The combination of intermediate doses of thalidomide and dexamethasone reduces bone marrow micro-vessel density but not serum levels of angiogenic cytokines in patients with refractory/relapsed multiple myeloma

2004 ◽  
Vol 22 (4) ◽  
pp. 159-168 ◽  
Author(s):  
E. Hatjiharissi ◽  
E. Terpos ◽  
M. Papaioannou ◽  
C. Hatjileontis ◽  
V. Kaloutsi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Serum Levels ◽  
Vessel Density ◽  
Micro Vessel Density ◽  
Angiogenic Cytokines

Circulating Angiogenic Cytokines Are Elevated in Patients with Smoldering Myeloma; Implications Into Disease Biology

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5059-5059
Author(s):  
Maria Gkotzamanidou ◽  
Evangelos Terpos ◽  
Athanasios Papatheodorou ◽  
Evangelos Eleutherakis-Papaiakovou ◽  
Meletios Athanasios Dimopoulos ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Hematologic Malignancy ◽  
Prognostic Significance ◽  
Serum Levels ◽  
Bone Marrow Infiltration ◽  
Early Event ◽  
Healthy Controls ◽  
Angiogenic Switch ◽  
Angiogenic Cytokines

Abstract Abstract 5059 Angiogenesis is a critical step in the evolution of carcinogenesis in solid tumors and hematologic malignancies and is considered to be an early event in tumorigenesis. Multiple myeloma (MM) is a hematologic malignancy in which a preceding monoclonal gammopathy (MGUS) is considered a precursor. Asymptomatic/smoldering MM (SMM) is associated with a substantial risk of progression to MM and according to current recommendations these patients should be followed without therapy. Thus evolution from MGUS to SMM and to symptomatic myeloma is now considered as the model describing the natural history of the disease. In order to study the role and evolution of circulating angiogenesis related cytokines, we studied their levels in patients with MGUS, asymptomatic MM and symptomatic MM, before the initiation of first line therapy. We also studied possible associations of these cytokines with features of the disease in patients with SMM that could help identify possible markers of early evolution. We measured serum levels of vascular endothelial growth factor (VEGF), angiogenin, angiopoietin (angp)-1 and -2, using standard ELISA methodology (R&D Systems, Minneapolis, MN, USA). The definition of MGUS, SMM and symptomatic MM was based on the published IMWG criteria. All above cytokines were also measured in 21 individuals with MGUS, in 174 newly diagnosed, untreated MM patients (31 with SMM) and in 44 age- and gender-matched healthy controls. We focused our analysis on patients with SMM. The median age was 63.5 years (range 40–83 years) and 55% were males. The median bone marrow infiltration in trephine biopsy was 20% (range: 12%-75%). Sixty-one per cent had IgG, 29% had IgA isotype while 3% had light chain only myeloma and 6% had biclonal myeloma. The median (range) serum levels for VEGF were 406.5 pg/ml (186.3–797.6 pg/ml), for angp-1 were 31064 pg/ml (18220–50856 pg/ml), for angp-2 were 1434 pg/ml (486.1–4004.5 pg/ml), for angp-1 to angp-2 ratio were 20.8 (6.5–78.1), for angiogenin were 262732.6 pg/ml (138670–1003040 pg/ml) and for bFGF were 12.082 pg/ml (non-detected to 123.37 pg/ml). There were no significant correlations of the levels of angiogenesis related cytokines with serum beta-2 microglobulin levels, the levels of the monoclonal protein, IgA versus IgG isotype, serum LDH levels or age. Patients with extensive bone marrow infiltration (≥60%) had significantly higher levels of ang-2 (p=0.017) and significantly lower angp-1/angp-2 ratio (p=0.004) compared to all others. Compared to healthy controls, patients with SMM had higher levels of angp-1 (p=0.05) and angp-2 (p=0.03) but their respective ratio was not significantly different (p=0.272). Serum levels of VEGF were significantly higher in SMM patients than in controls (mean 429 pg/ml vs. 196 pg/ml, p<0.001). Similarly serum levels of angiogenin were significantly higher in SMM (mean 304028 pg/ml vs 190245 pg/ml, p<0.001). When patients with SMM compared to MGUS patients, there were no significant differences for any of the studied angiogenesis related cytokines. Compared to patients with symptomatic MM, patients with SMM had higher levels of angp-1 (p<0.001) and lower level of angp-2 (p<0.001) resulting in a significantly lower angp-1/angp-2 ratio, indicating a switch to increased vessel-formation activity, while the levels of VEGF were similar. The above results indicate that early in the evolution of the disease (MGUS to SMM to Symptomatic MM) there is an angiogenic switch which is manifested by an increase in the levels of angiogenic cytokines that promote neovasculogenesis (such as VEGF, angp-2 and angiogenin) and a gradual suppression of cytokines that balance their effects (such as angp-1). A possible prognostic significance of the circulating levels of angiogenic cytokines in patients with SMM that could help identify patients at higher risk for progression to symptomatic MM needs further study. Disclosures: No relevant conflicts of interest to declare.

