Haematologica 2003 - Supplements

More documents

Recommendations

Info

087 Serum levels of carboxy-terminal telopeptide of type-I collagen (ICTP) are elevated in patients with multiple myeloma with skeletal abnormalities in MRI, who lack osteolyses in conventional radiography Christian Jakob, Ivana Zavrski, Ulrike Heider, Claudia Fleissner, Jan Eucker, Kurt Possinger, Orhan Sezer Department of Hematology and Oncology, Universitätsklinikum Charité, 10098 Berlin, Germany. Introduction: Osteoclastic bone destruction is a major clinical problem in multiple myeloma. Increased bone resorption activity can even be present before osteolytic lesions can be discovered by conventional radiography. Magnetic resonance imaging (MRI) of the spine was established as a diagnostic tool to depict bone abnormalities with greater sensitivity than conventional radiography especially in early myeloma. In addition to common imaging techniques, type-I collagen degradation products such as the carboxy-terminal telopeptide of type-I collagen (ICTP) were introduced as novel biochemical parameters reflecting bone resorption activity in multiple myeloma. In the present study we investigated whether increased serum levels of ICTP can predict abnormal MRI patterns in multiple myeloma patients. Furthermore the prognostic relevance of elevated ICTP and abnormal MRI was evaluated. Magnetic resonance images of the spine were performed in 32 untreated patients with multiple myeloma in stages I-III (Durie and Salmon), who had no osteolytic lesions in conventional radiography. Simultaneously serum levels of ICTP were measured by a competitive radioimmunoassay (Orion Diagnostics, Espoo, Finland). Results: Serum levels of ICTP were significantly (P = 0.002) elevated in patients with abnormal bone MRI compared to those patients with normal MRI findings. The positive and negative predictive value of serum ICTP for predicting bone abnormalities in MRI was 85% and 84%, respectively. Both serum ICTP and MRI were identified as prognostic factors for event-free survival (P < 0.001 and P = 0.003, respectively). Fig. 1. Boxplots of ICTP serum levels in two groups of multiple myeloma patients: normal versus abnormal MRI. Mann-Whitney U test: P = 0.002. Fig. 2. ROC-curve for the relation of elevated serum ICTP levels and abnormal MRI findings. Conclusions: Our results demonstrate for the first time that abnormal skeletal MRI findings are accompanied by an increase in serum ICTP levels in myeloma patients who lack osteolyses in conventional radiography. We conclude that ICTP can be used as a surrogate parameter to identify multiple myeloma patients with normal skeletal surveys who have a high probability of myeloma bone disease and should be evaluated by sensitive diagnostic procedures such as MRI. 088 Conception of the inverse relationship between the proliferation and apoptosis activity in plasma cell compartments of patients with MGUS and multiple myeloma V. Scudla, M. Ordeltova, J. Bacovsky, M. Vytrasova, P. Horak 3rd Department of Internal Medicine, Faculty Hospital, Palacky University, Olomouc, Czech Republic Background. Multiple myeloma (MM) is a clonal lymphoproliferative disease characterized by slow proliferative activity and different resistance to apoptosis with latent accumulation of myeloma cells in the bone marrow. Aim. The aim of this study was comparison of contemporaneously measured plasma cell proliferative and apoptotic indices in MGUS and in various phases of MM e.g. smoldering (SMM), stable/plateau (PMM) and the active (progressive/relapsing) phases of multiple myeloma (AMM). Methods. Analyzed group consists of 30 MGUS, 21 SMM, 82 patients examined at the time of MM diagnosis (DMM) and 64 patients analyzed during various phases of the disease. Plasma cell proliferative activity was measured using propidium iodide/CD138 index (PC- PI/CD138) while rate of apoptosis with help of annexin – V FITC/CD138 index (PC-AI/CD138). To estimate the statistical significance t-test and ANOVA test were used. Results. The MGUS individuals had overall low PC-PI index (M-1.8%) and relatively high levels of PC-AI index (M-9.1%), the relation was statistically significant (p-0.000). The patients with SMM had also low levels of PC-PI (M-1.7%) and high values of PC-AI (M- 10.8%), the relation was also significant (p- 0.000). The symptomatic DMM patients had PC-PI median level 2.5% and PC-AI median value 6.2%, the relation of these both indices was statistically significant (p- 0.000). In the group of patients evaluated during various phases of MM after previous conventional or HD-therapy with ASCT support PC-PI median was 2.6% and PC-AI median 7.2 %, the relation was statistically significant (p- 0.000). Statistical comparison of PC-PI and also S127
