole-body residence time of 159 hours (range, 130-196 hours). There was rapid uptake within the viscera; however, tumor uptake was slower. Activity in normal viscera decreased proportional to the whole body; however, tumor sites presented a slow clearance (T(1/2), 86-191 hours). The mean absorbed dose to whole-body was 67 cGy (range, 51-89 hours), whereas the dose to tumor sites was 963 cGy (range, 363-1517 cGy). Despite lack of a "blocking" antibody, 1 of 9 patients attained a complete remission and 1 a partial remission. These data demonstrate this radiopharmaceutical to be an encouraging agent for the treatment of lymphoma particularly if methods to protect the normal viscera are developed.

Authors
Rizzieri, DA; Akabani, G; Zalutsky, MR; Coleman, RE; Metzler, SD; Bowsher, JE; Toaso, B; Anderson, E; Lagoo, A; Clayton, S; Pegram, CN; Moore, JO; Gockerman, JP; DeCastro, C; Gasparetto, C; Chao, NJ; Bigner, DD
MLA Citation
Rizzieri, DA, Akabani, G, Zalutsky, MR, Coleman, RE, Metzler, SD, Bowsher, JE, Toaso, B, Anderson, E, Lagoo, A, Clayton, S, Pegram, CN, Moore, JO, Gockerman, JP, DeCastro, C, Gasparetto, C, Chao, NJ, and Bigner, DD. "Phase 1 trial study of 131I-labeled chimeric 81C6 monoclonal antibody for the treatment of patients with non-Hodgkin lymphoma." Blood 104.3 (August 1, 2004): 642-648.
PMID
15100153
Source
pubmed
Published In
Blood
Volume
104
Issue
3
Publish Date
2004
Start Page
642
End Page
648
DOI
10.1182/blood-2003-12-4264

Adult recipients of umbilical cord blood transplants after nonmyeloablative preparative regimens.

We report the outcome of 13 patients with advanced malignancies who underwent nonmyeloablative conditioning therapy followed by infusion of partially matched unrelated cord blood cells. The median age of these patients was 49 years, and their median weight was 65.7 kg. The median nucleated cell dose infused was 2.07 x 10(7)/kg. Eight of the 13 patients demonstrated donor chimerism between 4 weeks and 6 months, and subsequent conversion to full donor chimerism was achieved in 5 patients. Three patients were alive and free of disease at 158 to 1054 days, with a median survival of 288 days after transplantation. The 100-day event-free survival is 69%, and overall survival is 77%. At 1 year, the event-free and overall survival was 43%. Treatment-related mortality observed within the first 100 days after transplantation was low: 1 previously extensively pretreated patient died of multiorgan failure. This result provides a basis for further exploring this potentially curative approach to selected patients who lack matched related or unrelated hematopoietic stem cell donors.

Authors
Chao, NJ; Koh, L-P; Long, GD; Gasparetto, C; Horwitz, M; Morris, A; Lassiter, M; Sullivan, KM; Rizzieri, DA
MLA Citation
Chao, NJ, Koh, L-P, Long, GD, Gasparetto, C, Horwitz, M, Morris, A, Lassiter, M, Sullivan, KM, and Rizzieri, DA. "Adult recipients of umbilical cord blood transplants after nonmyeloablative preparative regimens." Biol Blood Marrow Transplant 10.8 (August 2004): 569-575.
PMID
15282535
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
10
Issue
8
Publish Date
2004
Start Page
569
End Page
575
DOI
10.1016/j.bbmt.2004.05.001

Pulmonary sarcoidosis following stem cell transplantation: is it more than a chance occurrence?

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.

Authors
Bhagat, R; Rizzieri, DA; Vredenburgh, JJ; Chao, NJ; Folz, RJ
MLA Citation
Bhagat, R, Rizzieri, DA, Vredenburgh, JJ, Chao, NJ, and Folz, RJ. "Pulmonary sarcoidosis following stem cell transplantation: is it more than a chance occurrence?." Chest 126.2 (August 2004): 642-644.
PMID
15302757
Source
pubmed
Published In
Chest
Volume
126
Issue
2
Publish Date
2004
Start Page
642
End Page
644
DOI
10.1378/chest.126.2.642

Low-dose weekly paclitaxel for recurrent or refractory aggressive non-Hodgkin lymphoma.

BACKGROUND: Many patients with recurrent, intermediate or high-grade non-Hodgkin lymphoma (NHL) may not respond to or are not candidates for aggressive salvage chemotherapy. Effective, less toxic regimens are needed. Although high-dose taxanes have not been reported to be very effective for the treatment of lymphoma, different delivery rates may allow for different mechanisms of action to be manifest and result in a different toxicity profile and response rate. The current study tested this hypothesis by using low-dose, weekly paclitaxel in patients with recurrent or refractory NHL. METHODS: Adults age > 18 years with refractory or recurrent, aggressive NHL who were not considered curable with standard high-dose therapy received paclitaxel at a dose of 80 mg/m2 weekly for 5 weeks for 2 cycles. RESULTS: Thirty-four patients with refractory NHL and 4 patients with recurrent disease were treated. Approximately 45% of the patients had achieved a prior disease remission. The median number of prior regimens received was 3, 74% of the patients had an International Prognostic Index of > or = 3 at the time of study entry, and 29% had failed high-dose therapy with autologous hematopoietic support. Only one patient encountered severe toxicity (sepsis). Myelosuppression was reported to occur in approximately 20% of patients. A total of 10 patients (26%) achieved a complete disease response and 4 patients (11%) achieved a partial response. CONCLUSIONS: In the current study, low-dose, weekly paclitaxel therapy was found to provide a well tolerated and less toxic approach to the treatment of refractory NHL, with encouraging responses noted in heavily pretreated patients. However, evaluation in patients with an earlier stage of disease is warranted.

Authors
Rizzieri, DA; Sand, GJ; McGaughey, D; Moore, JO; DeCastro, C; Chao, NJ; Vredenburgh, JJ; Gasparetto, C; Long, GD; Anderson, E; Foster, T; Toaso, B; Adams, D; Niedzwiecki, D; Gockerman, JP
MLA Citation
Rizzieri, DA, Sand, GJ, McGaughey, D, Moore, JO, DeCastro, C, Chao, NJ, Vredenburgh, JJ, Gasparetto, C, Long, GD, Anderson, E, Foster, T, Toaso, B, Adams, D, Niedzwiecki, D, and Gockerman, JP. "Low-dose weekly paclitaxel for recurrent or refractory aggressive non-Hodgkin lymphoma." Cancer 100.11 (June 1, 2004): 2408-2414.
PMID
15160345
Source
pubmed
Published In
Cancer
Volume
100
Issue
11
Publish Date
2004
Start Page
2408
End Page
2414
DOI
10.1002/cncr.20245

Hematopoietic stem cell dose correlates with the speed of immune reconstitution after stem cell transplantation.

In the current study, we tested whether higher numbers of hematopoietic stem cells correlate with the speed of immune reconstitution in a congenic transplantation model (C57BL/Ka, CD45.1, Thy1.1-->C57BL/6, CD45.2, Thy1.2) using purified hematopoietic stem cells (c-Kit(+)Thy1.1(low)Lin(-/low)Sca-1(+)). There were 3 different doses of stem cells used (400, 1000, and 5000). Phenotypic analyses in peripheral blood and spleen demonstrated that higher numbers of infused stem cells are associated with more rapid regeneration of T cells (CD4(+), CD8(+), naive CD4(+), naive CD8(+)) and B cells at early time points. The numbers of T and B cells eventually became equivalent between different dose groups at late time points. Production of interleukin-2 and inter-feron-gamma per T cell was similar regardless of stem cell dose even when tested at the time when there were significant differences in peripheral T-cell counts. The improved immune recovery was attributed to a more rapid regeneration of donor-type immune cells. Higher numbers of total thymocytes and signal joint T-cell receptor excision circles were observed in the higher dose stem cell recipients, suggesting that accelerated regeneration of T cells was due to enhanced thymopoiesis.

Authors
Chen, BJ; Cui, X; Sempowski, GD; Domen, J; Chao, NJ
MLA Citation
Chen, BJ, Cui, X, Sempowski, GD, Domen, J, and Chao, NJ. "Hematopoietic stem cell dose correlates with the speed of immune reconstitution after stem cell transplantation." Blood 103.11 (June 1, 2004): 4344-4352.
PMID
14976038
Source
pubmed
Published In
Blood
Volume
103
Issue
11
Publish Date
2004
Start Page
4344
End Page
4352
DOI
10.1182/blood-2003-07-2534

Posttransplant lymphoproliferative disorder following nonmyeloablative allogeneic stem cell transplantation.

Posttransplantation lymphoproliferative disorder (PTLD) is a well-recognized complication of conventional bone marrow/stem cell and solid organ transplantation. However, not much is known about PTLD following the more recently introduced nonmyeloablative allogeneic stem cell transplantation (NMST). This study reports the findings from two cases of PTLD following NMST and compares them to the one previously reported case. The donor origin of the PTLD was determined using short tandem repeat analysis, and B- and T-cell clonalities were evaluated by polymerase chain reaction. Two cases of PTLD evolved in a total of 70 patients who have undergone NMST at our institution from 1999 to 2003. Both patients received conditioning with Fludarabine/Cytoxan/Campath 1H (alemtuzumab, anti-CD52 antibody) and T-cell-depleted donor cells with Campath-1H. Both PTLDs were EBV positive (by immunohistochemistry and in situ hybridization) with diffuse large B-cell lymphoma morphology. Our findings indicate the incidence of PTLD following NMST is 3% (2 of 70 patients from our institution and 1 of 30 from the previously reported case). All three PTLDs arose 6 to 7 months after NMST and were rapidly fatal. The pathology of the PTLD in all cases was donor origin, EBV positive, diffuse large B-cell lymphoma.

Authors
Snyder, MJ; Stenzel, TT; Buckley, PJ; Lagoo, AS; Rizzieri, DA; Gasparetto, C; Vredenburgh, JJ; Chao, NJ; Gong, JZ
MLA Citation
Snyder, MJ, Stenzel, TT, Buckley, PJ, Lagoo, AS, Rizzieri, DA, Gasparetto, C, Vredenburgh, JJ, Chao, NJ, and Gong, JZ. "Posttransplant lymphoproliferative disorder following nonmyeloablative allogeneic stem cell transplantation." Am J Surg Pathol 28.6 (June 2004): 794-800.
PMID
15166672
Source
pubmed
Published In
American Journal of Surgical Pathology
Volume
28
Issue
6
Publish Date
2004
Start Page
794
End Page
800

Transfer of allogeneic CD62L- memory T cells without graft-versus-host disease.

The major challenge in allogeneic hematopoietic cell transplantation is how to transfer allogeneic T-cell immunity without causing graft-versus-host disease (GVHD). Here we report a novel strategy to selectively prevent GVHD by depleting CD62L(+) T cells (naive and a subset of memory T cells). In unprimed mice, CD62L(-) T cells (a subset of memory T cells) failed to proliferate in response to alloantigens (which the mice have never previously encountered) and were unable to induce GVHD in allogeneic hosts. CD62L(-) T cells contributed to T-cell reconstitution by peripheral expansion as well as by promoting T-cell regeneration from bone marrow stem/progenitor cells. CD62L(-) T cells from the animals previously primed with a tumor cell line (BCL1) were able to inhibit the tumor growth in vivo but were unable to induce GVHD in the third-party recipients. This novel technology may allow transfer of allogeneic recall antitumor and antimicrobial immunity without causing GVHD.

Authors
Chen, BJ; Cui, X; Sempowski, GD; Liu, C; Chao, NJ
MLA Citation
Chen, BJ, Cui, X, Sempowski, GD, Liu, C, and Chao, NJ. "Transfer of allogeneic CD62L- memory T cells without graft-versus-host disease." Blood 103.4 (February 15, 2004): 1534-1541.
PMID
14551132
Source
pubmed
Published In
Blood
Volume
103
Issue
4
Publish Date
2004
Start Page
1534
End Page
1541
DOI
10.1182/blood-2003-08-2987

Hematopoietic stem cell transplantation

Authors
Chao, N
MLA Citation
Chao, N. "Hematopoietic stem cell transplantation." Current Opinion in Hematology 11.6 (2004): 373-374.
PMID
15548990
Source
scival
Published In
Current Opinion in Hematology
Volume
11
Issue
6
Publish Date
2004
Start Page
373
End Page
374
DOI
10.1097/01.moh.0000144500.82861.c0

A phase III, randomized, double-blind, placebo-controlled, study of iseganan for the reduction of stomatitis in patients receiving stomatotoxic chemotherapy

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 9 mg 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 ≥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. © 2003 Elsevier Ltd. All rights reserved.

Authors
Giles, FJ; Rodriguez, R; Weisdorf, D; Wingard, JR; Martin, PJ; Fleming, TR; Goldberg, SL; Anaissie, EJ; Bolwell, BJ; Chao, NJ; Shea, TC; Brunvand, MM; Vaughan, W; Petersen, F; Schubert, M; Lazarus, HM; Maziarz, RT; Silverman, M; Beveridge, RA; Redman, R; Pulliam, JG; Devitt-Risse, P; Fuchs, HJ; Hurd, DD
MLA Citation
Giles, FJ, Rodriguez, R, Weisdorf, D, Wingard, JR, Martin, PJ, Fleming, TR, Goldberg, SL, Anaissie, EJ, Bolwell, BJ, Chao, NJ, Shea, TC, Brunvand, MM, Vaughan, W, Petersen, F, Schubert, M, Lazarus, HM, Maziarz, RT, Silverman, M, Beveridge, RA, Redman, R, Pulliam, JG, Devitt-Risse, P, Fuchs, HJ, and Hurd, DD. "A phase III, randomized, double-blind, placebo-controlled, study of iseganan for the reduction of stomatitis in patients receiving stomatotoxic chemotherapy." Leukemia Research 28.6 (2004): 559-565.
PMID
15120931
Source
scival
Published In
Leukemia Research
Volume
28
Issue
6
Publish Date
2004
Start Page
559
End Page
565
DOI
10.1016/j.leukres.2003.10.021

Minors come of age: Minor histocompatibility antigens and graft-versus-host disease

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. © 2004 American Society for Blood and Marrow Transplantation.

Authors
Chao, NJ
MLA Citation
Chao, NJ. "Minors come of age: Minor histocompatibility antigens and graft-versus-host disease." Biology of Blood and Marrow Transplantation 10.4 (2004): 215-223.
PMID
15077220
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
10
Issue
4
Publish Date
2004
Start Page
215
End Page
223
DOI
10.1016/j.bbmt.2003.10.003

Lipid formulations of amphotericin B preserve and stabilize renal function in HSCT recipients

The current study assessed renal function based on medical records in adult hematopoietic stem cell transplant (HSCT) recipients with proven or probable invasive fungal infection (IFI) transplanted between 1995 and 2000. We confirm that amphotericin B deoxycholate (AmB-d) is nephrotoxic in a large percentage of HSCT recipients. Due to nephrotoxicity, defined as serum creatinine (SCr) > 2.5 mg/dl or a 100% increase in SCr from baseline, 88% of patients treated with AmB-d were switched to a lipid formulation of amphotericin B (LFAB). In total, 53% of patients initiated on AmB-d were switched within the first week of therapy. Significantly more patients (70.6%) treated with AmB-d experienced a 100% increase in SCr from baseline compared to patients treated with either AmBisome (44.4%) or Abelcet (41.2%). A Cox Proportional Hazards Model revealed that, compared to patients initiated on AmBisome or Abelcet, the risk of nephrotoxicity (RR = 1.5 vs AmBisome; RR = 1.7 vs Abelcet), dialysis (RR = 2.4 vs AmBisome; RR = 1.4 vs Abelcet), and death (RR = 2.0 vs AmBisome; RR = 1.1 vs Abelcet) were all increased for patients initiated on AmB-d. Study results suggest that renal function improves and mortality declines when an LFAB is given to HSCT patients as initial therapy rather than as second-line therapy, the current practice. © 2004 Nature Publishing Group All rights reserved.

Authors
Miller, CB; Waller, EK; Klingemann, HG; Dignani, MC; Anaissie, EJ; Cagnoni, PJ; McSweeney, P; Fleck, PR; Fruchtman, SM; McGuirk, J; Chao, NJ
MLA Citation
Miller, CB, Waller, EK, Klingemann, HG, Dignani, MC, Anaissie, EJ, Cagnoni, PJ, McSweeney, P, Fleck, PR, Fruchtman, SM, McGuirk, J, and Chao, NJ. "Lipid formulations of amphotericin B preserve and stabilize renal function in HSCT recipients." Bone Marrow Transplantation 33.5 (2004): 543-548.
PMID
14730342
Source
scival
Published In
Bone Marrow Transplantation
Volume
33
Issue
5
Publish Date
2004
Start Page
543
End Page
548
DOI
10.1038/sj.bmt.1704408

Stem cell transplantation (cord blood transplants).

Allogeneic stem cell transplantation is an accepted treatment modality for selected malignant and non-malignant diseases. However, the ability to identify suitably matched related or unrelated donors can be difficult in some patients. Alternative sources of stem cells such as cord blood provide a readily available graft for such patients. Data accumulated over the past several years have demonstrated that the use of cord blood is an accepted source of stem cells for pediatric patients. Since the cell numbers of hematopoietic progenitors in cord blood is limited and the collection can occur only in a single occasion, its use in adult patients can be more problematic. Here, new developments in the use of cord blood for adults and studies aimed at expansion of cord blood cells and immune reconstitution are described. In Section I, Dr. Nelson Chao describes the early data in cord blood transplantation in adult patients. The patient outcomes are reviewed and analyzed for various factors such as cell dose, HLA typing, and patient selection that could have contributed to the final outcome of these adult patients. Myeloablative as well as nonmyeloablative approaches are presented. Discussion of the various benefits and risks are presented. More recent data from multiple single institutions as well as larger registry data comparisons are also provided. Analyses of these studies suggest methods to improve on the outcome. These newer data should lead to a logical progression in the use of cord blood cells in adult patients. In Section II, Dr. Stephen Emerson describes the historical efforts associated with expansion of hematopoietic stem cells, specifically with cord blood cells. These efforts to expand cord blood cells continue with novel methods. Moreover, a better understanding of stem cell biology and signaling is critical if we are to be able to effectively expand these cells for clinical use. An alternative, more direct, approach to expanding stem cells could be achieved by specific genetic pathways known or believed to support primitive HSC proliferation such as Notch-1 receptor activation, Wnt/LEF-1 pathway induction, telomerase or the Homeobox (Hox) gene products. The clinical experience with the use of expanded cord blood cells is also discussed. In Section III, Dr. Kenneth Weinberg describes immune reconstitution or lack thereof following cord blood transplantation. One of the hallmarks of successful hematopoietic stem cell transplantation is the ability to fully reconstitute the immune system of the recipient. Thus, the relationship between stem cell source and the development of T lymphocyte functions required for protection of the recipient from infection will be described, and cord blood recipients will be compared with those receiving other sources of stem cells. T cell development is described in detail, tracking from prethymic to postthymic lymphocytes with specific attention to umbilical cord blood as the source of stem cells. Moreover, a discussion of the placenta as a special microenvironment for umbilical cord blood is presented. Strategies to overcome the immunological defects are presented to improve the outcome of these recipients.

Authors
Chao, NJ; Emerson, SG; Weinberg, KI
MLA Citation
Chao, NJ, Emerson, SG, and Weinberg, KI. "Stem cell transplantation (cord blood transplants)." Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program (2004): 354-371.
PMID
15561692
Source
scival
Published In
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program
Publish Date
2004
Start Page
354
End Page
371

Umbilical cord blood transplantation in adults using myeloablative and nonmyeloablative preparative regimens

Unrelated umbilical cord blood (UCB) transplantation has recently been explored in an increasing number of adult patients. The relative ease of procurement and the lower-than-anticipated risk of severe acute graft-versus-host disease has made UCB transplantation an appealing alternative to bone marrow-derived hematopoietic stem cells. The use of reduced-intensity or nonmyeloablative preparative regimens to allow engraftment of UCB broadens the scope of patients who may benefit from allogeneic immunotherapy, including elderly and medically infirm patients with no matched sibling donor. This review summarizes the available data on the use of UCB as an alternative source of hematopoietic stem cell transplantation in adult patients. © 2004 American Society for Blood and Marrow Transplantation.

Authors
Koh, L-P; Chao, NJ
MLA Citation
Koh, L-P, and Chao, NJ. "Umbilical cord blood transplantation in adults using myeloablative and nonmyeloablative preparative regimens." Biology of Blood and Marrow Transplantation 10.1 (2004): 1-22.
PMID
14752775
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
10
Issue
1
Publish Date
2004
Start Page
1
End Page
22
DOI
10.1016/j.bbmt.2003.09.009

Unrelated umbilical cord blood transplantation in adult patients.

Since January 1996, we have administered myeloablative therapy followed by infusion of unrelated umbilical cord blood cells in 57 adult patients with high-risk disease. The median age was 31 years (range, 18-58 years), and the median weight was 70 kg (range, 46-110 kg). Two patients were treated for genetic disorders and 55 for advanced hematologic malignancies. The preparative regimens were total body irradiation or busulfan based, both with antithymocyte globulin. HLA matching between donor and recipient was 3 of 6 in 3 patients, 4 of 6 in 44 patients, 5 of 6 in 8 patients, and 6 of 6 in 2 patients. The median nucleated cell dose was 1.50 x 10(7)/kg (range, 0.54-2.78 x 10(7)/kg), and the median CD34(+) cell dose was 1.37 x 10(5)/kg (range, 0.02-12.45 x 10(5)/kg). All patients received granulocyte colony-stimulating factor after transplantation until neutrophil recovery. Graft-versus-host disease prophylaxis consisted of cyclosporine and steroids. The median number of days to an absolute neutrophil count of 500/microL was 26 (range, 12-55 days). The median time to an untransfused platelet count of >20000/microL was 84 days (range, 35-167 days). Seventeen patients developed grade II to IV acute GVHD. The median survival of the entire group was 91 days (range, 10-2251 days). Eleven patients were alive at a median follow-up of 1670 days (range, 67-2251 days), 1 with autologous recovery and 1 with relapsed lymphoma. The actuarial projected 3-year survival is 19%. Infection was the primary cause of death. These results suggest that unrelated umbilical cord blood transplantation is a viable option for adult patients and should be explored in patients with earlier-stage disease.

Authors
Long, GD; Laughlin, M; Madan, B; Kurtzberg, J; Gasparetto, C; Morris, A; Rizzieri, D; Smith, C; Vredenburgh, J; Halperin, EC; Broadwater, G; Niedzwiecki, D; Chao, NJ
MLA Citation
Long, GD, Laughlin, M, Madan, B, Kurtzberg, J, Gasparetto, C, Morris, A, Rizzieri, D, Smith, C, Vredenburgh, J, Halperin, EC, Broadwater, G, Niedzwiecki, D, and Chao, NJ. "Unrelated umbilical cord blood transplantation in adult patients." Biol Blood Marrow Transplant 9.12 (December 2003): 772-780.
PMID
14677117
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
9
Issue
12
Publish Date
2003
Start Page
772
End Page
780
DOI
10.1016/j.bbmt.2003.08.007

Growth hormone accelerates immune recovery following allogeneic T-cell-depleted bone marrow transplantation in mice.

OBJECTIVE: To test in a murine model whether recombinant human growth hormone can promote immune recovery after allogeneic T-cell-depleted bone marrow transplantation. MATERIALS AND METHODS: Lethally irradiated (8.5 Gy) BALB/c mice (H2(d)) were transplanted with 5 x 10(6) T cell-depleted bone marrow cells from C57BL/6 mice (H2(b)). Recipient mice were injected intraperitoneally with recombinant human growth hormone (20 microg/dose/day) or saline for the first 4 weeks after transplantation. These animals were followed for phenotypic and functional immune recovery. RESULTS: Administration of human recombinant growth hormone improved the CD4(+) T-cell counts in peripheral blood on day +14 (44+/-14 vs 33+/-7/microL blood, p<0.05) and day +21 (281+/-109 vs 187+/-76/microL blood, p<0.01) compared with the saline control. These differences were no longer significant by day +28 despite continued growth hormone administration. Similar effects were also observed on CD8(+) T cells and B220(+) B cells. The improvements in peripheral T-cell counts were at least partially as a result of enhanced thymopoiesis because there was an increase in total thymocytes after treatment with growth hormone. T-cell-depleted bone marrow recipients treated with growth hormone rejected the third-party grafts faster than those treated with saline control (median survival time: 20 days vs 26 days, p<0.05). CONCLUSIONS: These data demonstrated that recombinant human growth hormone can accelerate phenotypic and functional immune reconstitution following allogeneic T-cell-depleted bone marrow transplantation in mice.

Authors
Chen, BJ; Cui, X; Sempowski, GD; Chao, NJ
MLA Citation
Chen, BJ, Cui, X, Sempowski, GD, and Chao, NJ. "Growth hormone accelerates immune recovery following allogeneic T-cell-depleted bone marrow transplantation in mice." Exp Hematol 31.10 (October 2003): 953-958.
PMID
14550811
Source
pubmed
Published In
Experimental Hematology
Volume
31
Issue
10
Publish Date
2003
Start Page
953
End Page
958

Augmentation of umbilical cord blood (UCB) transplantation with ex vivo-expanded UCB cells: results of a phase 1 trial using the AastromReplicell System.

Allogeneic stem cell transplantation with umbilical cord blood (UCB) cells is limited by the cell dose a single unit provides recipients. Ex vivo expansion is one strategy to increase the number of cells available for transplantation. Aastrom Biosciences developed an automated continuous perfusion culture device for expansion of hematopoietic stem cells (HSCs). Cells are expanded in media supplemented with fetal bovine serum, horse serum, PIXY321, flt-3 ligand, and erythropoietin. We performed a phase 1 trial augmenting conventional UCB transplants with ex vivo-expanded cells. The 28 patients were enrolled on the trial between October 8, 1997 and September 30, 1998. UCB cells were expanded in the device, then administered as a boost to the conventional graft on posttransplantation day 12. While expansion of total cells and colony-forming units (CFUs) occurred in all cases, the magnitude of expansion varied considerably. The median fold increase was 2.4 (range, 1.0-8.5) in nucleated cells, 82 (range, 4.6-266.4) in CFU granulocyte-macrophages, and 0.5 (range, 0.09-2.45) in CD34+ lineage negative (lin-) cells. CD3+ cells did not expand under these conditions. Clinical-scale ex vivo expansion of UCB is feasible, and the administration of ex vivo-expanded cells is well tolerated. Augmentation of UCB transplants with ex vivo-expanded cells did not alter the time to myeloid, erythroid, or platelet engraftment in 21 evaluable patients. Recipients of ex vivo-expanded cells continue to have durable engraftment with a median follow-up of 47 months (range, 41-51 months). A randomized phase 2 study will determine whether augmenting UCB transplants with ex vivo-expanded UCB cells is beneficial.

Authors
Jaroscak, J; Goltry, K; Smith, A; Waters-Pick, B; Martin, PL; Driscoll, TA; Howrey, R; Chao, N; Douville, J; Burhop, S; Fu, P; Kurtzberg, J
MLA Citation
Jaroscak, J, Goltry, K, Smith, A, Waters-Pick, B, Martin, PL, Driscoll, TA, Howrey, R, Chao, N, Douville, J, Burhop, S, Fu, P, and Kurtzberg, J. "Augmentation of umbilical cord blood (UCB) transplantation with ex vivo-expanded UCB cells: results of a phase 1 trial using the AastromReplicell System." Blood 101.12 (June 15, 2003): 5061-5067.
PMID
12595310
Source
pubmed
Published In
Blood
Volume
101
Issue
12
Publish Date
2003
Start Page
5061
End Page
5067
DOI
10.1182/blood-2001-12-0290

4-hydroperoxycyclophosphamide--purged peripheral blood stem cells for autologous transplantation in patients with acute myeloid leukemia.

We have performed a phase I dose escalation of 4-Hydroperoxycyclophosphamide (4HC) purging of autologous peripheral blood progenitor cells (PBPCs) to improve the outcome of autologous transplantation for patients with myeloid leukemia. Peripheral blood stem cells were mobilized after cytosine arabinoside of 2 g/m(2) every 12 hours x 8 doses with etoposide of 40 mg/kg total dose infused over 4 days, followed by growth factor support. The preparative regimen included Busulfan of 1 mg/kg orally every 6 hours x 16 doses, followed by etoposide of 60 mg/kg x 1 day (the patient with chronic myeloid leukemia received cyclophosphamide of 60 mg/kg/d x 2 days in lieu of etoposide). PBPCs purged with 4HC were infused following this induction. Toxicities included grade 3 or 4 skin rashes, stomatitis/mucositis, and delay in time to hematopoietic recovery. The maximum tolerated dose of 4HC used to purge PBPCs in this trial was 20 microg/mL, which resulted in an average of 18 days for white blood cells and 28 days for platelet recovery. With a median follow-up of 2.25 years in surviving patients, the 3-year disease free survival rate is 44% and the overall survival rate is 89%. These data suggest that autologous PBPCs are more sensitive than marrow purged with 4HC, tolerating less intense purging, although a survival advantage may still be seen and should be assessed in larger studies. Approaches to minimize stomatitis and protect normal stem cells from the toxicity of 4HC may improve the tolerance and efficacy of this approach.

Authors
Rizzieri, DA; Talbot, JT; Long, GD; Vredenburgh, JJ; Gasparetto, C; Smith, CS; Colvin, MO; Adams, D; Morris, A; Dodge, R; Loftis, J; Waters-Pick, B; Reese, M; Carawan, H; Koh, LP; Chao, NJ
MLA Citation
Rizzieri, DA, Talbot, JT, Long, GD, Vredenburgh, JJ, Gasparetto, C, Smith, CS, Colvin, MO, Adams, D, Morris, A, Dodge, R, Loftis, J, Waters-Pick, B, Reese, M, Carawan, H, Koh, LP, and Chao, NJ. "4-hydroperoxycyclophosphamide--purged peripheral blood stem cells for autologous transplantation in patients with acute myeloid leukemia." Biol Blood Marrow Transplant 9.3 (March 2003): 183-188.
PMID
12652469
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
9
Issue
3
Publish Date
2003
Start Page
183
End Page
188
DOI
10.1053/bbmt.2003.50011

Phase I evaluation of prolonged-infusion gemcitabine with fludarabine for relapsed or refractory acute myelogenous leukemia.

PURPOSE: The purpose of this study was to determine the maximum tolerated duration of infusion of gemcitabine at 10 mg/m(2)/min in combination with fludarabine at 25 mg/m(2) daily for 5 days in the treatment of relapsed or refractory acute myelogenous leukemia. EXPERIMENTAL DESIGN: Eighteen patients with relapsed or refractory acute myelogenous leukemia were enrolled. The median age was 54.5 years (range, 21-80 years). Patients received a 30-min infusion of fludarabine at 25 mg/m(2) daily for 5 days. i.v. gemcitabine was given as a single infusion at 10 mg/m(2)/min with the duration adjusted following a modified continuous reassessment method. RESULTS: After 18 patients, the maximum recommended duration of infusion of gemcitabine in combination with fludarabine was selected as a 15-h infusion given at 10 mg/m(2)/min (9,000 mg/m(2)). Severe stomatitis or esophagitis was the most common nonhematological dose-limiting toxicity. Myelosuppression was universal. Febrile neutropenia was common, and 3 of 18 (17%) patients developed bacteremia. Occasional nausea, vomiting, or diarrhea was also reported. There were three complete responses and two partial responses for an overall response rate of 28%. CONCLUSIONS: Prolonged-infusion gemcitabine at a fixed dose rate of 10 mg/m(2)/min for 15 h with 25 mg/m(2)/day fludarabine for 5 days is a tolerable induction regimen for relapsed or refractory leukemia. Stomatitis, esophagitis, febrile neutropenia, and myelosuppression should be anticipated; however, this regimen may be beneficial in patients with relapsed or refractory leukemia.

Authors
Rizzieri, DA; Ibom, VK; Moore, JO; DeCastro, CM; Rosner, GL; Adams, DJ; Foster, T; Payne, N; Thompson, M; Vredenburgh, JJ; Gasparetto, C; Long, GD; Chao, NJ; Gockerman, JP
MLA Citation
Rizzieri, DA, Ibom, VK, Moore, JO, DeCastro, CM, Rosner, GL, Adams, DJ, Foster, T, Payne, N, Thompson, M, Vredenburgh, JJ, Gasparetto, C, Long, GD, Chao, NJ, and Gockerman, JP. "Phase I evaluation of prolonged-infusion gemcitabine with fludarabine for relapsed or refractory acute myelogenous leukemia." Clin Cancer Res 9.2 (February 2003): 663-668.
PMID
12576433
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
9
Issue
2
Publish Date
2003
Start Page
663
End Page
668

Depletion of host reactive T cells by photodynamic cell purging and prevention of graft versus host disease

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.