scholarly journals New Insights in Anti-Angiogenesis in Multiple Myeloma

2018 ◽  
Vol 19 (7) ◽  
pp. 2031 ◽  
Author(s):  
Domenico Ribatti ◽  
Angelo Vacca
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cells ◽  
Recent Literature ◽  
Therapeutic Agents ◽  
Bone Marrow Microenvironment ◽  
Clinical Settings ◽  
Preclinical Models ◽  
Direct Production ◽  
Angiogenic Cytokines

Angiogenesis is a constant hallmark of multiple myeloma (MM) progression and involves direct production of angiogenic cytokines by plasma cells and their induction within the bone marrow microenvironment. This article summarizes the more recent literature data concerning the employment of anti-angiogenic therapeutic agents actually used in preclinical models and clinical settings for the treatment of multiple myeloma.

Secretome Analyses of Primary Bone Marrow Fibroblasts Isolated From MGUS and Multiple Myeloma Show a Stepwise Occurrence of Alterations.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1801-1801
Author(s):  
Johannes Drach ◽  
Astrid Slany ◽  
Thomas Mohr ◽  
Johannes Griss ◽  
Christoph C Zielinski ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Growth Factor ◽  
Plasma Cell ◽  
Conflicts Of Interest ◽  
Cell Clone ◽  
Serum Levels ◽  
Plasma Cell Dyscrasia ◽  
Healthy Donors ◽  
Bone Marrow Fibroblasts

Abstract Abstract 1801 Poster Board I-827 The microenvironment of tumor cells in the bone marrow was demonstrated to contribute to tumor promotion and survival. The role of bone marrow fibroblasts (BMFs) in supporting the malignant plasma cell clone in multiple myeloma (MM) has been established, but it remains unclear to which extent the BM microenvironment in general and BMFs in particular are involved in the progression of monoclonal gammopathy of undetermined significance (MGUS) to MM. Therefore we performed proteomics studies on the secretome of BMFs isolated from healthy donors, patients suffering from MGUS and patients suffering from MM. Compared to normal background, BMFs derived from MGUS secreted elevated levels of proteins indicating mitogenic activity and moderate inflammation. These proteins included periostin, IL-6, CXCL5 and CSF-1. Insulin-like growth factor II, which is normally not expressed by normal BMFs, was secreted by BMF cells derived from MGUS as well as from MM. In addition to those and other proteins, BMF cells derived from MM were found to specifically secrete stem cell growth factor, MMP-28 and stanniocalcin-1. These data indicate a step-wise alteration of BMF secretion activity related to the stage of the underlying plasma cell dyscrasia. Therefore BMF might support the progression from MGUS to MM. In order to correlate the secretion performance of BMF with blood serum levels of candidate marker proteins, Luminex assays are employed. Based upon these results, it is our aim to identify serum biomarkers which allow to assess the functional state of BMF and thus the risk for the progression of MGUS to MM. Disclosures No relevant conflicts of interest to declare.

