The ability of statins to protect low density lipoprotein from oxidation in hypercholesterolemic patients.

OBJECTIVE: It is unclear at the present time whether hydroxy-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA reductase inhibitors; statins) exert a protective effect on low-density lipoproteins (LDL) oxidation in vivo. In addition, it is speculated that pharmacological differences between statins may account for differences in their antioxidative capacities. This is of clinical relevance, because there is strong evidence that oxidized LDL initiates the atherosclerosis process. MATERIAL AND METHODS: In a controlled, randomized, double-blind study we compared the effects of three different statins (simvastatin, pravastatin and atorvastatin) on the ability to protect LDL from oxidation in 70 hypercholesterolemic but otherwise healthy subjects. Statins were administered in doses which were nearly equi-effective in lowering LDL-cholesterol. Changes in LDL oxidation were measured using diene conjugation (DIENES) and thiobarbituric acid reactive substances (TBARS) at entry and three months after beginning therapy with the statins. RESULTS: Levels of DIENES, usually generated during the early phases of lipid peroxidation, were significantly reduced by 10.2 +/- 5.5% (mean +/- SEM; p < 0.03), 6.0 +/- 2.0% (p < 0.005) versus baseline in the case of pravastatin and atorvastatin but simvastatin had no significant effect with a mean reduction of 5.5 +/- 6.4% (p > 0.23). Levels of TBARS, reflecting late phases of LDL oxidation, showed no significant changes against baseline (p > 0.34). Pooled data (n = 70) indicated that statins reduce DIENES levels by approximately 9% versus baseline (p < 0.005) but had no significant effect on TBARS levels (p > 0.29) after three months of therapy. CONCLUSION: This study showed that atorvastatin and pravastatin were capable of protecting LDL from oxidation in vivo in the early treatment phase. Pooled data levels of DIENES were significantly affected by statin therapy over a period of 3 months. No protective effect appeared to be present in the late phases of oxidation evaluated using measurement of TBARS but it should be noted that the clinical impact of such observations are currently discussed controversially in the literature.

Advances in the biology and therapeutic management of multiple myeloma.

During the past decade, new developments have increased our understanding of the biological features of multiple myeloma (MM), and novel therapeutic approaches have improved the outcome and quality of life. The importance of both the malignant clone and the bone marrow environment for disease evolution and propagation has been recognized, and therapeutic approaches that target both components of the disease process appear to be most promising. Along this line, thalidomide has been observed to exert activity in chemotherapy-refractory MM and thus expands the therapeutic armamentarium against MM. Use of high-dose melphalan with autologous stem cell transplantation has resulted in an improved rate of complete remissions as well as prolonged event-free and overall survival. Novel treatment strategies exploiting anti-myeloma immunity (nonmyeloablative allogeneic transplantation, vaccination) are being investigated and carry the potential to further improve the outcome of patients with MM.

Absence of clonal chromosomal relationship between concomitant B-CLL and multiple myeloma--a report on two cases.

B-cell chronic lymphocytic leukemia (B-CLL) and multiple myeloma (MM) are chronic B-cell malignancies that represent different stages of B-cell maturation. Occasionally, both diseases are present in the same patient, and this raises the question of clonal associations between the two neoplasms. We here report on two patients with concomitant B-CLL and MM. Clonal chromosomal abnormalities in both lymphocytic cells and plasma cells were studied by interphase fluorescence in situ hybridization (FISH) using a panel of 24 chromosome- and region-specific DNA probes. In the first patient, cytogenetics revealed 47, X, t(Y;22)(p11;q10), +12, dell4(q21q32). By FISH, +12 was present in lymphoid cells, but not in plasma cells. MM cells were characterized by multiple chromosomal gains (1, 11q23) and losses (5q, 10, 13q14, 15, 17p13, Y), which were all undetectable in lymphoid cells. The second patient, in whom no clonal abnormalities were obtained by conventional cytogenetic analysis, had lymphoid cells with loss of 8q24 by FISH. In contrast, evidence for a gain of 8q24 (consistent with amplification of c-myc) was obtained in 13% of plasma cells. Plasma cells were further characterized by gains of chromosomes 1, 3, 11, 18, and Y. We thus conclude that this comprehensive molecular cytogenetic analysis demonstrates the existence of two clonally distinct B-cell malignancies in both patients.