Authors
Goggins, TF; Chao, N
MLA Citation
Goggins, TF, and Chao, N. "Depletion of host reactive T cells by photodynamic cell purging and prevention of graft versus host disease." Leukemia and Lymphoma 44.11 (2003): 1871-1879.
PMID
14738138
Source
scival
Published In
Leukemia and Lymphoma
Volume
44
Issue
11
Publish Date
2003
Start Page
1871
End Page
1879
DOI
10.1080/1042819031000119226

New developments in allotransplant immunology.

After allogeneic stem cell transplantation, the establishment of the donor's immune system in an antigenically distinct recipient confers a therapeutic graft-versus-malignancy effect, but also causes graft-versus-host disease (GVHD) and protracted immune dysfunction. In the last decade, a molecular-level description of alloimmune interactions and the process of immune recovery leading to tolerance has emerged. Here, new developments in understanding alloresponses, genetic factors that modify them, and strategies to control immune reconstitution are described. In Section I, Dr. John Barrett and colleagues describe the cellular and molecular basis of the alloresponse and the mechanisms underlying the three major outcomes of engraftment, GVHD and the graft-versus-leukemia (GVL) effect. Increasing knowledge of leukemia-restricted antigens suggests ways to separate GVHD and GVL. Recent findings highlight a central role of hematopoietic-derived antigen-presenting cells in the initiation of GVHD and distinct properties of natural killer (NK) cell alloreactivity in engraftment and GVL that are of therapeutic importance. Finally, a detailed map of cellular immune recovery post-transplant is emerging which highlights the importance of post-thymic lymphocytes in determining outcome in the critical first few months following stem cell transplantation. Factors that modify immune reconstitution include immunosuppression, GVHD, the cytokine milieu and poorly-defined homeostatic mechanisms which encourage irregular T cell expansions driven by immunodominant T cell-antigen interactions. In Section II, Prof. Anne Dickinson and colleagues describe genetic polymorphisms outside the human leukocyte antigen (HLA) system that determine the nature of immune reconstitution after allogeneic stem cell transplantation (SCT) and thereby affect transplant outcomethrough GVHD, GVL, and transplant-related mortality. Polymorphisms in cytokine gene promotors and other less characterized genes affect the cytokine milieu of the recipient and the immune reactivity of the donor. Some cytokine gene polymorphisms are significantly associated with transplant outcome. Other non-HLA genes strongly affecting alloresponses code for minor histocompatibility antigens (mHA). Differences between donor and recipient mHA cause GVHD or GVL reactions or graft rejection. Both cytokine gene polymorphisms (CGP) and mHA differences resulting on donor-recipient incompatibilities can be jointly assessed in the skin explant assay as a functional way to select the most suitable donor or the best transplant approach for the recipient. In Section III, Dr. Nelson Chao describes non-pharmaceutical techniques to control immune reconstitution post-transplant. T cells stimulated by host alloantigens can be distinguished from resting T cells by the expression of a variety of activation markers (IL-2 receptor, FAS, CD69, CD71) and by an increased photosensitivity to rhodamine dyes. These differences form the basis for eliminating GVHD-reactive T cells in vitro while conserving GVL and anti-viral immunity. Other attempts to control immune reactions post-transplant include the insertion of suicide genes into the transplanted T cells for effective termination of GVHD reactions, the removal of CD62 ligand expressing cells, and the modulation of T cell reactivity by favoring Th2, Tc2 lymphocyte subset expansion. These technologies could eliminate GVHD while preserving T cell responses to leukemia and reactivating viruses.

Authors
Barrett, AJ; Rezvani, K; Solomon, S; Dickinson, AM; Wang, XN; Stark, G; Cullup, H; Jarvis, M; Middleton, PG; Chao, N
MLA Citation
Barrett, AJ, Rezvani, K, Solomon, S, Dickinson, AM, Wang, XN, Stark, G, Cullup, H, Jarvis, M, Middleton, PG, and Chao, N. "New developments in allotransplant immunology." Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program (2003): 350-371.
PMID
14633790
Source
scival
Published In
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program
Publish Date
2003
Start Page
350
End Page
371

Dendritic cell recovery following nonmyeloablative allogeneic stem cell transplants.

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.

Authors
Morse, MA; Rizzieri, D; Stenzel, TT; Hobeika, AC; Vredenburgh, JJ; Chao, NJ; Clay, TM; Mosca, PJ; Lyerly, HK
MLA Citation
Morse, MA, Rizzieri, D, Stenzel, TT, Hobeika, AC, Vredenburgh, JJ, Chao, NJ, Clay, TM, Mosca, PJ, and Lyerly, HK. "Dendritic cell recovery following nonmyeloablative allogeneic stem cell transplants." J Hematother Stem Cell Res 11.4 (August 2002): 659-668.
PMID
12201954
Source
pubmed
Published In
Journal of hematotherapy & stem cell research
Volume
11
Issue
4
Publish Date
2002
Start Page
659
End Page
668
DOI
10.1089/15258160260194802

Prevention of graft-versus-host disease while preserving graft-versus-leukemia effect after selective depletion of host-reactive T cells by photodynamic cell purging process.

In this study, we investigated the possibility of selective depletion of donor alloantigen-specific T cells from C57BL/6 (H-2(b)) mice to prevent graft-versus-host disease (GVHD). These cells were first activated with irradiated BALB/c (H-2(d)) host spleen cells in a 5-day mixed lymphocyte culture. Following this activation, a photoactive rhodamine derivative called 4,5-dibromorhodamine 123 (TH9402), was added. This compound is selectively retained in the mitochondria of activated host-reactive cells but not tumor- or third-party-specific resting cells. The treated cells were subsequently exposed to visible light (514 nm) to deplete the TH9402-enriched activated host-reactive cells. Treatment with photodynamic cell purging process (PDP) inhibited antihost responses measured by cytotoxic T lymphocytes (CTL) by 93%, and interferon-gamma production by 66%. By contrast, anti-BCL1 (BALB/c-origin leukemia/lymphoma) and anti-third-party C3H/HeJ (H-2(k)) responses were preserved. PDP-treated primed C57BL/6 cells were further tested in vivo. All lethally irradiated BALB/c mice inoculated with BCL1 cells and T-cell-depleted bone marrow cells developed leukemia by day +30, with 50% mortality by 100 days. All mice died of GVHD after addition of 5 x 10(6) untreated primed C57BL/6 cells. However, addition of same numbers of PDP-treated cells allowed 90% of the recipients to survive more than 100 days without detectable BCL1 tumor cells and free of GVHD. Moreover, PDP-treated primed C57BL/6 cells retained the ability to induce GVHD in the third-party C3H/HeJ mice. These data suggest that PDP can selectively deplete host alloantigen-specific T cells for GVHD prevention and immune and antileukemia function preserve.

Authors
Chen, BJ; Cui, X; Liu, C; Chao, NJ
MLA Citation
Chen, BJ, Cui, X, Liu, C, and Chao, NJ. "Prevention of graft-versus-host disease while preserving graft-versus-leukemia effect after selective depletion of host-reactive T cells by photodynamic cell purging process." Blood 99.9 (May 1, 2002): 3083-3088.
PMID
11964269
Source
pubmed
Published In
Blood
Volume
99
Issue
9
Publish Date
2002
Start Page
3083
End Page
3088

Alemtuzumab in relapsed or refractory chronic lymphocytic leukemia and prolymphocytic leukemia.

Twenty-three adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or prolymphocytic leukemia (PLL) were treated for up to 12 weeks with the anti-CD52 monoclonal antibody alemtuzumab. Patients were a median of six years from diagnosis and had been treated with a median of four chemotherapy regimens (median of 24 total cycles) prior to enrollment. Fourteen patients (61%) had received prior monoclonal antibody therapy with rituximab. Adverse symptoms were primarily mild to moderate fever, rigor/chills, nausea/vomiting, or fatigue/malaise in up to 86% of patients. Patients with low blood counts at the initiation of alemtuzumab tolerated therapy well. A total of 17 patients were evaluable for disease response. Nine patients (53%) responded with complete remissions in the peripheral blood. Of these nine, five were evaluated by bone marrow biopsy with four complete responses (CR) and one partial response. Six of the nine presented with nodal disease at the start of alemtuzumab therapy with three CRs and three partial responses. Alemtuzumab is a monoclonal antibody that offers effective treatment for chemotherapy refractory CLL and PLL and is generally well tolerated in the outpatient setting.

Authors
McCune, SL; Gockerman, JP; Moore, JO; Decastro, CM; Bass, AJ; Chao, NJ; Long, GD; Vredenburgh, JJ; Gasparetto, C; Adams, D; Payne, N; Rizzieri, DA
MLA Citation
McCune, SL, Gockerman, JP, Moore, JO, Decastro, CM, Bass, AJ, Chao, NJ, Long, GD, Vredenburgh, JJ, Gasparetto, C, Adams, D, Payne, N, and Rizzieri, DA. "Alemtuzumab in relapsed or refractory chronic lymphocytic leukemia and prolymphocytic leukemia." Leuk Lymphoma 43.5 (May 2002): 1007-1011.
PMID
12148879
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
43
Issue
5
Publish Date
2002
Start Page
1007
End Page
1011
DOI
10.1080/10428190290021597

Mobilization of dendritic cells from patients with breast cancer into peripheral blood stem cell leukapheresis samples using Flt-3-Ligand and G-CSF or GM-CSF.

Treatment with myeloablative chemotherapy and autologous peripheral blood stem cell (PBSC) transplantation followed by vaccination with autologous dendritic cells (DCs) treated with tumor antigens is a promising therapeutic strategy for several types of cancer. Obtaining sufficient numbers of both PBSCs and DCs is central to this approach. Previously, it has been shown that administration of Flt-3-Ligand (FL) combined with either G-CSF or GM-CSF mobilizes large numbers of PBSCs in patients with cancer. In the current study, we sought to determine whether these same cytokines could simultaneously mobilize DCs into the PBSC leukapheresis collection. DCs were analysed in PBSC leukapheresis samples obtained from five patients with high-risk breast cancer who received G-CSF alone as priming prior to leukapheresis, four patients who received FL+G-CSF and five patients who received FL+GM-CSF. DCs were defined as cells with a lin(dim/-) HLA-DR+ CD11c+ phenotype. The proportions of DCs in the FL+G-CSF and FL+GM-CSF samples were significantly higher than in pre-mobilization peripheral blood and G-CSF leukapheresis samples. The mean yield of DCs/kg in the FL+GM-CSF samples was also significantly higher than the mean yield of DCs in the G-CSF samples. The FL+G-CSF and FL+GM-CSF mobilized DCs were immature by morphologic and phenotypic criteria but stimulated allogeneic T-cells at levels similar to DCs generated in culture from PBMCs. Overnight culture?of the immature DCs obtained from patients receiving either FL+G-CSF or FL+GM-CSF in TNF-alpha?resulted in the generation of mature DCs. In summary, administration of FL in combination with GM-CSF and G-CSF to patients with breast cancer can mobilize large numbers of immature DCs into PBSC leukapheresis collections.

Authors
Gasparetto, C; Gasparetto, M; Morse, M; Rooney, B; Vredenburgh, JJ; Long, GD; Rizzieri, DA; Loftis, J; Chao, NJ; Smith, C
MLA Citation
Gasparetto, C, Gasparetto, M, Morse, M, Rooney, B, Vredenburgh, JJ, Long, GD, Rizzieri, DA, Loftis, J, Chao, NJ, and Smith, C. "Mobilization of dendritic cells from patients with breast cancer into peripheral blood stem cell leukapheresis samples using Flt-3-Ligand and G-CSF or GM-CSF." Cytokine 18.1 (April 7, 2002): 8-19.
PMID
12090755
Source
pubmed
Published In
Cytokine
Volume
18
Issue
1
Publish Date
2002
Start Page
8
End Page
19

Addition of a second, different allogeneic graft accelerates white cell and platelet engraftment after T-cell-depleted bone marrow transplantation.

Significant delays in engraftment and lymphoid recovery are the 2 major challenges in cord blood transplantation. The cause for this delay is presumed to be the low numbers of hematopoietic precursors found in one unit of cord blood. One approach to increase the stem cell doses could be to combine cord blood units from different donors differing at the major histocompatibility complex (MHC). As a first step toward this goal, the kinetics of hematologic engraftment and immune reconstitution were compared between 1 unit (2.5 x 10(6) cells) of T-cell-depleted bone marrow cells from a single donor (C57BL/6 [H2(b)] or SJL/J [H2(s)]) and 2 units from different donors (C57BL/6 + SJL/J) after transplantation into lethally irradiated (8.5 Gy) BALB/c recipients (H2(d)). Addition of T-cell-depleted bone marrow from an MHC-mismatched allogeneic donor doubled the white blood counts compared with recipients of one single unit on days +10 and +14. Similar effects were also observed on platelets. The beneficial effect of additional cells on peripheral T-cell counts were first observed on day +14. Cells both from donors (C57BL/6 and/or SJL/J) and recipients (BALB/c) contributed to myeloid and lymphoid reconstitution. The chimeras containing cells from 3 strains of mice were able to mount a recall immune response. Our data suggest that combining stem cells from MHC-mismatched allogeneic donors is feasible, that it has beneficial effects on myeloid engraftment and T-cell phenotypic recovery, and that the long-term stable mixed chimeras are immunologically normal following T-cell-depleted bone marrow transplantation.

Authors
Chen, BJ; Cui, X; Chao, NJ
MLA Citation
Chen, BJ, Cui, X, and Chao, NJ. "Addition of a second, different allogeneic graft accelerates white cell and platelet engraftment after T-cell-depleted bone marrow transplantation." Blood 99.6 (March 15, 2002): 2235-2240.
PMID
11877303
Source
pubmed
Published In
Blood
Volume
99
Issue
6
Publish Date
2002
Start Page
2235
End Page
2240

Mechanisms of tolerance induced by PG490-88 in a bone marrow transplantation model.

BACKGROUND: PG490-88, a semisynthetic derivative of a novel compound PG490 (triptolide) purified from a Chinese herb (Tripterygium wilfordii Hook F), is effective in prevention of murine graft-versus-host disease (GVHD). METHODS: PG490-88 was administrated into recipients in a model (B10.D2 [H2d, Mls-2b, Mls-3b]-->BALB/c [H2d, Mls-2a, Mls-3a]) of lethal GVHD. Tolerance was evaluated by transplantation of neonatal hearts. The mechanisms of tolerance were studied. RESULTS: Host-specific tolerance was established in PG490-88-treated BALB/c recipients. Significant numbers of host reactive Vbeta3+ T cells (3.56+/-1.66% among CD4, 4.06+/-1.62% among CD8, P<0.0001 vs. normal BALB/c mice, P>0.05 vs. normal B10.D2 mice) were present in PG490-88-treated mice, suggesting that clonal deletion was not responsible for the observed tolerance. Spleen cells from PG490-88-treated mice could not respond to the host antigens measured by a popliteal lymph node weight gain assay. The unresponsiveness was unable to be overcome by supplementation of exogenous interleukin (IL)-2. Tolerant Vbeta3+ T cells obtained from PG490-88-treated mice proliferated normally to nonantigen-specific T cell receptor cross-linking. Neither antigen-specific nor nonantigen-specific suppressor cells were found in PG490-88-treated mice. The tolerant mice produced IL-4 rather than IL-2 and interferon (IFN)-gamma. CONCLUSIONS: Host-specific tolerance induced by PG490-88 in a murine bone marrow transplantation model is not due to deletion of alloreactive cells. Moreover, suppressor cells are not involved in the maintenance of tolerance. Rather, PG490-88 seems to lead to allogeneic tolerance either through the induction of a state of antigen-specific anergy of the responding T cells or through the induction of T-helper cell, type II (TH2) responses.

Authors
Chen, BJ; Chen, Y; Cui, X; Fidler, JM; Chao, NJ
MLA Citation
Chen, BJ, Chen, Y, Cui, X, Fidler, JM, and Chao, NJ. "Mechanisms of tolerance induced by PG490-88 in a bone marrow transplantation model." Transplantation 73.1 (January 15, 2002): 115-121.
PMID
11792990
Source
pubmed
Published In
Transplantation
Volume
73
Issue
1
Publish Date
2002
Start Page
115
End Page
121

A comparison of murine T-cell-depleted adult bone marrow and full-term fetal blood cells in hematopoietic engraftment and immune reconstitution.

Umbilical cord blood has been increasingly used as a source of hematopoietic stem cells. A major area of concern for the use of cord blood transplantation is the delay in myeloid and lymphoid recovery. To directly compare myeloid and lymphoid recovery using an animal model of bone marrow and cord blood as sources of stem cells, hematopoietic engraftment and immune recovery were studied following infusion of T-cell-depleted adult bone marrow or full-term fetal blood cells, as a model of cord blood in a murine allogeneic transplantation model (C57BL/6 [H-2(b)] --> BALB/c [H-2(d)]). Allogeneic full-term fetal blood has poorer radioprotective capacity but greater long-term engraftment potential on a cell-to-cell basis compared with T-cell-depleted bone marrow. Allogeneic full-term fetal blood recipients had decreased absolute numbers of T, B, and dendritic cells compared with bone marrow recipients. Splenic T cells in allogeneic full-term fetal blood recipients proliferated poorly, were unable to generate cytotoxic effectors against third-party alloantigens in vitro, and failed to generate alloantigen-specific cytotoxic antibodies in vivo. In addition, reconstituting T cells in fetal blood recipients had decreased mouse T-cell receptor delta single-joint excision circles compared with bone marrow recipients. At a per-cell level, B cells from fetal blood recipients did not proliferate as well as those found in bone marrow recipients. These results suggest that full-term fetal blood can engraft allogeneic hosts across the major histocompatibility barrier with slower hematopoietic engraftment and impaired immune reconstitution.

Authors
Chen, BJ; Cui, X; Sempowski, GD; Gooding, ME; Liu, C; Haynes, BF; Chao, NJ
MLA Citation
Chen, BJ, Cui, X, Sempowski, GD, Gooding, ME, Liu, C, Haynes, BF, and Chao, NJ. "A comparison of murine T-cell-depleted adult bone marrow and full-term fetal blood cells in hematopoietic engraftment and immune reconstitution." Blood 99.1 (January 1, 2002): 364-371.
PMID
11756193
Source
pubmed
Published In
Blood
Volume
99
Issue
1
Publish Date
2002
Start Page
364
End Page
371

Nonmyeloablative regimen preserves "niches" allowing for peripheral expansion of donor T-cells.

T-cell recovery following myeloablative preparatory regimens and cord blood transplantation in adult patients gen erally occurs between 1 and 3 years following allogeneic bone marrow transplantation. T-cell reconstitution may involve thymic education of donor-derived precursors or peripheral expansion of mature T-cells transferred in the graft. We measured quantitative and qualitative immunologic reconstitution, T-cell receptor spectratyping, and T-cell receptor excision circle (TREC) levels in adult recipients of umbilical cord blood transplants following a novel nonmyeloablative regimen. These results were compared to previously published results of similar patients receiving a myeloablative regimen and cord blood stem cells. With small numbers of patients treated so far, T-cells (CD3+) reached normal levels in adults 6 to 12 months following nonmyeloablative transplantation compared with 24 months in adults receiving a myeloablative regimen. At 12 months after transplantation, the numbers of phenotypically naive (CD45RA) T-cells were higher in those receiving the nonmyeloablative regimen. The T-cell repertoire in cord blood recipients treated with a nonmyeloablative regimen was markedly more diverse and robust compared with the repertoire in those receiving the myeloablative regimen at similar time points. TRECs (which are generated within the thymus and identify new thymic emigrants and those that have not divided) were detected 12 months after transplantation in the nonmyeloablative recipients, whereas TRECs were not detected in adults until 18 to 24 months in those receiving myeloablative regimens. Thus, in adults receiving a nonmyeloablative preparatory regimen, the quantitative and qualitative recovery of T-cells occurs through rapid peripheral expansion. The ability of patients receiving a nonmyeloablative regimen to recover within a few months suggests that the peripheral niches in which T-cells can proliferate are preserved in these patients compared to those receiving ablative regimens. Moreover, the presence of TREC-positive cells within 1 year suggests that thymic recovery is likewise accelerated in non myeloablative compared to myeloablative regimens.

Authors
Chao, NJ; Liu, CX; Rooney, B; Chen, BJ; Long, GD; Vredenburgh, JJ; Morris, A; Gasparetto, C; Rizzieri, DA
MLA Citation
Chao, NJ, Liu, CX, Rooney, B, Chen, BJ, Long, GD, Vredenburgh, JJ, Morris, A, Gasparetto, C, and Rizzieri, DA. "Nonmyeloablative regimen preserves "niches" allowing for peripheral expansion of donor T-cells." Biol Blood Marrow Transplant 8.5 (2002): 249-256.
PMID
12064361
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
8
Issue
5
Publish Date
2002
Start Page
249
End Page
256

High-dose chemotherapy and hematopoietic support for patients with high-risk primary breast cancer and involvement of 4 to 9 lymph nodes

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.

Authors
Stuart, MJ; Peters, WP; Broadwater, G; Hussein, A; Ross, M; Marks, LB; Folz, RJ; Long, GD; Rizzieri, D; Chao, NJ; Vredenburgh, JJ
MLA Citation
Stuart, MJ, Peters, WP, Broadwater, G, Hussein, A, Ross, M, Marks, LB, Folz, RJ, Long, GD, Rizzieri, D, Chao, NJ, and Vredenburgh, JJ. "High-dose chemotherapy and hematopoietic support for patients with high-risk primary breast cancer and involvement of 4 to 9 lymph nodes." Biology of Blood and Marrow Transplantation 8.12 (2002): 666-673.
PMID
12523579
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
8
Issue
12
Publish Date
2002
Start Page
666
End Page
673
DOI
10.1053/bbmt.2002.v8.abbmt080666

Immunosuppressive and antiinflammatory effects of triptolide and its prodrug PG-490-88

Triptolide is a diterpenoid triepoxide purified from Tripterygium wilfordii Hook F, an herb found in China. Triptolide inhibits T cell activation mainly through inhibition of interleukin-2 production. In contrast to the target of ciclosporin and FK506, the target of triptolide is at the purine-box/ARRE/NF-AT and NF-κB target sequences after specific binding to DNA. Triptolide also induces apoptosis of T cells by activating the caspase cascade. Moreover, triptolide can suppress the expression of multiple proinflammatory cytokines and mediators, which play important roles in the pathogenesis of autoimmune diseases, transplantation rejection and GVHD. Although data in humans is very limited, triptolide has been successfully used to treat rheumatoid arthritis in humans and prevent bleomycin-induced lung fibrosis in mice. Triptolide significantly prolongs the survival of allogeneic grafts in rats and completely prevents lethal GVHD in mice. Despite its narrow therapeutic window, triptolide is a very potent immunosuppressant and antiinflammatory agent with unique mechanisms of action.

Authors
Chen, BJ; Chao, NJ
MLA Citation
Chen, BJ, and Chao, NJ. "Immunosuppressive and antiinflammatory effects of triptolide and its prodrug PG-490-88." Drugs of the Future 27.1 (2002): 57-60.
Source
scival
Published In
Drugs of the Future
Volume
27
Issue
1
Publish Date
2002
Start Page
57
End Page
60
DOI
10.1358/dof.2002.027.01.647608

Successful allogeneic engraftment of mismatched unrelated cord blood following a nonmyeloablative preparative regimen.

Reduction in the toxicity of allogeneic transplantation with nonmyeloablative induction regimens has expanded the scope of practice to older and more debilitated patients. However, the limited availability of matched sibling donors requires that alternative donor sources be investigated. Reported here are 2 cases of patients with advanced hematologic malignancies without matched siblings, partially matched family members, or matched unrelated donors who successfully underwent nonmyeloablative conditioning therapy followed by infusion of partially matched, unrelated-donor cord blood cells. The patients are in remission and remain 100% donor as assessed by short tandem repeat analysis of the marrow 6 and 12 months following transplantation.

Authors
Rizzieri, DA; Long, GD; Vredenburgh, JJ; Gasparetto, C; Morris, A; Stenzel, TT; Davis, P; Chao, NJ
MLA Citation
Rizzieri, DA, Long, GD, Vredenburgh, JJ, Gasparetto, C, Morris, A, Stenzel, TT, Davis, P, and Chao, NJ. "Successful allogeneic engraftment of mismatched unrelated cord blood following a nonmyeloablative preparative regimen." Blood 98.12 (December 1, 2001): 3486-3488.
PMID
11719394
Source
pubmed
Published In
Blood
Volume
98
Issue
12
Publish Date
2001
Start Page
3486
End Page
3488

Acute graft-vs-host disease: pathobiology and management.

Acute graft-vs-host disease (GVHD) is a major obstacle to safe allogeneic hematopoietic stem cell transplantation (HSCT), leading to a significant morbidity and mortality. GVHD occurs when transplanted donor T lymphocytes react to foreign host cells. It causes a wide variety of host tissue injuries. This review focuses on the pathobiological basis, clinical aspects, and current management strategies of acute GVHD. Afferent phase of acute GVHD starts with myeloablative conditioning, i.e., before the infusion of the graft. Total-body irradiation (TBI) or high-dose chemotherapy regimens cause extensive damage and activation in host tissues, which release inflammatory cytokines and enhance recipient major histocompatibility complex (MHC) antigens. Recognition of the foreign host antigens by donor T cells and activation, stimulation, and proliferation of T cells is crucial in the afferent phase. Effector phase of acute GVHD results in direct and indirect damage to host cells. The skin, gastrointestinal tract, and liver are major target organs of acute GVHD. Combination drug prophylaxis in GVHD is essential in all patients undergoing allogeneic HSCT. Steroids have remained the standard for the treatment of acute GVHD. Several clinical trials have evaluated monoclonal antibodies or receptor antagonist therapy for steroid-resistant acute GVHD, with different successes in a variety of settings. There are some newer promising agents like mycophenolate mofetil, glutamic acid-lysine-alanine-tyrosine (GLAT), rapamycin, and trimetrexate currently entering in the clinical studies, and other agents are in development. Future experimental and clinical studies on GVHD will shed further light on the better understanding of the disease pathobiology and generate the tools to treat malignant disorders with allogeneic HSCT with specific graft-vs-tumor effects devoid of GVHD.

Authors
Goker, H; Haznedaroglu, IC; Chao, NJ
MLA Citation
Goker, H, Haznedaroglu, IC, and Chao, NJ. "Acute graft-vs-host disease: pathobiology and management." Exp Hematol 29.3 (March 2001): 259-277. (Review)
PMID
11274753
Source
pubmed
Published In
Experimental Hematology
Volume
29
Issue
3
Publish Date
2001
Start Page
259
End Page
277

High-dose therapy and autologous bone marrow transplantation for follicular lymphoma in first complete or partial remission: results of a phase II clinical trial.

Advanced stage follicular small cleaved and mixed cell lymphoma is characterized by relapse from remission and survival ranging from 6 to 12 years. Because young patients have the greatest compromise in longevity, the efficacy and toxicity of high-dose radiochemotherapy and bone marrow transplantation after conventional chemotherapy was evaluated in a prospective phase II clinical trial. Thirty-seven patients in a minimal disease state after conventional chemotherapy received fractionated total body irradiation and high-dose etoposide and cyclophosphamide, followed by purged autologous bone marrow. A reference sample of 188 patients of similar age, stage, and histology managed at this institution before 1988 was identified for comparison of patient characteristics and outcomes. Compared with reference patients, transplant recipients had a higher tumor burden at diagnosis. With a median follow-up of 6.5 years, the estimated 10-year survival after transplantation was 86%. There was a single lymphoma death yielding a 10-year disease-specific survival of 97%. There were 2 early transplant-related deaths and 2 late acute leukemia deaths. Ten patients relapsed, one with microscopic disease only. High tumor burden at diagnosis and incomplete response to chemotherapy adversely influenced survival in the reference but not in the transplanted patients. The estimated risk of death of 14% and relapse of 30% at 10 years in our transplanted follicular lymphoma patients, the majority of whom had high tumor burdens, compares favorably with our observations in appropriately matched reference patients.

Authors
Horning, SJ; Negrin, RS; Hoppe, RT; Rosenberg, SA; Chao, NJ; Long, GD; Brown, BW; Blume, KG
MLA Citation
Horning, SJ, Negrin, RS, Hoppe, RT, Rosenberg, SA, Chao, NJ, Long, GD, Brown, BW, and Blume, KG. "High-dose therapy and autologous bone marrow transplantation for follicular lymphoma in first complete or partial remission: results of a phase II clinical trial." Blood 97.2 (January 15, 2001): 404-409.
PMID
11154216
Source
pubmed
Published In
Blood
Volume
97
Issue
2
Publish Date
2001
Start Page
404
End Page
409

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.

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.

Authors
Boeckh, M; Bowden, RA; Storer, B; Chao, NJ; Spielberger, R; Tierney, DK; Gallez-Hawkins, G; Cunningham, T; Blume, KG; Levitt, D; Zaia, JA
MLA Citation
Boeckh, M, Bowden, RA, Storer, B, Chao, NJ, Spielberger, R, Tierney, DK, Gallez-Hawkins, G, Cunningham, T, Blume, KG, Levitt, D, and Zaia, JA. "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." Biol Blood Marrow Transplant 7.6 (2001): 343-351.
PMID
11464977
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
7
Issue
6
Publish Date
2001
Start Page
343
End Page
351

T-Cell recovery in adults and children following umbilical cord blood transplantation.

T-cell reconstitution following allogeneic stem cell transplantation may involve thymic education of donor-derived precursors or peripheral expansion of mature T cells transferred in the graft. T cell-receptor excision circles (sjTRECs) are generated within the thymus and identify new thymic emigrants and those that have not divided. We measured quantitative and qualitative immunologic reconstitution and sjTREC levels in adult and pediatric recipients of umbilical cord blood transplants (UCBTs). sjTRECs were detected at normal levels in all children, starting 12 months after transplantation. sjTRECs were not detected until 18 months after transplantation in adults, and then only at a 3-fold lower level than expected for age. We used complementarity-determining region 3 (CDR3) spectratyping to measure changes in T cell-receptor diversity occurring with restoration of thymic function. T-cell repertoires were skewed in adults and children at 12 to 18 months after transplantation but recovered to near-normal diversity at 2 to 3 years post-UCBT. T-cell repertoires appeared more diverse earlier in children (at 1 to 2 years post-UCBT) than in adults (at 3 to 4 years post-UCBT). We conclude that early T-cell recovery after UCBT occurs primarily through peripheral expansion of adoptively transferred donor T cells and results in skewing of the T-cell repertoire. The reappearance of sjTREC-containing cells after UCBT is associated with increasing numbers of phenotypicaly naive T cells, improved mitogen and recall antigen responses, and diversification of the T-cell repertoire. The delay in central T-cell recovery in adults relative to children may be due to differences in thymic function resulting from age-related atrophy, graft-versus-host disease, or the pharmacologic effects of prophylaxis and treatment of graft-versus-host disease.

