Elevated levels of shed syndecan-1 correlate with tumour mass and decreased matrix metalloproteinase-9 activity in the serum of patients with multiple myeloma

Sera from 20 myeloma patients and 12 normal controls were analysed for the presence of syndecan-1 and matrix metalloproteinase-9 (MMP-9). The level of syndecan-1 in the serum was elevated in 7/20 (35%) myeloma patients whilst 6/19 patients (31%) had decreased serum MMP-9 activity. The presence of increased syndecan-1 was associated with decreased serum MMP-9. Both elevated syndecan-1 and decreased MMP-9 were associated with higher marrow plasmacytosis, serum beta-2 microglobulin and paraprotein levels. These data provide evidence that the syndecan-1 ectodomain is shed in vivo . Quantitation of serum syndecan-1 may be a useful measure of tumour mass and may have important implications for myeloma biology.     

Elevated endothelin-1 levels are associated with decreased arterial elasticity in hypertensive patients

Endothelin-1 stimulates collagen synthesis and is increased in hypertension, but its effect on collagen degradation remains unknown. The current study tested the hypothesis that elevated endothelin-1 levels are associated with decreased collagenase activity, markers of collagen degradation, and arterial compliance in hypertensive patients. Normotensive (n = 10) and hypertensive (n = 13) patients who were not on any antihypertensive medication were recruited, and small and large artery elasticity index, systemic vascular resistance, pulse pressure, and blood pressure were determined using blood pressure waveform analysis. Large artery elasticity index and collagen degradation products were decreased whereas endothelin-1, systemic vascular resistance, and pulse pressure were elevated in hypertensive patients. Plasma endothelin-1 was negatively correlated with a cross-linked C-terminal telopeptide of collagen type I, a collagen degradation marker (r = -0.43; p = 0.04), collagenase matrix metalloproteinase-1 (r = -0.48; p = 0.02), and large artery elasticity (r = -0.45; p = 0.03) and positively correlated with pulse pressure (r = 0.68; p = 0.0005). These results suggest that endothelin-1 contributes to decreased arterial compliance in hypertension via inhibition of collagen degradation.     

Cholesterol levels in patients with multiple myeloma

Hypocholesterolemia is seen in solid tumors and some hematological malignancies. We assessed cholesterol levels and the relationship between these levels and types and stages of multiple myeloma (MM) in the patients with MM. One-hundred two patients (60 male and 42 female) of mean age 59 ± 11 years with MM were enrolled to this study. While 71.6% of the patients were Ig G type, 80.4% of the patients were at stage III. In the control group, there were 71 healthy persons (42 male and 29 female) of mean age 58 ± 8 years. The levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in the patients with MM were significantly lower than the controls (p < 0.001). There was no difference for the levels of very-low-density lipoprotein cholesterol and triglyceride between the two groups (p > 0.05). Lipid parameters were not different between Ig types (p > 0.05). The levels of TC and LDL-C in the patients with stage I were higher than those of stages II and III (p < 0.001 and p < 0.005, respectively). The levels of TC and LDL-C in the controls were not higher than the patients with stage I (p > 0.05). HDL-C levels in the patients with stage III were lower than controls (p < 0.001). Hypocholesterolemia are seen in the patients with MM. Hypocholesterolemia may be due to increased LDL clearance and utilization of cholesterol by myeloma cells. We did not receive any financial support, and this study has not been published in any journal.     

Elevated levels of soluble fibrin in patients with venous thromboembolism

The fibrin-related markers (FRMs), including soluble fibrin (SF), d-dimer and fibrin and fibrinogen degradation products (FDP) are considered to be useful for the diagnosis of thrombosis; however, evidence for the diagnosis of thrombosis by SF is still not well established. The present study was designed to evaluate the usefulness of SF in the diagnosis of venous thromboembolism (VTE). The plasma concentrations of FRMs were measured in 551 in-patients suspected to have a VTE. The plasma levels of SF, d-dimer and FDP were significantly higher in patients with VTE than patients without VTE and those were significantly higher in patients without VTE than in healthy volunteers. In a receiver operating characteristic analysis for the diagnosis of VTE, the area under the curve was 0.950 for SF, 0.933 for FDP and 0.805 for d-dimer. The appropriate cut-off values for the diagnosis were as follows SF 5.9 μg/ml, FDP 2.1 μg/ml and d-dimer 4.8 μg/ml. To obtain a 100% negative predictive value for the diagnosis of VTE, the SF was less than 5.2 μg/ml, FDP was less than 1.3 μg/ml, and d-dimer was less than 0.5 μg/ml. Our findings suggest that the SF assay is useful for the diagnosis and exclusion of VTE.     