Deletion of chromosome 13q14 detected by fluorescence in situ hybridization has prognostic impact on survival after high-dose therapy in patients with multiple myeloma.

Interphase cytogenetic analysis of chromosome 13q14 was performed in 28 patients with multiple myeloma (MM) receiving high-dose therapy followed by autologous (n=24) or allogeneic (n=4) stem cell support. Eleven (39%) patients were found to have a deletion of chromosome 13q14. Response rates to high-dose therapy were independent of the chromosome 13 status, but patients with a deletion of 13q14 had a significantly shorter progression-free (p=0.001) and overall survival (p=0.012) than patients with normal chromosome 13q14. Our results indicate that high-dose therapy appears promising in patients with normal chromosome 13, whereas in patients with a deletion of 13q14 innovative therapeutic concepts are warranted.

Deletions of chromosome 13q in monoclonal gammopathy of undetermined significance.

Since deletion of chromosome 13q is a clinically relevant feature in multiple myeloma (MM), we analyzed bone marrow plasma cells from 29 patients with monoclonal gammopathy of undetermined significance (MGUS) to investigate the chromosome 13 status in MGUS. Studies were performed by interphase fluorescence in situ hybridization (FISH) with a panel of 13q14-specific probes (RB1, D13S319, D13S25, D13S31). Plasma cells with a deletion of at least one of the 13q14 loci were detected in 13 patients (44.8%) with MGUS. In five patients (17.2%), deletions of all four 13q14-specific probes were observed, and the additional deletion of a 13q telomeric region (D13S327) suggested loss of the entire 13q arm or monosomy 13. Loss of 13q14 was observed to be monoallelic and to occur in 11.0 to 35.0% of plasma cells (cut-off levels for a deletion <10% with all probes). Nine of 17 patients (52.9%) with MM progressing from a pre-existing MGUS had evidence for a deletion of 13q14 as determined by FISH with the RB1 probe. These results suggest that deletion of 13q14 is an early event in the development of monoclonal gammopathies, but its role for the eventual progression to MM remains to be determined prospectively.

Multiple myeloma with deletion of chromosome 13q is characterized by increased bone marrow neovascularization.

Anti-angiogenesis therapy with thalidomide has been reported to have marked activity in multiple myeloma (MM). As cytogenetics is an independent prognostic factor in MM, we analysed bone marrow (BM) angiogenesis and cytogenetic abnormalities in 34 patients with active MM. BM microvessel density (MVD), as determined by staining with anti-CD34, was significantly higher in MM (MVD: 221 +/- 94 per mm2) than in controls (80 +/- 36; P < 0.0001). In patients with the presence of at least one unfavourable cytogenetic abnormality (deletion of 13q14, deletion of 17p13, aberrations of 11q), a significantly increased BM MVD was observed (254 +/- 93 vs. 160 +/- 60 in patients with absence of these abnormalities; P = 0.0035). Further analyses indicated that increased BM MVD was significantly correlated with deletion of 13q14 (259 +/- 96 vs. 188 +/- 80; P = 0. 026), but not with other cytogenetic, clinical and laboratory MM parameters. We conclude that BM neovascularization is particularly high in MM with deletion of 13q14, which provides a rationale for use of anti-angiogenic strategies in the treatment of MM with high-risk cytogenetics.

The biology of multiple myeloma.

Multiple myeloma (MM) is a B-cell malignancy originating from pre-switched, follicle center B-lymphocytes which differentiate to plasma cells accumulating in the bone marrow. MM cells are characterized by a profound genetic instability resulting in a complex set of numerical and structural chromosomal abnormalities. Among these abnormalities, translocations involving 14q32, the immunoglobulin heavy-chain locus, are the most frequent aberrations, but translocation partners are remarkably heterogeneous. Chromosome 13q14 may harbor a critical tumor suppressor gene since MM patients with deletion of 13q14 experience short overall survival after conventional-dose and high-dose chemotherapy. Bone marrow stroma cells support growth and survival of MM cells, which in turn influence the bone marrow microenvironment. This is particularly evident by the markedly increased bone marrow vascularization observed in most patients with active MM.