MR-Proanp and VEGF As Markers of Response to MEL-DEX Treatment in Systemic AL Amyloidosis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4970-4970
Author(s):  
Alessandro Moscetti ◽  
Giusy Antolino ◽  
Federica Resci ◽  
Daniela De Benedittis ◽  
Virginia Naso ◽  
...  
Keyword(s):  
Stress Responses ◽  
Plasma Cells ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Serum Levels ◽  
Response To Treatment ◽  
Al Amyloidosis ◽  
Significant Independent Predictor ◽  
Heart Involvement ◽  
Cell Mitogen

Abstract Abstract 4970 Background. The natriuretic peptides are a family of different biomarkers including NT-proBNP and MR-proANP. As recommended by guidelines, they are important in heart failure diagnosis and monitoring. MR-proANP (1–98) is the mid-regional portion of the active atrial natriuretic peptide prohormone (99–126) and is considered a significant independent predictor of death, adding prognostic value to NT-proBNP. Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen with angiogenic and nonangiogenic role in several disorders including cardiovascular ones. Moreover, it regulates multiple cellular stress responses, including survival, proliferation, migration and differentiation. Systemic AL amyloidosis represents a peculiar disease with a clinical heart involvement that needs of a specific monitoring in order to avoid poor outcome. Aims and Methods. The study was devoted to evaluate treatment related changes in cardiovascular activity by MR-proANP and VEGF serum levels in systemic AL amyloidosis. Blood samples were collected from 8 patients with systemic AL amyloidosis (median age 72. 8 yrs) admitted to our Unit and analyzed for serum MR-proANP (mean±SD) and VEGF levels (Kits Brahms MR-proANP Kryptor and Randox Evidence Biochips Arrays). According to age and disease risk stratification all patients were treated with upfront oral Mel-Dex association (Melphalan 9 mg/sm, Dexamethasone 20mg day 1–4 q28). From each patient 2 samples of peripheral blood were performed (T0: at exordium of disease and T1: at conclusion of the first course of treatment). The sera were frozen to −80°C until their use. The results were analyzed by paired t test and Person correlation, p values ≤ 0. 05 were considered statistically significant. Results. VEGF serum levels were significantly (p=0. 01) reduced at the end of the first course of treatment (M±SD: T0: 282. 3 ± 86. 23 pg/mL vs. T1: 189. 7 ± 64. 24 pg/mL). Also MR-proANP serum levels were significantly decreased (M±SD: T0: 204. 4 ± 28. 82 pmol/L vs. T1: 160. 2 ± 21. 05 pmol/L, p=0. 008; see figure). The decreases of VEGF and MR-proANP were significantly (r =0. 79; p=0. 02) related. Conclusions. MR-proANP serum levels reduction could be hypothized as related to the decrease of inflammatory activity of disease, including heart involvement and a consequent reduced probability of fatal events. Our hypothesis seems to be confirmed by VEGF serum level reduction suggesting an inhibition of new angiogenesis with reduced interactions between neoplastic plasma cells and bone marrow microenvironment. The effective role of treatment in reducing the disease activity is demonstrated by the significant correlation between VEGF and MR-proANP level decreases. MR-proANP and VEGF could be used to evaluate and select systemic AL amyloidosis patients with an early good response to treatment. Disclosures: No relevant conflicts of interest to declare.

Clinical Characteristics and Outcome of Primary AL Amyloidosis in Greece.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4729-4729
Author(s):  
Michalis Michail ◽  
Efstathios Kastritis ◽  
Sossana Delimpassi ◽  
Marie Christine Kyrtsonis ◽  
Evridiki Michali ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Autonomic Neuropathy ◽  
Congo Red ◽  
Plasma Cells ◽  
Primary Treatment ◽  
Response To Treatment ◽  
Light Chains ◽  
High Dose ◽  
Al Amyloidosis ◽  
Heart Involvement

Abstract Introduction: Primary systemic amyloidosis (AL) is a clonal plasma cells disorder characterized by deposition of amyloid fibrils derived from abnormal light chains, leading to multiorgan involvement and failure. There is no information regarding the clinical, laboratory, treatment characteristics and outcome of such patients in Greece. We performed a retrospective analysis in order to clarify these issues. Patients and Methods: Diagnosis of primary AL amyloidosis was based on positive Congo red staining, immunohistochemistry and the presence of typical clinical and laboratory features. Definition of organ involvement and treatment response was based on established criteria (Gertz et al Am J Hematol 2005). Results: between 1995 and 2007, we identified 109 patients with previously untreated systemic AL amyloidosis. Median age was 66.3 years; 51% were males and lambda-light chain was involved in 74% of patients. Bone marrow biopsy stained positive for Congo-red in 56.5%, immunohistochemical staining was performed in 80 cases: 63 (78.75%) stained positive for λ and 17 for κ light chains. A monoclonal protein by immunofixation was found in the serum and/or urine of 97 (87%) patients. More than 10% bone marrow plasma cells were found in 65%. B2microglobulin was elevated in 36% of patients (median value 2.8 mg/l). The most frequent symptoms at presentation were fatigue and weakness (81%). Heart was involved in 66 (59%), kidney in 79 (71%), liver in 21(19%), GI tract in 17 (16%) and soft tissue in 35 (32%) patients respectively. Symptoms of peripheral and/or autonomic neuropathy were present in 38 (35%) patients. More than two organs were involved in 50 patients (45%). Primary treatment with high-dose dexamethasone based regimens (VAD or pulse Dexamethasone) was used in 45% while 37% of patients were treated with melphalan and prednisone. Six patients (5%) were treated upfront with high dose melphalan and ASCT while another 6 patients were transplanted at a later stage of their disease. Hematologic response was achieved in 50 (46%) including 16 (14.5%) patients who achieved a CR. Organ responses were seen in 32 (29%) patients: 4 had cardiac, 21 renal and 7 liver response respectively while 11 patients had subjective improvement of peripheral or autonomic neuropathy. Median survival from initiation of treatment was 61 months and the 5 year-survival was 44%. Patients with heart involvement or with more than 2 affected organs had a worse prognosis. Survival was significantly longer for patients who responded to primary treatment than for those who did not (p=0.018). Conclusions: Greek patients with AL amyloidosis share the same characteristics with that of patients from other reported studies. Hematologic responses were noted in one-half and organ responses in one-third of patients. Prognosis depended primarily on the presence of heart involvement and on the lack of response to treatment.

