Haematologica 2003 - Supplements

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genes separating MGUS and MM was found considerably less than those separating normal and MM PCs. So far, this approach has failed to explicitly distinguish MM and MGUS, probably because of a lack of sufficient differences between these two conditions. Chromosomal abnormalities MGUS (n = 147) (%) 69/143 (48) SMM (n = 39) MGUS/SMM (n=186) MM (n = 669) (%) No. (%) P* (%) 18/38 (47) 87/181 (48) < 10 -9 477/653 (73) 9/39 (23) 28/186 (15) NS 105/669 (16) 14q32 rearrangements t(11;14) 149/147 (13) t(4;14) 3/147 (2) 1/39 (3) 4/186 (2) < .001 68/669 (10) t(14;16) 1/147 0/39 1/186 (< 1) NS 14/669 (2) del(13) 31/147 (21) 11/39 (28) 42/186 (23) < 10 -6 288/669 (43) *for difference with MM 1. Drach J, Angerler J, Schuster J, Rothermundt C, Thalhammer R, Haas OA, Jager U, Fiegl M, Geissler K, Ludwig H, et al. Interphase fluorescence in situ hybridization identifies chromosomal abnormalities in plasma cells from patients with monoclonal gammopathy of undetermined significance. Blood. 1995;86:3915-3921 2. Zandecki M, Obein V, Bernardi F, Soenen V, Flactif M, Lai JL, Francois M, Facon T. Monoclonal gammopathy of undetermined significance: chromosome changes are a common finding within bone marrow plasma cells. Br J Haematol. 1995;90:693-696 3. Zandecki M, Lai JL, Genevieve F, Bernardi F, Volle-Remy H, Blanchet O, Francois M, Cosson A, Bauters F, Facon T. Several cytogenetic subclones may be identified within plasma cells from patients with monoclonal gammopathy of undetermined significance, both at diagnosis and during the indolent course of this condition. Blood. 1997;90:3682-3690 4. Avet-Loiseau H, Facon T, Grosbois B, Magrangeas F, Rapp MJ, Harousseau JL, Minvielle S, Bataille R. Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation. Blood. 2002;99:2185-2191 5. Fonseca R, Bailey RJ, Ahmann GJ, Rajkumar SV, Hoyer JD, Lust JA, Kyle RA, Gertz MA, Greipp PR, Dewald GW. Genomic abnormalities in monoclonal gammopathy of undetermined significance. Blood. 2002;100:1417-1424 6. Davies FE, Dring AM, Li C, Rawstron AC, Shammas M, Hideshima T, Chauhan D, Tai IT, Auclair D, Robinson E, Wong WH, Munshi NC, Morgan GJ, K.C. A. The molecular basis of the transition of MGUS to multiple myeloma. Blood. 2002;100:102a (abstract) 7. Hardin J, Waddell m, Cheng J, Page D, Zhan F, Crowley J, Barlogie B, Shaughnessy J. Toward the development of diagnostic models capable of distinguishing multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), and normal plasma cells using global gene expression profiles. Blood. 2002;100:102a (abstract) P4.4 CIRCULATING PLASMA CELLS, LABELING INDEX, AND ANGIOGENESIS IN MGUS AND SMOLDERING MULTIPLE MYELOMA S. Vincent Rajkumar MD Mayo Clinic, Rochester, MN, USA Monoclonal gammopathy of undetermined significance (MGUS) affects nearly 2-3 percent of persons over 50 years of age. Patients with MGUS are at risk for progression to multiple myeloma (MM) or related malignancy at a rate of 1% per year, but do not require therapy. For the definition of MGUS, patients must have a serum monoclonal (M) protein
P4.5 CYTOKINES IN MGUS: THERAPEUTIC INTERVENTIONS TO PREVENT PROGRESSION John A. Lust, M.D., Ph.D. Kathleen A. Donovan, Ph.D. Mayo Clinic, Rochester, MN In previously published work, we demonstrated that detection of IL- 1β expression by RT/PCR or ISH was useful at differentiating active MM from MGUS. However, we were unable to differentiate the clinically benign condition, SMM from active MM using RNA based techniques. Therefore, we hypothesized that quantitative differences in IL-1β function may differentiate SMM from active MM. Measurement of IL-1β concentration by ELISA proved to be inadequate because of insufficient sensitivity. More importantly, ELISA measured only IL-1β concentration whereas IL-1β functional activity is modulated by several IL-1 family members such as IL-1 receptor antagonist and soluble IL-1 receptor. Therefore, we measured IL-1β functional activity with a bioassay using IL-6 production by bone marrow stromal cells as a highly sensitive surrogate marker. IL-1β bioactivity was determined by quantitating IL-6 production by cultured bone marrow stromal cells using an IL-6 ELISA. Ficoll