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What's New In Research - March 11, 2003
03.11.03
Pilot study of recombinant human soluble tumor necrosis factor (TNF) receptor (p75) fusion protein (TNFR:Fc; Enbrel) in patients with refractory multiple myeloma: increase in plasma TNFalpha levels during treatment.
Tsimberidou AM, Waddelow T, Kantarjian HM, Albitar M, Giles FJ.
Department of Leukemia, University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd, 77030, Houston, TX, USA
Leukemia Research Volume 27, Issue 5 , May 2003, Pages 375-380

Elevated tumor necrosis factor (TNF)-alpha levels are associated with poor prognosis in patients with multiple myeloma (MM). Enbrel is a TNF antagonist fusion protein consisting of the extracellular, ligand-binding domain of the human p75 TNF receptor linked to the Fc portion of human IgG1. Ten patients with refractory MM were treated with Enbrel 25mg s.c twice weekly for a minimum of eight median age was 63 years (range, 43-76). The total number of Enbrel doses was 191 (median 16; range, 3-55). TNFalpha plasma levels increased significantly during treatment with Enbrel. No objective response occurred. Acceleration of disease occurred in four patients. While well-tolerated, Enbrel did not have anti-myeloma activity as administered on this study.


Allogeneic Stem Cell Transplantation for Multiple Myeloma
Roberto Bellucci, Jerome Ritz
Center for Hematologic Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Rev Clin Exp Hematology Volume 6 Issue 3 Page 205 - September 2002

Abstract The sensitivity of myeloma cells to high dose chemotherapy has led to the use of allogeneic hematopoietic stem cell transplantation (HSCT) as a therapeutic modality in this disease. In addition to providing more effective chemotherapy, the transplantation of allogeneic stem cells also initiates the development of an allogeneic immune response directed against residual myeloma cells. Direct evidence for a graft vs. myeloma (GVM) effect is provided by the ability of donor lymphocyte infusion (DLI) to induce significant responses in 30-50% of patients with myeloma who have relapsed after allogeneic HSCT. Nevertheless, allogeneic stem cell transplantation is also associated with a high incidence of transplant related toxicities, including regimen-related toxicities, graft vs. host disease (GVHD) and opportunistic infections. DLI has been shown to enhance immune reconstitution after allogeneic HSCT in addition to inducing a GVM response. Current efforts are directed at reducing the toxicities associated with allogeneic HSCT, identification of the target antigens of GVM and the development of new strategies to selectively enhance the immune response to myeloma cells.


Simultaneous bilateral spontaneous pneumothorax in a patient with recurrent, extraosseous multiple myeloma
F Peters1, G Cathomas2, M Rothen1, R Thurnheer1 and J Rutishauser1
1University Clinic of Medicine, Kantonsspital, Bruderholz, Switzerland, 2Institute of Pathology, Kantonsspital, Liestal, Switzerland

Case Report

Abstract A patient with simultaneous bilateral spontaneous pneumothorax (SBSP) due to pulmonary and pleural manifestations of recurrent multiple myeloma is presented. The patient died in shock of unknown cause. The diagnosis was suspected from pleural fluid examination showing an exudate with numerous plasmocytes. Macroscopically and histologically, the visceral organs and the bone marrow were infiltrated with multiple monoclonal proliferations of plasma cells staining positively for IgG and lambda chains.

SBSP is a rare condition and may be caused by trauma, parenchymal lung disease, infections, or neoplasms. This is the first report of SBSP caused by pleuropulmonary infiltration of multiple myeloma.


