Haematologica 2003 - Supplements
Haematologica 2003 - Supplements Haematologica 2003 - Supplements
plasma cell levels, or degree of immuneparesis. In order to determine whether plasma cell biology can predict progressive disease characteristics, we assessed the CD19 expression of marrow plasma cells in 88 MGUS patients followed for a median of 34 months (range 12 – 55). Patients with predominantly CD19- plasma cells (the pattern seen in myeloma) had a high probability of disease progression: 10/39 (26%) showed evidence of increasing tumour burden at a median of 31 months. In contrast, those with a mixture of CD19+ (seen in normal bone marrow) and CD19- plasma cells had an extremely low probability of disease progression: only 1/49 patients (2%) had a rising paraprotein at 47 months (Log Rank P
016 NEUTRAL ENDOPEPTIDASE (CD10) KNOCKOUT MICE DEVELOP B CELL LYMPHOMAS AND PLASMACYTOSIS Scott A. Ely, MD MPH, Daniel M. Knowles, MD Weill Medical College of Cornell University, New York, NY BACKGROUND: Neutral endopeptidase (CD10) is a metalloprotease that reduces the cellular response to certain peptide hormones. CD10 has been found to play a role in B cell maturation. However, its precise function and mechanism of action are unknown. Moreover, the role of CD10 in lymphomagenesis has not been previously investigated. DESIGN: CD10 knockout mice (CD10KO) were sacrificed and autopsied at 6, 10, and 16 months and compared to wild type (WT) controls for changes in lymphoid compartments and for the development of tumors. Spleen, bone marrow, thymus, lymph node and tumor sections were analyzed for morphologic changes as well as for expression of B220 (CD45R), CD3, CD138, IgG, IgM, Igκ, and Igλ. Relative numbers of B, T, and plasma cell subsets (PCs) were compared using image analysis. RESULTS: At 6 months of age, there were no gross abnormalities in the mice (3KO and 3 WT). At 10 months, 3 WT mice were phenotypically normal, but 7 of 10 (70%) CD10KOs had large mesenteric masses that showed follicular hyperplasia and plasmacytosis, usually marked. At 16 months, 5 WT mice were phenotypically normal but all 5 CD10KOs had large mesenteric masses: 3 large B cell lymphomas and 2 nodular lesions, possibly follicular lymphomas. In addition, all the 16 month old CD10KOs had marked marrow IgM plasmacytosis. The percentage of IgG PCs was markedly reduced. CONCLUSION: This study shows that CD10 is required for normal B cell maturation and plasmacytogenesis. It appears that in the absence of CD10, there is a buildup of IgM PCs with failure to undergo normal immunoglobulin heavy chain class switching. In addition, these results suggest that CD10 may function as a tumor suppressor. 017 Hereditary Multiple Myeloma (MM): An International Consortium for MM Family Studies Patrice Watson, Ph.D., Stephano Tarantolo, M.D., Peter H. Wiernik, M.D., Dennis W. Weisenburger, M.D., David Hogg, M.D., Ph.D., Brigid Quinn-Laquer, MS, MT, Warren G. Sanger, Ph.D., Henry T. Lynch, M.D. Inherited genetic factors in the development of multiple myeloma (MM) have received limited attention; the rarity of extended MM families is an obstacle to progress. There have been several reports describing familial clustering of myeloma within families however a systematic approaches to delineate a genetic predisposition is lacking. We have identified 15 MM families with one or more members affected with MM. Many of the relatives in these families present with pancreatic cancer or malignant melanoma. Some of the families also have members with chronic lymphocytic leukemia or lymphoma, as well as solid tumors of the colon and breast. In two of the families, individuals have been diagnosed with monoclonal gammopathy of unknown significance (MGUS) in addition to the MM cases. We have collected biological specimens from 53 individuals in these families. Of the 53 samples, 27 have been tested for CDKN2A (p16) mutations. No alterations were detected in 26 of these, while one showed an alteration of unknown significance. We have plans to test all of the samples and any additional samples from new families for CDKN2A mutations, as well as, other candidate genes. We also plan to carry out general linkage studies to localize potential susceptibility genes. The occurrence of familial MM is an important phenomenon and discovery of its genetic basis may illuminate biological pathways of MM development and contribute to pharmacotherapeutic advances. However, a sufficient number of informative families are needed to accomplish these goals. Therefore we propose an international consortium to study familial MM and invite interested colleagues to participate. A web site is available, http://medicine.creighton.edu/HHCC for rapid communication between members in the consortium. 