purified bone marrow cells from patients with various plasmaproliferative disorders were cultured at 2 x 10 6 cells/ml for 48 hours. Supernatants were pooled, aliquoted and frozen at –80 0 C. Normal stromal cells (Clonetics, Walkersville, MD) were plated at 1 x 10 5 cells/ml and incubated at 37 0 C for 48 hours. After 48 hours, the stromal cells were washed and either IL-1β standards or patients’ supernatants were added with or without an IL-1β inhibitor (anti-IL- 1β antibody or IL-1 receptor antagonist). Cultures were incubated at 37 0 C for another 48 hours. Supernatants are harvested and frozen at - 80 0 C for analysis and subsequently analyzed for IL-6 using the Biosource ELISA kits according to the manufacturer’s specifications. Response of the stromal cells to IL-1β was calibrated with a standard curve using recombinant IL-1β. These cells respond to IL-1β in a sigmoid fashion with as little as 1 pg/ml of IL-1β inducing 20,000 pg/ml of IL-6. Culture supernatants of unsorted bone marrow cells from 77 untreated patients (2 normal, 12 MGUS, 18 MM, 45 SMM/IMM) were tested in this assay. Results were expressed as fold increase = [patient IL-6 – media control IL-6]/media control IL-6. A fold increase was utilized to allow for interassay comparison between different batches of stromal cells. IL-1β specificity was determined by inhibition of the IL-6 production with anti-IL-1β antibody. IL-1 specific IL-6 production showed that myeloma patients induced a 2.2 - 24.1 fold increase in IL-6 that was statistically different from the -0.25 - 1.9 fold increase by normal/MGUS patients (p90% in 41/53 patients tested (100% in 32/53). A logistic regression analysis was performed on 62 of the 75 patients that had been followed for at least a year or progressed during that time. Variables examined were % bone marrow plasma cells, plasma cell labeling index, albumin, M-protein level, beta-2 microglobulin, creatinine, calcium, hemoglobin, and stromal cell IL-6 production. Only two factors, stromal cell IL-6 production and bone marrow plasma cells, were found to be significant (p < .01) in predicting progression of SMM to myeloma. Subsequently, a Kaplan-Meier estimate was performed on the 45 patients with SMM/IMM. The time to progression was defined as the time from the date of the bone marrow on which the IL-1β bioassay was performed to the date of progression to active MM. Seventeen patients with SMM/IMM had a fold increase less than 1.6 and, to date, none of these patients have progressed to active disease. In contrast, 28 patients with SMM/IMM demonstrated a FI > 1.6 and 14 of these 28 patients have progressed to active MM with a median time to progression of approximately 2.5 years. Bone marrow cells from a patient with MM were sorted into CD138+ plasma cells and CD138- populations and examined for IL-6 production by the IL-1β stromal cell bioassay. The IL-6 production was induced predominantly by the CD138+ plasma cells. These results correlate with our previously published data by ISH demonstrating that the monoclonal plasma cells from virtually all myeloma patients express IL-1β mRNA. In addition, the IL-6 production was significantly inhibited with IL-1 receptor antagonist. The above studies served as the preclinical data for a Phase II trial of IL-1 receptor antagonist (IL-1Ra) in patients with SMM/IMM. We have now accrued eight patients in the clinical study using IL-1Ra in patients with SMM/IMM and preliminary studies are available on four. Patients that have > 10% bone marrow clonal plasma cells and/or an M-spike > 3 g/dL and do not require immediate chemotherapy are eligible. Patients receive 100 mg of Anakinra SQ qd. Clinical results are available on four patients with 1-3 months of follow-up. The underlying hypothesis is that IL-1β stimulates paracrine IL-6, the major growth factor for myeloma cells and that IL-1 receptor antagonist (IL-1Ra) will inhibit paracrine IL-6 production ultimately leading to apoptosis of the myeloma cell. Using CRP as a surrogate marker for IL-6 levels, all four patients demonstrated a reduction in CRP levels For example, Patient 1 had a reduction in CRP (mg/dL) from 3.82 to 0.825 to 0.122 or a 96% reduction; patient 2 a 74% reduction in CRP after 2 months. In a