Elevated plasma beta-thromboglobulin levels in multiple myeloma and in polycythaemia vera.

Plasma beta-thromboglobulin levels were determined in 22 multiple myeloma patients, in 15 patients with polycythaemia vera and in 70 healthy controls. In both multiple myeloma and polycythaemia vera significantly increased plasma concentrations of this platelet-specific protein were found.     

Interleukin-6 serum levels in patients with multiple myeloma

Summary Studying the prognostic value of serum interleukin-6 (IL-6) levels in multiple myeloma, we observed important daily variations in some patients. Therefore a unique serum IL-6 measurement should be interpreted with caution and requires confirmation by multiple determinations performed over a period of several days.     

Elevated soluble CD26 levels in patients with tuberculous pleurisy.

SETTING: Several reports have shown that tuberculous infection elicits a Th1-like immune response with increased levels of IFN-gamma. Recently, expression of CD26 on CD4+ lymphocytes has been shown to correlate with the production of Th1-like cytokines. We therefore hypothesized that CD26 expression might increase in tuberculous pleural effusion, and might thus be a possible marker for detecting tuberculous pleurisy. OBJECTIVE AND DESIGN: To test this hypothesis, we measured soluble CD26 levels in the serum and pleural fluid of patients with tuberculous pleurisy (TB; n = 13), carcinomatous pleurisy (CA, n = 17), empyema (EM, n = 6), and congestive heart failure (HF, n = 10). RESULTS: The pleural CD26 levels, but not the serum CD26 levels, in patients with tuberculous pleurisy were significantly higher than those in other groups, and were correlated with levels of adenosine deaminase and interferon-gamma in the tuberculous pleural effusion. Furthermore, when the cut-off value for p-CD26 was set at 544.5 ng/ml, the positive rate for the TB group was significantly higher than that for the CA, EM and HF groups (P < 0.05). CONCLUSION: These results suggest that elevation of soluble CD26 in pleural fluid is implicated in Th1-like immune response, and may be a useful marker for tuberculous pleurisy.     

sVE-cadherin and sCD146 serum levels in patients with multiple myeloma

The role of angiogenesis in multiple myeloma (MM) pathogenesis is well established. Angiogenesis is linked to the functional state of endothelial junctions that are modulated by the growth and activation of endothelial cells. CD146 and vascular endothelial-cadherin (VE-cadherin) are cell adhesion molecules localized at the endothelial junction. The aim of the study was to assess sVE-cadherin and sCD146 serum levels in MM patients. Forty-six untreated patients with MM were included in this study. In addition, 23 of 46 patients were analyzed again in partial remission after initial chemotherapy. Twenty-two samples from healthy volunteers were evaluated as the control. There was no significant difference in sCD146 level between MM patients and the control (511 +/- 177.2 vs. 460.9 +/- 156.9 ng/ml respectively). In untreated MM patients, sVE-cadherin level was significantly higher than in the control (1.36 +/- 0.55 vs. 0.63 +/- 0.56 ng/ml respectively; P < 0.05). In untreated MM patients, sVE-cadherin level was significantly higher than in MM patients in partial remission (1.36 +/- 0.55 vs. 0.5 +/- 0.33 respectively; P < 0.05). sVE-cadherin but not sCD146 serum level was increased in untreated MM patients and decreases after chemotherapy in patients in partial remission. VE-cadherin may reflect intensity of angiogenesis in MM and may be useful in prognosis of response to treatment.     

Elevated serum levels of soluble CD146 in patients with systemic sclerosis

CD146, a transmembrane glycoprotein member of the immunoglobulin superfamily, acts as an adhesion molecule that helps maintain the cell monolayer. Human endothelial cells expressing CD146 are involved in angiogenesis and inflammation. Recently, we developed a sandwich ELISA for detecting soluble CD146 (sCD146) in human serum specimens. The aim of this study is to determine serum levels of sCD146 in patients with systemic sclerosis (SSc) and to examine the relationship between sCD146 levels and clinical manifestations. We quantified serum sCD146 levels in 47 serum samples from patients fulfilling criteria for SSc, 23 serum samples from patients fulfilling criteria for rheumatoid arthritis (RA), and 25 healthy controls. We also investigated the relationship between sCD146 levels and various clinical characteristics with SSc patients. Levels of sCD146 were significantly higher in the 47 patients with SSc than in the 25 healthy controls and 23 patients with RA (12.50 vs. 6.91 vs. 9.95 ng/ml; p < 0.001). Serum sCD146 levels in SSc patients with pulmonary arterial hypertension (PAH) were lower than in SSc patients without PAH (10.12 vs.13.17 ng/ml; p < 0.01). The serum levels of sCD146 were elevated in patients with SSc. However, decreased sCD146 levels were observed in SSc patients with PAH. Further studies are necessary to elucidate the sources and the mechanisms.     