Mucosal injury in patients undergoing hematopoietic progenitor cell transplantation: new approaches to prophylaxis and treatment
J Filicko1, H M Lazarus2 and N Flomenberg1
1Hematologic Malignancies, Blood & Marrow Transplant Program, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA
2Department of Medicine, Comprehensive Cancer Center of the Uiversity Hospitals of Cleveland/Case Western Reserve University, Cleveland, OH, USA
Correspondence to: Dr J Filicko, Hematologic Malignancies, Blood & Marrow Transplant Program, Jefferson Medical College, Thomas Jefferson University, 125 South 9th Street, 801 Sheridan Building, Philadelphia, PA 19107, USA
Nature January (1) 2003, Volume 31, Number 1, Pages 1-10

Abstract Hematopoietic progenitor cell transplantation is often associated with severe mucosal toxicity. The need for parenteral analgesics and parenteral nutrition are evidence of the severity of the problem in individual patients. However, the increased risk for systemic infection related to bacteremia associated with the breakdown of mucosal barriers is a significant cause of morbidity and mortality as well. There is a multitude of grading scales, demonstrating the lack of consensus among clinicians in this area. Multiple agents have been used prophylactically and therapeutically to address mucositis. While efforts have been less successful in the past, the advent of newer agents including amifostine, keratinocyte growth factor, transforming growth factor beta and interleukin-11 provides hope that this toxicity will be significantly decreased in the near future.


Human IgG2 Can Form Covalent Dimers
Yoo EM, Wims LA, Chan LA, Morrison SL.
Department of Microbiology, Immunology, and Molecular Genetics and Molecular Biology Institute, University of California, Los Angeles, CA 90095
J Immunol 2003 Mar 15;170(6):3134-8

Unlike IgA and IgM, IgG has not yet been shown to form covalent polymers. However in the presence of specific Ag, murine IgG3 has been shown to polymerize through noncovalent interactions. In contrast to the noncovalent oligomers found with murine IgG3, we have detected covalent dimers in three different recombinant human IgG2 Abs produced in myeloma cells. Both IgG2,kappa and IgG2,lambda can form dimers. In addition, analysis of pooled human gamma globulin and several normal sera revealed the presence of IgG2 dimers. The IgG2 dimers are in contrast to the noncovalent IgG dimers found in pooled sera of multiple donors resulting from idiotype/anti-idiotype (Id/anti-Id) interactions. Cyanogen bromide cleavage analysis suggests that one or more Cys residues in the gamma2 hinge are involved in dimer assembly. The potential role of IgG2 dimers in immunity against carbohydrate Ags is discussed.


Identification of a functionally impaired positive regulatory domain I binding factor 1 transcription repressor in myeloma cell lines
Gyory I, Fejer G, Ghosh N, Seto E, Wright KL.
H. Lee Moffitt Cancer Center and Research Institute, Department of Interdisciplinary Oncology and Department of Biochemistry and Molecular Biology, University of South Florida, Tampa, FL 33612
J Immunol 2003 Mar 15;170(6):3125-33

B cell differentiation into a plasma cell requires expression of the positive regulatory domain zinc finger protein 1 gene (PRDM1) that encodes the positive regulatory domain I binding factor 1 (PRDI-BF1 or Blimp-1) protein. It represses the transcription of specific target genes, including c-myc, the MHC class II trans-activator, Pax-5, and CD23b. In this study we demonstrate the presence of an alternative protein product of the PRDM1 gene. The new protein, PRDI-BF1beta, has a disrupted PR domain and lacks the amino-terminal 101 aa of the originally described protein. PRDI-BF1beta has a dramatic loss of repressive function on multiple target genes, but maintains normal DNA-binding activity, nuclear localization, and association with histone deacetylases and deacetylase activity. Myeloma cell lines express the highest levels of PRDM1beta mRNA relative to the full-length form, while primary cells and several other cell lines have very low, but detectable, levels of PRDM1beta. RNA analysis and analysis of the PRDM1 promoters demonstrate that PRDI-BF1beta is generated from the same gene by alternative transcription initiation using an internal promoter. These newly described features of the PRDM1 gene are highly analogous to the PRDM2 (RIZ) and PRDM3 (MDS1-EVI1) genes, in which each express a truncated protein missing the PR domain. The expression of each of the truncated proteins is elevated in cancerous cells and may play an important role in the disease.


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