Authors
Klein, AK; Patel, DD; Gooding, ME; Sempowski, GD; Chen, BJ; Liu, C; Kurtzberg, J; Haynes, BF; Chao, NJ
MLA Citation
Klein, AK, Patel, DD, Gooding, ME, Sempowski, GD, Chen, BJ, Liu, C, Kurtzberg, J, Haynes, BF, and Chao, NJ. "T-Cell recovery in adults and children following umbilical cord blood transplantation." Biol Blood Marrow Transplant 7.8 (2001): 454-466.
PMID
11569891
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
7
Issue
8
Publish Date
2001
Start Page
454
End Page
466

Erratum - Acute graft-vs-host disease: Pathobiology and management (Experimental Hematology (2001) 29 (259-277))

Authors
Goker, H; Haznedaroglu, IC; Chao, NJ
MLA Citation
Goker, H, Haznedaroglu, IC, and Chao, NJ. "Erratum - Acute graft-vs-host disease: Pathobiology and management (Experimental Hematology (2001) 29 (259-277))." Experimental Hematology 29.5 (2001): 653--.
Source
scival
Published In
Experimental Hematology
Volume
29
Issue
5
Publish Date
2001
Start Page
653-
DOI
10.1016/S0301-472X(01)00665-8

Resistance of pancreatic carcinoma cells is reversed by coculturing NK-like T cells with dendritic cells pulsed with tumor-derived RNA and CA 19-9

Immunization with defined tumor antigens is limited to the small number of cancers in which specific tumor antigens have been defined but insufficient tumor material is available to produce an antitumor vaccine. In this study, we investigated whether pulsing dendritic cells (DC) using a liposomal transfer technique with a pancreatic tumor cell line-derived RNA can effectively activate NK-like T cells and tumor immunity. Pulsed DC were cocultured with NK-like T cells, i.e., CD3+CD56+ cells, as immunologic effector cells. Target cells resistant to NK-like T-cell-mediated lysis were used. Total tumor-derived RNA transfected into DC was found to completely reverse tumor cell resistance. Total tumor RNA transfection (30 μg) was found to be superior to poly(A)+ RNA transfection (5 μg) in inducing NK-like T lymphocytes. Interestingly, additional pulsing of DC with the CA 19-9 peptide in a CA 19-9-positive cell line further increased the sensitivity of pancreas carcinoma cells to NK-like T cells. Treatment of tumor RNA with RNase completely blocked the effect of RNA-transfected DC on NK-like T cells, suggesting that intact tumor-derived RNA is needed for reversal of tumor cell resistance. In conclusion, coculture of NK-like T cells with DC transfected with pancreatic tumor cell line-derived RNA reverses pancreatic tumor cell resistance by directly triggering NK-like T lymphocytes.

Authors
Ziske, C; Märten, A; Schöttker, B; Buttgereit, P; Schakowski, F; Gorschlüter, M; Rücker, AV; Scheffold, C; Chao, N; Sauerbruch, T; Schmidt-Wolf, IGH
MLA Citation
Ziske, C, Märten, A, Schöttker, B, Buttgereit, P, Schakowski, F, Gorschlüter, M, Rücker, AV, Scheffold, C, Chao, N, Sauerbruch, T, and Schmidt-Wolf, IGH. "Resistance of pancreatic carcinoma cells is reversed by coculturing NK-like T cells with dendritic cells pulsed with tumor-derived RNA and CA 19-9." Molecular Therapy 3.1 (2001): 54-60.
PMID
11162311
Source
scival
Published In
Molecular Therapy
Volume
3
Issue
1
Publish Date
2001
Start Page
54
End Page
60
DOI
10.1006/mthe.2000.0230

Efficacy and toxicity of a CCNU-containing high-dose chemotherapy regimen followed by autologous hematopoietic cell transplantation in relapsed or refractory Hodgkin's disease

High-dose CBV (cyclophosphamide, carmustine, and etoposide) in combination with autologous HCT achieves survival rates of approximately 50% at 5 years in recurrent or refractory Hodgkin's disease (HD). However, carmustine (BCNU) dose-dependent pulmonary toxicity occurs in 20% to 30% of patients. A decreased incidence of interstitial pneumonitis as well as a possible benefit in efficacy has been reported with lomustine (CCNU) compared to BCNU in the standard dose setting. In a dose-escalation study, we substituted CCNU for BCNU in the CBV regimen for 16 patients with HD (n = 12) or non-Hodgkin's lymphoma (n = 4). Based on the promising results, an additional 47 consecutive patients with HD were treated with the following regimen: CCNU (15 mg/kg) orally on day -6, etoposide (60 mg/kg) intravenously on day -4, and cyclophosphamide (100 mg/kg) intravenously on day -2. Peripheral blood progenitor cells and/or bone marrow were infused on day 0. With a median follow-up for the surviving patients of 3.2 years (range, 0.8-9.9 years), the 3-year overall survival rate was 57% (CI, ±15%), event-free survival was 52% (CI, ±14%), and freedom from progression was 68% (CI, ±14%). There were 21 deaths, 10 due to HD. Six patients died due to respiratory failure. Interstitial pneumonitis occurred in 63% of patients and could not be correlated with prior chest radiotherapy. This regimen demonstrated survival rates similar to those of historical studies that used the CBV regimen. However, the incidence of interstitial pneumonitis was in excess of expected.

Authors
Stuart, MJ; Chao, NS; Horning, SJ; Wong, RM; Negrin, RS; Johnston, LJ; Shizuru, JA; Long, GD; Blume, KG; Stockerl-Goldstein, KE
MLA Citation
Stuart, MJ, Chao, NS, Horning, SJ, Wong, RM, Negrin, RS, Johnston, LJ, Shizuru, JA, Long, GD, Blume, KG, and Stockerl-Goldstein, KE. "Efficacy and toxicity of a CCNU-containing high-dose chemotherapy regimen followed by autologous hematopoietic cell transplantation in relapsed or refractory Hodgkin's disease." Biology of Blood and Marrow Transplantation 7.10 (2001): 552-560.
PMID
11760087
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
7
Issue
10
Publish Date
2001
Start Page
552
End Page
560

Inhaled steroids as prophylaxis for delayed pulmonary toxicity syndrome in breast cancer patients undergoing high-dose chemotherapy and autologous stem cell transplantation.

PURPOSE: To evaluate the efficacy of inhaled fluticasone propionate (Flovent) as prophylaxis against delayed pulmonary toxicity syndrome (DPTS) and decline in pulmonary function in breast cancer patients undergoing high-dose chemotherapy with the conditioning regimen of cyclophosphamide, cisplatin, and carmustine (CPB) followed by autologous stem cell transplantation (ASCT). PATIENTS AND METHODS: Sixty-three consecutive patients with multinode-positive or metastatic breast cancer undergoing high-dose chemotherapy with CPB and ASCT who were treated at the Duke University Adult Bone Marrow Transplant Program. All patients were started on inhaled fluticasone propionate, 880 microg every 12 hours, for 12 weeks from the start date of their CPB conditioning regimen. Pulmonary function tests (PFTs) with a single-breath diffusing capacity of carbon monoxide (DLCO) were performed pre-ASCT as well as approximately 6 and 12 weeks post-ASCT. DPTS was defined as follows: (1) development of a nonproductive cough and dyspnea with or without fever, plus a fall in DLCO to less than 60% predicted; or (2) decline in DLCO to less than 50% predicted with or without symptoms. RESULTS: Pulmonary function tests were done on all patients pre-ASCT, on 56 of the 63 patients at a median of 44 days (range, 25 to 73 days) post-ASCT, and on 51 of the 63 patients at a median of 96 days (range, 50 to 190 days) post-ASCT. The PFTs showed an average of an 8% (+/-26%) and 21% (+/-22%) decline in DLCO. These declines compare favorably with our historical control group of 45 consecutive breast cancer patients undergoing ASCT with CPB as a conditioning regimen, who experienced average declines in DLCO of 29% (+/-18%) (P < .001) and 33% (+/-18%) (P < .001) at comparable time periods post-ASCT. Delayed pulmonary toxicity syndrome occurred in 35% of treated patients compared to 73% of the historical controls (P = .0003). No patients died of DPTS or pulmonary problems, and there were no fungal pneumonias. CONCLUSION: Inhaled fluticasone propionate may decrease the incidence of DPTS in patients treated with CPB as a conditioning regimen for ASCT, as well as help to preserve pulmonary function as measured by DLCO. These results are worthy of further study in a randomized clinical trial.

Authors
McGaughey, DS; Nikcevich, DA; Long, GD; Vredenburgh, JJ; Rizzieri, D; Smith, CA; Broadwater, G; Loftis, JS; McDonald, C; Morris, AK; Folz, RF; Chao, NF
MLA Citation
McGaughey, DS, Nikcevich, DA, Long, GD, Vredenburgh, JJ, Rizzieri, D, Smith, CA, Broadwater, G, Loftis, JS, McDonald, C, Morris, AK, Folz, RF, and Chao, NF. "Inhaled steroids as prophylaxis for delayed pulmonary toxicity syndrome in breast cancer patients undergoing high-dose chemotherapy and autologous stem cell transplantation." Biol Blood Marrow Transplant 7.5 (2001): 274-278.
PMID
11400949
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
7
Issue
5
Publish Date
2001
Start Page
274
End Page
278

Prevention of graft-versus-host disease by a novel immunosuppressant, PG490-88, through inhibition of alloreactive T cell expansion.

BACKGROUND: PG490-88 is a water soluble, semisynthetic derivative of a novel compound PG490 (triptolide) purified from the Chinese herb Tripterygium Wilfordii Hook F. METHODS: PG490-88 was administrated into recipient mice in a model (B10.D2-->BALB/c) of lethal graft-versus-host disease (GVHD) to study the effects of PG490-88 on GVHD and on the various steps involved in the pathological course of GVHD. RESULTS: Injection of PG490-88 i.p. at a dose of 0.535 mg/kg/day for the first 3 weeks after transplantation protected all the recipients from developing GVHD up to 100 days after transplantation. PG490-88 inhibited in vivo both CD4+Vbeta3+ and CD8+Vbeta3+ T cell (alloreactive T cells in this model) expansion in the spleen by 64.09 and 34.02%, respectively, at the time when Vbeta3+ cell expansion was in the logarithmic phase (day 3 after transplantation). Intracellular cytokine staining without further in vitro activation demonstrated 47.42% inhibition of IL-2 production among CD4+ spleen cells in PG490-88-treated mice as compared to GVHD control on day 3 after transplantation. In contrast, CD25 (alpha chain of interleukin-2 receptor) expression did not differ. CONCLUSIONS: PG490-88 is highly effective in prevention of murine GVHD. The immunosuppressive effect of PG490-88 is mediated by inhibition of alloreactive T cell expansion through interleukin-2 production.

Authors
Chen, BJ; Liu, C; Cui, X; Fidler, JM; Chao, NJ
MLA Citation
Chen, BJ, Liu, C, Cui, X, Fidler, JM, and Chao, NJ. "Prevention of graft-versus-host disease by a novel immunosuppressant, PG490-88, through inhibition of alloreactive T cell expansion." Transplantation 70.10 (November 27, 2000): 1442-1447.
PMID
11118087
Source
pubmed
Published In
Transplantation
Volume
70
Issue
10
Publish Date
2000
Start Page
1442
End Page
1447

Cyclosporin A-related cerebral vasculopathy.

The use of cyclosporin A has been associated with several side-effects, including neurotoxicity. The mechanism of toxicity is not well known. We report two patients treated with cyclosporin A who developed lesions in the cerebral white matter associated with abnormally elevated cerebral blood flow velocities on transcranial doppler ultrasound and abnormal vascular appearance on magnetic resonance angiography. Bone Marrow Transplantation (2000) 26, 801-804.

Authors
Shbarou, RM; Chao, NJ; Morgenlander, JC
MLA Citation
Shbarou, RM, Chao, NJ, and Morgenlander, JC. "Cyclosporin A-related cerebral vasculopathy." Bone Marrow Transplant 26.7 (October 2000): 801-804.
PMID
11042665
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
26
Issue
7
Publish Date
2000
Start Page
801
End Page
804
DOI
10.1038/sj.bmt.1702603

Conversion of indwelling chest port catheters to tunneled central venous catheters.

PURPOSE: To determine the safety and efficacy of the conversion of subcutaneous chest wall infusion ports to tunneled central venous catheters. MATERIALS AND METHODS: During a period of 34 months, 67 patients were referred for conversion of indwelling subcutaneous chest wall ports to tunneled central venous catheters as part of a bone marrow transplant protocol. Six patients were deemed unacceptable for conversion and the remaining 61 underwent successful conversion. All patients had functioning surgically placed single-lumen (n = 50) or double-lumen (n = 11) chest ports, which were removed to maintain the original venous access sites for placement of a tunneled central venous catheter, incorporating the chest wall pocket for tunneling, in 46 patients (75%). A new tunnel was created in the other 15 patients. There were no immediate complications and all patients were followed until catheter removal or patient demise with the catheter in place. RESULTS: 57 of 61 (93%) catheters were used without evidence of infection for 23-164 days (mean, 57 d) after placement. Two (3%) were removed (both at 26 days) because of persistent neutropenic fever without physical signs or laboratory evidence of catheter infection, and two (3%) were removed (at 11 and 77 days) because of proven catheter infection, yielding an overall infection rate of 1.2 per 1,000 catheter days. Two catheters required exchange and two required stripping because of decreased function, resulting in an overall catheter-related complication rate of 2.4 per 1,000 catheter days. CONCLUSIONS: Indwelling subcutaneous chest wall infusion ports can be safely converted to tunneled central venous catheters, even in an immunocompromised patient population, with a low risk of complications such as infection.

Authors
Brodwater, BK; Silber, JS; Smith, TP; Chao, NJ; Suhocki, PV; Ryan, JM; Newman, GE
MLA Citation
Brodwater, BK, Silber, JS, Smith, TP, Chao, NJ, Suhocki, PV, Ryan, JM, and Newman, GE. "Conversion of indwelling chest port catheters to tunneled central venous catheters." J Vasc Interv Radiol 11.9 (October 2000): 1137-1142.
PMID
11041469
Source
pubmed
Published In
JVIR: Journal of Vascular and Interventional Radiology
Volume
11
Issue
9
Publish Date
2000
Start Page
1137
End Page
1142

Progress in graft-versus-host disease.

Authors
Chao, NJ
MLA Citation
Chao, NJ. "Progress in graft-versus-host disease." J Hematother Stem Cell Res 9.3 (June 2000): 295-296.
PMID
10894349
Source
pubmed
Published In
Journal of hematotherapy & stem cell research
Volume
9
Issue
3
Publish Date
2000
Start Page
295
End Page
296
DOI
10.1089/15258160050079380

PG27, an extract of Tripterygium wilfordii hook f, induces antigen-specific tolerance in bone marrow transplantation in mice.

PG27, an active fraction purified from an extract of a Chinese herb, Tripterygium wilfordii hook f, was used to prevent graft-versus-host disease (GVHD) in a murine model. Lethally irradiated BALB/c (H-2(d)) recipients of B10.D2 (H-2(d)) donor grafts were given daily intraperitoneal injections of PG27 (40 mg/kg per day) for the first 35 days after transplantation. Control mice were given daily injections of solvent vehicle (Ethanol and Cremophor EL). All the control recipients (15/15) died of GVHD within 90 days, but all the recipients given prophylactic treatment with PG27 (15/15) survived beyond 100 days without any signs of GVHD. Furthermore, the GVHD-free recipients were used as donors, and their bone marrow and spleen cells were transplanted into lethally irradiated normal BALB/c (same party) or lethally irradiated normal C3H (H-2(k), third party) mice. Although 10 of 10 same-party recipients survived more than 100 days without any signs of GVHD, 10 of 10 third-party C3H recipients died of GVHD within 40 days. Further studies of PG27 in the murine BCL1 leukemia/lymphoma model demonstrated that animals treated with PG27 partially retained the graft-versus-leukemia (GVL) effect of the graft without GVHD. These results suggest that treatment with PG27 induces host-specific tolerance and retains the GVL effect of allogeneic marrow grafts. (Blood. 2000;95:705-710)

Authors
Chen, Y; Zeng, D; Schlegel, PG; Fidler, J; Chao, NJ
MLA Citation
Chen, Y, Zeng, D, Schlegel, PG, Fidler, J, and Chao, NJ. "PG27, an extract of Tripterygium wilfordii hook f, induces antigen-specific tolerance in bone marrow transplantation in mice." Blood 95.2 (January 15, 2000): 705-710.
PMID
10627483
Source
pubmed
Published In
Blood
Volume
95
Issue
2
Publish Date
2000
Start Page
705
End Page
710

Pulmonary toxicity of induction chemotherapy prior to standard or high-dose chemotherapy with autologous hematopoietic support.

We closely followed the pulmonary function of 150 consecutive high-risk breast cancer patients who underwent standard induction CAF (cyclophosphamide, doxorubicin, 5-fluorouracil) chemotherapy, followed by randomization to either standard-dose CPB (cyclophosphamide, cisplatin, bischloroethylnitrosourea [BCNU]) chemotherapy (SDC) or to high-dose CPB chemotherapy (HDC) with autologous bone marrow transplantation (ABMT) and peripheral blood progenitor cell support (PBPCS). Previously, we have described a delayed pulmonary toxicity syndrome (DPTS) which characterizes the pulmonary dysfunction after HDC and ABMT in this patient population. However, little is known concerning the role induction chemotherapy plays in its development. We found that after three cycles of induction CAF, the mean diffusing capacity of the lungs for carbon monoxide (DL(CO)) significantly decreased by 12.6%. Additionally, in patients receiving HDC, the mean DL(CO) further decreased to a nadir of 55.2 +/- 14.1% which was significantly lower than those receiving SDC (nadir: 80.7 +/- 12.3%). DPTS occurred in 72% of patients receiving HDC as compared with only 4% of patients receiving SDC. All individuals diagnosed with DPTS were treated with prednisone and the 2-yr follow-up of pulmonary function revealed a gradual improvement in mean DL(CO) such that there were no differences between HDC and SDC groups at the end of the study. No mortality was attributable to pulmonary toxicity in either group. After induction chemotherapy, but before HDC, bronchoalveolar lavage (BAL) demonstrated significant elevations in interleukin-6 (IL-6), IL-8, neutrophils, and lymphocytes. We conclude that induction CAF produces asymptomatic pulmonary dysfunction and inflammation which may prime the lungs for further injury by HDC and predispose to the development of DPTS. Fortunately, in this specific ABMT patient population, the early and judicious use of prednisone appears to improve pulmonary function in patients who develop DPTS.

Authors
Bhalla, KS; Wilczynski, SW; Abushamaa, AM; Petros, WP; McDonald, CS; Loftis, JS; Chao, NJ; Vredenburgh, JJ; Folz, RJ
MLA Citation
Bhalla, KS, Wilczynski, SW, Abushamaa, AM, Petros, WP, McDonald, CS, Loftis, JS, Chao, NJ, Vredenburgh, JJ, and Folz, RJ. "Pulmonary toxicity of induction chemotherapy prior to standard or high-dose chemotherapy with autologous hematopoietic support." Am J Respir Crit Care Med 161.1 (January 2000): 17-25.
PMID
10619792
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
161
Issue
1
Publish Date
2000
Start Page
17
End Page
25
DOI
10.1164/ajrccm.161.1.9903059

High-dose therapy with hematopoietic cell transplantation for patients with central nervous system involvement by non-Hodgkin's lymphoma.

Central nervous system (CNS) involvement by non-Hodgkin's lymphoma (NHL) carries a poor patient prognosis whether it occurs as a primary site of disease or secondarily in patients with systemic disease. In a group of 481 patients undergoing high-dose therapy with hematopoietic cell transplantation (HCT) for NHL, 15 patients (3.1%) were identified with CNS involvement. Two patients had primary CNS lymphoma, and 13 had secondary disease. All patients received intrathecal chemotherapy, and 13 received CNS radiotherapy before transplantation. Fourteen patients received systemic chemotherapy. At the time of transplantation, both patients with primary CNS lymphoma and 8 patients with secondary disease had achieved a complete response, 3 patients had achieved a partial response, 1 had failed induction therapy, and 1 had progression of CNS disease before high-dose therapy. Fourteen patients received carmustine, etoposide, and cyclophosphamide as the preparative regimen, and 1 patient received fractionated total body irradiation instead of carmustine. The 2 patients with primary CNS lymphoma were alive and free of disease, 1 at 1,085 days after HCT and 1 at 3,704 days after HCT. The actuarial 5-year event-free survival (EFS) was 46% +/- 26%, and overall survival (OS) was 41% +/- 28%. The median EFS and OS were 2.2 and 1.5 years, respectively. Three patients experienced symptomatic memory loss or intellectual decline after therapy, 1 patient developed paraplegia, and 1 patient had a thrombotic stroke 20 months after HCT. Despite treatment-related toxicities, 7 patients responding to quality-of-life questions at approximately 1 year after HCT gave their overall quality of life a median rating of 9 out of a possible 10 (range, 6-10). High-dose therapy with autologous HCT can produce extended EFS in patients with secondary CNS lymphoma and possibly in those with primary CNS NHL.

Authors
Alvarnas, JC; Negrin, RS; Horning, SJ; Hu, WW; Long, GD; Schriber, JR; Stockerl-Goldstein, K; Tierney, K; Wong, R; Blume, KG; Chao, NJ
MLA Citation
Alvarnas, JC, Negrin, RS, Horning, SJ, Hu, WW, Long, GD, Schriber, JR, Stockerl-Goldstein, K, Tierney, K, Wong, R, Blume, KG, and Chao, NJ. "High-dose therapy with hematopoietic cell transplantation for patients with central nervous system involvement by non-Hodgkin's lymphoma." Biol Blood Marrow Transplant 6.3A (2000): 352-358.
PMID
10905773
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
6
Issue
3A
Publish Date
2000
Start Page
352
End Page
358

Equivalence of 2 effective graft-versus-host disease prophylaxis regimens: results of a prospective double-blind randomized trial.

We have previously demonstrated a decrease in the incidence of acute graft-versus-host disease (GVHD) with the addition of methotrexate (MTX) to cyclosporine (CSP) and prednisone (PSE) chemotherapy in patients with leukemia. We have now completed a prospective randomized trial comparing the 3-drug regimen (CSP/MTX/PSE, including 3 doses of MTX) to the standard 2-drug regimen (CSP/MTX, including 4 doses of MTX) to investigate the benefit of PSE used up front for the prevention of acute and chronic GVHD. In the trial, 193 patients were randomized and 186 were included in the final analysis. All patients received a bone marrow graft from a fully histocompatible sibling donor. The preparatory regimen consisted of fractionated total-body irradiation (fTBI) and etoposide in all but 13 patients, who received fTBI and cyclophosphamide. The patients were randomized to receive either CSP/MTX/PSE or CSP/MTX. The 2 groups were well balanced with respect to diagnosis, disease stage, age, donor-recipient sex, and parity. In an intent-to-treat analysis, the incidence of acute GVHD was 18% (95% confidence interval [CI] 12-28) for the CSP/MTX/PSE group compared with 20% (CI 10-26) for the CSP/,MTX group (P = .60), with a median follow up of 2.2 years. Overall survival was 65% for those receiving CSP/MTX/PSE and 72% for those receiving CSP/MTX (P = .10); the relapse rate was 15% for the CSP/MTX/PSE group and 12% for the CSP/MTX group (P = .83). The incidence of chronic GVHD was similar (46% versus 52%; P = .38), with a follow-up of 0.7 to 6.0 years. Of interest, 21 patients went off study due to GVHD (5 in the CSP/MTX/PSE group and 16 in the CSP/MITX group [P = .02]), and 11 patients went off study because of alveolar hemorrhage (3 in the CSP/MTX/PSE group and 8 in the CSP/MTX group [P = .22]). The addition of PSE did not result in a higher incidence of infectious complications, bacterial (66% versus 58%), viral (77% versus 66%), or fungal (20% versus 20%), in those receiving CSP/MTX/PSE versus CSP/MTX, respectively. These data suggest that the addition of PSE was associated with a somewhat lower incidence of early posttransplantation complications but did not have a positive impact on the incidence of acute or chronic GVHD or event-free or overall survival.

Authors
Chao, NJ; Snyder, DS; Jain, M; Wong, RM; Niland, JC; Negrin, RS; Long, GD; Hu, WW; Stockerl-Goldstein, KE; Johnston, LJ; Amylon, MD; Tierney, DK; O'Donnell, MR; Nademanee, AP; Parker, P; Stein, A; Molina, A; Fung, H; Kashyap, A; Kohler, S; Spielberger, R; Krishnan, A; Rodriguez, R; Forman, SJ; Bluzme, KG
MLA Citation
Chao, NJ, Snyder, DS, Jain, M, Wong, RM, Niland, JC, Negrin, RS, Long, GD, Hu, WW, Stockerl-Goldstein, KE, Johnston, LJ, Amylon, MD, Tierney, DK, O'Donnell, MR, Nademanee, AP, Parker, P, Stein, A, Molina, A, Fung, H, Kashyap, A, Kohler, S, Spielberger, R, Krishnan, A, Rodriguez, R, Forman, SJ, and Bluzme, KG. "Equivalence of 2 effective graft-versus-host disease prophylaxis regimens: results of a prospective double-blind randomized trial." Biol Blood Marrow Transplant 6.3 (2000): 254-261.
PMID
10871150
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
6
Issue
3
Publish Date
2000
Start Page
254
End Page
261

Four-cycle high-dose therapy with hematopoietic support for metastatic breast cancer: no improvement in outcomes compared with single-course high-dose therapy.

Multiple-cycle high-dose therapy with autologous hematopoietic progenitor cell (AHPC) support has been used to deliver dose-intensive therapy. We have used this approach as well as single-cycle high-dose therapy in treating patients with metastatic breast cancer. We present the outcomes of multiple-cycle high-dose therapies and compare them with those resulting from single-course high-dose therapies performed at a single institution. Fifty-five patients received 4 cycles of intensive chemotherapy with AHPC support. Three multicycle regimens were sequentially applied. Twenty patients were enrolled to receive 4 cycles of high-dose mitoxantrone, thiotepa, and cyclophosphamide. Nineteen subsequent patients received this regimen modified by the incorporation of paclitaxel. Sixteen patients received 2 cycles of high-dose melphalan, thiotepa, and paclitaxel and 2 cycles of mitoxantrone, thiotepa, and paclitaxel. The results of all 3 multiple-cycle therapies are compared with those of 55 contemporaneous patients with metastatic breast cancer who received a single course of high-dose cyclophosphamide and thiotepa or cyclophosphamide, cisplatin, and BCNU (carmustine) with hematopoietic cell rescue. Multiple-cycle therapy was associated with more infectious complications, increased transfusion requirements, and increased hospital admissions. However, there were no significant differences in outcomes between the groups. For 55 patients who received multiple-cycle therapy, the actuarial 3-year overall survival rate was 36% (95% confidence interval [CI] 23%-49%); freedom from progression and event-free survival were both 15% (CI 5%-25%). The median time to disease progression and median survival were 1.0 and 1.6 years, respectively. For the 55 patients who underwent a single course of high-dose therapy, the 3-year overall survival was also 36% (CI 18%-54%), whereas freedom from progression and event-free survival were both 19% (CI 7%-31%). The median time to progression and median survival were 0.8 and 2.2 years, respectively. Within the constraints of this patient population, the outcomes of 4 cycles of high-dose therapy with AHPC support were not superior to those resulting from single courses of high-dose therapy in the treatment of patients with metastatic breast cancer.

Authors
Hu, WW; Negrin, RS; Stockerl-Goldstein, K; Johnston, LJ; Shizuru, JA; Wong, RM; Chao, NJ; Long, GD; Feiner, RH; Blume, KG
MLA Citation
Hu, WW, Negrin, RS, Stockerl-Goldstein, K, Johnston, LJ, Shizuru, JA, Wong, RM, Chao, NJ, Long, GD, Feiner, RH, and Blume, KG. "Four-cycle high-dose therapy with hematopoietic support for metastatic breast cancer: no improvement in outcomes compared with single-course high-dose therapy." Biol Blood Marrow Transplant 6.1 (2000): 58-69.
PMID
10708000
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
6
Issue
1
Publish Date
2000
Start Page
58
End Page
69

Unrelated placental blood in marrow transplantation.

Authors
Kurtzberg, J; Martin, P; Chao, N; Stevens, C; Rubinstein, P
MLA Citation
Kurtzberg, J, Martin, P, Chao, N, Stevens, C, and Rubinstein, P. "Unrelated placental blood in marrow transplantation." Stem Cells 18.2 (2000): 153-154.
PMID
10742391
Source
pubmed
Published In
Stem Cells
Volume
18
Issue
2
Publish Date
2000
Start Page
153
End Page
154
DOI
10.1634/stemcells.18-2-153

Graft-versus-host disease prevention by rapamycin: cellular mechanisms.

Understanding the cellular mechanisms that lead to graft-versus-host disease (GVHD) may lead to alternative approaches in the prevention or therapy of this disease process. In this manuscript, we investigated the mechanisms of action of the immunosuppressive drug rapamycin for the prevention of GVHD. GVHD-free long-term survival was achieved in BALB/c (H2d, Mls-2a, Mls-3a) recipients of B10.D2/nSnJ (H-2d, Mls-2a, Mls-3a) bone marrow and spleen cells after a 30-day course of high-dose rapamycin (5 mg/kg per day). Low responses to recipient and third-party cells in a mixed lymphocyte reaction (MLR) were observed as well as decreased mature T-cell numbers in the spleen. This low response was not due to defective interleukin (IL)-2 production, because exogenous IL-2 did not improve the responses in the MLR. However, GVHD-free long-term survival was associated with a large number of infiltrating mononuclear cells in the target organs of GVHD. This observation suggested the possibility that these cells were responsible for suppressing the immune response. Regulatory cells, which could suppress both antirecipient and third-party responses in vitro, were demonstrated to be present in the spleens of these GVHD-free long-term survivors. These results suggest that in addition to impaired cellular immune function, the presence of non-specific regulatory cells (ie, suppression) may contribute to maintenance of GVHD-free long-term survival induced by short-course rapamycin.

Authors
Chen, BJ; Morris, RE; Chao, NJ
MLA Citation
Chen, BJ, Morris, RE, and Chao, NJ. "Graft-versus-host disease prevention by rapamycin: cellular mechanisms." Biol Blood Marrow Transplant 6.5A (2000): 529-536.
PMID
11071258
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
6
Issue
5A
Publish Date
2000
Start Page
529
End Page
536

Mechanisms of tolerance induced by PG490-88 in a bone marrow transplantation model

PG490-88 is a semisyntheüc derivative of a novel compound PG490 (triptolide) purified from a Chinese herb (Tripterygium Wilfordii Hook F). Host specific tolerance in vivo was demonstrated in PG490-88-treated BALB/c recipients (H2d, Mls-21, Mls-3") of bone marrow and spleen cells from B10.D2 mice (H2d, Mls-2", Mls-3") by transplantation of recipient or third party neonatal hearts into the pinna of the ears of recipients. The mechanisms of tolerance were studied further in this model. Since all Vβ3 T cells, which recognize the superantigens Mls-2 and Mls-3 and are present in donor B l O.D2 mice but not in recipient BALB/c mice, are activated and cause GVHD in BALB/c recipients, all Vβ3+ T cells are considered host reactive T cells in this model. Therefore, the roles of clonal deletion/anergy can be studied by following the fate of Vβ3 T cells. As shown in the figure, significant numbers of host reactive Vβ3 CD4+ T cells (3.56+1.66 %), which were significant higher than those in normal BALB/c mice (0.27±0.12, P<0.0001) and were comparable with those in normal B l O.D2 mice (6.18±0.51, P>0.05), were present in PG490-88-treated mice. Simulât results were obtained on CD8 T cells. t r(Figure Presented) 6 NomulBALWc 5 OT-d«plet»d bone marrow T 4 OPG49M8 I I 3 ONwrnil BIO D2 BH These results suggest that clonal deletion was not responsible for the observed tolerance induced by PG490-88, In contrast, Vβ3- T cells were completely deleted in the control Tdepleted bone marrow recipients. Vβ3 T cells obtained from PG490-88-treated recipients which were demonstrated to be tolerant to host antigens proliferated normally in response to T cell receptor crosslinking mediated by anti-CD3 antibody. Neither antigen specific nor antigen nonspecific suppressor cells were found in PG490-88-treated mice. Taken together, the host specific tolerance induced by PG490-88 in a murine BMT model is not due to deletion of alloreactive cells. Moreover, suppressor cells are not involved in the maintenance of tolerance. Rather, PG490-88 appears to lead to allotolerance through the induction of a state of antigen specific anergy of the responding T cells.