PC-AI levels of MGUS and SMM patients with patients in PMM phase did not bring any significant differences, the medians of their values were very similar (PC-PI: M -1.8, 1.7 and 2.1%; PC- AI: M-9.1, 10.8 and 9.0 %). The statistically significant differences of PC-PI and PC-AI were found, if comparing MGUS and SMM patients with group of AMM patients marked by a higher level of the PC-PI (M-1.8 and 1.7 vs. 3.2 %, p- 0.000) eventually by lower values of the PC-AI (M-9.1 and 10.8 vs. 4.8 %). In contrast to AMM patients, in the PMM phase significantly lower PC-PI levels (M-2.1 vs. 3.2%, p- 0.000) and significantly higher PC-AI values (M-9.1 vs. 4.8%, p-0.000) were found. Conclusion. Our results supported the conception of usually inverse relationship between the proliferative and apoptotic activity of the plasma cell compartments of patients with MGUS, smoldering and overt/symptomatic forms of MM. The patients with MGUS, SMM and PMM phases have usually low proliferative and high apoptotic level, whereas patients in the AMM phase have usually high proliferative and low apoptotic level. These results suggest that not only proliferative but also apoptotic properties of myeloma cells are important from the point of view of clinical and laboratory manifestation of MM. 089 Aberrant methylation of tumor suppressor genes in patients with Multiple Myeloma and Monoclonal Gammopathy of Undetermined significance Sonja Seidl, Jutta Ackermann, Hannes Kaufmann, Christoph C. Zielinski, Johannes Drach and Sabine Zöchbauer-Müller Clinical Division of Oncology, University Hospital, Vienna, Austria Aberrant methylation (referred to as methylation) of normally unmethylated CpG islands in the promotor region of tumor suppressor genes (TSGs) has been associated with transcriptional inactivation of these genes in human cancer. So far, several genes have been identified which are frequently methylated in malignant diseases. However, only little is known about methylation of these genes in patients with multiple myeloma (MM), plasma cell leukemia (PCL) or monoclonal gammopathy of undetermined significance (MGUS). Thus, we investigated the frequency of methylation of the genes p16, TIMP-3, p15, CDH1, DAPK, p73, RASSF1A, p14, MGMT and RARbeta in bone marrow aspirates from patients with MM (N = 109), PCL (N=7) and from patients with MGUS (N = 29) by methylation specific PCR. Methylation of the genes p16, TIMP-3, p15, CDH1, DAPK, p73, RASSF1A, p14, MGMT and RARbeta was detected in 34%, 27%, 26%, 24%, 20%, 17%, 16%, 7%, 5%, and 0% in MM patients, respectively. Aberrant methylation of at least one of the genes was detected in 77% of MM patients. The frequency of methylation in PCL was similar to MM patients in the case of TIMP-3, p15, DAPK, p73, RASSF1A, p14, MGMT and RARbeta but was higher in the case of p16 (57%) and CDH1 (57%). In MGUS patients, the frequency of methylation was similar to MM patients for most of the genes. However, the frequency of p15 methylation was lower. Interestingly, methylation of CDH1 was not found in any of the MGUS patients (P = 0,004). We also analysed bone marrow specimens from healthy bone marrow donors and patients with localized non- Hodgkin’s lymphomas. However, we did not observe methylation of any of these genes in control specimens. The methylation results will be compared with clinical characteristics as well as specific chromosomal alterations from these patients. In conclusion, our data demonstrate that methylation of several genes is a frequent event in patients with MM. Methylation of CDH1 was not detected in MGUS patients, but in MM patients and in an even higher percentage in patients with PCL suggesting that CDH1 methylation is an indicator of disease progression in this hematologic malignancy. 