Elevated soluble HLA II protein levels in patients with alpha-1 antitrypsin deficiency with or without COPD

Elevated levels of human leukocyte antigen (HLA) proteins have been reported in several pathologic conditions that are associated with increased concentrations of white blood cells (e.g., infection, inflammation, and lymphoproliferative disorders). The mechanisms by which HLA proteins are solubilized from cell membranes are insufficiently understood. We hypothesized that HLA proteins may be cleaved from cell membranes by insufficiently inhibited leukocytic elastase, as expected in alpha-1 antitrypsin deficiency (A1ATD), resulting in elevated plasma levels of soluble HLA (sHLA) proteins. Using an enzyme-linked immunosorbent assay, we measured sHLA II levels in the peripheral blood of patients with A1ATD with or without co-existing chronic obstructive pulmonary disease (COPD), with COPD only, and in a control group. Mean (±SD) sHLA II plasma levels were 110 ± 200 pg/mL in patients with A1ATD and COPD (Group 1), 10 ± 30 pg/mL in patients with COPD without A1ATD (Group 2), 70 ± 90 pg/mL in patients with A1ATD without COPD (Group 3), and 10 ± 30 pg/mL in healthy donors (Group 4). Soluble HLA II plasma levels were significantly higher in Group 1 (P = .001) and Group 3 (P = .002) versus Group 4. Our preliminary results suggest that leukocytic elastase and probably other proteinases solubilize HLA proteins from cell membranes. This mechanism would operate in inflammation with elevated leukocytic elastase levels but more so with inflammation and A1ATD, where elastase would be insufficiently inhibited. If this mechanism is verified, plasma sHLA levels could potentially be used to measure cell damage due to proteinases and, therefore, for monitoring the therapeutic efficacy of alpha-1 antitrypsin (A1AT) augmentation therapy.     

Elevated serum concentrations of activated hepatocyte growth factor activator in patients with multiple myeloma

Objectives: Hepatocyte growth factor (HGF) is a potential key factor in multiple myeloma. Conversion of pro‐HGF to its active form is a critical limiting step for its biological effects. We aimed to examine the levels of the most potent activator, the hepatocyte growth factor activator (HGFA), in serum and bone marrow plasma of patients with multiple myeloma. Methods: The activated form of HGFA was measured by an enzyme‐linked immunosorbent assay in serum (n = 49) and bone marrow plasma (n = 16) from multiple myeloma patients, and in serum from healthy controls (n = 24). Results: The median concentrations of activated HGFA in myeloma and control sera were 39.7 (range 6.2–450.0) and 17.6 ng/mL (range 4.8–280.6), respectively. The difference was statistically significant (P = 0.037). The median concentration of activated HGFA in bone marrow plasma was 6.1 ng/mL (range 3.5–30.0). Conclusion: We here show for the first time that the activated form of HGFA is present at high levels in serum and bone marrow of myeloma patients, thus providing a necessary prerequisite for the activation of HGF.     

Enrichment of functional CD8 memory T cells specific for MUC1 in bone marrow of patients with multiple myeloma

Multiple myeloma (MM) is one of the most common hematologic malignancies. Despite extensive therapeutical approaches, cures remain rare exceptions. An important issue for future immunologic treatments is the characterization of appropriate tumor-associated antigens. Recently, a highly glycosylated mucin MUC1 was detected on a majority of multiple myeloma cell lines. We analyzed bone marrow and peripheral blood of 68 patients with HLA-A2-positive myeloma for the presence and functional activity of CD8 T cells specific for the MUC1-derived peptide LLLLTVLTV. Forty-four percent of the patients with MM contained elevated frequencies of MUC1-specific CD8 T cells in freshly isolated samples from peripheral blood (PB) or bone marrow (BM) compared with corresponding samples from healthy donors. BM-residing T cells possessed a higher functional capacity upon specific reactivation than PB-derived T cells with regard to interferon gamma (IFN-gamma) secretion, perforin production, and cytotoxicity.     