Authors
Chen, BJ; Cui, X; Fidler, JM; Chao, NJ
MLA Citation
Chen, BJ, Cui, X, Fidler, JM, and Chao, NJ. "Mechanisms of tolerance induced by PG490-88 in a bone marrow transplantation model." Blood 96.11 PART II (2000): 309b-.
Source
scival
Published In
Blood
Volume
96
Issue
11 PART II
Publish Date
2000
Start Page
309b

Dendritic cell (DC) reconstitution after nonmyeloablative allogeneic stem cell transplants

Non-myeloablative allogeneic peripheral blood stem cell transplants {mini-allo PBSCT) are being evaluated as a lower toxicity alternative to conventional allogeneic transplantation for harnessing graft versus tumor effects. Induction of anti-tumor immunity post-transplant requires donor derived DC be available to process and present antigen to the donor lymphocytes. Because the kinetics of DC reconstitution after mini-allo PBSCT are unknown, we have initiated a study to evaluate DC number and function in 8 donor/recipient pairs prior to the preparative regimen and at various times after PBSC reinfusion. Peripheral blood mononuclear cells (PBMC) were separated over Ficoll and stained for FACS with antibodies to CD lie, HLA DR, and CD 14 to detect myeloid DC1, or lineage markers, CD123, HLA-DR, and CD1 le to detect lymphoid DC2. To determine the number of DC that can be generated from PBMC, we cultured the plastic adherent PBMC in serum free medium containing GM-CSF (800U/ml) and IL-4 (500U/ml) for 7 days and determined the percentage of large HLA DR+ cells by FACS. Diagnoses were AML 1, NHL 4, MDS 1, ET 1, and thalassemia 1. The preparative regimen was cyclophosphamide, fludarabine, and CAMPATH-1. Donor-derived G-CSF mobilized leukaphereses were depleted of T cells with CAMPATH-1 and reinfused. Five patients have reached day 14 following reinfusion. One failed to engraft, and the remainder achieved 43-99% donor chimerism in the bone marrow by RFLP analysis. Two patients died of disease progression. The median number of CD1 lc+CD14-HLA-DR+DC was 2.3% of the recipient PBMC prior to the preparative regimen, 1.5% of the donor leukapheresis PBMC, and 0.9% of the recipient peripheral blood at day 14 (P=NS). In two recipients who had CD1 lc-CD123bright DC2 measured after transplant, they were 0% and 0.7% of the PBMC compared to 0.13% and 0.26% in the donor leukapheresis. The median yield of DC generated from PBMC was 14% in the donor leukaphereses and 17% in the recipient peripheral blood at day 14 (P=NS). Three recipients had DC yields of < 1 % prior to the preparative regimen. This preliminary data suggests that myeloid DC 1 and DC precursors are present in the peripheral blood at the time of myeloid re-engraftment two weeks after mini-allo PBSCT. We are currently evaluating a) whether these DC are of donor or recipient origin, b) whether DC numbers stabilize at subsequent time points, c) whether DC function following transplant is diminished from pre-transplant levels. These results will guide studies of anti-tumor immunization following transplantation.

Authors
Morse, MA; Rizzieri, D; Hobeika, AC; Chao, N; Lyerly, HK
MLA Citation
Morse, MA, Rizzieri, D, Hobeika, AC, Chao, N, and Lyerly, HK. "Dendritic cell (DC) reconstitution after nonmyeloablative allogeneic stem cell transplants." 2000.
Source
scival
Published In
Blood
Volume
96
Issue
11 PART II
Publish Date
2000
Start Page
305b

Addition of stem cells from allogeneic donors accelerates engraftment and immune reconstitution after stem cell transplantation

Umbilical cord blood is a valuable source of hematopoietic stem cells. However, stem cell numbers are limited and there are significant delays in engraftment and immune reconstitution. Since full matching at the major histocompatibility complex (MHC) appears to be less critical in cord blood transplantation, one approach to increase the stem cell doses may be to combine cord blood units from different donors. The kinetics of hématologie engraftment and immune reconstitution were compared between one unit (2.5xlO')of T-depleted bone marrow cells from one single donor (C57BL/6 [H2b] or SJL/ J [H2s) and two units from different donors (C57BL/6+SJL/J) after transplantation into lethally irradiated (8.5Gy) BALB/c recipients (H2d). The dose of 2.5xl06 is the minimum required for rescuing the majority of the recipients. As shown in the figure, addition of one unit of stem cells from MHC mismatched allogeneic donor doubled the white blood counts on day+10 and +14. The differences were no longer significant on day +21, with the white counts only half of the pre-transplantation level. Similar effects were also observed on platelet count and hematocrit. The differences on peripheral T and B cell counts were first observed on day +21 and were not significant on day +60. Kinetics of chimerism demonstrated that cells from both donor (C57BL/6 and/or SJL/J) or recipient (BALB/c) contributed to myeloid and lymphoid reconstitution. However, when the stem cell doses in one single unit were increased to 1 x 107, the beneficial effects were not observed. The chimeras, containing cells from all three strains of mice survived in good health for more than 200 days after transplantation and were able to mount a recall immune response upon the challenge of ovalbumin in vivo. Our data suggest that addition of stem cells from MHC mismatched allogeneic donors is feasible and has beneficial effects on engraftment and immune reconstitution in a murine model of stem cell transplantation.

Authors
Chen, BJ; Cui, X; Chao, NJ
MLA Citation
Chen, BJ, Cui, X, and Chao, NJ. "Addition of stem cells from allogeneic donors accelerates engraftment and immune reconstitution after stem cell transplantation." Blood 96.11 PART I (2000): 171a-.
Source
scival
Published In
Blood
Volume
96
Issue
11 PART I
Publish Date
2000
Start Page
171a

Favorable Treatment Outcome in Non-Hodgkin's Lymphoma Patients with "Poor" Mobilization of Peripheral Blood Progenitor Cells

Our purpose was to evaluate the outcome and costs of high-dose chemotherapy and autologous peripheral blood progenitor cell (PBPC) transplantation in patients with the inability to mobilize sufficient numbers of PBPCs to allow rapid engraftment after PBPC transplantation. We treated 172 consecutive non-Hodgkin's lymphoma (NHL) patients with cyclophosphamide and granulocyte colony-stimulating factor followed by apheresis to collect PBPCs. The cells were separated on a Percoll gradient and purged with monoclonal antibodies and complement. The patients were categorized as "good" mobilizers if a collection of ≥2 × 106 CD34+ cells/kg was obtained (n = 138, 80%) or "poor" mobilizers if <2 × 106 CD34+ cells/kg were obtained (n = 34, 20%). With a median follow-up of 3.5 years, there is no statistically significant difference in actuarial event-free survival, overall survival, or relapse for good mobilizers compared with poor mobilizers. However, there was a trend toward increasing nonrelapse, transplantation-related mortality of 11.8% for poor mobilizers versus 3.6% for good mobilizers (P = .08) and early death from all causes including relapse within 120 days (poor 20.6% versus good 8.7%, P = .06). The total cost for bone marrow transplantation-related care was significantly higher, at $140,264 for poor mobilizers versus $80.833 for good mobilizers (P = .0001). The population of patients with NHL who mobilize PBPCs poorly into the circulation have a higher cost for posttransplant support. However, there is no significant difference in relapse, event-free survival, or overall survival for such patients compared with those who mobilize PBPCs easily.

Authors
Stockerl-Goldstein, KE; Reddy, SA; Horning, SJ; Blume, KG; Chao, NJ; Hu, WW; Johnston, LJ; Long, GD; Strober, S; Wong, RM; Feiner, RH; Kohler, S; Negrin, RS
MLA Citation
Stockerl-Goldstein, KE, Reddy, SA, Horning, SJ, Blume, KG, Chao, NJ, Hu, WW, Johnston, LJ, Long, GD, Strober, S, Wong, RM, Feiner, RH, Kohler, S, and Negrin, RS. "Favorable Treatment Outcome in Non-Hodgkin's Lymphoma Patients with "Poor" Mobilization of Peripheral Blood Progenitor Cells." Biology of Blood and Marrow Transplantation 6.5 (2000): 506-512.
PMID
11063379
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
6
Issue
5
Publish Date
2000
Start Page
506
End Page
512

Graft-Versus-Host Disease Prevention by Rapamycin: Cellular Mechanisms

Understanding the cellular mechanisms that lead to graft-versus-host disease (GVHD) may lead to alternative approaches in the prevention or therapy of this disease process. In this manuscript, we investigated the mechanisms of action of the immunosuppressive drug rapamycin for the prevention of GVHD. GVHD-free long-term survival was achieved in BALB/c (H2d, Mls-2a, Mls-3a) recipients of B10.D2/nSnJ (H-2d, Mls-2a, Mls-3a) bone marrow and spleen cells after a 30-day course of high-dose rapamycin (5 mg/kg per day). Low responses to recipient and third-party cells in a mixed lymphocyte reaction (MLR) were observed as well as decreased mature T-cell numbers in the spleen. This low response was not due to defective interleukin (IL)-2 production, because exogenous IL-2 did not improve the responses in the MLR. However, GVHD-free long-term survival was associated with a large number of infiltrating mononuclear cells in the target organs of GVHD. This observation suggested the possibility that these cells were responsible for suppressing the immune response. Regulatory cells, which could suppress both antirecipient and third-party responses in vitro, were demonstrated to be present in the spleens of these GVHD-free long-term survivors. These results suggest that in addition to impaired cellular immune function, the presence of non-specific regulatory cells (ie, suppression) may contribute to maintenance of GVHD-free long-term survival induced by short-course rapamycin.

Authors
Chen, BJ; Morris, RE; Chao, NJ
MLA Citation
Chen, BJ, Morris, RE, and Chao, NJ. "Graft-Versus-Host Disease Prevention by Rapamycin: Cellular Mechanisms." Biology of Blood and Marrow Transplantation 6.5 A (2000): 529-536.
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
6
Issue
5 A
Publish Date
2000
Start Page
529
End Page
536

High-Dose Therapy with Hematopoietic Cell Transplantation for Patients with Central Nervous System Involvement by Non-Hodgkin's Lymphoma

Central nervous system (CNS) involvement by non-Hodgkin's lymphoma (NHL) carries a poor patient prognosis whether it occurs as a primary site of disease or secondarily in patients with systemic disease. In a group of 481 patients undergoing high-dose therapy with hematopoietic cell transplantation (HCT) for NHL, 15 patients (3.1%) were identified with CNS involvement. Two patients had primary CNS lymphoma, and 13 had secondary disease. All patients received intrathecal chemotherapy, and 13 received CNS radiotherapy before transplantation. Fourteen patients received systemic chemotherapy. At the time of transplantation, both patients with primary CNS lymphoma and 8 patients with secondary disease had achieved a complete response, 3 patients had achieved a partial response, 1 had failed induction therapy, and 1 had progression of CNS disease before high-dose therapy. Fourteen patients received carmustine, etoposide, and cyclophosphamide as the preparative regimen, and 1 patient received fractionated total body irradiation instead of carmustine. The 2 patients with primary CNS lymphoma were alive and free of disease, 1 at 1085 days after HCT and 1 at 3704 days after HCT. The actuarial 5-year event-free survival (EFS) was 46% ± 26%, and overall survival (OS) was 41% ± 28%. The median EFS and OS were 2.2 and 1.5 years, respectively. Three patients experienced symptomatic memory loss or intellectual decline after therapy, 1 patient developed paraplegia, and 1 patient had a thrombotic stroke 20 months after HCT. Despite treatment-related toxicities, 7 patients responding to quality-of-life questions at approximately 1 year after HCT gave their overall quality of life a median rating of 9 out of a possible 10 (range, 6-10). High-dose therapy with autologous HCT can produce extended EFS in patients with secondary CNS lymphoma and possibly in those with primary CNS NHL.

Authors
Alvarnas, JC; Negrin, RS; Horning, SJ; Hu, WW; Long, GD; Schriber, JR; Stockerl-Goldstein, K; Tierney, K; Wong, R; Blume, KG; Chao, NJ
MLA Citation
Alvarnas, JC, Negrin, RS, Horning, SJ, Hu, WW, Long, GD, Schriber, JR, Stockerl-Goldstein, K, Tierney, K, Wong, R, Blume, KG, and Chao, NJ. "High-Dose Therapy with Hematopoietic Cell Transplantation for Patients with Central Nervous System Involvement by Non-Hodgkin's Lymphoma." Biology of Blood and Marrow Transplantation 6.3 A (2000): 352-358.
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
6
Issue
3 A
Publish Date
2000
Start Page
352
End Page
358

A predictive model for relapse in high-risk primary breast cancer patients treated with high-dose chemotherapy and autologous stem-cell transplant.

High-dose chemotherapy (HDCT) is currently under evaluation for high-risk primary breast cancer (HRPBC), defined by extensive axillary nodal involvement or inflammatory breast carcinoma. Phase II studies of HDCT for HRPBC show that 30-40% of patients eventually relapse. We retrospectively reviewed 176 patients enrolled in clinical trials of HDCT for HRPBC at the University of Colorado and analyzed 23 potential predictive variables for relapse. All of the patients received the same regimen, with cyclophosphamide, cisplatin, and BCNU. Nine patients who experienced a toxic death were excluded from this analysis. The resulting predictive model was subsequently tested in an independent patient set treated at Duke University with the same HDCT regimen. Nodal ratio (number of involved nodes:number of sampled nodes), tumor size, grade, stage, estrogen receptor, progesterone receptor, and clinical inflammatory breast carcinoma correlated with risk of relapse. Nodal ratio, tumor size, and the combined estrogen receptor/progesterone receptor status were independent predictors. A scoring system using those three variables determines the risk of relapse, with a sensitivity and specificity of 60 and 90%, respectively, and a positive and negative predictive value of 65 and 88%, respectively. The differences in relapse-free survival and overall survival between high- and low-score patients were highly significant (P<0.000001). This model was subsequently validated in the Duke patient set. This model can identify two subgroups of HRPBC patients with low (12%) and high (65%) risk for recurrence after HDCT. Future research that tests new therapies will focus on those patients with a high score.

Authors
Nieto, Y; Cagnoni, PJ; Shpall, EJ; Xu, X; Murphy, J; Vredenburgh, J; Chao, NJ; Bearman, SI; Jones, RB
MLA Citation
Nieto, Y, Cagnoni, PJ, Shpall, EJ, Xu, X, Murphy, J, Vredenburgh, J, Chao, NJ, Bearman, SI, and Jones, RB. "A predictive model for relapse in high-risk primary breast cancer patients treated with high-dose chemotherapy and autologous stem-cell transplant." Clin Cancer Res 5.11 (November 1999): 3425-3431.
PMID
10589754
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
5
Issue
11
Publish Date
1999
Start Page
3425
End Page
3431

A feasibility study of multiple cycle therapy with melphalan, thiotepa, and paclitaxel followed by mitoxantrone, thiotepa, and paclitaxel with autologous hematopoietic cell support for metastatic breast cancer.

Dose-intensive chemotherapy appears to be important in the treatment of patients with recurrent solid tumors. Expanding upon our prior experience, we report the results of our most recent approach to administering dose-intensive therapy using four cycles of moderately high-dose chemotherapy with hematopoietic cell support for patients with metastatic breast cancer. This outpatient therapy includes high-dose melphalan, thiotepa, and paclitaxel for two cycles followed by mitoxantrone, thiotepa, and paclitaxel for two cycles, with each cycle supported with autologous peripheral blood progenitor cells (PBPCs). Between December 1994 and June 1996, 16 patients with recurrent or refractory breast cancer were enrolled in this prospective study. They had received a median of two previous chemotherapy regimens, with a median of nine prior cycles of chemotherapy. For mobilization of autologous PBPCs, patients received cyclophosphamide, 4 g/m2, followed by granulocyte colony-stimulating factor (G-CSF). PBPCs were collected by apheresis. Each day's collection was divided into four equal fractions, and each fraction was infused after each cycle of combination therapy. Cycles 1 and 2 consisted of melphalan, 80 mg/m2, thiotepa, 300 mg/m2, and paclitaxel, 200 mg/m2. Cycles 3 and 4 were comprised of mitoxantrone, 30 mg/m2, and thiotepa and paclitaxel at the same doses as in the first two cycles. The cyclophosphamide infusion was administered in the hospital, whereas all subsequent infusions of chemotherapy and PBPCs were performed on an outpatient basis. The first seven patients were randomized to receive alternate cycle G-CSF or placebo on day +1 of each cycle. Including the initial pulse of cyclophosphamide, 67 (84%) of a planned 80 total courses of chemotherapy were delivered. Of the planned 64 cycles of high-dose combination chemotherapy, 52 cycles (81%) were delivered. Treatment was discontinued for progressive disease (one patient) or morbidity (five patients). Twelve of 16 patients completed at least three cycles of therapy. Nine patients completed all four cycles. One death resulted from fungal sepsis. In 20 cycles delivered to the first seven patients, day +1 G-CSF versus placebo was administered, with a median WBC recovery of 10 versus 13 days, respectively (P = 0.048 in cycle 1). The median duration of response was almost 9 months, and the median survival was 18 months after therapy. With a median follow-up of 1.5 years and longest follow-up of 4.2 years, two patients continue to be without evidence of disease. The 3-year event-free survival, freedom from progression, and overall survival are 19%, 20%, and 31%, respectively. This four-cycle regimen of high-dose combination therapy supported with hematopoietic progenitor cells is feasible, but it is associated with a range of posttransplant complications. The efficacy of such a treatment would have to be substantially superior to that of other currently available therapies, including single autologous transplant procedures, to justify the prolonged period of treatment, multiple episodes of pancytopenia, and associated toxicities, including infectious risks. G-CSF administration after each PBPC infusion appears to accelerate time to neutrophil recovery but does not affect red cell or platelet engraftment.

Authors
Hu, WW; Long, GD; Stockerl-Goldstein, KE; Johnston, LJ; Chao, NJ; Negrin, RS; Blume, KG
MLA Citation
Hu, WW, Long, GD, Stockerl-Goldstein, KE, Johnston, LJ, Chao, NJ, Negrin, RS, and Blume, KG. "A feasibility study of multiple cycle therapy with melphalan, thiotepa, and paclitaxel followed by mitoxantrone, thiotepa, and paclitaxel with autologous hematopoietic cell support for metastatic breast cancer." Clin Cancer Res 5.11 (November 1999): 3411-3418.
PMID
10589752
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
5
Issue
11
Publish Date
1999
Start Page
3411
End Page
3418

Prognostic and predictive factors for patients with metastatic breast cancer undergoing aggressive induction therapy followed by high-dose chemotherapy with autologous stem-cell support.

PURPOSE: We performed a retrospective review to determine predictive and prognostic factors in patients with metastatic breast cancer who received induction therapy, and, if they responded to treatment, high-dose chemotherapy. PATIENTS AND METHODS: Patients with metastatic breast cancer received induction therapy with doxorubicin, fluorouracil, and methotrexate (AFM). Partial responders then received immediate high-dose chemotherapy, whereas those who achieved complete remission were randomized to immediate or delayed high-dose chemotherapy with hematopoietic stem-cell support. We performed a retrospective review of data from these patients and used Cox proportional hazards regression models for analyses. RESULTS: The overall response rate for the 425 patients enrolled was 74% (95% confidence interval, 70% to 78%). Multivariate analysis of data from all 425 patients revealed that positive estrogen receptor status (P =.0041), smaller metastatic foci ( 2 cm) (P =. 0165), a longer disease-free interval from initial diagnosis to diagnosis of metastases ( 2 years) (P =.0051), and prior treatment with tamoxifen (P =.0152) were good prognostic signs for overall survival. Patients who had received prior adjuvant therapy (P =.0001) and those who developed liver metastases (P =.0001) had decreased long-term survival. In the subgroup of responders to AFM induction, multivariate analysis showed that those with visceral metastases did less well (P =.0006), as did patients who had received prior adjuvant therapy (P =.0023). However, those who had received tamoxifen therapy in the adjuvant setting did better (P =. 0143). CONCLUSION: The chance for long-term remission with induction therapy with AFM and high-dose chemotherapy is increased for hormone receptor positive-patients with nonvisceral metastases who have not received prior adjuvant chemotherapy and have long disease-free intervals.

Authors
Rizzieri, DA; Vredenburgh, JJ; Jones, R; Ross, M; Shpall, EJ; Hussein, A; Broadwater, G; Berry, D; Petros, WP; Gilbert, C; Affronti, ML; Coniglio, D; Rubin, P; Elkordy, M; Long, GD; Chao, NJ; Peters, WP
MLA Citation
Rizzieri, DA, Vredenburgh, JJ, Jones, R, Ross, M, Shpall, EJ, Hussein, A, Broadwater, G, Berry, D, Petros, WP, Gilbert, C, Affronti, ML, Coniglio, D, Rubin, P, Elkordy, M, Long, GD, Chao, NJ, and Peters, WP. "Prognostic and predictive factors for patients with metastatic breast cancer undergoing aggressive induction therapy followed by high-dose chemotherapy with autologous stem-cell support." J Clin Oncol 17.10 (October 1999): 3064-3074.
PMID
10506601
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
17
Issue
10
Publish Date
1999
Start Page
3064
End Page
3074
DOI
10.1200/JCO.1999.17.10.3064

Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prevention of acute graft-vs.-host disease: effect on chronic graft-vs.-host disease and long-term survival.

Graft-vs.-host disease (GVHD) is a major predictor of outcome following allogeneic bone marrow transplantation (BMT). For patients alive at day 100 after BMT, the presence or absence of chronic GVHD is one of the most important determinants of survival and quality of life. We wished to determine the effects on chronic GVHD of two regimens used for the prophylaxis of acute GVHD: cyclosporine, methotrexate, and prednisone (CSA/MTX/PSE) and cyclosporine and prednisone (CSA/PSE). One hundred forty-nine evaluable patients were entered into the acute GVHD study. As of 31 March 1997, 63 months after the last patient underwent BMT, the median survival time was 4.5 years (range 0.09-9.9). The incidence of chronic GVHD was independent of the prophylactic regimen (55 vs. 54%), and extensive chronic GVHD occurred in 25 and 24% of patients receiving CSA/MTX/PSE and CSA/PSE, respectively. Of note, the median Karnofsky performance status of both groups was 100% (range 70-100%), reflecting the low incidence of extensive chronic GVHD. Survival rates free of chronic GVHD were 52 vs. 42% (p = 0.29) for patients receiving CSA/MTX/PSE vs. CSA/PSE. The incidence of relapse was also similar in both groups of patients. These data suggest that the combinations of CSA/MTX/PSE and CSA/PSE result in comparable chronic GVHD-free survival without an increase in leukemic relapse.

Authors
Ross, M; Schmidt, GM; Niland, JC; Amylon, MD; Dagis, AC; Long, GD; Nademanee, AP; Negrin, RS; O'Donnell, MR; Parker, PM; Smith, EP; Snyder, DS; Stein, AS; Wong, RM; Forman, SJ; Blume, KG; Chao, NJ
MLA Citation
Ross, M, Schmidt, GM, Niland, JC, Amylon, MD, Dagis, AC, Long, GD, Nademanee, AP, Negrin, RS, O'Donnell, MR, Parker, PM, Smith, EP, Snyder, DS, Stein, AS, Wong, RM, Forman, SJ, Blume, KG, and Chao, NJ. "Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prevention of acute graft-vs.-host disease: effect on chronic graft-vs.-host disease and long-term survival." Biol Blood Marrow Transplant 5.5 (1999): 285-291.
PMID
10534058
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
5
Issue
5
Publish Date
1999
Start Page
285
End Page
291

Pathophysiologic mechanisms of acute graft-vs.-host disease.

Graft-vs.-host disease (GVHD) remains the major toxicity of allogeneic bone marrow transplantation. Mechanistic studies in experimental animal models provide a better understanding of the complex relationships and cascade of events mediated by cellular and inflammatory factors. Also, advances in basic immunology have cleared the way for a more precise view of allogeneic reactions between donor and host. In addition, the use of mutant mice lacking critical cytolytic proteins has helped map out the molecular pathways by which GVHD targets organ damage. In this article, these mechanisms are reviewed and synthesized into a coherent conceptual framework, providing a state-of-the-art summary of the pathophysiology of acute GVHD.

Authors
Ferrara, JL; Levy, R; Chao, NJ
MLA Citation
Ferrara, JL, Levy, R, and Chao, NJ. "Pathophysiologic mechanisms of acute graft-vs.-host disease." Biol Blood Marrow Transplant 5.6 (1999): 347-356. (Review)
PMID
10595812
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
5
Issue
6
Publish Date
1999
Start Page
347
End Page
356

Secondary myelodysplasia and acute leukemia in breast cancer patients after autologous bone marrow transplant.

PURPOSE: To determine the incidence of myelodysplasia (MDS) and/or acute leukemia (AL) in breast cancer patients after high-dose chemotherapy (HDC) with a single conditioning regimen and autologous bone marrow transplant (ABMT), and analyze the cytogenetic abnormalities that arise after HDC. PATIENTS AND METHODS: We retrospectively reviewed the records of 864 breast cancer patients who underwent ABMT at Duke University Medical Center, Durham, NC, from 1985 through 1996 who received the same preparative regimen of cyclophosphamide 1,875 mg/m2 for 3 days, cisplatin 55 mg/m2 for 3 days, and BCNU 600 mg/m2 for 1 day (CPB). Pretransplant cytogenetics were analyzed in all patients and posttransplant cytogenetics were evaluated in four of five patients who developed MDS/AL. RESULTS: Five of 864 patients developed MDS/AL after HDC with CPB and ABMT. The crude cumulative incidence of MDS/AL was 0.58%. The Kaplan-Meier curve shows a 4-year probability of developing MDS/AL of 1.6%. Pretransplant cytogenetics performed on these five patients were all normal. Posttransplant cytogenetics were performed on four of five patients and they were abnormal in all four, although only one patient had the most common cytogenetic abnormality associated with secondary MDS/AL (chromosome 5 and/or 7 abnormality). CONCLUSION: Whereas MDS/AL is a potential complication of HDC with CPB and ABMT, the incidence in this series of patients with breast cancer was relatively low compared with that reported in patients with non-Hodgkin's lymphoma who underwent ABMT. The cytogenetic abnormalities reported in this group of breast cancer patients were not typical of those seen in prior reports of secondary MDS/AL and appear to have occurred after HDC.

Authors
Laughlin, MJ; McGaughey, DS; Crews, JR; Chao, NJ; Rizzieri, D; Ross, M; Gockerman, J; Cirrincione, C; Berry, D; Mills, L; Defusco, P; LeGrand, S; Peters, WP; Vredenburgh, JJ
MLA Citation
Laughlin, MJ, McGaughey, DS, Crews, JR, Chao, NJ, Rizzieri, D, Ross, M, Gockerman, J, Cirrincione, C, Berry, D, Mills, L, Defusco, P, LeGrand, S, Peters, WP, and Vredenburgh, JJ. "Secondary myelodysplasia and acute leukemia in breast cancer patients after autologous bone marrow transplant." J Clin Oncol 16.3 (March 1998): 1008-1012.
PMID
9508184
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
16
Issue
3
Publish Date
1998
Start Page
1008
End Page
1012
DOI
10.1200/JCO.1998.16.3.1008

Fractionated total-body irradiation, etoposide, and cyclophosphamide followed by allogeneic bone marrow transplantation for patients with high-risk or advanced-stage hematological malignancies.

Myeloablative therapy followed by allogeneic bone marrow transplantation (BMT) has proven to be curative therapy in patients with hematologic malignancies. Relapse, however, remains a major cause of treatment failure for patients with advanced disease. During the past 15 years, we have gained considerable experience with the combination of fractionated total-body irradiation (FTBI) and etoposide followed by allogeneic BMT for hematologic malignancies. In an attempt to decrease post-transplant relapse rates, 67 patients under the age of 50 years with high-risk or advanced-stage hematological malignancies received an intensified regimen of FTBI and etoposide plus cyclophosphamide followed by BMT from a genotypically-matched related donor. The regimen consisted of 1320 cGy of FTBI in 11 fractions, 60 mg/kg of etoposide (VP-16), and 60 mg/kg of cyclophosphamide (CY). Fifty-three patients received cyclosporine and prednisone for graft-vs.-host disease (GVHD) prophylaxis and 14 patients received cyclosporine, methotrexate, and prednisone. Diagnosis at BMT included 45 patients with acute leukemia, 7 patients with chronic leukemia, and 15 patients with high-grade non-Hodgkin's lymphoma (NHL). Actuarial disease-free survival (DFS) at 3 years was 42% +/- 12% for the entire group with a median follow-up of 50 months (range 20-74) for 28 patients who remain alive in continued complete remission (CR). Actuarial 3-year-DFS was 38% +/- 14% in 52 patients with acute or chronic leukemia and 60% +/- 25% in 15 patients with NHL with relapse rates of 45% +/- 16% and 21% +/- 11%, respectively. DFS at 3 years was 40% +/- 18% in 32 patients with acute leukemia in 1st relapse or 2nd CR or chronic myelogenous leukemia in accelerated phase, and was 32% +/- 22% in 20 patients with more advanced disease. Regimen related mortality occurred in 9 patients (4, veno-occlusive disease of the liver; 2, multi-organ failure; 1, diffuse alveolar hemorrhage; 1, central nervous system (CNS) hemorrhage; 1, adult respiratory distress syndrome (ARDS). The combination of FTBI, etoposide, and cyclophosphamide followed by allogeneic BMT is an effective and relatively well-tolerated regimen for patients with advanced hematologic malignancies. The role for this regimen should be further defined by prospective clinical trials.

Authors
Long, GD; Amylon, MD; Stockerl-Goldstein, KE; Negrin, RS; Chao, NJ; Hu, WW; Nademanee, AP; Snyder, DS; Hoppe, RT; Vora, N; Wong, R; Niland, J; Reichardt, VL; Forman, SJ; Blume, KG
MLA Citation
Long, GD, Amylon, MD, Stockerl-Goldstein, KE, Negrin, RS, Chao, NJ, Hu, WW, Nademanee, AP, Snyder, DS, Hoppe, RT, Vora, N, Wong, R, Niland, J, Reichardt, VL, Forman, SJ, and Blume, KG. "Fractionated total-body irradiation, etoposide, and cyclophosphamide followed by allogeneic bone marrow transplantation for patients with high-risk or advanced-stage hematological malignancies." Biol Blood Marrow Transplant 3.6 (December 1997): 324-330.
PMID
9502300
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
3
Issue
6
Publish Date
1997
Start Page
324
End Page
330

Value of skin biopsies in assessing prognosis and progression of acute graft-versus-host disease.

Skin biopsies are commonly performed after allogeneic bone marrow transplantation (BMT) to help establish the origin of a new skin rash in a transplant recipient. Histologic criteria and a grading system for acute graft-versus-host reaction of the skin are well established. Histologic diagnosis, however, can be difficult and is based on interpretation of subtle changes that show significant overlap with features seen in other entities that can be responsible for a skin rash in the posttransplantation period such as drug reactions, viral exanthems, and the effects of chemotherapy. We retrospectively reviewed 179 skin biopsies from 137 patients who had undergone allogeneic BMT. We compared 98 skin biopsies from 71 patients with acute graft-versus-host disease (GvHD) with 81 biopsies from 66 patients who underwent biopsy to exclude GvHD but did not go on to develop the disease on clinical grounds. Two observers reviewed each slide without knowledge of the clinical situation and graded 16 histologic parameters. No single parameter (e.g., dyskeratotic keratinocytes, basal vacuolization, satellitosis, necrotic cells in appendages) achieved statistical significance on univariate analysis. A search for factors to separate GvHD biopsies from non-GvHD biopsies using logistic regression failed to reveal a single best predictor or a combination of predictors. We conclude that skin biopsies after allogeneic BMT are of limited use in predicting the progression of a skin rash to clinical grade II or higher GvHD.

Authors
Kohler, S; Hendrickson, MR; Chao, NJ; Smoller, BR
MLA Citation
Kohler, S, Hendrickson, MR, Chao, NJ, and Smoller, BR. "Value of skin biopsies in assessing prognosis and progression of acute graft-versus-host disease." Am J Surg Pathol 21.9 (September 1997): 988-996.
PMID
9298874
Source
pubmed
Published In
American Journal of Surgical Pathology
Volume
21
Issue
9
Publish Date
1997
Start Page
988
End Page
996

Treatment of non-Hodgkin's lymphoma with high-dose therapy and hematopoietic stem cell support.

Standard therapies for advanced low-grade lymphomas are not likely to provide a cure, prompting the use of more aggressive approaches. Patients with low-grade lymphoma who receive high-dose therapy with stem cell support appear to have a prolonged disease-free survival, although the benefit to overall survival remains unproven. Patients with chemotherapy-sensitive intermediate- or high-grade relapsed disease have improved survival with high-dose therapy, and those with high-risk disease may benefit from early consolidation while in first remission. Significant questions remain in terms of the proper timing of high-dose therapy, appropriate stratification by risk factors, the value of purging, the role of radiotherapy after transplantation, and the most appropriate source of stem cells for transplantation.

Authors
Rizzieri, DA; Chao, NJ
MLA Citation
Rizzieri, DA, and Chao, NJ. "Treatment of non-Hodgkin's lymphoma with high-dose therapy and hematopoietic stem cell support." Curr Opin Oncol 9.5 (September 1997): 420-427. (Review)
PMID
9327219
Source
pubmed
Published In
Current Opinion in Oncology
Volume
9
Issue
5
Publish Date
1997
Start Page
420
End Page
427

T helper 2-dominant antilymphoma immune response is associated with fatal outcome.