018 Risk Factors For Multiple Myeloma: A Possible Role For Breast Implants Robert A. Vescio,1 Stuart L. Silverman,2 Ann S. Hamilton,3 James R. Berenson,1 1. Dept. of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA2. Dept. of Preventative Medicine, University of Southern California, Los Angeles, CA, USA3. Dept. of Medicine, GLA VAHS and UCLA, Los Angeles, CA, USA Although autoimmune like symptoms have been attributed to silicone gel-filled breast implant (SGBI) exposure, few studies have documented this link. Dr. Potter’s group discovered that silicone gel removed from commercial mammary implants and injected intraperitoneally into BALB/c mice induced multiple myeloma (MM) development at high rates. We subsequently noted a high incidence of breast implant exposure in our clinical practice. As a pilot study, serum samples were obtained from a cohort of 630 women with SGBIs followed in a rheumatology practice. Elevated quantitative immunoglobulin levels were found in 23% of the samples and a monoclonal gammopathy was present in 1.7% of a smaller 284 patient cohort. Consequently, we initiated a case-control trial to determine the incidence of SGBI exposure in women diagnosed with MM. California Cancer Registry data was used to contact women who developed MM between the years 1991 and 1997. It had been estimated that 91% of women with SGBIs are < 60 years of age so only such women were interviewed to reduce study cost. A spouse proxy was interviewed if available for deceased cases. Cases were asked about occupational, medical and social history. In order to match socioeconomic status, controls of similar age and ethnicity were ascertained by random digit phone dialing using the area code and prefix of the corresponding case. Up to 5 controls were interviewed for each of the 208 Caucasian cases. Control women were required to be within 5 years of age of the case. Spouse proxies were also interviewed and served as the control for cases in which a proxy was used. All exposures occurring in the cases and controls after the date of MM diagnosis were excluded in the analysis. Breast implant usage was associated with an unadjusted odds ratio of 2.31 on univariate analysis (95% C.L. 1.01-5.26, p=0.048). Prior work on a farm, in an airplane, around microwaves, or use of a computer were also risk factors for MM development. A higher incidence of complications such as pain and contracture was noted in the cases with breast implants vs. controls with breast implants after chi-squared analysis. The adjusted odds ratio for breast implants with contracture was 4.74 (95% C.L. 1.44-15.68, p=0.01). These results suggest that breast implant exposure may contribute to the development of MM. A larger national registry study or prospective analysis of women currently receiving SGBIs may be required to increase statistical power and conclusively link or refute this association. The higher incidence of MM in farm workers has been noted by others and S95
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plasma cell levels, or degree of immuneparesis. In order to<br />
determine whether plasma cell biology can predict progressive<br />
disease characteristics, we assessed the CD19 expression of<br />
marrow plasma cells in 88 MGUS patients followed for a median<br />
of 34 months (range 12 – 55).<br />
Patients with predominantly CD19- plasma cells (the pattern seen<br />
in myeloma) had a high probability of disease progression: 10/39<br />
(26%) showed evidence of increasing tumour burden at a median<br />
of 31 months. In contrast, those with a mixture of CD19+ (seen in<br />
normal bone marrow) and CD19- plasma cells had an extremely<br />
low probability of disease progression: only 1/49 patients (2%)<br />
had a rising paraprotein at 47 months (Log Rank P
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