similar fashion, urine NTX (nmole/L), which is a marker of osteoclast activity was decreased in three patients (a followup urine was not available on one of the patients). Patient #1 has also had an increase in her hemoglobin from 10.1 to 11.9. Monoclonal protein levels have remained stable in three of the patients so far. However, patient #2 demonstrated a gradual decline in the CRP with IL-1Ra that paralleled a reduction in the serum monoclonal protein (see Figure). Toxicity has been minimal with mild injection site reactions during the first month of therapy. One patient developed an asymptomatic Grade 4 neutropenia and the IL-1Ra was held. The patient’s counts returned to normal within 1 week and the IL- 1Ra was restarted at 100mg qod. Although preliminary, these results demonstrate that IL-1Ra has biologic activity in patients with SMM/IMM and support the hypothesis that upregulation of IL-1β production is a critical event in the transition of SMM/IMM to active myeloma. Donovan KA, Lacy MQ, Kline MP, Ahmann GJ, Heimbach JA, Kyle RA, Lust JA:. Contrast in cytokine expression between patients with monoclonal gammopathy of undetermined significance or multiple myeloma. Leukemia 12:593-600, 1998 Lust JA, Donovan KA: Novel therapeutic strategies. Cancer Research Therapy and Control 6:225-226, 1998. Lacy MQ, Donovan KA, Heimbach JK, Ahmann GJ, Lust JA: Comparison of interleukin-1β expression by in situ hybridization in monoclonal gammopathy of undetermined significance and multiple myeloma. Blood 93(1):300-305, January 1, 1999. Lust JA and Donovan KA: Role of IL-1β in the Pathogenesis of Multiple Myeloma. Hematology/Oncology Dec. 1999, 13(6):1117-1125. Donovan KA, Lacy MQ, Gertz MA, Lust JA. IL-1β Expression in IgM Monoclonal Gammopathy and Its Relationship to Multiple Myeloma. Leukemia, March 2002, 16:382-385. S34
Page 1 and 2: Focussed Symposia Arsenic trioxide
Page 3 and 4: assess whether such a program will
Page 5 and 6: The overall response rate was noted
Page 7 and 8: Figure 5A Table 1: VEL + THAL for R
Page 9 and 10: naturally occurring OPG. Present tr
Page 11 and 12: 0.505). Finally, the multiple event
Page 13 and 14: CLINICOPATHOLOGICAL DEFINITION OF W
Page 15 and 16: Plenary Sessions 1. Development of
Page 17 and 18: clonotypic IgH VDJ signature confir
Page 19 and 20: can be considered as two entities,
Page 21 and 22: immunofluorescence staining for DKK
Page 23 and 24: P2.3 DEVELOPMENT OF A MULTIPLE MYEL
Page 25 and 26: P2.5 MOLECULAR CYTOGENETICS OF MYEL
Page 27 and 28: clear that the biggest challenge fo
Page 29 and 30: esponse and have demonstrated that
Page 31 and 32: variable region of the idiotypic im
Page 33 and 34: 4. From MGUS to symptomatic MM Fig.
Page 35: (MRI); some have claimed that level
Page 39 and 40: preventing phosphorylation of p70S6
Page 41 and 42: transducing component of the interl
Page 43 and 44: survive initial drug exposure and a
Page 45 and 46: quiescent counterpart, the human um
Page 47 and 48: transcriptional activity of NF-êB;
Page 49 and 50: manifestations and anomalous protei
Page 51 and 52: P7.4 ROLE OF SERUM FREE LIGHT CHAIN
Page 53 and 54: P7.6 IMMUNOPHENOTYPIC INVESTIGATION
Page 55 and 56: presumably through the circulation,
Page 57 and 58: 9. Chemotherapy, maintenance treatm
Page 59 and 60: stratified according to their antim
Page 61 and 62: explore higher doses of zoledronic
Page 63 and 64: initial therapy. However, the role
Page 65 and 66: P10.2.2 SINGLE VERSUS TANDEM HIGH D
Page 67 and 68: With a median follow-up of 38 month
Page 69 and 70: cells could be harvested following
Page 71 and 72: 11. What is the role of allogeneic
Page 73 and 74: found that 75% of patients who were
Page 75 and 76: patients with responsive disease 3
Page 77 and 78: 9. Giralt S, Estey E, Albitar M, et
Page 79 and 80: Badros A, Barlogie B, Siegel E, et
Page 81 and 82: Figure 3b. Event-free Survival 4-Ye
Page 83 and 84: improve patient outcome in MM. Impo
Page 85 and 86: myeloma and in 40% of previously un
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degrade OPG in the same way as myel
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P12.2.5 MONOCLONAL ANTIBODY THERAPY
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myeloma. Blood 2001; 98:210-216. 6.