The precise role of the endogenous immune system in modulating cancer development remains unclear. Tumor cells are generally thought to be nonimmunogenic because they are of 'self' origin. However, tumor-reactive lymphocytes can be isolated from patients with many types of cancer. It is unclear what role these lymphocytes play and why they fail to protect the host. Using a murine B-cell leukemia/lymphoma (BCL1) model, we showed the development of a vigorous antitumor T-cell response in the tumor-susceptible host. Specific T-cell responses against BCL1 developed as early as day 4. However, the nature of this nonprotective response is different from the protective response produced in a major histocompatibility complex-matched tumor-resistant host. Susceptible hosts developed a T helper 2 (Th2)-dominant response, whereas resistant hosts developed a Th1-dominant response to BCL1. Cytolytic activity against BCL1 developed in both resistant and susceptible hosts, but in the susceptible host, this response was weaker and delayed compared with that in the resistant host. Thus, tumor susceptibility does not necessarily mean the absence of an antitumor immune response. Rather, the nature of the antitumor immune response is critical in determining clinical outcome.

Authors
Lee, PP; Zeng, D; McCaulay, AE; Chen, YF; Geiler, C; Umetsu, DT; Chao, NJ
MLA Citation
Lee, PP, Zeng, D, McCaulay, AE, Chen, YF, Geiler, C, Umetsu, DT, and Chao, NJ. "T helper 2-dominant antilymphoma immune response is associated with fatal outcome." Blood 90.4 (August 15, 1997): 1611-1617.
PMID
9269780
Source
pubmed
Published In
Blood
Volume
90
Issue
4
Publish Date
1997
Start Page
1611
End Page
1617

Studies on the mechanism and specificity of the effect of the synthetic random copolymer GLAT on graft-versus-host disease.

Graft-versus-host disease (GVHD), which occurs when donor T-cells recognize multiple minor host histocompatibility antigens as non-self, presents the major limitation to successful allogeneic bone-marrow transplantation. The synthetic random copolymer of the amino acids, L-Glu, L-Lys, L-Ala and L-Tyr, termed GLAT, with promiscuous binding to multiple MHC class II alleles, reduces the incidence, onset and severity of disease in the BIO.D2 --> BALB/c model of lethal GVHD. GLAT inhibited the proliferative response towards host of both spleen cells from mice with GVHD and also of the effector T cell line established from these mice. Administration of GLAT for a limited period after transplantation completely abolished the cytotoxic activity toward host cells exerted by spleen cells from mice with GVHD. Whereas spleen and bone marrow cells from control mice with GVHD secreted IL-2 and INF-gamma when cocultured with host cells, these inflammatory cytokines could not be detected in supernatants of cells from GLAT treated mice. Moreover spleens and bone marrow cells from GLAT treated mice secreted small but significant amounts of IL-4 and IL-6 when cocultured with GLAT, suggesting that GLAT not only inhibits pro-GVHD cytokines but also causes a beneficial effect by inducing secretion of Th2 type cytokines. GLAT binds strongly to MHC molecules of host as well as donor haplotype. D-GLAT, identical to GLAT but composed of D-amino acids is also effective in preventing GVHD. D-GLAT does not cross-react with L-GLAT, but still binds strongly to MHC-class II molecules. These findings indicate that MHC blocking is involved in the therapeutic effect of GLAT on GVHD. The cumulative data demonstrate that GLAT modulates the effector mechanisms involved in GVHD, and can be potentially used for the prevention of GVHD across minor histocompatibility barriers.

Authors
Aharoni, R; Schlegel, PG; Teitelbaum, D; Roikhel-Karpov, O; Chen, Y; Arnon, R; Sela, M; Chao, NJ
MLA Citation
Aharoni, R, Schlegel, PG, Teitelbaum, D, Roikhel-Karpov, O, Chen, Y, Arnon, R, Sela, M, and Chao, NJ. "Studies on the mechanism and specificity of the effect of the synthetic random copolymer GLAT on graft-versus-host disease." Immunol Lett 58.2 (July 1997): 79-87.
PMID
9271317
Source
pubmed
Published In
Immunology Letters
Volume
58
Issue
2
Publish Date
1997
Start Page
79
End Page
87

Graft-versus-host disease: the viewpoint from the donor T cell.

Authors
Chao, NJ
MLA Citation
Chao, NJ. "Graft-versus-host disease: the viewpoint from the donor T cell." Biol Blood Marrow Transplant 3.1 (April 1997): 1-10. (Review)
PMID
9209735
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
3
Issue
1
Publish Date
1997
Start Page
1
End Page
10

Administration of a CD31-derived peptide delays the onset and significantly increases survival from lethal graft-versus-host disease.

The CD31 monoclonal antibody, LYP21, binds to the CD31 domain 6 and inhibits the human mixed-lymphocyte reaction (MLR) in a specific and dose-dependent fashion. A synthetic CD31 peptide based on human CD31 epitope (amino acids 551 to 574) recognized by LYP21 is equally effective in inhibiting the MLR. In this study, we used the murine homolog of CD31 peptide 551 to 574 and a control peptide to study the role of CD31 molecule on T-cell activation. In vitro, CD31 peptide inhibited the MLR across several major and minor histocompatibility differences in a specific and dose-dependent fashion, similar to the results observed in the human system. Maximal inhibition was achieved at a dose of 200 microg/mL. In the cytotoxic T-lymphocyte (CTL) assay, CD31 peptide inhibited CTL responses by 97%. To study the in vivo effect of this peptide, graft-versus-host disease (GVHD) across minor histocompatibility barriers was induced in the B10.D2 (H-2d) --> BALB/c (H-2d) model. BALB/c recipients received CD31 peptide (100 microg/d), or phosphate-buffered saline (PBS), or control peptide (100 microg/d) intraperitoneally (IP) for the first 5 weeks. CD31 peptide delayed onset of graft-versus-host disease and significantly increased long-term survival. Twelve of 14 mice receiving CD31 peptide survived more than 100 days after transplantation, as compared with none of 10 mice receiving PBS and none of five mice receiving control peptide (P = .0001). Long-term engraftment of allogeneic bone marrow was documented in all transplanted mice by polymerase chain reaction (PCR) analysis of microsatellite region in the interleukin (IL)-1beta gene. Our data suggest that the CD31 molecule has an important functional role in T-cell activation in vitro and in vivo.

Authors
Chen, Y; Schlegel, PG; Tran, N; Thompson, D; Zehnder, JL; Chao, NJ
MLA Citation
Chen, Y, Schlegel, PG, Tran, N, Thompson, D, Zehnder, JL, and Chao, NJ. "Administration of a CD31-derived peptide delays the onset and significantly increases survival from lethal graft-versus-host disease." Blood 89.4 (February 15, 1997): 1452-1459.
PMID
9028970
Source
pubmed
Published In
Blood
Volume
89
Issue
4
Publish Date
1997
Start Page
1452
End Page
1459

High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin's disease: analysis of the Stanford University results and prognostic indices.

One hundred nineteen patients with relapsed or refractory Hodgkin's disease (HD) received high-dose therapy followed by autologous hematopoietic progenitor cell transplantation. Three preparatory regimens, selected on the basis of prior therapy and pulmonary status, were employed. Twenty-six patients without a history of prior chest or pelvic irradiation were treated with fractionated total body irradiation, etoposide (VP) 60 mg/kg and cyclophosphamide (Cy) 100 mg/kg. Seventy-four patients received BCNU 15 mg/kg with identical doses of VP and Cy. A group of 19 patients with a limited diffusing capacity or history of pneumonitis received a novel high-dose regimen consisting of CCNU 15 mg/kg, VP 60 mg/kg and Cy 100 mg/kg. Twenty-nine patients (24%) had failed induction therapy and 35 (29%) had progressive HD within 1 year of initial chemotherapy. At 4 years actuarial survival was 52%, event-free survival was 48% and freedom from progression (FFP) was 62%. No significant differences were seen in survival data with the three preparatory regimens. Six patients died within 100 days of transplantation and 5 died at a later date of transplant-related complications. Secondary malignancies have developed in 6 patients, including myelodysplasia/leukemia in four patients and solid tumors in two patients. Regression analysis identified systemic symptoms at relapse, disseminated pulmonary or bone marrow disease at relapse and more than minimal disease at the time of transplantation as significant prognostic factors for overall and event-free survival and FFP. Patients with none of these factors enjoyed an 85% FFP at 4 years compared with 41% for patients with one or more unfavorable prognostic factors (P = .0001). Our results confirm the efficacy of high-dose therapy and autografting in recurrent or refractory HD. Although longer follow-up is necessary to address ultimate cure rates and toxicity, our data indicate that a desire to reduce late effects should drive future research efforts in favorable patients whereas new initiatives are needed for those with less favorable prognoses.

Authors
Horning, SJ; Chao, NJ; Negrin, RS; Hoppe, RT; Long, GD; Hu, WW; Wong, RM; Brown, BW; Blume, KG
MLA Citation
Horning, SJ, Chao, NJ, Negrin, RS, Hoppe, RT, Long, GD, Hu, WW, Wong, RM, Brown, BW, and Blume, KG. "High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin's disease: analysis of the Stanford University results and prognostic indices." Blood 89.3 (February 1, 1997): 801-813.
PMID
9028311
Source
pubmed
Published In
Blood
Volume
89
Issue
3
Publish Date
1997
Start Page
801
End Page
813

Influence of age on the outcome of 500 autologous bone marrow transplant procedures for hematologic malignancies.

PURPOSE: To determine the effect of age on the outcome of autologous bone marrow transplantation (ABMT) and/or peripheral-blood progenitor-cell (PBPC) transplantation. PATIENTS AND METHODS: A retrospective analysis was performed on 500 consecutive patients who ranged in age from 1 to 65 years (median, 40) with non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), multiple myeloma (MM), or acute nonlymphoblastic leukemia (AML) who underwent autologous hematopoietic-cell transplant procedures at Stanford University Medical Center. RESULTS: The actuarial 5-year event-free survival (EFS) rate was 44%, the relapse rate 47%, and the regimen-related mortality (RRM) rate 8.6%. Disease status at time of transplantation, categorized as either minimal or advanced disease, was the strongest predictive factor for EFS (relative risk (RR) for advanced-disease group, 1.8; P < .0003) and relapse rate (RR for advanced-disease group, 1.9; P < .0004). Patients with minimal or advanced disease had an EFS rate of 48% and 30% and relapse rates of 43% and 72%, respectively. The EFS rate of patients less than 50 years verus > or = 50 years of age was 46% versus 34% (P = .03). Cox regression analysis showed that age was predictive for EFS (RR for patients 50 to 65 years, 1.4; P = .03). The actuarial RRM rate for these age groups was 7.4% versus 12.7% (P = .07), respectively. Multivariate analysis demonstrated that age (odds ratio [OR] for patients 50 to 65 years, 1.9; P < .05) and period of transplantation (OR for most recent years [1991 to 1995], 0.6; P = .06) were the most predictive factors for RRM. CONCLUSION: Although age greater than 50 years is associated with an inferior outcome following autologous hematopoietic-cell transplantation, it does not appear to be warranted to limit this potentially curative procedure based solely on age. The upper age limit of high-dose therapy with autologous progenitor-cell and/ or bone marrow support remains to be defined.

Authors
Kusnierz-Glaz, CR; Schlegel, PG; Wong, RM; Schriber, JR; Chao, NJ; Amylon, MD; Hu, WW; Negrin, RS; Lee, Y; Blume, KG; Long, GD
MLA Citation
Kusnierz-Glaz, CR, Schlegel, PG, Wong, RM, Schriber, JR, Chao, NJ, Amylon, MD, Hu, WW, Negrin, RS, Lee, Y, Blume, KG, and Long, GD. "Influence of age on the outcome of 500 autologous bone marrow transplant procedures for hematologic malignancies." J Clin Oncol 15.1 (January 1997): 18-25.
PMID
8996120
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
15
Issue
1
Publish Date
1997
Start Page
18
End Page
25
DOI
10.1200/JCO.1997.15.1.18

High dose etoposide-based myeloablative therapy followed by autologous blood progenitor cell rescue in the treatment of multiple myeloma.

BACKGROUND: A number of studies have demonstrated that high dose chemotherapy, with or without radiotherapy, with autologous marrow and/or peripheral blood progenitor cell support can result in improved overall and complete response rates in patients with multiple myeloma, and a minority of patients become long term survivors. Based on their favorable experience with high dose etoposide-based regimens in patients with Hodgkin's disease and non-Hodgkin's lymphoma, the authors explored the use of these regimens prior to autologous progenitor cell rescue in patients with multiple myeloma. METHODS: Thirty-four patients (median age, 49 years; range, 38-65) with multiple myeloma who were responsive to standard chemotherapy were enrolled in this study. Blood progenitor cells were collected after treatment with cyclophosphamide at a dose of 4 g/m2 followed by granulocyte-colony stimulating factor (G-CSF) at a dose of approximately 10 micrograms/kg/day subcutaneously, and the collection continued daily until the target number of mononuclear cells had been obtained. The preparative regimen consisted of fractionated total body irradiation (FTBI) of 1200 centigray in 10 fractions on Day -8 to Day -5, etoposide 60 mg/kg intravenously (i.v.) on Day -4, and cyclophosphamide 100 mg/kg i.v. on Day -2. Day 0 was the day of progenitor cell infusion. Patients who were older than 50 years or had received prior radiation therapy that precluded FTBI received carmustine 15 mg/kg i.v. or lomustine 15 mg/kg orally on Day -6 rather than FTBI. G-CSF (5 micrograms/kg/day) was begun the day after progenitor cell infusion and continued until engraftment. RESULTS: Recovery of granulocytes to 500/microL occurred at a median of 9 days (range, 7-13), and platelet recovery to 20,000/microL occurred without transfusion at 9 days (range, 6-88) after progenitor cell infusion. Thirty-two patients were evaluable for response. Eleven patients (34%) achieved a complete remission, 17 (53%) achieved a partial remission, and 4 (13%) had stable disease following high dose therapy and progenitor cell rescue. The actuarial event free survival at 4 years for the entire group was 26%, and overall survival was 36%. The median time to progression of disease was 13 months (range, 2-42). Two patients died of regimen-related toxicity, one of venoocclusive disease of the liver and the other of multiorgan failure. In a multivariate analysis, only the extent of prior therapy was a significant prognostic factor for event free survival, and no significant factors were identified for overall survival. CONCLUSIONS: High dose etoposide-based myeloablative regimens followed by autologous blood progenitor cell rescue are relatively well tolerated and effective for the treatment of multiple myeloma, and a minority of patients become long term disease free survivors.

Authors
Long, GD; Chao, NJ; Hu, WW; Negrin, RS; Wong, RM; Blume, KG
MLA Citation
Long, GD, Chao, NJ, Hu, WW, Negrin, RS, Wong, RM, and Blume, KG. "High dose etoposide-based myeloablative therapy followed by autologous blood progenitor cell rescue in the treatment of multiple myeloma." Cancer 78.12 (December 15, 1996): 2502-2509.
PMID
8952558
Source
pubmed
Published In
Cancer
Volume
78
Issue
12
Publish Date
1996
Start Page
2502
End Page
2509

Immunomodulatory peptides with high binding affinity for class II MHC molecules for the prevention of graft-versus-host disease.

Graft-versus-host disease (GVHD) represents the major barrier to successful allogeneic bone marrow transplantation. Positive and negative selection studies have unequivocally demonstrated that donor T cells are responsible for the induction phase of GVHD. Inhibition of the early steps of T cell antigen recognition leading to graft-versus-host disease has become an area of intense investigation. Peptides with high binding affinity for class II MHC molecules have been shown to compete for the single class II binding site and to inhibit T cell proliferative responses in vitro. Recent work has extended this approach to the prevention of murine GVHD in vivo.

Authors
Schlegel, PG; Chao, NJ
MLA Citation
Schlegel, PG, and Chao, NJ. "Immunomodulatory peptides with high binding affinity for class II MHC molecules for the prevention of graft-versus-host disease." Leuk Lymphoma 23.1-2 (September 1996): 11-16. (Review)
PMID
9021680
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
23
Issue
1-2
Publish Date
1996
Start Page
11
End Page
16
DOI
10.3109/10428199609054796

Polymyositis as a manifestation of chronic graft-versus-host disease.

A syndrome indistinguishable from idiopathic polymyositis occurred in 11 patients as a manifestation of chronic GVHD. All patients had elevation of creatine phosphokinase (CPK). Immunohistology demonstrated the effector cells in the muscle infiltrates as cytotoxic T cells, a finding similar to idiopathic polymyositis. Polymyositis is a rarely reported complication of chronic graft-versus-host disease (GVHD) with only 8 cases described in the literature. We encountered this syndrome in a small but significant percentage of our patients with chronic GVHD. Polymyositis associated with chronic GVHD does not affect the overall prognosis for the patient. Moreover, polymyositis can be the only manifestation of chronic GVHD. Awareness of this complication is important because it can be confused with other causes of muscle weakness after bone marrow transplantation. Finally, prompt initiation of corticosteroid therapy results in a rapid improvement of the associated symptoms.

Authors
Parker, P; Chao, NJ; Ben-Ezra, J; Slatkin, N; Openshaw, H; Niland, JC; Linker, CA; Greffe, BS; Kashyap, A; Molina, A; Nademanee, A; O'Donnell, MR; Planas, I; Sheibani, K; Smith, EP; Snyder, DS; Spielberger, R; Stein, AS; Stepan, DE; Blume, KG; Forman, SJ
MLA Citation
Parker, P, Chao, NJ, Ben-Ezra, J, Slatkin, N, Openshaw, H, Niland, JC, Linker, CA, Greffe, BS, Kashyap, A, Molina, A, Nademanee, A, O'Donnell, MR, Planas, I, Sheibani, K, Smith, EP, Snyder, DS, Spielberger, R, Stein, AS, Stepan, DE, Blume, KG, and Forman, SJ. "Polymyositis as a manifestation of chronic graft-versus-host disease." Medicine (Baltimore) 75.5 (September 1996): 279-285. (Review)
PMID
8862349
Source
pubmed
Published In
Medicine
Volume
75
Issue
5
Publish Date
1996
Start Page
279
End Page
285

A synthetic random basic copolymer with promiscuous binding to class II major histocompatibility complex molecules inhibits T-cell proliferative responses to major and minor histocompatibility antigens in vitro and confers the capacity to prevent murine graft-versus-host disease in vivo.

Graft-versus-host disease (GVHD) is a T-cell-mediated disease of transplanted donor T cells recognizing host alloantigens. Data presented in this report show, to our knowledge, for the first time that a synthetic copolymer of the amino acids L-Glu, L-Lys, L-Ala, and L-Tyr (molecular ratio, 1.9:6.0:4.7:1.0; Mr, 6000-8500) [corrected], termed GLAT, with promiscuous binding to multiple major histocompatibility complex class II alleles is capable of preventing lethal GVHD in the B10.D2 --> BALB/c model (both H-2d) across minor histocompatibility barriers. Administration of GLAT over a limited time after transplant significantly reduced the incidence, onset, and severity of disease. GLAT also improved long-term survival from lethal GVHD: 14/25 (56%) of experimental mice survived > 140 days after transplant compared to 2/26 of saline-treated or to 1/10 of hen egg lysozyme-treated control mice (P < 0.01). Long-term survivors were documented to be fully chimeric by PCR analysis of a polymorphic microsatellite region in the interleukin 1beta gene. In vitro, GLAT inhibited the mixed lymphocyte culture in a dose-dependent fashion across a variety of major barriers tested. Furthermore, GLAT inhibited the response of nylon wool-enriched T cells to syngeneic antigen-presenting cells presenting minor histocompatibility antigens. Prepulsing of the antigen-presenting cells with GLAT reduced the proliferative response, suggesting that GLAT inhibits antigen presentation.

Authors
Schlegel, PG; Aharoni, R; Chen, Y; Chen, J; Teitelbaum, D; Arnon, R; Sela, M; Chao, NJ
MLA Citation
Schlegel, PG, Aharoni, R, Chen, Y, Chen, J, Teitelbaum, D, Arnon, R, Sela, M, and Chao, NJ. "A synthetic random basic copolymer with promiscuous binding to class II major histocompatibility complex molecules inhibits T-cell proliferative responses to major and minor histocompatibility antigens in vitro and confers the capacity to prevent murine graft-versus-host disease in vivo." Proc Natl Acad Sci U S A 93.10 (May 14, 1996): 5061-5066.
PMID
8643529
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
93
Issue
10
Publish Date
1996
Start Page
5061
End Page
5066

Paradoxical effect of thalidomide prophylaxis on chronic graft-vs.-host disease.

Thalidomide has been reported to be an effective agent for the treatment of chronic graft-vs.-host disease (GVHD). To determine its efficacy as a prophylactic agent for the prevention of chronic GVHD, a prospective randomized double-blind study was performed. A total of 59 patients were randomized to receive either placebo or thalidomide (200 mg orally twice a day) beginning 80 days after allogeneic bone marrow transplantation (BMT). Fifty-four evaluable patients were analyzed, 26 received placebo, and 28 received thalidomide. The characteristics of patients were well-balanced between the two groups. Following the first interim analysis conducted by the Data Safety Monitoring Board using an intent-to-treat approach, a statistically significant difference in the incidence of chronic GVHD was found. Patients receiving thalidomide developed chronic GVHD more often than patients receiving placebo (p = 0.06). Moreover, an apparent overall survival advantage was noted for patients receiving placebo compared to those receiving thalidomide (p = 0.006). Adjustment for possible confounding factors did not eliminate these negative effects of thalidomide. These results demonstrate that while thalidomide is an effective agent for the therapy of chronic GVHD, its use at the doses administered for the prophylaxis of chronic GVHD resulted in a paradoxical outcome with a higher incidence of chronic GVHD and a lower overall survival. We conclude that the early use of thalidomide results in a shift in the balance between GVHD and induction of tolerance. These data demonstrate again the importance of phase III double-blind controlled randomized studies.

Authors
Chao, NJ; Parker, PM; Niland, JC; Wong, RM; Dagis, A; Long, GD; Nademanee, AP; Negrin, RS; Snyder, DS; Hu, WW; Gould, KA; Tierney, DK; Zwingenberger, K; Forman, SJ; Blume, KG
MLA Citation
Chao, NJ, Parker, PM, Niland, JC, Wong, RM, Dagis, A, Long, GD, Nademanee, AP, Negrin, RS, Snyder, DS, Hu, WW, Gould, KA, Tierney, DK, Zwingenberger, K, Forman, SJ, and Blume, KG. "Paradoxical effect of thalidomide prophylaxis on chronic graft-vs.-host disease." Biol Blood Marrow Transplant 2.2 (May 1996): 86-92.
PMID
9118303
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
2
Issue
2
Publish Date
1996
Start Page
86
End Page
92

Influence of preparatory regimen and source of hematopoietic cells on outcome of autotransplantation for non-Hodgkin's lymphoma.

The use of high-dose chemotherapy with or without total-body irradiation (TBI) followed by autologous hematopoietic cell transplantation is associated with improved survival for relapsed or refractory non-Hodgkin's lymphoma (NHL). Previous reports comparing preparatory regimens with or without TBI followed by autologous bone marrow transplantation (ABMT) or peripheral blood progenitor cell transplantation (PBPCT) for these patients did not demonstrate any survival difference between the different modalities. No randomized studies comparing survival for patients with NHL transplanted with radiochemotherapy vs. chemotherapy alone have been reported. We treated 221 patients with high-risk, relapsed or refractory NHL with either chemotherapy alone or radiochemotherapy followed by ABMT or PBPCT. The patients were assigned preparatory regimens in a non-randomized manner and this analysis was performed to evaluate differences in outcome with the two preparatory regimens. Actuarial five-year event-free survival (EFS) was similar in patients receiving fractionated total-body irradiation (FTBI) plus etoposide (VP-16) and cyclophosphamide (Cy) compared with chemotherapy alone consisting of carmustine (BCNU) plus identical doses of VP-16 and Cy (52% vs. 46%, p = 0.08). Overall survival (OS) favored radiochemotherapy (61%) compared with chemotherapy alone (53%, p = 0.02). The relapse rate was the same in both groups (41%), whereas the transplantation-related mortality (TRM) was similar in patients receiving chemotherapy alone and those receiving radiochemotherapy (13% vs. 7% respectively, p = 0.30). Proportional hazards analysis of significant variables including preparatory regimen found only the number of prior relapses to be predictive of EFS. Fewer number of prior relapses, radiochemotherapy and PBPCT were significant predictors of favorable OS. In additional analyses, the improved OS of the radiochemotherapy regimen was confirmed only for patients receiving ABMT but was not a significant predictor of outcome in patients transplanted with PBPCT. From these retrospective data we conclude: 1) PBPCT resulted in survival superior to that of ABMT; 2) the risk of relapse is similar with either preparatory regimen; 3) patients with fewer prior relapses enjoyed superior overall and event-free survival as well as fewer relapses; and 4) there were no significant differences in the two preparatory regimens when combined with PBPCT in relapsed or refractory NHL.

Authors
Stockerl-Goldstein, KE; Horning, SJ; Negrin, RS; Chao, NJ; Hu, WW; Long, GD; Hoppe, RT; Amylon, MD; Brown, BW; Wong, RM; Blume, KG
MLA Citation
Stockerl-Goldstein, KE, Horning, SJ, Negrin, RS, Chao, NJ, Hu, WW, Long, GD, Hoppe, RT, Amylon, MD, Brown, BW, Wong, RM, and Blume, KG. "Influence of preparatory regimen and source of hematopoietic cells on outcome of autotransplantation for non-Hodgkin's lymphoma." Biol Blood Marrow Transplant 2.2 (May 1996): 76-85.
PMID
9118302
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
2
Issue
2
Publish Date
1996
Start Page
76
End Page
85

Polymorphism of adhesion molecule CD31 and its role in acute graft-versus-host disease.

BACKGROUND: Graft-versus-host disease (GVHD) caused by poorly defined minor (i.e., other than HLA) histocompatibility antigens remains a serious problem in recipients of bone marrow transplants. We sought to determine whether the CD31 adhesion molecule is a minor alloantigen. METHODS: We directly sequenced samples of complementary DNA (cDNA) encoding CD31 molecules from 21 unrelated normal subjects. Sequence-specific primers were then designed to amplify alleles by the polymerase chain reaction, thereby permitting CD31 typing of genomic DNA from additional normal subjects. To assess the relevance of CD31 matching to bone marrow transplantation, we performed CD31 typing of 46 recipients of bone marrow (32 without GVHD and 14 with severe [grade III or IV] acute GVHD) and their HLA-identical sibling donors. The immunoreactivity of CD31 phenotypes with anti-CD31 monoclonal antibodies was compared by flow cytometry. RESULTS: Direct sequencing of cDNA for CD31 from the 21 normal subjects identified a single polymorphism, CTG-->GTG (Leu-->Val), at codon 125; we designated the resulting alleles CD31.L and CD31.V, respectively. The CD31 genotypes of these and 142 other unrelated subjects were of the expected frequencies. Among the transplant recipients, 71 percent of those with acute GVHD had CD31 genotypes that were not identical to the donor's genotype, as compared with 22 percent of the recipients without GVHD (P = 0.004). The binding of anti-CD31 monoclonal antibodies as measured by fluorescence-activated cell sorting correlated with the CD31 types of homozygous cell lines. CONCLUSIONS: The adhesion molecule CD31 is polymorphic. When donor and recipient genotypes are not identical, the risk of GVHD increases. Prospective CD31 typing may reduce the risk of acute GVHD.

Authors
Behar, E; Chao, NJ; Hiraki, DD; Krishnaswamy, S; Brown, BW; Zehnder, JL; Grumet, FC
MLA Citation
Behar, E, Chao, NJ, Hiraki, DD, Krishnaswamy, S, Brown, BW, Zehnder, JL, and Grumet, FC. "Polymorphism of adhesion molecule CD31 and its role in acute graft-versus-host disease." N Engl J Med 334.5 (February 1, 1996): 286-291.
PMID
8532023
Source
pubmed
Published In
The New England journal of medicine
Volume
334
Issue
5
Publish Date
1996
Start Page
286
End Page
291
DOI
10.1056/NEJM199602013340502

Pharmacokinetics of high-dose oral CCNU in bone marrow transplant patients.

PURPOSE: CCNU (lomustine) and other nitrosourea compounds are rapidly metabolized to alkylating moieties, which are active against various malignancies. In humans, CCNU undergoes biotransformation to the geometric isomers of 4'-hydroxyCCNU. The pharmacokinetics of trans-and cis-4'-hydroxyCCNU were determined in five patients with Hodgkin's or non-Hodgkin's lymphoma receiving sequential doses of CCNU (15 mg/kg), etoposide (60 mg/kg) and cyclophosphamide (100 mg/kg) prior to autologous bone marrow transplantation. METHODS: Plasma concentrations of the isomeric forms of the metabolites were determined by high-performance liquid chromatography. Data were analysed using noncompartmental pharmacokinetic methods. RESULTS: Formation of the trans-isomer predominated over that of the cis-isomer, with an average exposure ratio of 1.4 (range 1.0-2.1). Peak plasma concentrations occurred between 1 and 4.1 h postdosing and averaged 1.56 mg/l for the trans-isomer and 1.10 mg/l for cis isomer. Peak plasma concentrations and systemic exposures varied approximately six- and ninefold, respectively, reflecting significant interindividual variability in alkylating activity after high doses of CCNU. Plasma half-lives of the metabolites were 3.1 h (range 1.1-4.5 h) for the trans-isomer and 3.5 h (range 1.3-6.4 h) for the cis- isomer, and varied linearly with increasing patient body weight. There was no significant difference in plasma half-lives after high-dose CCNU administration observed in this study and those reported previously after the administration of substantially lower doses of CCNU. CONCLUSION: Despite linearity in the pharmacokinetics of the isomeric forms of 4'-hydroxyCCNU at high doses, large interindividual variability in exposure to the CCNU metabolites was observed. Potential saturation of metabolic pathways to the isomers at these doses may manifest as toxic symptoms since alkylating moieties formed directly from the parent, CCNU, may be associated with greater toxicity than those formed from the isomeric forms of the 4'-hydroxylated metabolite.

Authors
Kastrissios, H; Chao, NJ; Blaschke, TF
MLA Citation
Kastrissios, H, Chao, NJ, and Blaschke, TF. "Pharmacokinetics of high-dose oral CCNU in bone marrow transplant patients." Cancer Chemother Pharmacol 38.5 (1996): 425-430.
PMID
8765435
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
38
Issue
5
Publish Date
1996
Start Page
425
End Page
430
DOI
10.1007/s002800050506

Purging peripheral blood progenitor cells with 4-hydroperoxycyclophosphamide (4-HC)

Authors
Geiler, CR; Baker, J; Wells, S; Schlegel, PG; Chao, NJ
MLA Citation
Geiler, CR, Baker, J, Wells, S, Schlegel, PG, and Chao, NJ. "Purging peripheral blood progenitor cells with 4-hydroperoxycyclophosphamide (4-HC)." Cancer Research Therapy and Control 5.1 (1996): 23-27.
Source
scival
Published In
Cancer Research, Therapy and Control
Volume
5
Issue
1
Publish Date
1996
Start Page
23
End Page
27

Erratum: A synthetic random basic copolymer with promiscuous binding to class II major histocompatibility complex molecules (Proceedings of the National Academy of Science of the United States of America (May 14, 1996) 93:10 (5061-5066))

Authors
Schlegel, PG; Aharoni, R; Chen, Y; Chen, J; Teitelbaum, D; Arnon, R; Sela, M; Chao, NJ
MLA Citation
Schlegel, PG, Aharoni, R, Chen, Y, Chen, J, Teitelbaum, D, Arnon, R, Sela, M, and Chao, NJ. "Erratum: A synthetic random basic copolymer with promiscuous binding to class II major histocompatibility complex molecules (Proceedings of the National Academy of Science of the United States of America (May 14, 1996) 93:10 (5061-5066))." Proceedings of the National Academy of Sciences of the United States of America 93.16 (1996): 8796--.
Source
scival
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
93
Issue
16
Publish Date
1996
Start Page
8796-

Prevention and treatment of graft-versus-host disease.

Graft-versus-host disease remains a formidable barrier in allogeneic bone marrow transplantation. Studies have shown that effective prophylaxis results in improved overall survival for patients following allogeneic bone marrow transplantation. Various methods to prevent GVHD have been devised over the years including drug therapy, monoclonal antibodies, and T-cell depletion. Many of these prophylaxis regimens have been successful in improving the outcome in patients, with some regimens resulting in only a 9% incidence of acute GVHD in selected patients. Yet, GVHD remains an important problem for those patients in whom prophylaxis fails. Therapy for GVHD has relied on drugs and monoclonal antibodies, and the results of therapy for severe GVHD have been unsatisfactory. As immunologic understanding of the afferent and efferent phases of GVHD continues to be elucidated, more targeted therapy will be introduced and hopefully will result in better outcomes.