Increased serum levels of MIP-1alpha correlate with bone disease and angiogenic cytokines in patients with multiple myeloma

2013 ◽  
Vol 31 (1) ◽  
Author(s):  
George Tsirakis ◽  
Parascevi Roussou ◽  
Constantina A. Pappa ◽  
Anna Kolovou ◽  
Chrysoula Vasilokonstantaki ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Serum Levels ◽  
Angiogenic Cytokines

scholarly journals Syndecan-1 and angiogenic cytokines in multiple myeloma: correlation with bone marrow angiogenesis and survival

2005 ◽  
Vol 128 (2) ◽  
pp. 210-217 ◽  
Author(s):  
Niels Frost Andersen ◽  
Therese Standal ◽  
Johan Lanng Nielsen ◽  
Lene Heickendorff ◽  
Magne Borset ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Angiogenic Cytokines

scholarly journals An oral absorbent, AST-120, Restores Vascular Growth and Blood Flow in Ischemic Muscles in Diabetic Mice via Modulation of Macrophage Transition

2020 ◽  
Author(s):  
Hsin-Lei Huang ◽  
Chin-Sung Kuo ◽  
Ting-Yung Chang ◽  
Ruey-Hsing Chou ◽  
I-Chun Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Blood Flow ◽  
Bone Marrow Cells ◽  
Macrophage Polarization ◽  
Plasma Concentrations ◽  
Limb Ischemia ◽  
Serum Levels ◽  
Diabetic Mice ◽  
Peripheral Vasculature ◽  
Angiogenic Cytokines

Abstract Background Diabetes has a pronounced effect on the peripheral vasculature. The accumulation of advanced glycation end products (AGEs) is regarded as the crucial mechanism responsible for vascular damage in diabetes, but it is not easy to be avoided from food. In this study, we aimed to investigate the effects of an oral absorbent, AST-120, on the accumulation of AGEs and changes in blood flow recovery in diabetic mice. Methods The mice were divided into four groups, wild-type (WT) mice without treatment, WT mice treated with 5% AST-120 mixed into with pulverized chow, streptozotocin-induced diabetes mellitus (DM) mice, and DM mice treated with 5% AST-120. Six weeks after hind-limb ischemia surgery, blood flow reperfusion, histology, plasma AGE, and cytokine were examined. Bone marrow cells were cultured and derived into macrophages to evaluate the effects of AGEs on macrophage polarization. Results Plasma AGEs were significantly increased in diabetic mice. AST-120 could bind to AGEs and reduced their plasma concentrations. Histological analysis revealed fewer collateral vessels with corresponding impairment of blood flow recovery in diabetic mice. In these mice, AGE-positive and AGE receptor-positive macrophages were numerous in ischemic limbs when compared with non- diabetic mice. In diabetic mice, macrophages in ischemic tissues demonstrated greater M1 polarization than M2 polarization; this pattern was reversed in the AST-120 treatment group. The change in macrophage polarization was associated with corresponding expression of pro-inflammatory and pro-angiogenic cytokines in the ischemic tissues. In cell cultures, AGEs triggered the transformation of bone marrow-derived macrophages into M1 phenotype. The alterations in the polarization of macrophages were reversed after treatment with AST-120. Conclusions Oral administration of AST-120 decreased the serum levels of AGEs in diabetic mice and improved neovascularization of ischemic limbs. This benefit may be due to, at least partially, the alterations in macrophage polarization and the associated changes in inflammatory and angiogenic cytokines.

Prognostic value of bone marrow microvessel density and angiogenic cytokines in patients with multiple myeloma undergoing autologous stem cell transplant

2011 ◽  
Vol 52 (7) ◽  
pp. 1281-1289 ◽  
Author(s):  
Gülsan Türköz Sucak ◽  
Şahika Zeynep Aki ◽  
Bilgehan YüzbaşioĞlu ◽  
Nalân Akyürek ◽  
Münci YaĞci ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Microvessel Density ◽  
Prognostic Value ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Angiogenic Cytokines