Circulating levels and clinical significance of soluble CD86 in myeloma patients

Circulating soluble CD86 (sCD86) levels are elevated in a number of leukaemias and are an independent prognostic factor in acute myeloid leukaemia. We investigated the clinical significance of circulating sCD86 in 299 patients from the UK Medical Research Council myeloma VIth trial, where patients received ABCM [adriamycin, carmustine (BCNU), cyclophosphamide, melphalan] either alone or with prednisolone (ABCM + P). Serum levels of sCD86 were significantly elevated (P = 0.0001) in myeloma patients and using the median normal donor level (0.621 ng/ml) as a cut-off point, 70% of patients had elevated levels (range = 0.015-15.87 ng/ml, median = 1.1 ng/ml). In univariate analysis elevated sCD86 levels were associated with significantly shorter (P < 0.001) survival (median = 22 vs. 51 months) and event-free survival (median = 14 vs. 31 months) in ABCM + P but not ABCM patients. Multivariate analysis demonstrated that sCD86 was a significant, independent prognostic marker of both overall [risk ratio (RR) = 2.04, P = 0.0006] and event-free (RR = 1.95, P = 0.0004) survival in ABCM + P patients. In conclusion, this study demonstrated that sCD86 levels are a significant independent prognostic marker in at least some myeloma treatment groups and its biological role and prognostic value should be further investigated.     

Elevated soluble intercellular adhesion molecule-1 levels in patients with systemic lupus erythematosus: relation to insulin resistance

OBJECTIVE: Intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are members of the immunoglobulin supergene family and play a central role in cell-to-cell and in cell-to-extracellular matrix-mediated immune responses. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a wide variety of immunological abnormalities. The relationship between soluble adhesion molecules and insulin resistance has been observed in different populations. However, the association of circulating levels of soluble cell adhesion molecules with insulin resistance and/or hyperinsulinemia in patients with SLE has not been extensively established. METHODS: We evaluated the relationship of soluble ICAM-1 (sICAM-1) and VCAM-1 (sVCAM-1) to insulin resistance in 68 patients with SLE and 34 age-matched healthy controls. RESULTS: Patients with SLE had significantly higher fasting insulin levels, homeostasis model assessment insulin resistance (HOMA-IR), HOMA beta-cell, and plasma levels of sICAM-1 and sVCAM-1 than controls. SLE patients with HOMA-IR in the top quartile had the highest plasma levels of sICAM-1. However, there was no statistical difference in plasma levels of sVCAM-1 between patients in the respective quartiles of insulin sensitivity-related variables. Plasma levels of sICAM-1, but not sVCAM-1, were significantly correlated with fasting insulin (r = 0.327, p = 0.006), HOMA-IR (r = 0.278, p = 0.022), and HOMA beta-cell (r = 0.359, p = 0.003). In addition, fasting insulin was responsible for sICAM-1 variability in patients with SLE. CONCLUSION: The elevation of plasma levels of sICAM-1 was associated with a status of insulin resistance in patients with SLE.     

Elevated levels of soluble ICAM-1 in serum of patients with acute myeloid leukemia undergoing bone marrow transplantation

Serum soluble ICAM-1 concentrations were measured in 10 patients with or without chronic graft-vs.-host disease (GVHD) after allogeneic bone marrow transplantation. The serum soluble ICAM-1 levels in the patients with chronic GVHD were significantly higher than that in the patients without chronic GVHD. The data indicated that serum soluble ICAM-1 is a useful parameter for predicting chronic GVHD. © 1996 Wiley-Liss, Inc.     

Clinical significance of serum erythropoietin levels in patients with multiple myeloma]

Serum erythropoietin (Epo) levels were measured in 53 patients with multiple myeloma (MM), 49 normal subjects and 53 patients with some hematological diseases including aplastic anemia (AA), iron deficiency anemia, etc. to study the significance of erythropoietin in anemia of MM. The serum Epo level was 72.0 +/- 94.4 mIU/ml (mean +/- SD) in MM patients, which was significantly higher than in normal subjects (24.1 +/- 6.1 mIU/ml), but lower than in AA patients (7069.9 +/- 9406 mIU/ml). A significant inverse correlation was found between the hemoglobin (Hb) levels and the logarithmic values of serum Epo levels (r = -0.543, p < 0.05) in MM patients. This inverse correlation was stronger (r = -0.636, p < 0.05) in MM patients without renal dysfunction than in whole MM patients, while no correlation was observed in MM patients with renal dysfunction. These results indicate that MM patients with renal dysfunction have a low ability to synthesize Epo and that the supplemental therapy of recombinant Epo is effective to improve their anemia. In addition, the circadian rhythm of serum Epo level was lower in the morning than in the afternoon in both MM patients and normal controls. Serum Epo levels after chemotherapy in MM patients were elevated temporarily and then decreased in spite of no change of blood Hb level.