Authors
Chao, NJ; Schlegel, PG
MLA Citation
Chao, NJ, and Schlegel, PG. "Prevention and treatment of graft-versus-host disease." Ann N Y Acad Sci 770 (December 29, 1995): 130-140. (Review)
PMID
8597355
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
770
Publish Date
1995
Start Page
130
End Page
140

Mobilization of peripheral blood progenitor cells by hematopoietic growth factors.

The anti-tumor effect and toxicity of chemotherapeutic agents are dose-related. The dose-response curve for these agents is sigmoidal with a threshold, a lag phase, a linear phase and a plateau phase. The aim of cancer chemotherapy is to exploit the difference between the response curves for the tumor and normal tissues. In the laboratory and in some animal models, the dose-response curve for many agents demonstrates a log-linear relationship between dose and cell kill so that a doubling of the drug dose may increase cell kill by ten-fold. The more effective a drug is, the steeper the dose-response curve. Dose may be an important variable in the outcome of therapy, however, this dose-response relationship has been difficult to demonstrate because a dose-response effect may not be evident for most human tumors in the dose ranges used in clinical trials.

Authors
Chao, NJ
MLA Citation
Chao, NJ. "Mobilization of peripheral blood progenitor cells by hematopoietic growth factors." Can J Oncol 5 Suppl 1 (December 1995): 43-46.
PMID
8853524
Source
pubmed
Published In
The Canadian journal of oncology
Volume
5 Suppl 1
Publish Date
1995
Start Page
43
End Page
46

Preemptive ganciclovir administration based solely on asymptomatic pulmonary cytomegalovirus infection in allogeneic bone marrow transplant recipients: long-term follow-up.

The use of ganciclovir at the time of cytomegalovirus (CMV) infection but before disease onset has been termed "preemptive" therapy. This preemptive ganciclovir administration has been shown to be an effective method for preventing severe CMV disease after allogeneic bone marrow transplantation (BMT), but the optimal method of CMV surveillance is not clear. The purpose of this study was to evaluate effectiveness, side effects, and long-term outcome of preemptive ganciclovir therapy in allogeneic BMT recipients when ganciclovir is prescribed solely on the basis of CMV detection in day +35 bronchoalveolar lavage (BAL). In a consecutive cohort of 202 HLA-matched recipients of sibling donor marrow transplantations, 163 received prospective BAL and were given preemptive ganciclovir if CMV-positive; 39 had disqualifying complications and were not eligible for BAL. Over the 36-month follow-up, CMV disease occurred in 21 (10%) of the 202 BMT recipients; there was one CMV-related death. In the 60 subjects (37% of the total 163) who received preemptive ganciclovir based on positive CMV-BAL, two (3%) developed CMV disease during the first 120 days post-BMT and two more developed late disease. Among the 103 BAL-negative subjects, CMV disease occurred in eight (8%) during the first 120 days and in three (3%) at > 120 days. Forty-three percent of all CMV disease occurred either before day +35 BAL (four cases) or at late times after BMT (five cases). The negative predictive value of BAL was 91%, allowing for the occurrence of 52% of all CMV disease in subjects considered CMV-BAL-negative. Nevertheless, using this treatment method, no significant differences in neutropenia rates or in 36-month survival were noted in the high-risk group having pulmonary CMV infection (compared with the group without pulmonary CMV). Thus, a strategy of preemptive ganciclovir based on a single BAL can reduce the complications caused by CMV; however, improved surveillance methods are necessary to eliminate all CMV disease.

Authors
Zaia, JA; Schmidt, GM; Chao, NJ; Rizk, NW; Nademanee, AP; Niland, JC; Horak, DA; Lee, J; Gallez-Hawkins, G; Kusnierz-Glaz, CR
MLA Citation
Zaia, JA, Schmidt, GM, Chao, NJ, Rizk, NW, Nademanee, AP, Niland, JC, Horak, DA, Lee, J, Gallez-Hawkins, G, and Kusnierz-Glaz, CR. "Preemptive ganciclovir administration based solely on asymptomatic pulmonary cytomegalovirus infection in allogeneic bone marrow transplant recipients: long-term follow-up." Biol Blood Marrow Transplant 1.2 (December 1995): 88-93.
PMID
9118297
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
1
Issue
2
Publish Date
1995
Start Page
88
End Page
93

Inhibition of T cell costimulation by VCAM-1 prevents murine graft-versus-host disease across minor histocompatibility barriers.

Activation of T cells leading to graft-vs-host disease (GVHD) requires two signaling events: the Ag-specific signal generated through the engagement of the TCR/CD3 complex with antigenic peptide fragments presented by MHC molecules on APCs and the second signal provided through additional costimulatory ligands. T cells have preferential costimulatory requirements depending on their state of activation-induced maturation. In the present study, we investigated the role of the receptor-ligand pair VLA-4 (alpha 4 beta 1) and VCAM-1 in allogeneic T cell responses in vitro and in vivo. Anti-VCAM-1 mAb effectively inhibited mixed lymphocyte culture (MLC) across several major MHC barriers and secondary MLC across minor histocompatibility Ags (95.5% and 90.0% inhibition, respectively). In contrast, anti-VLA-4 mAb inhibited a CD8(+)-mediated primed CTL response in vitro by 100%, yet had little effect on proliferative responses. In the B10.D2/nSnJ-->BALB/c (both H-2d) system of GVHD, BALB/c received anti-VCAM-1, or anti-VLA-4 or controls NS-1 or Y13-259 for the first 5 wk after transplant. Anti-VLA-4 mAb delayed the onset of GVHD, but failed to reduce incidence, severity or GVHD-related mortality. In contrast, anti-VCAM-1 reduced the incidence of GVHD from 100% (18/18) in control animals to 53.3% (8/15) (p < 0.01) on day 70 post-transplant and significantly decreased GVHD-related mortality. Sixty percent (9/15) of anti-VCAM-1 recipients survived more than 180 days after transplant. Long-term engraftment of allogeneic bone marrow was documented in all transplanted mice by PCR analysis of a microsatellite region in the IL-1 beta gene.

Authors
Schlegel, PG; Vaysburd, M; Chen, Y; Butcher, EC; Chao, NJ
MLA Citation
Schlegel, PG, Vaysburd, M, Chen, Y, Butcher, EC, and Chao, NJ. "Inhibition of T cell costimulation by VCAM-1 prevents murine graft-versus-host disease across minor histocompatibility barriers." J Immunol 155.8 (October 15, 1995): 3856-3865.
PMID
7561092
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
155
Issue
8
Publish Date
1995
Start Page
3856
End Page
3865

Multiple cycles of high dose chemotherapy supported by hematopoietic progenitor cells as treatment for patients with advanced malignancies.

BACKGROUND: Retrospective studies suggest that dose intensity is an important determinant of outcome in the treatment of patients with a variety of malignant diseases such as breast cancer, ovarian cancer, and lymphoma. Unfortunately, these results have not been clearly substantiated in prospective randomized trials. One problem with these studies may be that the degree of dose escalation is not sufficient to result in an improved outcome because the chemotherapy doses are limited by hematopoietic toxicity. In an attempt to deliver more dose-intensive therapy, the feasibility of the administration of multiple cycles of high dose chemotherapy with hematopoietic progenitor cell and growth factor support was investigated in patients with advanced malignancies. METHODS: Nineteen patients with metastatic breast cancer and six patients with refractory non-Hodgkin's lymphoma were initially treated with etoposide (VP-16) (2 gm/m2) and granulocyte-colony stimulating factor (G-CSF). Peripheral blood hematopoietic progenitor cells were collected by leukapheresis and cryopreserved as the patients' leukocyte counts recovered from the nadir induced by VP-16. Patients were then treated with four cycles of mitoxantrone (18 mg/m2), thiotepa (150-200 mg/m2) and cyclophosphamide (4500-5000 mg/m2) as a 48-72 hour continuous infusion followed by infusion of one-quarter of their progenitor cells 48 hours later. All patients also received G-CSF (5 micrograms/kg/day) until engraftment. RESULTS: A total of 88 of a planned 100 cycles of therapy were administered to these 25 patients. The median time to recovery of an absolute neutrophil count of 500/microliters or greater was 13-14 days (range, 7-18 days) and time to recovery of a platelet count of 20,000/microliters or greater was 13-14 days (range, 7-16 days) after the initiation of each cycle of chemotherapy. The median number of platelet transfusions required after each cycle was 2-3 (range, 0-18 transfusions) and the number of erythrocyte transfusions was 4 (range, 0-10). The most common toxicity was diarrhea. Prophylactic intravenous antibiotics were administered to avoid fever with neutropenia. Two patients developed interstitial pneumonitis and one patient died. One heavily pretreated patient failed to engraft after the first cycle. Reversible veno-occlusive disease of the liver developed in one patient after the fourth cycle of therapy. Four patients progressed while on therapy. Eight patients were disease free and 13 patients had a partial response or had a positive bone scan as the only evidence of disease at the completion of therapy. Seven patients, two with lymphoma and five with breast cancer (28%), remain progression free with a median follow-up of 24.7 months (range, 17-28 months). CONCLUSIONS: Support with hematopoietic progenitor cells and growth factors allows the timely administration of repetitive cycles of high dose chemotherapy, resulting in a significant increase in dose intensity with acceptable toxicity.

Authors
Long, GD; Negrin, RS; Hoyle, CF; Kusnierz-Glaz, CR; Schriber, JR; Blume, KG; Chao, NJ
MLA Citation
Long, GD, Negrin, RS, Hoyle, CF, Kusnierz-Glaz, CR, Schriber, JR, Blume, KG, and Chao, NJ. "Multiple cycles of high dose chemotherapy supported by hematopoietic progenitor cells as treatment for patients with advanced malignancies." Cancer 76.5 (September 1, 1995): 860-868.
PMID
8625190
Source
pubmed
Published In
Cancer
Volume
76
Issue
5
Publish Date
1995
Start Page
860
End Page
868

Does thalidomide affect IL-2 response and production?

The exact mechanism of immunosuppression by thalidomide is poorly understood. A common denominator in the pathogenesis of graft-vs.-host disease, graft rejection, reactional lepromatous leprosy, and autoimmune disorders modulated by thalidomide is the activation of T lymphocytes culminating in the synthesis of interleukin-2 (IL-2), the expression of high-affinity IL-2 receptors, and the induction of proliferation. We investigated the effect of thalidomide on the production of IL-2 by the human leukemia cell line Jurkat through induction of IL-2 gene enhancer activity and through the presence of IL-2 in supernatants. beta-galactosidase activity, encoded by a reporter lac z construct and controlled by a transcription factor in thalidomide-treated PMA- and ionomycin-stimulated Jurkat cells, was similar (97 +/- 1.33%; p > 0.1) to non-thalidomide-treated controls at all drug concentrations tested. IL-2 enhancer-driven beta-galactose activity of thalidomide-treated and stimulated cells was also similar to that of untreated controls (p > 0.2). The IL-2 production of activated nontransfected Jurkat cells was gauged by using the IL-2-dependent cell line HT-2 as a readout and by ELISA. Jurkat cells were subcloned by limiting dilution. Bulk cultures and three subclones (J.5.2.5., J.5.2.9., and J.5.3.8.) were assayed at 6, 12, and 24 hours after PHA/PMA-induced stimulation. No inhibitory effect on the IL-2 production by thalidomide could be detected at any of the drug concentrations tested (5-30 micrograms/mL), whereas 10 to 100 ng/mL of cyclosporine inhibited the IL-2 production by 95 to 100%. In addition, we observed neither inhibition of IL-2-dependent proliferation of HT-2 nor inhibition of PHA-induced proliferation of peripheral mononuclear cells by thalidomide at all drug concentrations used (5-30 micrograms/mL). These results do not support the possibility of a modulatory effect on the immune response by thalidomide via IL-2 production and IL-2 response.

Authors
Fernandez, LP; Schlegel, PG; Baker, J; Chen, Y; Chao, NJ
MLA Citation
Fernandez, LP, Schlegel, PG, Baker, J, Chen, Y, and Chao, NJ. "Does thalidomide affect IL-2 response and production?." Exp Hematol 23.9 (August 1995): 978-985.
PMID
7635184
Source
pubmed
Published In
Experimental Hematology
Volume
23
Issue
9
Publish Date
1995
Start Page
978
End Page
985

Long-term follow-up of allogeneic bone marrow recipients for Philadelphia chromosome-positive acute lymphoblastic leukemia.

Authors
Chao, NJ; Blume, KG; Forman, SJ; Snyder, DS
MLA Citation
Chao, NJ, Blume, KG, Forman, SJ, and Snyder, DS. "Long-term follow-up of allogeneic bone marrow recipients for Philadelphia chromosome-positive acute lymphoblastic leukemia." Blood 85.11 (June 1, 1995): 3353-3354. (Letter)
PMID
7756668
Source
pubmed
Published In
Blood
Volume
85
Issue
11
Publish Date
1995
Start Page
3353
End Page
3354

Transplantation of enriched and purged peripheral blood progenitor cells from a single apheresis product in patients with non-Hodgkin's lymphoma.

High-dose chemotherapy with or without radiotherapy followed by autologous transplantation of hematopoietic progenitor cells is an effective treatment for patients with high-risk or relapsed non-Hodgkin's lymphoma. Chemotherapy and/or hematopoietic growth factors have been used to mobilize progenitor cells in the peripheral blood for transplantation. However, the mobilized blood cell products have been found to be frequently contaminated with tumor cells, and techniques have not been developed to purge tumor cells from these products. In addition, the minimum number of hematopoietic progenitor cells required for engraftment has not yet been fully elucidated. We treated 21 patients with a single infusion of cyclophosphamide (4 g/m2) followed by daily administration of granulocyte colony-stimulating factor (G-CSF). After recovery of the white blood cell count, a single 3-hour apheresis collection was performed. The apheresis product was then applied to a discontinuous Percoll gradient. The low-density fractions resulting from this separation procedure were enriched for CD34+ progenitor cells (total cell yield, 19.5%; CD34+ cell recovery, 81.2%). These enriched cellular products were treated with a panel of anti-B cell or anti-T cell monoclonal antibodies and complement in an effort to remove residual tumor cells. After treatment of the patient with myeloablative therapies, the enriched and purged cells were reinfused. Hematologic recovery was rapid, with median neutrophil engraftment in 10 days [absolute neutrophil count (ANC), greater than 0.5 x 10(9)/L] and 11 days (ANC, greater than 1.0 x 10(9)/L). Median platelet transfusion independence required 13 days. The rapidity of multilineage engraftment correlated with the number of CD34+ cells per kilogram that were infused. Patients who received more than 2 x 10(6) CD34+ cells per kilogram had rapid hematologic engraftment, whereas those patients transplanted with less than 2 x 10(6) CD34+ cells per kilogram had slower platelet recovery. Modeling studies using a lymphoma cell line with a t(14; 18) chromosomal translocation demonstrated the successful removal of tumor cells assayed using the polymerase chain reaction (PCR) after the processing and purging. Four of the 21 patients had PCR-detectable lymphoma cells in the bone marrow and peripheral blood; however, the enriched and purged blood products reinfused in all four did not contain detectable tumor cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Authors
Negrin, RS; Kusnierz-Glaz, CR; Still, BJ; Schriber, JR; Chao, NJ; Long, GD; Hoyle, C; Hu, WW; Horning, SJ; Brown, BW
MLA Citation
Negrin, RS, Kusnierz-Glaz, CR, Still, BJ, Schriber, JR, Chao, NJ, Long, GD, Hoyle, C, Hu, WW, Horning, SJ, and Brown, BW. "Transplantation of enriched and purged peripheral blood progenitor cells from a single apheresis product in patients with non-Hodgkin's lymphoma." Blood 85.11 (June 1, 1995): 3334-3341.
PMID
7538824
Source
pubmed
Published In
Blood
Volume
85
Issue
11
Publish Date
1995
Start Page
3334
End Page
3341

A new preparatory regimen for autologous bone marrow transplantation for patients with lymphoma.

BACKGROUND: This trial studied the feasibility and efficacy of a new preparatory regimen for autologous bone marrow transplantation for patients with advanced lymphoid malignancies. METHODS: Twenty-one patients with Hodgkin's disease (n = 12) and non-Hodgkin's lymphoma (n = 9) were treated in this study. Lomustine was substituted for carmustine) in a dose-escalation study with an initial dose of 6 mg/kg and increasing by 3 mg/kg in groups of four patients. The preparatory regimen consisted of lomustine (6-15 mg/kg) orally on Day -6, etoposide (60 mg/kg) intravenously (i.v.) on Day -4, and cyclophosphamide (100 mg/kg) i.v. on Day -2. Peripheral blood progenitor cells and/or bone marrow were infused on Day 0. RESULTS: Lomustine was well tolerated in all patients with no significant toxicity specific to this drug. Engraftment was prompt: the time to achieving greater than or equal to 500 granulocytes/microliters was 12 days (range, 9-16 days) and the time to achieving greater than or equal to 25,000 platelets/microliters without transfusion support was 16 days (range, 9-22 days). Five patients experienced interstitial pneumonitis, three of whom had active or recent interstitial pneumonitis before bone marrow transplantation, and one who just completed mantle irradiation. Three patients died from this preparatory regimen, one of progressive interstitial pneumonitis, one of Legionella pneumonia, and one of multiorgan failure. Three patients with non-Hodgkin's lymphoma relapsed. Fourteen patients are currently alive and disease free to date. The actuarial are currently alive and disease free to date. The actuarial disease free survival was 57%, with a median follow-up of 23 months (range, 1-48 months). CONCLUSION: The preparatory regimen consisting of lomustine/etoposide/cyclophosphamide is active in treating patients with lymphomas. Further trials with high doses of lomustine are warranted.

Authors
Chao, NJ; Kastrissios, H; Long, GD; Negrin, RS; Horning, SJ; Wong, RM; Blaschke, TF; Blume, KG
MLA Citation
Chao, NJ, Kastrissios, H, Long, GD, Negrin, RS, Horning, SJ, Wong, RM, Blaschke, TF, and Blume, KG. "A new preparatory regimen for autologous bone marrow transplantation for patients with lymphoma." Cancer 75.6 (March 15, 1995): 1354-1359.
PMID
7882286
Source
pubmed
Published In
Cancer
Volume
75
Issue
6
Publish Date
1995
Start Page
1354
End Page
1359

Drug prophylaxis for acute graft-versus-host disease

Authors
Chao, NJ; Schlegel, PG; Nademanee, AP; Blume, KG; Forman, SJ
MLA Citation
Chao, NJ, Schlegel, PG, Nademanee, AP, Blume, KG, and Forman, SJ. "Drug prophylaxis for acute graft-versus-host disease." Bone Marrow Transplantation 15.SUPPL. 1 (1995): S94-S97.
Source
scival
Published In
Bone Marrow Transplantation
Volume
15
Issue
SUPPL. 1
Publish Date
1995
Start Page
S94
End Page
S97

Erratum: Does thalidomide affect IL-2 response and production? (Experimental Hematology, 23, 9 (1995), 978-987)

Authors
Fernandez, LP; Schlegel, PG; Baker, J; Chen, Y; Chao, NJ
MLA Citation
Fernandez, LP, Schlegel, PG, Baker, J, Chen, Y, and Chao, NJ. "Erratum: Does thalidomide affect IL-2 response and production? (Experimental Hematology, 23, 9 (1995), 978-987)." Experimental Hematology 23.12 (1995): 1324--.
Source
scival
Published In
Experimental Hematology
Volume
23
Issue
12
Publish Date
1995
Start Page
1324-

Busulfan/cyclophosphamide as conditioning regimen for allogeneic bone marrow transplantation for myelodysplasia

Purpose: A non-radiation-containing regimen of busulfan and cyclophosphamide (BU/CY) was evaluated for toxicity, relapse, and long-term survival in patients who received allogeneic bone marrow transplantation (BMT) for myelodysplasia (MDS). Patients and Methods: Thirty-eight patients with MDS, including eight with therapy-related MDS, were prepared for BMT using BU/CY. Results: Fourteen patients remain in first remission 18 to 60 months posttransplant. Five patients relapsed after BMT, and four of these patients died. Eight additional patients died of acute or chronic graft- versus-host disease (GVHD), and 11 died of regimen-related toxicity, primarily systemic mycoses. Overall survival rate at 2 years was 45% (95% confidence interval [CI], 0.30 to 0.61), with a 24% probability of relapse (95% CI, 0.10 to 0.49). Regimen-related toxicity was manifested primarily as hepatic dysfunction in 72% of patients, with 16% developing overt venoocclusive disease (VOD). Conclusion: Non-radiation-containing preparative regimens offer long-term survival in allogeneic BMT for MDS that is comparable to that of radiation-containing regimens, and are useful in patients with therapy-related MDS. Monitoring BU levels may reduce regimen- related mortality and improve survival.

Authors
O'Donnell, MR; Long, GD; Parker, PM; Niland, J; Nademanee, A; Amylon, M; Chao, N; Negrin, RS; Schmidt, GM; Slovak, ML; Smith, EP; Snyder, DS; Stein, AS; Traweek, T; Blume, KG; Forman, SJ
MLA Citation
O'Donnell, MR, Long, GD, Parker, PM, Niland, J, Nademanee, A, Amylon, M, Chao, N, Negrin, RS, Schmidt, GM, Slovak, ML, Smith, EP, Snyder, DS, Stein, AS, Traweek, T, Blume, KG, and Forman, SJ. "Busulfan/cyclophosphamide as conditioning regimen for allogeneic bone marrow transplantation for myelodysplasia." Journal of Clinical Oncology 13.12 (1995): 2973-2979.
PMID
8523063
Source
scival
Published In
Journal of Clinical Oncology
Volume
13
Issue
12
Publish Date
1995
Start Page
2973
End Page
2979

Thalidomide as salvage therapy for chronic graft-versus-host disease

Thalidomide has been reported to be an effective agent for treatment of chronic graft-versus-host disease (CGVHD). To determine the efficacy of this agent in patients with refractory CGVHD a total of 80 patients who failed to respond to prednisone (PSE) or PSE and cyclosporine (CSA) were treated with thalidomide. Sixteen patients (20%) had a sustained response, 9 with a complete remission and 7 with a partial response. Twenty-nine patients (36%) had thalidomide discontinued because of side effects, which included sedation, constipation, neuritis, skin rash, and neutropenia. Side effects were reversible with drug discontinuation except for mild residual neuritis in one case. Rashes and neutropenia have not previously been reported as thalidomide side effects when used for CGVHD treatment. We conclude thalidomide is immunosuppressive and active in the treatment of CGVHD. A high incidence of reversible side effects limited dose intensity and reduced the number of patients who could benefit from treatment.

Authors
Parker, PM; Chao, N; Nademanee, A; O'Donnell, MR; Schmidt, GM; Snyder, DS; Stein, AS; Smith, EP; Molina, A; Stepan, DE; Kashyap, A; Planas, I; Spielberger, R; Somlo, G; Margolin, K; Zwingenberger, K; Wilsman, K; Negrin, RS; Long, GD
MLA Citation
Parker, PM, Chao, N, Nademanee, A, O'Donnell, MR, Schmidt, GM, Snyder, DS, Stein, AS, Smith, EP, Molina, A, Stepan, DE, Kashyap, A, Planas, I, Spielberger, R, Somlo, G, Margolin, K, Zwingenberger, K, Wilsman, K, Negrin, RS, and Long, GD. "Thalidomide as salvage therapy for chronic graft-versus-host disease." Blood 86.9 (1995): 3604-3609.
PMID
7579470
Source
scival
Published In
Blood
Volume
86
Issue
9
Publish Date
1995
Start Page
3604
End Page
3609

Prevention of graft-versus-host disease by peptides binding to class II major histocompatibility complex molecules.

Graft-versus-host disease across minor histocompatibility barriers was induced in two different models by transplanting allogeneic bone marrow and spleen cells into irradiated H-2-compatible recipient mice. In this report, we show that administration of peptides with high binding affinity for the respective class II major histocompatibility complex molecules after transplantation is capable of preventing the development of graft-versus-host disease in two different murine models. The peptides used were myelin basic protein residues 1 through 11 with alanine at position 4 (Ac 1-11[4A]) for I-Au (A alpha uA beta u), and the antigenic core sequence 323 through 339 of ovalbumin with lysine and methionine extension (KM core) for I-As (A alpha sA beta s). In both systems, the mechanism of prevention was found to be major histocompatibility complex-associated, because nonbinding control peptides did not have any effect. Engraftment of allogeneic bone marrow cells was shown by polymerase chain reaction analysis of DNA polymorphisms in a microsatellite region within the murine interleukin-5 gene.

Authors
Schlegel, PG; Aharoni, R; Smilek, DE; Fernandez, LP; McDevitt, HO; Tran, N; Vaysburd, M; Chao, NJ
MLA Citation
Schlegel, PG, Aharoni, R, Smilek, DE, Fernandez, LP, McDevitt, HO, Tran, N, Vaysburd, M, and Chao, NJ. "Prevention of graft-versus-host disease by peptides binding to class II major histocompatibility complex molecules." Blood 84.8 (October 15, 1994): 2802-2810.
PMID
7522644
Source
pubmed
Published In
Blood
Volume
84
Issue
8
Publish Date
1994
Start Page
2802
End Page
2810

Granulocyte colony-stimulating factor after allogeneic bone marrow transplantation.

Hematopoietic growth factors have been shown to be effective in reducing the period of neutropenia after autologous bone marrow transplantation (BMT). Initial concerns over potential aggravation of graft-versus-host disease (GVHD) and increase in the incidence of relapse in patients with myeloid leukemias influenced the number of studies using hematopoietic growth factors after allogeneic BMT. We report the experience with 50 patients treated at a single institution using granulocyte colony-stimulating factor (G-CSF) after allogeneic sibling (n = 30) and matched unrelated (n = 20) BMT. The time to an absolute neutrophil count > or = 500/microL was significantly faster in patients who received G-CSF and cyclosporine and prednisone for GVHD prophylaxis when compared with historical control patients receiving the same GVHD prophylaxis (10 v 13 days, P < .01). A similar accelerated myeloid engraftment was observed for those patients who received the addition of methotrexate for GVHD prophylaxis when compared with historical control patients receiving the same GVHD prophylaxis regimen (16 v 19 days, P < .05). The median time to engraftment for patients receiving a matched unrelated BMT and G-CSF was 17 days (range 13 to 26). We did not observe any increase in GVHD or early mortality in the matched related sibling BMT. The incidence of acute GVHD in the matched unrelated BMT recipients was also low at 21%; however, 9 patients (45%) died within 100 days of the date of BMT, similar to the experience reported with granulocyte-macrophage CSF. This study confirms the efficacy of G-CSF in accelerating myeloid engraftment after allogeneic matched sibling BMT. The higher early mortality associated with patients receiving matched unrelated BMT suggests that randomized controlled trials using G-CSF after allogeneic BMT should be performed.

Authors
Schriber, JR; Chao, NJ; Long, GD; Negrin, RS; Tierney, DK; Kusnierz-Glaz, C; Lucas, KS; Blume, KG
MLA Citation
Schriber, JR, Chao, NJ, Long, GD, Negrin, RS, Tierney, DK, Kusnierz-Glaz, C, Lucas, KS, and Blume, KG. "Granulocyte colony-stimulating factor after allogeneic bone marrow transplantation." Blood 84.5 (September 1, 1994): 1680-1684.
PMID
7520782
Source
pubmed
Published In
Blood
Volume
84
Issue
5
Publish Date
1994
Start Page
1680
End Page
1684

Fractionated total-body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 94 patients with chronic myelogenous leukemia in chronic phase.

Ninety-four consecutive patients with chronic myelogenous leukemia in first clinical chronic phase, median age of 34.0 years (range, 6.8 to 52.4 years), with a histocompatible sibling donor, were treated with fractionated total body irradiation (1,320 cGy) and high-dose etoposide (60 mg/kg) followed by allogeneic bone marrow transplantation (BMT). The median time from diagnosis to BMT was 7.0 months (range, 2.3 to 72.0 months). Sixty patients were treated before BMT with hydroxyurea alone, four patients with busulfan alone, one patient with interferon alone, and the other 29 patients were treated with various combinations of these drugs. Cumulative probabilities of overall survival, event-free survival, and relapse at 5 years were 73%, 64%, and 14%, respectively. The median follow-up time for surviving patients was 38 months, ranging from 12 to 88 months. By stepwise Cox regression analysis, significant prognostic variables were age at transplant, acute graft-versus-host disease > or = grade II, cytomegalovirus-associated interstitial pneumonitis, and years from diagnosis to BMT.

Authors
Snyder, DS; Negrin, RS; O'Donnell, MR; Chao, NJ; Amylon, MD; Long, GD; Nademanee, AP; Stein, AS; Parker, PM; Smith, EP
MLA Citation
Snyder, DS, Negrin, RS, O'Donnell, MR, Chao, NJ, Amylon, MD, Long, GD, Nademanee, AP, Stein, AS, Parker, PM, and Smith, EP. "Fractionated total-body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 94 patients with chronic myelogenous leukemia in chronic phase." Blood 84.5 (September 1, 1994): 1672-1679.
PMID
8068956
Source
pubmed
Published In
Blood
Volume
84
Issue
5
Publish Date
1994
Start Page
1672
End Page
1679

A randomized study of erythropoietin and granulocyte colony-stimulating factor (G-CSF) versus placebo and G-CSF for patients with Hodgkin's and non-Hodgkin's lymphoma undergoing autologous bone marrow transplantation.

Anemia is a universal finding in patients undergoing autologous bone marrow transplantation (BMT). Effective therapies to increase the number of autologous red blood cells could result in a lower morbidity and mortality associated with red blood cell transfusions. We examined whether the addition of erythropoietin (Epo) to intensive therapy supported by progenitor cell transplantation and granulocyte colony-stimulating factor (G-CSF) would result in a lower requirement for red blood cell transfusions. Thirty-five patients with lymphoma were randomized to receive Epo versus placebo. Epo (600 U/kg three times per week) or placebo was begun 3 weeks before administration of high-dose therapy. Epo was held during the week of the preparatory regimen, and restarted on the day after BMT. All patients also received G-CSF following BMT. No significant differences were noted between the two groups in terms of patient characteristics at pretreatment or post-BMT evaluation. There were no differences in the total number of red blood cell units transfused (median Epo: 8 v placebo: 6, P = .22) nor the number of platelet transfusions given (median Epo: 12 v placebo 5, P = .14). Engraftment of granulocytes (absolute neutrophil count > or = 500/microL) occurred in a median of 12 days (range, 9 to 33) for the patients receiving Epo and G-CSF, compared with a median of 10 days (range, 8 to 22) for those receiving placebo and G-CSF (P = .70). Likewise, there were no differences in the time to platelet count > or = 20,000/microL without further transfusions with a median of 22 days (range, 15 to 150+) for those receiving Epo and G-CSF compared with a median of 20 days (range, 11 to 54) for those patients receiving placebo and G-CSF (P = .28). The combination of G-CSF and Epo as administered in this study appears to be safe but does not result in an improvement in the total number of red blood cell transfusions or total number of single donor platelet units transfused.

Authors
Chao, NJ; Schriber, JR; Long, GD; Negrin, RS; Catolico, M; Brown, BW; Miller, LL; Blume, KG
MLA Citation
Chao, NJ, Schriber, JR, Long, GD, Negrin, RS, Catolico, M, Brown, BW, Miller, LL, and Blume, KG. "A randomized study of erythropoietin and granulocyte colony-stimulating factor (G-CSF) versus placebo and G-CSF for patients with Hodgkin's and non-Hodgkin's lymphoma undergoing autologous bone marrow transplantation." Blood 83.10 (May 15, 1994): 2823-2828.
PMID
7514046
Source
pubmed
Published In
Blood
Volume
83
Issue
10
Publish Date
1994
Start Page
2823
End Page
2828

Role of etoposide (VP-16) in preparatory regimens for patients with leukemia or lymphoma undergoing allogeneic bone marrow transplantation.