090 Bcl-2 and poly-ADP-ribosyl polymerasis expression in plasma cells of MGUS and multiple myeloma patients: a comparative study V. Scudla, Z. Kolar, J. Bacovsky, M. Vytrasova 3rd Department of Internal Medicine and Department of Pathology, Faculty Hospital, Palacky University, Olomouc, Czech Republic Background. Multiple myeloma (MM) is a plasma cell malignancy, in which different proliferative activity and resistance to apoptosis of plasma cells play an important role in pathophysiology and clinical manifestation of this disease. Bcl-2 oncoprotein plays a very important role in hemopoietic cells by preventing apoptosis. Disregulation of this process may be important for oncogenesis due to illegitimate cell survival and increase in the chances for cells to acquire additional gene defects that promote aberrant growth and proliferation. The real clinical impact of bcl-2 or PARP (poly-ADP-ribosyl polymerasis) expression in monoclonal gammopathies is not adequately known in this time. Aims. The aims of this study was the contemporaneous measurement of the bcl-2 (i), bcl-2 (m), PARP and Ki-67 expression intensity in plasma cells and correlations of these markers in the patients with MGUS (n-10), smoldering multiple myeloma (S-MM, n-11), patients evaluated at the time of MM diagnosis (D-MM, n-45) and in the various phases of the disease (R-MM, n-25). Methods. Immunoenzymatic methods were applied using McAb against bcl-2 protein (i and m), PARP and Ki-67 while the intensity of protein expression was assessed by the semiquantitative histomorphometry method (LUCIA M system, Prague) in the bone marrow biopsy samples. Data were analyzed and the groups compared using Pearson’s and ANOVA tests. Results. The intensity of bcl-2 (i) expression in plasma cells was weak and statistically insignificant in all four analyzed groups. The intensity expression of the bcl-2 (m) was also weak in patients with MGUS, S-MM and R-MM but high in D-MM patients, with statistical significance in comparison of MGUS, S- MM and R-MM vs D-MM (p- 0.011, 0.008 and 0.001). The intensity of PARP expression was significantly different in comparison of MGUS, S-MM and R-MM vs D-MM patients (p- 0.018, 0.000 and 0.000). There was observed a statistically significant correlation of the bcl-2(i) vs bcl-2(m) plasma cells activity in the situation of MGUS (p < 0.05), S-MM ( p < 0.001) and R-MM (p < 0.001) but no significant difference in D-MM. The significant relationship was also observed in comparison of bcl-2(m) vs PARP myeloma cells expression in the R-MM but not in the case of MGUS, S-MM and D-MM. There was no correlation of bcl-2(i), bcl-2(m) and PARP expression in comparison of Ki-67 proliferative rate of plasma cells in all four evaluated groups. Conclusion. There was demonstrated that the expression activity of bcl-2 (m) and PARP in plasma cells in overt form of MM (D-MM and R-MM) is statistic significantly higher than in MGUS or S-MM. Bcl-2(m) may play a significant role in the pathogenesis of malignant gammopathies, extending the survival of myeloma cells by protecting them from apoptosis and increasing the chance for cells to acquire new additional gene defect. Supported by grant of IGA MH CR. S128
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 and 36:
(MRI); some have claimed that level
Page 37 and 38:
P4.5 CYTOKINES IN MGUS: THERAPEUTIC
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
Page 87 and 88: degrade OPG in the same way as myel
Page 89 and 90: P12.2.5 MONOCLONAL ANTIBODY THERAPY
Page 91 and 92: myeloma. Blood 2001; 98:210-216. 6.
Page 93 and 94: MHC molecules, in effectively prese
Page 95 and 96: mice demonstrate that class II-spec
Page 97 and 98: detected in 293 and NIH3T3 cells. S
Page 99 and 100: hypothesis that (1) CCND1 and FGFR3
Page 101 and 102: patient samples. In addition, the p
Page 103 and 104: 016 NEUTRAL ENDOPEPTIDASE (CD10) KN
Page 105 and 106: 2. Genetic heterogeneity in MM: imp
Page 107 and 108: evidence from two t(11;14) cases wh
Page 109 and 110: immunoglobulin heavy chain (IgH) lo
Page 111 and 112: 034 Instability of Pericentromeric
Page 113 and 114: clusters were found, the first was
Page 115 and 116: MGUS but most likely not crucial fo
Page 117 and 118: Objective: To compare the impact on
Page 119 and 120: 4 patients had MMSET/IgH but did no
Page 121 and 122: and clonal PC from MGUS, MM and PCL
Page 123 and 124: 059 VEGF receptor expresion in Mult
Page 125 and 126: two HLA-A2+ myeloma patients with C