Retrospective analysis of cytogenetic and clinical characteristics on 65 patients with multiple myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5075-5075
Author(s):  
Li Yang ◽  
Jingsong He ◽  
Xiaojian Meng ◽  
Guoqing Wei ◽  
Wenjun Wu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Retrospective Analysis ◽  
Clinical Features ◽  
Elevated Serum ◽  
Serum Levels ◽  
Fish Analysis ◽  
Molecular Cytogenetic ◽  
Cytogenetic Aberrations ◽  
Conventional Cytogenetics

Abstract Abstract 5075 Multiple myeloma (MM) is a malignant disorder characterized by abnormal proliferation of monoclonal, immunoglobulin producing plasma cells in the bone marrow. Studies with large samples have shown that molecular cytogenetic changes play an important role in the prognosis of MM. Based upon these findings, we tested cytogenetic aberrations of 65 patients with MM by conventional cytogenetics analysis and FISH technique in this study. Retrospective study was done on these cases for clinical features. Methods: This is a retrospective analysis of 65 patients with MM diagnosed between June 2007 and May 2010 including 13 relapsed cases and 52 newly diagnosed patients. Patients received bortezomib-based combination chemotherapy including bortezomib plus dexamethasone (BD) and the triplet combinations (bortezomib, adriamycin, dexamethasone (BAD), bortezomib, cytoxan, dexamethasone (BCD) and bortezomib, melphalan, prednisone (BMP) or traditional chemotherapy including doxorubicin, vincristine plus dexamethasone (VAD), melphalan plus dexamethasone (MP), melphalan, dexamethasone plus thalidomide (MPT)). To further clarify the correlation between cytogenetic and clinical features on patients with multiple myeloma, we used conventional cytogenetics analysis with R-banding technique and interphase fluorescence in situ hybridization (FISH) to describe the molecular cytogenetic characterization of bone marrow nucleated cells from 65 patients. SPSS (version 18.0) software was used for data analysis, χ2 tests or Fisher's exact test was used for betweengroup comparison of the discrete variables and Log- Rank was used for survival analysis. p<0.05 reflects the remarkable significance. Results: 16.9% of patients (11/65) showed abnormal cytogenetic aberrations including 90.9% (10/11) cases with ultra complex aberration and complex aberration via conventional cytogenetics. In addition, we were able to show aberrations in 49.2% (32/65) of patients by interphase FISH analysis. Abnormalities of 13q14, 1q21, 14q32 and 17p13 were detected in 27.7% (18/65), 13.8% (9/65), 16.9% (11/65), and 29.2% (19/65) by FISH, respectively. 1q21 amplification is strongly associated with 13q14 mutation (P=0.008), demonstrating significant correlation between two. Abnormality of 13q14 deletion or 1q21 amplification were associated with lower levels of albumin (P<0.05). Patients with 13q14 deletion frequently had stage III disease by DS and ISS staging, and compared with patients not detected on FISH analysis, they tended to have elevated serum levels of β2-microglobulin at diagnosis (P<0.05). 17p13 deletion coexistent with 13q14 deletion frequently correlate with elevated serum levels of β2-microglobulin and advanced clinical staging. The median progression-free survival (PFS) of patients with 17p13 deletion or 17p13/13q14 aberrations were both 11.0m, significantly lower than patients with no detected abnormality (median PFS 19.0m) (P<0.05). The median overall survival (OS) of patients with FISH negtive results was 38.0m, significantly higher than those with 13q14, 14q32 or 1q21 abnormality and 17p13/13q14 or more than three abnormalities (P<0.05). Conclusions: This study validates myeloma cells are prone to show complex aberration and FISH is superior in the detection of cytogenetic aberrations to conventional cytogenetics analysis for patients with multiple myeloma. 1q21 had significant correlation to 13q abnormality. 17p13 deletion coexist with 13q14 deletion and 14q32 rearrangeent were used to associate with poor prognosis. 17p13 deletion or 17p13/13q14 deletion was associated with poorer PFS while abnormality of 13q14, 1q21,14q32, 17p13/13q14 or more than 3 abnormalities were correlate with poorer OS. Disclosures: No relevant conflicts of interest to declare.

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