In 1983, we began a series of clinical trials with the goal of reducing the relapse rate following allogeneic BMT for hematologic malignancies. Because of its anti-leukemic activity, the drug VP-16 was chosen and combined with total body irradiation (TBI). The first series (trial I) consisted of patients who had advanced leukemia. This trial showed a relapse rate of 32% and a disease-free survival rate of 43%. Thereafter, this regimen was tested in a randomized trial (trial II) under the auspices of the Southwest Oncology Group (SWOG study 8612). The FTBI/VP-16 regimen was compared with the combination of busulfan and cyclophosphamide (BU/CY). A recent analysis indicates a disease-free advantage for patients prepared with FTBI/VP-16; however this difference is not statistically significant. In another trial (trial III), patients in their first remission of leukemia were prepared with the FTBI/VP-16 regimen and long-term disease-free survival was found to be 60-70% with a relapse rate of approximately 10%. These results compare favorably with data obtained with alternative preparatory regimens. The FTBI/VP-16 regimen is currently being compared to the 'standard' regimen, FTBI/CY, in a prospective trial (trial IV). Since the regimen-related toxicity has been relatively low, we have added one dose of CY 60 mg/kg to the FTBI/VP-16 combination. This regimen (trial V) is currently being tested in patients with advanced leukemia. The preliminary results of this ongoing trial indicate further improvement in disease-free survival through a reduction of the post-transplant relapse rate.

Authors
Blume, KG; Long, GD; Negrin, RS; Chao, NJ; Kusnierz-Glaz, C; Amylon, MD
MLA Citation
Blume, KG, Long, GD, Negrin, RS, Chao, NJ, Kusnierz-Glaz, C, and Amylon, MD. "Role of etoposide (VP-16) in preparatory regimens for patients with leukemia or lymphoma undergoing allogeneic bone marrow transplantation." Bone Marrow Transplant 14 Suppl 4 (1994): S9-10. (Review)
PMID
7728133
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
14 Suppl 4
Publish Date
1994
Start Page
S9
End Page
10

Fractionated total-body irradiation, etoposide, and cyclophosphamide plus autografting in Hodgkin's disease and non-Hodgkin's lymphoma

Purpose: High-dose etoposide was incorporated into a regimen of fractionated total-body irradiation (FTBI) and high-dose cyclophosphamide before autologous transplant with the goal to enhance the antitumor effect of the myeloablative regimen in poor-risk lymphoid malignancies. Patients and Methods: Ninety-six patients, 24 with recurrent or refractory Hodgkin's disease and 72 with poor-risk non-Hodgkin's lymphoma (NHL), were treated on this study. Cytoreduction with conventional therapy was attempted before administration of the preparatory regimen. The preparatory regimen consisted of 12 Gy total-body irradiation administered in 10 1.2-Gy fractions on day - 8 through day -5, etoposide 60 mg/kg on day -4, and cyclophosphamide 100 mg/kg on day -2. Patients with NHL received bone marrow purged with a panel of monoclonal antibodies and complement on day 0, while patients with Hodgkin's disease received peripheral-blood stem cells alone or with unmanipulated bone marrow. Results: The major morbidities of transplant were mucositis and skin toxicity. Eight patients (8.6%) died of regimen-related toxicities within 100 days of transplant. Engraftment was related to the rescue product; the median time to a neutrophil count more than 500/μL was 10 days for patients with Hodgkin's disease and 16 days for NHL patients. With a maximum follow-up duration of longer than 5 years, the 3-year actuarial survival rate is 57%. At 3 years, the actuarial freedom from progression (FFP) rate is 55% and the event-free survival rate is 47% for patients with Hodgkin's disease, while the respective figures for NHL patients are 60% and 53%. Among 32 patients with intermediate- and high- grade lymphoma transplanted subsequent to first relapse, 70% are free of lymphoma and 60% are event-free at ≥3 years. Conclusion: The preparatory regimen consisting of FTBI, etoposide, and cyclophosphamide demonstrates relative efficacy in patients with Hodgkin's disease and NHL selected for high-dose therapy. Longer follow-up duration is needed to determine the rate of cure and to assess late complications. Major remaining challenges for high-dose therapy are a more inclusive strategy for all poor-risk patients and the need to reduce posttransplant relapses.

Authors
Horning, SJ; Negrin, RS; Chao, NJ; Long, GD; Hoppe, RT; Blume, KG
MLA Citation
Horning, SJ, Negrin, RS, Chao, NJ, Long, GD, Hoppe, RT, and Blume, KG. "Fractionated total-body irradiation, etoposide, and cyclophosphamide plus autografting in Hodgkin's disease and non-Hodgkin's lymphoma." Journal of Clinical Oncology 12.12 (1994): 2552-2558.
PMID
7989928
Source
scival
Published In
Journal of Clinical Oncology
Volume
12
Issue
12
Publish Date
1994
Start Page
2552
End Page
2558

Fractionated total body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 99 patients with acute leukemia in first complete remission.

Ninety-nine consecutive patients with acute leukemia in first complete remission under age 50 (median age 27 years; age range 1 to 47 years) with a histocompatible sibling donor were treated with fractionated total body irradiation (1,320 cGy) and high-dose etoposide (60 mg/kg) followed by allogeneic bone marrow transplantation. Sixty-one patients were diagnosed with acute myelogenous leukemia (AML), 34 patients with acute lymphoblastic leukemia (ALL), 3 patients with biphenotypic acute leukemia, and 1 patient with acute undifferentiated leukemia. Thirty of the 34 patients with ALL had at least one of the following high-risk factors: age greater than 30, white blood cell count at presentation > 25,000/microL, extramedullary disease, certain chromosomal translocations, or the need for greater than 4 weeks of induction chemotherapy to achieve first complete remission. Cumulative probabilities of disease-free survival and relapse at 3 years were 61% and 12%, respectively, for the 61 patients with AML and 64% and 12%, respectively, for the 34 patients with ALL. By stepwise Cox regression analysis, significant prognostic variables for patients with acute myelogenous leukemia were the presence of acute graft-versus-host disease and increasing age, whereas for patients with acute lymphoblastic leukemia, significant variables were age and the development of cytomegalovirus-associated interstitial pneumonia. Complications related to graft-versus-host disease and relapse of leukemia were the major causes of death.

Authors
Snyder, DS; Chao, NJ; Amylon, MD; Taguchi, J; Long, GD; Negrin, RS; Nademanee, AP; O'Donnell, MR; Schmidt, GM; Stein, AS
MLA Citation
Snyder, DS, Chao, NJ, Amylon, MD, Taguchi, J, Long, GD, Negrin, RS, Nademanee, AP, O'Donnell, MR, Schmidt, GM, and Stein, AS. "Fractionated total body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 99 patients with acute leukemia in first complete remission." Blood 82.9 (November 1, 1993): 2920-2928.
PMID
8219241
Source
pubmed
Published In
Blood
Volume
82
Issue
9
Publish Date
1993
Start Page
2920
End Page
2928

Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prophylaxis of acute graft-versus-host disease.

BACKGROUND: Acute graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation remains a serious problem. In a clinical trial, we tested the combination of cyclosporine and prednisone with and without methotrexate for the prevention of GVHD. METHODS: One hundred fifty patients with either acute leukemia in first complete remission, chronic myelogenous leukemia in first chronic phase, or lymphoblastic lymphoma in first complete remission were enrolled in the study. All the patients were given fractionated total-body irradiation (1320 cGy) and etoposide (60 mg per kilogram of body weight) in preparation for transplantation, and received bone marrow from genotypically histocompatible donors. To prevent GVHD, they were randomly assigned to prophylactic treatment with either cyclosporine, methotrexate, and prednisone or cyclosporine and prednisone without methotrexate. All the patients received standardized supportive care after transplantation, including intravenous gamma globulin. RESULTS: Patients receiving cyclosporine, methotrexate, and prednisone had a significantly lower incidence of acute GVHD of grades II to IV (9 percent) than those receiving cyclosporine and prednisone (23 percent, P = 0.02). Multivariate regression analysis demonstrated that an increased risk of acute GVHD was associated with an elevated serum creatinine concentration (P = 0.006) and treatment with cyclosporine and prednisone alone (P = 0.02). The lower incidence of acute GVHD was not associated with a higher rate of relapse of leukemia or lymphoma. There was no significant difference in disease-free survival at three years between the two treatment groups (64 percent with the three-drug regimen vs. 59 percent with the two-drug regimen, P = 0.57). CONCLUSIONS: The combination of cyclosporine, methotrexate, and prednisone was more effective in preventing acute GVHD of grades II to IV than was the combination of cyclosporine and prednisone without methotrexate.

Authors
Chao, NJ; Schmidt, GM; Niland, JC; Amylon, MD; Dagis, AC; Long, GD; Nademanee, AP; Negrin, RS; O'Donnell, MR; Parker, PM
MLA Citation
Chao, NJ, Schmidt, GM, Niland, JC, Amylon, MD, Dagis, AC, Long, GD, Nademanee, AP, Negrin, RS, O'Donnell, MR, and Parker, PM. "Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prophylaxis of acute graft-versus-host disease." N Engl J Med 329.17 (October 21, 1993): 1225-1230.
PMID
8413388
Source
pubmed
Published In
The New England journal of medicine
Volume
329
Issue
17
Publish Date
1993
Start Page
1225
End Page
1230
DOI
10.1056/NEJM199310213291703

The efficacy of granulocyte colony-stimulating factor following autologous bone marrow transplantation for non-Hodgkin's lymphoma with monoclonal antibody purged bone marrow.

Cloned colony-stimulating factors have been shown to accelerate myeloid recovery following autologous bone marrow transplantation. Studies with granulocyte-macrophage colony-stimulating factor (GM-CSF) have demonstrated efficacy in accelerating neutrophil recovery in patients rescued from myeloablative therapy. In our previous study, however, the subset of patients who received monoclonal antibody and complement purged bone marrow grafts followed by GM-CSF recovered neutrophil counts at the same rate as placebo-treated patients. We have now performed a phase II trial to assess whether granulocyte colony-stimulating factor (G-CSF) results in accelerated engraftment in this group of patients. Twenty-three consecutive patients with recurrent non-Hodgkin's lymphoma received G-CSF (10.5 +/- 1.2 micrograms/kg per day) following myeloablative therapy consisting of etoposide (60 mg/kg), cyclophosphamide (100 mg/kg), and either carmustine (15 mg/kg) or fractionated total body irradiation (1200 cGy). All patients received bone marrow grafts which had been purged with a panel of monoclonal antibodies directed against either B or T cell determinants plus complement. Peripheral blood mononuclear cells (PBMC) were not administered to any of the patients in this study. Twenty-one patients engrafted at a median absolute neutrophil count (ANC) greater than 500/microliters at day 12 and ANC greater than 1000/microliters at day 14. The time to myeloid engraftment was significantly shortened compared to our previous experience with either GM-CSF or placebo following identical preparatory regimens (p < 0.01). G-CSF is capable of accelerating myeloid engraftment in patients receiving monoclonal antibody purged bone marrow grafts following myeloablative therapy when compared to historical control groups treated with placebo or GM-CSF.

Authors
Schriber, JR; Negrin, RS; Chao, NJ; Long, GD; Horning, SJ; Blume, KG
MLA Citation
Schriber, JR, Negrin, RS, Chao, NJ, Long, GD, Horning, SJ, and Blume, KG. "The efficacy of granulocyte colony-stimulating factor following autologous bone marrow transplantation for non-Hodgkin's lymphoma with monoclonal antibody purged bone marrow." Leukemia 7.10 (October 1993): 1491-1495.
PMID
7692189
Source
pubmed
Published In
Leukemia
Volume
7
Issue
10
Publish Date
1993
Start Page
1491
End Page
1495

Epstein-Barr virus-associated lymphoproliferative disorder following autologous bone marrow transplantation for non-Hodgkin's lymphoma.

Authors
Chao, NJ; Berry, GJ; Advani, R; Horning, SJ; Weiss, LM; Blume, KG
MLA Citation
Chao, NJ, Berry, GJ, Advani, R, Horning, SJ, Weiss, LM, and Blume, KG. "Epstein-Barr virus-associated lymphoproliferative disorder following autologous bone marrow transplantation for non-Hodgkin's lymphoma." Transplantation 55.6 (June 1993): 1425-1428.
PMID
8390736
Source
pubmed
Published In
Transplantation
Volume
55
Issue
6
Publish Date
1993
Start Page
1425
End Page
1428

Granulocyte colony-stimulating factor "mobilized" peripheral blood progenitor cells accelerate granulocyte and platelet recovery after high-dose chemotherapy.

Hematopoietic growth factors have been used to accelerate engraftment after bone marrow transplantation and to "mobilize" peripheral blood progenitor cells (PBPC). We report on the data in 85 consecutive patients with Hodgkin's disease who were treated in a single institution using different methods to obtain PB progenitor cells. Use of granulocyte colony-stimulating factor for mobilization resulted in a significantly accelerated time to recovery of granulocytes (10 days v 12 days, P < .01) when compared with "nonmobilized" PBPC recipients. Similarly, use of mobilized PBPC resulted in a significantly accelerated time to platelet engraftment (13 days v 30 days, P < .001) when compared with "nonmobilized" recipients. Moreover, there was a statistically significant difference in total costs in favor of the group receiving "mobilized" PBPC.

Authors
Chao, NJ; Schriber, JR; Grimes, K; Long, GD; Negrin, RS; Raimondi, CM; Horning, SJ; Brown, SL; Miller, L; Blume, KG
MLA Citation
Chao, NJ, Schriber, JR, Grimes, K, Long, GD, Negrin, RS, Raimondi, CM, Horning, SJ, Brown, SL, Miller, L, and Blume, KG. "Granulocyte colony-stimulating factor "mobilized" peripheral blood progenitor cells accelerate granulocyte and platelet recovery after high-dose chemotherapy." Blood 81.8 (April 15, 1993): 2031-2035.
PMID
7682454
Source
pubmed
Published In
Blood
Volume
81
Issue
8
Publish Date
1993
Start Page
2031
End Page
2035

Extended follow-up in 212 long-term allogeneic bone marrow transplant survivors. Issues of quality of life.

A group of 235 allogeneic marrow recipients were contacted at least one year following their BMT to obtain information on their quality of life; 212 (90%) agreed to participate in this survey. A total of 162 adults and 50 pediatric survivors were interviewed during clinic visits (5%) or over the telephone (95%). Changes in productive activity and marital status at the time of interview were studied, as well as the presence of physical symptoms and perception of a general sense of well-being. Older transplant recipients were observed to have a significantly higher incidence of chronic graft-versus-host disease, common colds, and skin changes when compared with pediatric transplant recipients (P < 0.01). Older subjects were also more likely to require any type of regular medication. Younger survivors were rated with a higher Karnofsky performance status and global subjective score. There were no significant differences between patients who received TBI as part of the conditioning regimen and those who did not, with the exception of increased cataract development in pediatric patients receiving TBI (P < 0.008). We conclude that most allogeneic marrow transplant survivors, especially those individuals of younger age at the time of their transplants, are doing well in the domains tested.

Authors
Schmidt, GM; Niland, JC; Forman, SJ; Fonbuena, PP; Dagis, AC; Grant, MM; Ferrell, BR; Barr, TA; Stallbaum, BA; Chao, NJ
MLA Citation
Schmidt, GM, Niland, JC, Forman, SJ, Fonbuena, PP, Dagis, AC, Grant, MM, Ferrell, BR, Barr, TA, Stallbaum, BA, and Chao, NJ. "Extended follow-up in 212 long-term allogeneic bone marrow transplant survivors. Issues of quality of life." Transplantation 55.3 (March 1993): 551-557.
PMID
8456476
Source
pubmed
Published In
Transplantation
Volume
55
Issue
3
Publish Date
1993
Start Page
551
End Page
557

Busulfan/etoposide--initial experience with a new preparatory regimen for autologous bone marrow transplantation in patients with acute nonlymphoblastic leukemia.

Current intensive chemotherapy for acute nonlymphoblastic leukemia (ANLL) results in a complete remission in the majority of patients. Unfortunately, the duration of remission is short and most of the patients will experience a relapse of their underlying disease. Autologous bone marrow (BM) transplantation is being explored as a treatment modality designed to improve relapse-free survival. We have conducted a phase II trial exploring the combination of busulfan (16 mg/kg) and etoposide (60 mg/kg) in an attempt to improve antitumor efficacy using this novel preparative regimen. To date, 50 patients (48 with ANLL and 2 patients with biphenotypic acute leukemia) have been treated. The first 20 patients received unmanipulated BM; 28 patients subsequently received 4-hydroperoxycyclophosphamide (4-HC) (60 micrograms/mL)-purged bone marrow, and 2 patients with biphenotypic acute leukemia received both 4-HC (60 micrograms/mL) and etoposide (5 micrograms/mL)-purged BM. Thirty-four patients were in first complete remission (CR1), 12 patients in second complete remission (CR2), and 4 patients in relapse. The median time from first complete remission to BM harvest was 3 months (range, 0.8 to 4) compared with median time of 2 months (range, 1.5 to 5.0) for patients in second complete remission. The median time from harvest to transplant was 1 month for both groups (range, 0.4 to 36). A median of 0.7 x 10(8) (range, 0.2 to 1.4) mononuclear cells were infused. Patients achieved an absolute neutrophil count of > or = 500/microL at a median of 26 days (range, 13 to 96), an untransfused platelet count > or = 20,000/microL at a median of 56 days (range, 15 to 278) and a sustained hematocrit > or = 30% at a median of 50 days (range, 19 to 116). Twenty-six patients are alive and in continued CR. Follow-up of the surviving patients ranged from 6 months to 66 months with a median follow-up of 31 months. Patients receiving purged BM have an actuarial disease-free survival of 57% with a relapse rate of 28% compared with patients receiving unpurged BM whose actuarial disease-free survival is 32% with a relapse rate of 62% (P = .06 for relapse rate). The most significant extramedullary toxicities for this regimen are hepatic and cutaneous (including mucositis). The BU/VP-16 regimen is associated with a significant proportion of patients surviving disease free, especially in the group receiving purged BM. Whether this regimen offers a substantial improvement in disease-free survival over currently used regimens will require a prospective randomized study.

Authors
Chao, NJ; Stein, AS; Long, GD; Negrin, RS; Amylon, MD; Wong, RM; Forman, SJ; Blume, KG
MLA Citation
Chao, NJ, Stein, AS, Long, GD, Negrin, RS, Amylon, MD, Wong, RM, Forman, SJ, and Blume, KG. "Busulfan/etoposide--initial experience with a new preparatory regimen for autologous bone marrow transplantation in patients with acute nonlymphoblastic leukemia." Blood 81.2 (January 15, 1993): 319-323.
PMID
8422458
Source
pubmed
Published In
Blood
Volume
81
Issue
2
Publish Date
1993
Start Page
319
End Page
323

Effects of the methoxymorpholino derivative of doxorubicin and its bioactivated form versus doxorubicin on human leukemia and lymphoma cell lines and normal bone marrow.

The methoxymorpholino derivative of doxorubicin (MMDX; FCE 23672) has recently entered clinical trials because of its broad spectrum of preclinical antitumor activity and non-cross-resistance in multidrug-resistant (MDR) tumor models. MMDX is activated in the liver to a > 10 times more potent metabolite that cross-links DNA. To assess the potential of this drug in hematologic malignancies, we studied the myelotoxicity in vitro and antitumor effect of MMDX as well as its bioactivated form (MMDX+) in a panel of 14 different human leukemia and lymphoma cell lines. The tumor specificity of MMDX in CEM and K562 cells was similar to that of doxorubicin (DOX), and that of MMDX+ was slightly superior. All of the 14 cell lines were found to be more sensitive to MMDX and MMDX+ than were granulocyte-macrophage progenitors. On a molar basis, MMDX was approximately 3-100 times more active than DOX, and MMDX+ was 10-1,000 times more potent than DOX. The cytotoxic effect of MMDX and MMDX+ in two P-glycoprotein-positive MDR sublines was greatly improved in comparison with that of DOX. Whereas the response to DOX in the different leukemia and lymphoma cell lines was highly heterogeneous, the response to MMDX and MMDX+ was rather homogeneous. The novel anthracycline MMDX and its bioactivated form MMDX+ are highly active against this panel of human leukemia and lymphoma cell lines and demonstrate potentially greater selectivity for tumor cells in vitro as compared with normal bone marrow precursors.

Authors
Kühl, JS; Durán, GE; Chao, NJ; Sikic, BI
MLA Citation
Kühl, JS, Durán, GE, Chao, NJ, and Sikic, BI. "Effects of the methoxymorpholino derivative of doxorubicin and its bioactivated form versus doxorubicin on human leukemia and lymphoma cell lines and normal bone marrow." Cancer Chemother Pharmacol 33.1 (1993): 10-16.
PMID
8269583
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
33
Issue
1
Publish Date
1993
Start Page
10
End Page
16

Graft versus host disease following allogeneic bone marrow transplantation.

Graft versus host disease is a major barrier in allogeneic bone marrow transplantation. The associated morbidity and mortality need to be understood and prevented if possible, as the potential indications for bone marrow transplantation continue to broaden. Areas of investigation include the cellular effector arm as well as the cytokines associated with the expression of the disease.

Authors
Chao, NJ
MLA Citation
Chao, NJ. "Graft versus host disease following allogeneic bone marrow transplantation." Curr Opin Immunol 4.5 (October 1992): 571-576. (Review)
PMID
1418721
Source
pubmed
Published In
Current Opinion in Immunology
Volume
4
Issue
5
Publish Date
1992
Start Page
571
End Page
576

Use of etoposide in combination with cyclosporin for purging multidrug-resistant leukemic cells from bone marrow in a mouse model.

Cyclosporin (CsA) is a potent modulator of multidrug resistance (MDR) and has been combined with etoposide (VP-16) to purge MDR leukemic cells from human bone marrow (BM) in vitro. We studied the feasibility of this approach in an in vivo model for autologous BM transplantation using the murine leukemia cell line P388 and its MDR variant P388/ADR. Colony-forming assays with 2-h drug exposure revealed a tumor selectivity of VP-16 for P388 cells compared to normal murine marrow granulocyte-macrophage colony-forming units (CFU-GM), whereas P388/ADR cells were resistant to VP-16. Simultaneous incubation with CsA restored sensitivity in these cells. Almost 4 logs of cell kill were achieved by treating P388/ADR cells with 60 microM VP-16 plus 2.5 microM CsA (combination A) or 40 microM VP-16 plus 10 microM CsA (combination B), whereas there was a 2.5-log reduction of CFU-GM at these doses. Even though the myelotoxicity of VP-16 was increased by the addition of CsA, this effect was nonspecific as shown by a similar chemosensitization in sensitive P388 as well as in P388/VP 2.5 cells, an atypical MDR variant lacking P-glycoprotein. In vivo experiments addressed the ability of BM treated with VP-16 and CsA to rescue lethally irradiated mice and to purge leukemic cells. In total, 1/14 lethally irradiated mice died due to sepsis within 10 days after receiving 15 x 10(6) BM cells treated ex vivo with combination A in contrast to 1/4 for combination B. All 16 surviving animals demonstrated long-term engraftment. When simulated remission marrow contaminated with 0.1% P388/ADR was purged with VP-16 (60 microM) or CsA (2.5 microM) alone, all mice died from leukemia before day 16 after transplantation (median 14.3 and 12.2 days). In contrast, nine of ten animals receiving similar marrow purged with combination A survived > 60 days without any evidence of disease (p < 0.01). We conclude that combining VP-16 and CsA was effective in purging MDR leukemia cells from transplanted BM in this murine model.

Authors
Kühl, JS; Sikic, BI; Blume, KG; Chao, NJ
MLA Citation
Kühl, JS, Sikic, BI, Blume, KG, and Chao, NJ. "Use of etoposide in combination with cyclosporin for purging multidrug-resistant leukemic cells from bone marrow in a mouse model." Exp Hematol 20.9 (October 1992): 1048-1054.
PMID
1468539
Source
pubmed
Published In
Experimental Hematology
Volume
20
Issue
9
Publish Date
1992
Start Page
1048
End Page
1054

Dynamic assessment of quality of life after autologous bone marrow transplantation.

To determine the quality of life in adult patients after autologous bone marrow transplantation (BMT), we administered a questionnaire to a cohort of patients seen at a single referral-based center. The sample included adults 18 years and older during the 1 year following an autologous BMT. Both disease-free patients and those who relapsed with 1-year of follow-up data available were included. Of 59 eligible patients, 58 (98%) responded to the questionnaire. Patients completed a telephone questionnaire administered by a nurse specialist in the field of BMT approximately every 90 days. At the time of initial contact on day +90, the mean quality of life was 7.8 (range, 1 to 10) on a scale of 1 to 10, with 10 being the best. By the end of the first year of follow-up, the mean quality of life was 8.9 (range, 3 to 10). Seventy-eight percent of the patients were employed. Twenty-one percent lost weight during the first year, with the majority reporting voluntary weight loss. Fourteen percent reported difficulties with sexual activity. Only 5% reported difficulty with sleeping or with frequent colds. One patient felt that her appearance was worse, and none of the patients reported a poor appetite. Eighty-eight percent of surviving adult patients reported an above-average to excellent quality of life 1 year following autologous BMT. This outcome is encouraging and suggests that this procedure is not associated with long-term morbidity in the surviving adult patient.

Authors
Chao, NJ; Tierney, DK; Bloom, JR; Long, GD; Barr, TA; Stallbaum, BA; Wong, RM; Negrin, RS; Horning, SJ; Blume, KG
MLA Citation
Chao, NJ, Tierney, DK, Bloom, JR, Long, GD, Barr, TA, Stallbaum, BA, Wong, RM, Negrin, RS, Horning, SJ, and Blume, KG. "Dynamic assessment of quality of life after autologous bone marrow transplantation." Blood 80.3 (August 1, 1992): 825-830.
PMID
1638031
Source
pubmed
Published In
Blood
Volume
80
Issue
3
Publish Date
1992
Start Page
825
End Page
830

G-CSF and peripheral blood progenitor cells.

Authors
Chao, NJ; Long, GD; Negrin, RS; Schriber, JR; Raimondi, CM; Brown, SL; Blume, KG
MLA Citation
Chao, NJ, Long, GD, Negrin, RS, Schriber, JR, Raimondi, CM, Brown, SL, and Blume, KG. "G-CSF and peripheral blood progenitor cells." Lancet 339.8806 (June 6, 1992): 1410-. (Letter)
PMID
1375969
Source
pubmed
Published In
The Lancet
Volume
339
Issue
8806
Publish Date
1992
Start Page
1410

Expression of multidrug resistance gene mdr1 mRNA in a subset of normal bone marrow cells.

The multidrug resistance gene mdr1, encoding P-glycoprotein (P-gp), can be expressed at high levels in tumour cells derived from normal tissues with constitutive high expression of this gene. In myelogenous leukaemia, the incidence of increased expression of mdr1 gene contrasts with the low expression of this gene in normal bone marrow (b.m.). To detect cells expressing mdr1 gene in normal and post-chemotherapy b.m., we used in situ RNA hybridization and RNA phenotyping by the polymerase chain reaction for mdr1 mRNA detection. The presence of P-gp was evaluated by immunocytochemistry with MRK16. Fifteen b.m. (eight normal and seven post chemotherapy) were tested by in situ hybridization and either PCR (three b.m.) or immunocytochemistry (11 b.m.) or both (one b.m.). With in situ mRNA hybridization, a subset (7.7% +/- 3.1%) of b.m. cells expressed mdr1 mRNA in all cases tested, with no significant differences between normal b.m. and post chemotherapy b.m. 18% of myeloid recognizable cells and 7% of the cells with lymphoid morphology expressed mdr1 mRNA. By RNA phenotyping, the four samples tested for in situ hybridization and two additional post chemotherapy b.m. expressed mdr1. MRK16 was unable to detect a significant number of cells expressing P-gp either by immunocytochemistry in the 12 b.m. tested for in situ hybridization (0% in nine cases; 0.4%, 1% and 3% of positive cells in three cases), or by flow cytometry in six additional normal b.m. (0-1.4% positive cells).

Authors
Marie, JP; Brophy, NA; Ehsan, MN; Aihara, Y; Mohamed, NA; Cornbleet, J; Chao, NJ; Sikic, BI
MLA Citation
Marie, JP, Brophy, NA, Ehsan, MN, Aihara, Y, Mohamed, NA, Cornbleet, J, Chao, NJ, and Sikic, BI. "Expression of multidrug resistance gene mdr1 mRNA in a subset of normal bone marrow cells." Br J Haematol 81.2 (June 1992): 145-152.
PMID
1353683
Source
pubmed
Published In
British Journal of Haematology
Volume
81
Issue
2
Publish Date
1992
Start Page
145
End Page
152

Granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjunct to autologous hemopoietic stem cell transplantation for lymphoma.

OBJECTIVE: To determine the hemopoietic effects of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients having autologous hemopoietic stem cell transplantation for Hodgkin or non-Hodgkin lymphoma. DESIGN: Placebo or GM-CSF was administered after bone marrow or peripheral blood stem cell transplantation or both in a randomized, double-blind phase III trial by daily intravenous infusion (10 micrograms/kg body weight) until absolute neutrophil counts reached greater than or equal to 1000/mm3 on 3 consecutive days. SETTING: Bone marrow transplantation unit in a university hospital. PATIENTS: Sixty-nine consecutive patients with Hodgkin or non-Hodgkin lymphoma received GM-CSF (36 patients) or placebo (33 patients). MEASUREMENTS AND MAIN RESULTS: Patients who received GM-CSF achieved absolute neutrophil counts greater than or equal to 500/mm3 (median, 12 compared with 16 days, P = 0.02) and absolute neutrophil counts greater than or equal to 1000/mm3 (median, 15 compared with 24 days, P less than 0.001) more quickly than patients who received placebo. Multivariate analysis indicated that use of GM-CSF, peripheral blood stem cells, and unpurged bone marrow were the strongest predictors for early neutrophil recovery greater than 500/mm3. Bacterial infections were significantly reduced in the GM-CSF group (P = 0.04). Delayed engraftment (neutrophils less than 500/mm3 at day 30) occurred in 26% and 17% of the placebo and GM-CSF groups, respectively, and correlated with the absence of detectable myeloid progenitor cells (colony-forming units-granulocyte macrophage, CFU-GM) (P less than 0.001) in marrow aspirate specimens obtained on day 15. Time to platelet independence, duration of hospital stay, severe adverse reactions, relapse, and disease-free survival rates did not differ significantly between the two groups. CONCLUSIONS: Administration of GM-CSF after autologous hemopoietic stem cell transplantation in patients with lymphoma resulted in accelerated myeloid recovery, particularly in patients who received peripheral blood stem cells and nonpurged bone marrow, and was associated with a decreased incidence of bacterial infections.

Authors
Advani, R; Chao, NJ; Horning, SJ; Blume, KG; Ahn, DK; Lamborn, KR; Fleming, NC; Bonnem, EM; Greenberg, PL
MLA Citation
Advani, R, Chao, NJ, Horning, SJ, Blume, KG, Ahn, DK, Lamborn, KR, Fleming, NC, Bonnem, EM, and Greenberg, PL. "Granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjunct to autologous hemopoietic stem cell transplantation for lymphoma." Ann Intern Med 116.3 (February 1, 1992): 183-189.
PMID
1345803
Source
pubmed
Published In
Annals of internal medicine
Volume
116
Issue
3
Publish Date
1992
Start Page
183
End Page
189

In vitro and in vivo activity of murine lymphokine-activated killer cells after cryopreservation.

The in vitro and in vivo effects of cryopreservation on the cytotoxic activity of murine lymphokine-activated killer (LAK) cells were studied. LAK cells were generated by incubation of spleen lymphocytes of BALB/c mice for 3 days with recombinant interleukin-2 (rIL-2) and subsequent cryopreservation. Cytotoxicity was determined in a 51Cr release assay. After thawing, cytotoxic activity was reduced (40.4% 51Cr release at an effector:target cell ratio of 40:1 as compared to 68.5% 51Cr release before freezing) and could be restored to precryopreserved levels by reincubation with rIL-2 for 2 days after thawing (78.8% 51Cr release). These cells were then tested in BALB/c mice injected with RAW 112 cells, a pre-B-cell lymphoma line. The results demonstrate that the survival rate of mice injected with cryopreserved and restimulated LAK cells (50% survival greater than 180 days after injection) did not differ significantly from that of mice injected with fresh unfrozen LAK cells (60% survival greater than 120 days, 50% survival greater than 180 days). Cryopreserved LAK cells have potential use in adoptive immunotherapy.

Authors
Schmidt-Wolf, IG; Aihara, M; Negrin, RS; Blume, KG; Chao, NJ
MLA Citation
Schmidt-Wolf, IG, Aihara, M, Negrin, RS, Blume, KG, and Chao, NJ. "In vitro and in vivo activity of murine lymphokine-activated killer cells after cryopreservation." Transfusion 32.1 (January 1992): 42-45.
PMID
1731434
Source
pubmed
Published In
Transfusion
Volume
32
Issue
1
Publish Date
1992
Start Page
42
End Page
45

Purging multidrug resistant cells from bone marrow.