Page 127 and 128: molecules expressed on the surface
Page 129 and 130: Recognition of these antigens appea
Page 131 and 132: Diagnosis requires a single area of
Page 133 and 134: 081 Incidence of solid tumors in co
Page 135: Growth Factor (VEGF), Hepatocyte Gr
Page 139 and 140: 093 The predominant pathway of tran
Page 141 and 142: was associated with I.V. line, whil
Page 143 and 144: 103 Vascular amyloidosis induces se
Page 145 and 146: 5. Signal transduction pathways and
Page 147 and 148: integrin in IGF-1-triggered MM cell
Page 149 and 150: 118 IL-6- Induced Phosphorylation o
Page 151 and 152: 123 THE IGF/IGF-1R SYSTEM IS A MAJO
Page 153 and 154: human myeloma cell line (HMCL) to a
Page 155 and 156: ligation or dexamethasone (Georgii-
Page 157 and 158: 6. Role of microenvironment 6.1 Cel
Page 159 and 160: 141 Human myeloma cells adhere to f
Page 161 and 162: 145 STUDY OF BONE MARROW ANGIOGENES
Page 163 and 164: patients, the growth of primary mye
Page 165 and 166: tibia (con=49.1±0.7mg/cm2 vs 5T2=4
Page 167 and 168: 157 The Nitrogen-Containing Bisphos
Page 169 and 170: 7. New prognostic criteria for clas
Page 171 and 172: atio of >3. This system has subdivi
Page 173 and 174: Patient 1 (IgG/κ);IgG - 16.5 days,
Page 175 and 176: 176 Pro-inflammatory and angiogenic
Page 177 and 178: 180 Clinical study on the bone lesi
Page 179 and 180: 7.2 Imaging studies 185 99mTc-MIBI
Page 181 and 182: 189 Factors Predicting Occult Spina
Page 183 and 184: vivo detected resonances was invest
Page 185 and 186: Support Unit (CTSU) with flexibilit
Page 187 and 188:
(β2m) & C reactive protein (CRP).
Page 189 and 190:
plasmids carrying the clonotypic in
Page 191 and 192:
newly diagnosed multiple myeloma as
Page 193 and 194:
216 Transgenic expression of Myc an
Page 195 and 196:
221 Prolonged survival in the 5T2MM
Page 197 and 198:
9. Chemotherapy, maintenance, treat
Page 199 and 200:
229 EFFECTIVENESS OF STANDARD CHEMO
Page 201 and 202:
234 Melphalan and Dexamethasone- Is
Page 203 and 204:
Methods. We investigated the VECD p
Page 205 and 206:
9.2 Renal complications. 243 MERIT
Page 207 and 208:
cost of SRE-related care was $10,24
Page 209 and 210:
those with Hb >13 g/dL. Analysis of
Page 211 and 212:
sustained response, lasting from 52
Page 213 and 214:
proportion of bone abnormality. IgD
Page 215 and 216:
disease. The lack of response to in
Page 217 and 218:
yielding a median of 3x106/kg CD34
Page 219 and 220:
patients(pts) aged ≥60 yrs. We co
Page 221 and 222:
PBSC mobilizing regimen utilizing C
Page 223 and 224:
their leukocytes and platelets. No
Page 225 and 226:
25 Gy to marrow. The tracer dose wa
Page 227 and 228:
non-CR after the first transplant a
Page 229 and 230:
296 PERIPHERAL BLOOD STEM CELL TRAN
Page 231 and 232:
References Effect of dose-intensive
Page 233 and 234:
with cyclosporine A and methotrexat
Page 235 and 236:
11.Role of novel therapies targetin
Page 237 and 238:
312 Thalidomide as Rescue of Relaps
Page 239 and 240:
patients, light chain in 1 patients
Page 241 and 242:
platelets of 207 (76-402), B2M of 3
Page 243 and 244:
325 Low Dose Thalidomide plus Dexam
Page 245 and 246:
in 5 pts (11%), M protein decreased
Page 247 and 248:
time from diagnosis was 3.7 years a
Page 249 and 250:
339 Thalidomide, Clarithromycin and
Page 251 and 252:
344 COMBINATION OF THALIDOMIDE, DEX
Page 253 and 254:
experienced early death during the
Page 255 and 256:
untreated patients with high tumor
Page 257 and 258:
357 Thalidomide protects endothelia
Page 259 and 260:
362 EOSINOPHILIA IS A VERY COMMON F
Page 261 and 262:
11.5 CC 4047, PS 341 and arsenic tr
Page 263 and 264:
without chromosome 13. Mean IC50 fo
Page 265 and 266:
myeloma patients. Phase I data indi
Page 267 and 268:
11.6 Other drugs 380 EFFECT OF STI5
Page 269 and 270:
significant inhibition of cell prol
Page 271 and 272:
which acts to prevent the synthesis
Page 273 and 274:
of B and its metabolites, however,
Page 275 and 276:
and 10 months after start of therap
Page 277 and 278:
terminal kinase (JNK) pathway which
Page 279 and 280:
lymphocytes was tested by Ellispot.
Page 281 and 282:
411 Dendritic Cell-Based Idiotype V
Page 283 and 284:
Author Index Abe M 74 160 Abelman W
Page 285 and 286:
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
show all

Haematologica 2003 - Supplements

Create successful ePaper yourself

Delete template?

Save as template?