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MHC molecules, in effectively prese
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mice demonstrate that class II-spec
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detected in 293 and NIH3T3 cells. S
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hypothesis that (1) CCND1 and FGFR3
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patient samples. In addition, the p
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016 NEUTRAL ENDOPEPTIDASE (CD10) KN
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2. Genetic heterogeneity in MM: imp
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evidence from two t(11;14) cases wh
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immunoglobulin heavy chain (IgH) lo
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034 Instability of Pericentromeric
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clusters were found, the first was
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MGUS but most likely not crucial fo
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Objective: To compare the impact on
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4 patients had MMSET/IgH but did no
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and clonal PC from MGUS, MM and PCL
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059 VEGF receptor expresion in Mult
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two HLA-A2+ myeloma patients with C
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molecules expressed on the surface
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Recognition of these antigens appea
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Diagnosis requires a single area of
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081 Incidence of solid tumors in co
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Growth Factor (VEGF), Hepatocyte Gr
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PC-AI levels of MGUS and SMM patien
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093 The predominant pathway of tran
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was associated with I.V. line, whil
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103 Vascular amyloidosis induces se
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5. Signal transduction pathways and
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integrin in IGF-1-triggered MM cell
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118 IL-6- Induced Phosphorylation o
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123 THE IGF/IGF-1R SYSTEM IS A MAJO
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human myeloma cell line (HMCL) to a
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ligation or dexamethasone (Georgii-
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6. Role of microenvironment 6.1 Cel
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141 Human myeloma cells adhere to f
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145 STUDY OF BONE MARROW ANGIOGENES
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patients, the growth of primary mye
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tibia (con=49.1±0.7mg/cm2 vs 5T2=4
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157 The Nitrogen-Containing Bisphos
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7. New prognostic criteria for clas
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atio of >3. This system has subdivi
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Patient 1 (IgG/κ);IgG - 16.5 days,
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176 Pro-inflammatory and angiogenic
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180 Clinical study on the bone lesi
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7.2 Imaging studies 185 99mTc-MIBI
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189 Factors Predicting Occult Spina
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vivo detected resonances was invest
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Support Unit (CTSU) with flexibilit
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(β2m) & C reactive protein (CRP).
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plasmids carrying the clonotypic in
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newly diagnosed multiple myeloma as
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216 Transgenic expression of Myc an
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221 Prolonged survival in the 5T2MM
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9. Chemotherapy, maintenance, treat
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229 EFFECTIVENESS OF STANDARD CHEMO
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234 Melphalan and Dexamethasone- Is
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Methods. We investigated the VECD p
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9.2 Renal complications. 243 MERIT
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cost of SRE-related care was $10,24
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those with Hb >13 g/dL. Analysis of
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sustained response, lasting from 52
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proportion of bone abnormality. IgD
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disease. The lack of response to in
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yielding a median of 3x106/kg CD34
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patients(pts) aged ≥60 yrs. We co
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PBSC mobilizing regimen utilizing C
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their leukocytes and platelets. No
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25 Gy to marrow. The tracer dose wa
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non-CR after the first transplant a
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296 PERIPHERAL BLOOD STEM CELL TRAN
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References Effect of dose-intensive
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with cyclosporine A and methotrexat
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11.Role of novel therapies targetin
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312 Thalidomide as Rescue of Relaps
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patients, light chain in 1 patients
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platelets of 207 (76-402), B2M of 3
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325 Low Dose Thalidomide plus Dexam
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in 5 pts (11%), M protein decreased
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time from diagnosis was 3.7 years a
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339 Thalidomide, Clarithromycin and
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344 COMBINATION OF THALIDOMIDE, DEX
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experienced early death during the
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untreated patients with high tumor
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357 Thalidomide protects endothelia
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362 EOSINOPHILIA IS A VERY COMMON F
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11.5 CC 4047, PS 341 and arsenic tr
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without chromosome 13. Mean IC50 fo
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myeloma patients. Phase I data indi
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11.6 Other drugs 380 EFFECT OF STI5
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significant inhibition of cell prol
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which acts to prevent the synthesis
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of B and its metabolites, however,
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and 10 months after start of therap
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terminal kinase (JNK) pathway which
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lymphocytes was tested by Ellispot.
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411 Dendritic Cell-Based Idiotype V
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Author Index Abe M 74 160 Abelman W
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De La Serna J 291 De Laurenzi A P11
Page 287 and 288:
Hull DR 338 Hullen C P10.2.1 Humes
Page 289 and 290:
Morra E 249 280 359 Morris CM 226 M
Page 291 and 292:
Siegel D 70 115 250 Sierra J 304 30
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