Authors
Chao, NJ; Aihara, M; Kühl, JS; Sikic, BI; Blume, KG
MLA Citation
Chao, NJ, Aihara, M, Kühl, JS, Sikic, BI, and Blume, KG. "Purging multidrug resistant cells from bone marrow." Prog Clin Biol Res 377 (1992): 13-23. (Review)
PMID
1438409
Source
pubmed
Published In
Progress in Clinical and Biological Research
Volume
377
Publish Date
1992
Start Page
13
End Page
23

Use of etoposide in combination with cyclosporine for purging multidrug resistant leukemic cells from bone marrow in a mouse model.

Authors
Kühl, JS; Sikic, BI; Blume, KG; Chao, NJ
MLA Citation
Kühl, JS, Sikic, BI, Blume, KG, and Chao, NJ. "Use of etoposide in combination with cyclosporine for purging multidrug resistant leukemic cells from bone marrow in a mouse model." Prog Clin Biol Res 377 (1992): 25-34.
PMID
1438422
Source
pubmed
Published In
Progress in Clinical and Biological Research
Volume
377
Publish Date
1992
Start Page
25
End Page
34

Allogeneic bone marrow transplantation for high-risk acute lymphoblastic leukemia during first complete remission.

Fifty-three patients with high-risk acute lymphoblastic leukemia (ALL) under age 50 with a histocompatible sibling donor received high-dose radiochemotherapy followed by allogeneic bone marrow transplantation (BMT). The high-risk factors used to identify the patients were: white blood cell count at initial presentation, cytogenetic abnormalities, age, extramedullary leukemic infiltration, and time from initial therapy to complete remission. Patients with one or more of the above risk factors who received BMT have a disease-free survival of 61% with a median follow-up of 66 months (range 11 months to 10.6 years), and an actuarial relapse rate of 10%. This study demonstrates that patients with high-risk ALL achieve a significant disease-free survival and cure rate with the use of allogeneic fully matched sibling BMT. However, a properly designed prospective study comparing the outcome of BMT with the best currently available chemotherapy data is required to define the ultimate role of BMT in this group of patients.

Authors
Chao, NJ; Forman, SJ; Schmidt, GM; Snyder, DS; Amylon, MD; Konrad, PN; Nademanee, AP; O'Donnell, MR; Parker, PM; Stein, AS
MLA Citation
Chao, NJ, Forman, SJ, Schmidt, GM, Snyder, DS, Amylon, MD, Konrad, PN, Nademanee, AP, O'Donnell, MR, Parker, PM, and Stein, AS. "Allogeneic bone marrow transplantation for high-risk acute lymphoblastic leukemia during first complete remission." Blood 78.8 (October 15, 1991): 1923-1927.
PMID
1912575
Source
pubmed
Published In
Blood
Volume
78
Issue
8
Publish Date
1991
Start Page
1923
End Page
1927

Allogeneic bone marrow transplantation as therapy for primary induction failure for patients with acute leukemia.

The survival of patients with acute leukemia who do not achieve a remission with primary therapy is very poor. High-dose chemoradiotherapy followed by allogeneic bone marrow transplantation (BMT) has been shown to be effective therapy for patients with acute and chronic leukemia. Therefore, we determined the long-term disease-free survival of patients who did not achieve a remission and were then treated with high-dose therapy and bone marrow allografting from matched sibling donors. Twenty-one patients (median age, 28 years) who did not achieve a remission with induction chemotherapy were subsequently treated with allogeneic BMT. After BMT, 90% achieved a complete remission. Six died of complications of the therapy, and six patients relapsed between 27 and 448 days after BMT. Nine patients (43%; median age, 25 years) are alive between 556 and 4,174 days after BMT. The cumulative probability of disease-free survival at 10 years is 43%. This study suggests that allogeneic BMT can be an effective therapy to achieve long-term control of acute leukemia, even in those patients who do not achieve a remission with primary therapy.

Authors
Forman, SJ; Schmidt, GM; Nademanee, AP; Amylon, MD; Chao, NJ; Fahey, JL; Konrad, PN; Margolin, KA; Niland, JC; O'Donnell, MR
MLA Citation
Forman, SJ, Schmidt, GM, Nademanee, AP, Amylon, MD, Chao, NJ, Fahey, JL, Konrad, PN, Margolin, KA, Niland, JC, and O'Donnell, MR. "Allogeneic bone marrow transplantation as therapy for primary induction failure for patients with acute leukemia." J Clin Oncol 9.9 (September 1991): 1570-1574.
PMID
1875218
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
9
Issue
9
Publish Date
1991
Start Page
1570
End Page
1574
DOI
10.1200/JCO.1991.9.9.1570

Importance of bone marrow cytogenetic evaluation before autologous bone marrow transplantation for Hodgkin's disease.

Alkylating agents used either with or without radiation therapy have been associated with the development of myelodysplastic syndrome (MDS) and acute nonlymphoblastic leukemia (ANLL) after treatment of both malignant and nonmalignant disorders. This report describes seven patients with recurrent Hodgkin's disease (HD) evaluated for bone marrow transplantation (BMT) who developed chromosomal abnormalities, and emphasizes the importance of bone marrow cytogenetic studies before bone marrow harvest. Three patients with histologically normal bone marrow underwent autologous BMT and subsequently developed an MDS or ANLL. Four patients had the clonal abnormality detected before bone marrow harvest and did not proceed to BMT.

Authors
Chao, NJ; Nademanee, AP; Long, GD; Schmidt, GM; Donlon, TA; Parker, P; Slovak, ML; Nagasawa, LS; Blume, KG; Forman, SJ
MLA Citation
Chao, NJ, Nademanee, AP, Long, GD, Schmidt, GM, Donlon, TA, Parker, P, Slovak, ML, Nagasawa, LS, Blume, KG, and Forman, SJ. "Importance of bone marrow cytogenetic evaluation before autologous bone marrow transplantation for Hodgkin's disease." J Clin Oncol 9.9 (September 1991): 1575-1579.
PMID
1875219
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
9
Issue
9
Publish Date
1991
Start Page
1575
End Page
1579
DOI
10.1200/JCO.1991.9.9.1575

A combined approach for purging multidrug-resistant leukemic cell lines in bone marrow using a monoclonal antibody and chemotherapy.

Selective removal of malignant cells (purging) from bone marrow (BM) is a concern in autologous BM transplantation (ABMT). Use of vincristine, etoposide, or doxorubicin for purging could be rendered ineffective by the presence of multidrug-resistant (MDR) tumor cells. To circumvent this particular problem, we investigated whether 17F9, a monoclonal IgG2b antibody directed against the cell surface product of the MDR gene, P-glycoprotein, is effective in selective removal of MDR cells from BM when used with rabbit complement (C'). Using two different cell lines we have demonstrated that 17F9 + C' selectively lyses MDR-positive cells. Three rounds of antibody + C' resulted in 96.4% +/- 3.6% kill of K562/DOX and 100% +/- 0% of CEM/VLB cells. Mixtures of malignant cells and normal BM resulted in 99.85% removal of K562/DOX and 99.91% removal of CEM/VLB clonogenic cells. This treatment did not affect normal committed precursors compared with C' alone. The addition of the cytotoxic agent etoposide (VP-16) following antibody purging results in a 4.6 log reduction of malignant cells. Furthermore, this antibody was effective when used against patients' leukemic blasts. These results suggest the use of 17F9 + C' is effective and selective for removal of MDR cells from BM before ABMT and the addition of VP-16 enhances the purging efficacy.

Authors
Aihara, M; Aihara, Y; Schmidt-Wolf, G; Schmidt-Wolf, I; Sikic, BI; Blume, KG; Chao, NJ
MLA Citation
Aihara, M, Aihara, Y, Schmidt-Wolf, G, Schmidt-Wolf, I, Sikic, BI, Blume, KG, and Chao, NJ. "A combined approach for purging multidrug-resistant leukemic cell lines in bone marrow using a monoclonal antibody and chemotherapy." Blood 77.9 (May 1, 1991): 2079-2084.
PMID
1673356
Source
pubmed
Published In
Blood
Volume
77
Issue
9
Publish Date
1991
Start Page
2079
End Page
2084

Corticosteroid therapy for diffuse alveolar hemorrhage in autologous bone marrow transplant recipients.

Authors
Chao, NJ; Duncan, SR; Long, GD; Horning, SJ; Blume, KG
MLA Citation
Chao, NJ, Duncan, SR, Long, GD, Horning, SJ, and Blume, KG. "Corticosteroid therapy for diffuse alveolar hemorrhage in autologous bone marrow transplant recipients." Ann Intern Med 114.2 (January 15, 1991): 145-146.
PMID
1984392
Source
pubmed
Published In
Annals of internal medicine
Volume
114
Issue
2
Publish Date
1991
Start Page
145
End Page
146

The Stanford experience with high-dose etoposide cytoreductive regimens and autologous bone marrow transplantation in Hodgkin's disease and non-Hodgkin's lymphoma: Preliminary data

Seventy-seven Hodgkin's disease and non-Hodgkin's lymphoma (NHL) patients received high-dose etoposide in combination with cyclophosphamide and either fractionated total body irradiation (TBI) (n = 28) or carmustine (n = 49) prior to autologous bone marrow transplantation. Marrow from NHL patients was purged in vitro with a panel of monoclonal B- and T-cell antibodies and complement. Six toxic deaths (8%) occurred, all in patients who received carmustine. With a median follow-up of 1 year, 57 patients are alive and free from progressive disease. The 1-year actuarial survival and freedom from progression are 85 and 73% in fractionated TBI/etoposide/cyclophosphamide-treated patients and 79 and 72% in carmustine/etoposide/cyclophosphamide-treated patients. Forty-five of these patients participated in prospective trials for which eligibility criteria were (1) less than 25% curability with conventional therapy; (2) achievement of minimal disease state with conventional therapy; and (3) transplantation early in the course of disease. One-year actuarial survival for 18 patients with relapsed Hodgkin's disease is 80% and for 21 relapsed intermediate and high-grade NHL patients, 70%. One NHL Burkitt's patient was transplanted on a protocol for high-risk intermediate and high-grade NHL in first remission. Five patients with follicular mixed or small cleaved NHL were also transplanted in first remission.

Authors
Horning, SJ; Chao, NJ; Negrin, RS; Hoppe, RT; Kwak, LW; Long, GD; Stallbaum, B; O'Connor, P; Blume, KG
MLA Citation
Horning, SJ, Chao, NJ, Negrin, RS, Hoppe, RT, Kwak, LW, Long, GD, Stallbaum, B, O'Connor, P, and Blume, KG. "The Stanford experience with high-dose etoposide cytoreductive regimens and autologous bone marrow transplantation in Hodgkin's disease and non-Hodgkin's lymphoma: Preliminary data." January 1, 1991.
Source
scopus
Published In
Annals of Oncology
Volume
2
Issue
SUPPL. 1
Publish Date
1991
Start Page
47
End Page
50

The Stanford experience with high-dose etoposide cytoreductive regimens and autologous bone marrow transplantation in Hodgkin's disease and non-Hodgkin's lymphoma: preliminary data.

Seventy-seven Hodgkin's disease and non-Hodgkin's lymphoma (NHL) patients received high-dose etoposide in combination with cyclophosphamide and either fractionated total body irradiation (TBI) (n = 28) or carmustine (n = 49) prior to autologous bone marrow transplantation. Marrow from NHL patients was purged in vitro with a panel of monoclonal B- and T-cell antibodies and complement. Six toxic deaths (8%) occurred, all in patients who received carmustine. With a median follow-up of 1 year, 57 patients are alive and free from progressive disease. The 1-year actuarial survival and freedom from progression are 85 and 73% in fractionated TBI/etoposide/cyclophosphamide-treated patients and 79 and 72% in carmustine/etoposide/cyclophosphamide-treated patients. Forty-five of these patients participated in prospective trials for which eligibility criteria were (1) less than 25% curability with conventional therapy; (2) achievement of minimal disease state with conventional therapy; and (3) transplantation early in the course of disease. One-year actuarial survival for 18 patients with relapsed Hodgkin's disease is 80% and for 21 relapsed intermediate and high-grade NHL patients, 70%. One NHL Burkitt's patient was transplanted on a protocol for high-risk intermediate and high-grade NHL in first remission. Five patients with follicular mixed or small cleaved NHL were also transplanted in first remission.

Authors
Horning, SJ; Chao, NJ; Negrin, RS; Hoppe, RT; Kwak, LW; Long, GD; Stallbaum, B; O'Connor, P; Blume, KG
MLA Citation
Horning, SJ, Chao, NJ, Negrin, RS, Hoppe, RT, Kwak, LW, Long, GD, Stallbaum, B, O'Connor, P, and Blume, KG. "The Stanford experience with high-dose etoposide cytoreductive regimens and autologous bone marrow transplantation in Hodgkin's disease and non-Hodgkin's lymphoma: preliminary data." Ann Oncol 2 Suppl 1 (January 1991): 47-50.
PMID
2043498
Source
pubmed
Published In
Annals of Oncology
Volume
2 Suppl 1
Publish Date
1991
Start Page
47
End Page
50

A randomized, controlled trial of prophylactic ganciclovir for cytomegalovirus pulmonary infection in recipients of allogeneic bone marrow transplants

Background. Cytomegalovirus (CMV)-associated interstitial pneumonia is a major cause of death after allogeneic bone marrow transplantation. We conducted a controlled trial of ganciclovir in recipients of bone marrow transplants who had asymptomatic pulmonary CMV infection. We also sought to identify risk factors for the development of CMV interstitial pneumonia. Methods. After bone marrow transplantation, 104 patients who had no evidence of respiratory disease underwent routine bronchoalveolar lavage on day 35. The 40 patients who had positive cultures for CMV were randomly assigned to either prophylactic ganciclovir or observation alone. Ganciclovir (5 mg per kilogram of body weight intravenously) was given twice daily for two weeks and then five times per week until day 120. Results. Of the 20 culture-positive patients who received prophylactic ganciclovir, 5 (25 percent) died or had CMV pneumonia before day 120, as compared with 14 of the 20 culture-positive control patients (70 percent) who were not treated prophylactically (relative risk, 0.36; P = 0.01). No patient who received the full course of ganciclovir prophylaxis went on to have CMV interstitial pneumonia. Four patients treated with ganciclovir had maximal serum creatinine levels ≥221 μmol per liter (2.5 mg per deciliter), as compared with none of the controls (P = 0.029). Of the 55 CMV-negative patients who could be evaluated, 12 (22 percent) had CMV pneumonia - a significantly lower rate than in the untreated CMV-positive control patients (relative risk, 0.33; P = 0.003). The strongest predictors of CMV pneumonia were a lavage-fluid culture that was positive for CMV and a CMV-positive blood culture, both from specimens obtained on day 35. Conclusions. In recipients of allogeneic bone marrow, asymptomatic CMV infection of the lung is a major risk factor for subsequent CMV interstitial pneumonia. Prophylactic ganciclovir is effective in preventing the development of CMV interstitial pneumonia in patients with asymptomatic infection.

Authors
Schmidt, GM; Horak, DA; Niland, JC; Duncan, SR; Forman, SJ; Zaia, JA; Hogan, JM; Faucett, C; Hill, LR; Wall, FJ; Gallez-Hawkins, G; Morton-Blackshere, A; Nademanee, AP; O'Donnell, MR; Parker, P; Snyder, DS; Smith, E; Stein, A; Margolin, K; Somlo, G; Kovacs, AA; Chao, NJ; Blume, KG; DeArmond, B; Buhles, W; DuMond, C; Sullivan, V
MLA Citation
Schmidt, GM, Horak, DA, Niland, JC, Duncan, SR, Forman, SJ, Zaia, JA, Hogan, JM, Faucett, C, Hill, LR, Wall, FJ, Gallez-Hawkins, G, Morton-Blackshere, A, Nademanee, AP, O'Donnell, MR, Parker, P, Snyder, DS, Smith, E, Stein, A, Margolin, K, Somlo, G, Kovacs, AA, Chao, NJ, Blume, KG, DeArmond, B, Buhles, W, DuMond, C, and Sullivan, V. "A randomized, controlled trial of prophylactic ganciclovir for cytomegalovirus pulmonary infection in recipients of allogeneic bone marrow transplants." New England Journal of Medicine 324.15 (1991): 1005-1011.
Source
scival
Published In
New England Journal of Medicine
Volume
324
Issue
15
Publish Date
1991
Start Page
1005
End Page
1011

Modulation of etoposide (VP-16) cytotoxicity by verapamil or cyclosporine in multidrug-resistant human leukemic cell lines and normal bone marrow.

We studied the effects of two modulators of multidrug resistance (MDR), cyclosporine and verapamil, on the cytotoxicity of etoposide (VP-16) in normal human bone marrow; two human leukemia cell lines, K562 and CEM; their MDR variants, K562/DOX and CEM/VLB; and mixtures of normal marrow and leukemic cells. VP-16 was selectivity toxic to the parental leukemic cells, with IC-50 values of 2 microM for CEM cells, 1.5 microM for K562 cells, and 12 microM for normal marrow CFU-GM. This selectivity was lost in the MDR variant leukemia cells, with IC-50s of 20 microM in K562/DOX and 8 microMs in CEM/VLB. Cyclosporine, 6 microMs, and verapamil, 20 microM, alone were nontoxic to bone marrow CFU-GM, and did not significantly increase the toxicity of VP-16 to normal marrow cells or to the two drug-sensitive leukemic cell lines. However, cyclosporine specifically enhanced the cytotoxicity of VP-16 in the MDR leukemia cells, reducing the IC-50 to the same level as the parental sensitive cells. Verapamil was considerably less effective. In a mixing experiment that included K562/DOX cells and normal bone marrow, cyclosporine increased the toxicity of VP-16 to the resistant leukemic cells by nearly 20-fold. Because the cytotoxic effect of cyclosporine is additive for resistant tumor cells, its combination with VP-16 may be useful in the purging of contaminating tumor cells prior to autologous bone marrow transplantation.

Authors
Chao, NJ; Aihara, M; Blume, KG; Sikic, BI
MLA Citation
Chao, NJ, Aihara, M, Blume, KG, and Sikic, BI. "Modulation of etoposide (VP-16) cytotoxicity by verapamil or cyclosporine in multidrug-resistant human leukemic cell lines and normal bone marrow." Exp Hematol 18.11 (December 1990): 1193-1198.
PMID
2226679
Source
pubmed
Published In
Experimental Hematology
Volume
18
Issue
11
Publish Date
1990
Start Page
1193
End Page
1198

CEPP(B): an effective and well-tolerated regimen in poor-risk, aggressive non-Hodgkin's lymphoma.

Eighty-three patients with intermediate- or high-grade non-Hodgkin's lymphoma were treated with CEPP(B) (cyclophosphamide, etoposide [VP-16], procarbazine, and prednisone with or without bleomycin) chemotherapy at Stanford University Medical Center (Stanford, CA) from January 1982 through June 1989. Sixty-nine received CEPP(B) as second-line or subsequent therapy after relapse from previous combination chemotherapy, and 14 patients received CEPP(B) as first-line therapy. Of 75 patients evaluable for response, 30 patients (40%) achieved a complete response (CR) and 24 patients (32%) achieved a partial response (PR), providing an overall response rate of 72%. Complete responses were recorded on 21 of 61 (34%) patients with recurrent disease and 9 of the 14 patients who received CEPP(B) as first line therapy (64%). Myelosuppression was the major side effect of treatment, resulting in eight neutropenic-febrile episodes from a total of 253 courses. A single fatal toxic event occurred on a patient who developed adult respiratory distress syndrome. Overall, CEPP(B) was well-tolerated and proved to be effective palliative therapy for patients with non-Hodgkin's lymphoma after relapse. As such, CEPP(B) may be considered for cytoreduction before ablative therapy and bone marrow transplantation. CEPP(B) may also be considered for initial therapy in selected patients who cannot tolerate doxorubicin-containing regimens.

Authors
Chao, NJ; Rosenberg, SA; Horning, SJ
MLA Citation
Chao, NJ, Rosenberg, SA, and Horning, SJ. "CEPP(B): an effective and well-tolerated regimen in poor-risk, aggressive non-Hodgkin's lymphoma." Blood 76.7 (October 1, 1990): 1293-1298.
PMID
2207307
Source
pubmed
Published In
Blood
Volume
76
Issue
7
Publish Date
1990
Start Page
1293
End Page
1298

Bone marrow transplantation: what is the question?

Authors
Chao, NJ; Blume, KG
MLA Citation
Chao, NJ, and Blume, KG. "Bone marrow transplantation: what is the question?." Ann Intern Med 113.5 (September 1, 1990): 340-341.
PMID
2382915
Source
pubmed
Published In
Annals of internal medicine
Volume
113
Issue
5
Publish Date
1990
Start Page
340
End Page
341

Assessment of purging with multidrug resistance (MDR) modulators and VP-16: results of long-term marrow culture.

We studied the effects of two modulators of multidrug resistance (MDR), cyclosporine and verapamil, on the cytotoxicity of etoposide (VP-16) in normal bone marrow cells. VP-16 was toxic to normal bone marrow at concentrations greater than 50 microM, resulting in no granulocyte-macrophage colony-forming units (CFU-GM) in short-term methylcellulose cultures. However, in long-term marrow cultures (LTMC) treatment with VP-16 without the addition of MDR modulators resulted in only a twofold decrease in total cell number at a VP-16 concentration of 50 microM, compared to media alone in the adherent cell layer, and approximately 20% recovery of CFU-GM. The addition of MDR modulators did not result in excessive cytotoxicity, reducing the total CFU-GM by two- to threefold even at the higher VP-16 concentration. Therefore, these modulators in conjunction with VP-16 can be safely used on normal bone marrow cells and may provide an effective method to purge MDR-tumor cells.

Authors
Aihara, M; Sikic, BI; Blume, KG; Chao, NJ
MLA Citation
Aihara, M, Sikic, BI, Blume, KG, and Chao, NJ. "Assessment of purging with multidrug resistance (MDR) modulators and VP-16: results of long-term marrow culture." Exp Hematol 18.8 (September 1990): 940-944.
PMID
2387345
Source
pubmed
Published In
Experimental Hematology
Volume
18
Issue
8
Publish Date
1990
Start Page
940
End Page
944

Bone marrow transplantation. Part II--autologous.

Autologous bone marrow transplantation provides an effective form of "rescue" following high-dose therapy used for treating certain malignant diseases. The high doses of radiotherapy or chemotherapy, or both, should allow for greater tumor cell kill if dose-response to therapy exists for that tumor. The use of autologous bone marrow obviates the need for an HLA-identical donor, and the need for pretransplant immunosuppression; no graft-versus-host disease would ensue. We review in part II the history and background, methods of obtaining autologous stem cells, and details of the results achievable with this type of therapy. We discuss potential difficulties with autologous transplantation, as well as possible future areas of research.

Authors
Chao, NJ; Blume, KG
MLA Citation
Chao, NJ, and Blume, KG. "Bone marrow transplantation. Part II--autologous." West J Med 152.1 (January 1990): 46-51. (Review)
PMID
2408234
Source
pubmed
Published In
Western Journal of Medicine
Volume
152
Issue
1
Publish Date
1990
Start Page
46
End Page
51

Bone marrow transplantation from histocompatible sibling donors for patients with acute lymphoblastic leukemia.

Authors
Blume, KG; Schmidt, GM; Chao, NJ; Forman, SJ
MLA Citation
Blume, KG, Schmidt, GM, Chao, NJ, and Forman, SJ. "Bone marrow transplantation from histocompatible sibling donors for patients with acute lymphoblastic leukemia." Haematol Blood Transfus 33 (1990): 636-637.
PMID
2323664
Source
pubmed
Published In
Haematology and blood transfusion
Volume
33
Publish Date
1990
Start Page
636
End Page
637

Bone marrow transplantation for hematologic malignancies: the Stanford experience.

Allogeneic and autologous BMTs are highly effective and successful treatment modalities for selected patients. Use of BMT earlier in the course of disease yields better results when compared to patients with more advanced disease. Recent advances such as use of cloned growth factors, cytokines, etc..., will continue to contribute to lessen morbidity and mortality. Finally, as investigators understand, prevent, and treat expected side effects from BMTs, the patients' burden in terms of physical, psychological, and financial costs should lessen substantially.

Authors
Chao, NJ; Amylon, MD; Long, GD; Negrin, RS; Hoppe, RT; Horning, SJ; Blume, KG
MLA Citation
Chao, NJ, Amylon, MD, Long, GD, Negrin, RS, Hoppe, RT, Horning, SJ, and Blume, KG. "Bone marrow transplantation for hematologic malignancies: the Stanford experience." Clin Transpl (1990): 157-163.
PMID
2103141
Source
pubmed
Published In
Clinical transplants
Publish Date
1990
Start Page
157
End Page
163

Lymphokine-activated killer cell activity after cryopreservation.

The effect of cryopreservation on the cytotoxic activity of lymphokine-activated killer (LAK) cells was studied. LAK cells were generated by incubating peripheral blood lymphocytes for 3-5 days with recombinant interleukin-2 (rIL-2) and then cryopreserved using a programmed freezer. Cytotoxicity was determined in a 51Cr release assay. After thawing, the LAK cells had reduced cytotoxicity (25.5-39.1% as compared to the original lytic units). Cytotoxic activity could be restored to pre-cryopreserved levels by reincubation with rIL-2 for 2 days after thawing. Thus, maximal cytotoxicity of cryopreserved LAK cells could be achieved by incubation with rIL-2 before and after the freezing process. The level of cytotoxicity was comparable to that of LAK cells from fresh peripheral blood lymphocytes. Cryopreserved LAK cells may have potential in adoptive immunotherapy.

Authors
Schmidt-Wolf, IG; Aihara, M; Negrin, RS; Blume, KG; Chao, NJ
MLA Citation
Schmidt-Wolf, IG, Aihara, M, Negrin, RS, Blume, KG, and Chao, NJ. "Lymphokine-activated killer cell activity after cryopreservation." J Immunol Methods 125.1-2 (December 20, 1989): 185-189.
PMID
2607152
Source
pubmed
Published In
Journal of Immunological Methods
Volume
125
Issue
1-2
Publish Date
1989
Start Page
185
End Page
189

Bone marrow transplantation. Part I--Allogeneic.

Major progress in experimental and clinical research has made allogeneic bone marrow transplantation a highly effective therapy for a variety of malignant and nonmalignant diseases. Allogeneic bone marrow transplantation from histocompatible donors is now the therapy of choice for some of these disorders. We review in part I the history, technical approach, complications, and the results achievable with this therapeutic approach. Further experimentation and future goals are also discussed.

Authors
Chao, NJ; Blume, KG
MLA Citation
Chao, NJ, and Blume, KG. "Bone marrow transplantation. Part I--Allogeneic." West J Med 151.6 (December 1989): 638-643. (Review)
PMID
2694621
Source
pubmed
Published In
Western Journal of Medicine
Volume
151
Issue
6
Publish Date
1989
Start Page
638
End Page
643

Molecular characterization of MHC class II antigens (beta 1 domain) in the BB diabetes-prone and -resistant rat.

The BB or BB/Worcester (BB/W) rat is widely recognized as a model for human insulin-dependent diabetes mellitus (IDDM). Of at least three genes implicated in genetic susceptibility to IDDM in this strain, one is clearly linked to the major histocompatibility complex (MHC). In an attempt to define the diabetogenic gene(s) linked to the MHC of the BB rat, cDNA clones encoding the class II MHC gene products of the BB diabetes-prone and diabetes-resistant sublines have been isolated and sequenced. For comparison, the beta 1 domain of class II genes of the Lewis rat (RT1L) were sequenced. Analysis of the sequence data reveals that the first domain of RT1.D beta and RT1.B beta chain of the BB rat are different from other rat or mouse class II sequences. However, these sequences were identical in both the BB diabetes-prone and BB diabetes-resistant sublines. The significance of these findings is discussed in relation to MHC class II sequence data in IDDM patients and in the nonobese diabetic (NOD) mouse strain.

Authors
Chao, NJ; Timmerman, L; McDevitt, HO; Jacob, CO
MLA Citation
Chao, NJ, Timmerman, L, McDevitt, HO, and Jacob, CO. "Molecular characterization of MHC class II antigens (beta 1 domain) in the BB diabetes-prone and -resistant rat." Immunogenetics 29.4 (1989): 231-234.
PMID
2784784
Source
pubmed
Published In
Immunogenetics
Volume
29
Issue
4
Publish Date
1989
Start Page
231
End Page
234

A molecular basis for MHC class II - Associated autoimmunity

Class II major histocompatibility (MHC) molecules have an immunoregulatory role. These cell-surface glycoproteins present fragments of protein antigens (or peptides) to thymus-derived lymphocytes (T cells). Nucleotide sequence polymorphism in the genes that encode the class II MHC products determines the specificity of the immune response and is correlated with the development of autoimmune diseases. This study identifies certain class II polymorphic amino acid residues that are strongly associated with susceptibility to insulin-dependent diabetes mellitus, rheumatoid arthritis, and pemphigus vulgaris. These findings implicate particular class II MHC isotypes in susceptibility to each disease and suggest new prophylactic and therapeutic strategies.

Authors
Todd, JA; Acha-Orbea, H; Bell, JI; Chao, N; Fronek, Z; Jacob, CO; McDermott, M; Sinha, AA; Timmerman, L; Steinman, L; McDevitt, HO
MLA Citation
Todd, JA, Acha-Orbea, H, Bell, JI, Chao, N, Fronek, Z, Jacob, CO, McDermott, M, Sinha, AA, Timmerman, L, Steinman, L, and McDevitt, HO. "A molecular basis for MHC class II - Associated autoimmunity." Science 240.4855 (1988): 1003-1009.
PMID
3368786
Source
scival
Published In
Science
Volume
240
Issue
4855
Publish Date
1988
Start Page
1003
End Page
1009

Retroperitoneal fibrosis following treatment for Hodgkin's disease

Authors
Chao, N; Levine, J; Horning, SJ
MLA Citation
Chao, N, Levine, J, and Horning, SJ. "Retroperitoneal fibrosis following treatment for Hodgkin's disease." Journal of Clinical Oncology 5.2 (1987): 231-232.
PMID
3100728
Source
scival
Published In
Journal of Clinical Oncology
Volume
5
Issue
2
Publish Date
1987
Start Page
231
End Page
232

Molecular composition of an antigen-specific, Ly-1 T suppressor inducer factor. One molecule binds antigen and is I-J-; another is I-J+, does not bind antigen, and imparts an Igh-variable region-linked restriction.

Immunized Ly-1+2-T cells (Ly-1 cells) make an antigen-specific soluble suppressor product (Lyl-1 TsiF) that will induce Ly-2+ cells to express suppressive activity but only if the Ly-2+ and the Ly-1 producer cell share genetic polymorphisms that are linked to the Igh locus and in particular that part where the Igh-V (or VH) is encoded. Ly-1 TsiF can be separated into entities, one binds antigen and does not express I-J determinants, and the other is I-J+ and does not bind antigen. Neither of these "subfactors" has biological activity, but a 50:50 mixture of them reconstitutes biological activity that expresses the antigen specificity of the antigen-binding molecule. Any of the three heterologous erythrocytes (antigens) studied can be used for immunization to produce the I-J+ nonantigen-binding factor, i.e., the I-J+ moiety makes no contribution to the factor's specificity. It does, however, determine the intact factor's Igh-V linked restriction. Thus, the antigen combining site of the factor is irrelevant to the factor's Igh-V restriction but crucial for its specificity. The I-J+ molecule does not bind antigen nor influence the factor's antigen specificity but expresses the Igh-V polymorphism (or anti-Igh-V polymorphism) that is required for the transmission of an inductive signal to the factor's Ly-2+ acceptor cell.

Authors
Yamauchi, K; Chao, N; Murphy, DB; Gershon, RK
MLA Citation
Yamauchi, K, Chao, N, Murphy, DB, and Gershon, RK. "Molecular composition of an antigen-specific, Ly-1 T suppressor inducer factor. One molecule binds antigen and is I-J-; another is I-J+, does not bind antigen, and imparts an Igh-variable region-linked restriction." The Journal of experimental medicine 155.3 (March 1982): 655-665.
PMID
6174662
Source
epmc
Published In
The Journal of Experimental Medicine
Volume
155
Issue
3
Publish Date
1982
Start Page
655
End Page
665
DOI
10.1084/jem.155.3.655
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