Heart Function In Systemic and Localized AL Amyloidosis: Role of NT-ProBNP and MPC-1

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5006-5006
Author(s):  
Francesca Saltarelli ◽  
Alessandro Moscetti ◽  
Guglielmo Bruno ◽  
Bruno Monarca ◽  
Gerardo Salerno ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Heart Function ◽  
Systemic Disease ◽  
Plasma Concentrations ◽  
Serum Levels ◽  
Mononuclear Phagocytes ◽  
Systemic Amyloidosis ◽  
Al Amyloidosis ◽  
Heart Involvement ◽  
Localized Amyloidosis

Abstract Abstract 5006 In AL amyloidosis typical sites of amyloid buildup are heart, skin, gastrointestinal tract, liver, kidneys, and blood vessels. To evaluate the heart involvement in systemic and localized amyloidosis proBNP, peptide (NT-proBNP; 76 amino acids) and MPC-1 were investigated. NT-proBNP have been described as useful marker for the diagnosis heart disease, and its plasma concentrations correlate with the functional classification of patients according to the New York Heart Association (NYHA). MCP-1 is a chemokine that activates mononuclear phagocytes by promoting leukocyte–endothelium binding and migration to sites of inflammation. The MCP-1 levels seem to be related to the severity of cardiac alteration, as demonstrated by the coronary angiogram. NT-proBNP and MPC-1 serum levels were performed in systemic or localized AL amyloidosis to evaluate if there was a difference in the heart involvement. Blood samples were collected from 8 patients with systemic amyloidosis and from 4 patients with localized amyloidosis. To analyze the results of NT-proBNP and MPC-1, Mann-Whitney test was performed. NT-proBNP serum values were significantly (p=0.007) increased in systemic disease. Also, MPC-1 serum levels were significantly (p=0.004) higher in the patients with systemic disease (350.52±58.70 pg/ml) if compared to the group of localized amyloidosis (147.82±26.03 pg/ml). On the basis of our results, the heart seem to be functionally more involved in AL systemic amyloidosis than in localized disease, as demonstrated by the higher NT-proBNP and MPC-1 serum values. Disclosures: No relevant conflicts of interest to declare.

Outcomes and Treatments of Relapsed AL Amyloidosis Following Stem Cell Transplant

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1858-1858 ◽  
Author(s):  
Rahma Warsame ◽  
Soo-Mee Bang ◽  
Shaji K. Kumar ◽  
Martha Q Lacy ◽  
Francis K Buadi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplant ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Treatment Options ◽  
Autologous Stem Cell Transplant ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Post Transplant

Abstract Abstract 1858 Systemic light chain amyloidosis (AL amyloidosis) is a condition where clonal plasma cells produce misfolded insoluble immunoglobulin light chains that deposit in various organs causing progressive organ dysfunction. Chemotherapy and autologous stem cell transplant (ASCT) when eligible is the standard treatment options for patients with AL amyloidosis. There are several studies who report long term outcomes of patient post ASCT. However, there is a paucity of literature describing the outcomes of patients who have received ASCT but have relapsed. We performed a retrospective study to assess the outcomes and treatment regimens employed following relapse after ASCT. Between 1996 and 2009, 410 patients received ASCT at the Mayo Clinic as first line therapy. Of those 410 patients 42 patients died within 3 months of transplant, 64 patients died without documented relapse, 158 patients were alive without documented progression, and 146 patients had documented progression. Those 146 patients are the subject of our study. The median time to hematologic relapse was 2 years (range: 0.2–15.5 years). At relapse, 59 patients were treated with IMiD based therapy, 36 with alkylator based therapy, 24 with bortezomib, 15 with steroids, and 5 with second ASCT. The respective hematologic response rates were 58%, 33%, 50%, 53%, and 60%. The remaining six patients were not evaluable for response for one other following reasons: organ transplants; no further therapy; inevaluable disease. With a median post relapse follow up of 3.6 years, the median overall survival (OS) from the first post ASCT relapse was 4.6 years. The median post transplant follow up was 6.1 years, the median OS for these patients was 7.3 years from the time of transplant. These data provide novel information about outcomes after SCT relapse, which should be useful not only for patients and doctors but also for investigators designing studies for salvage therapies post-transplant. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Immunoglobulin Light-Chain Amyloidosis: From Basics to New Developments in Diagnosis, Prognosis and Therapy

2016 ◽  
Vol 135 (3) ◽  
pp. 172-190 ◽  
Author(s):  
Eli Muchtar ◽  
Francis K. Buadi ◽  
Angela Dispenzieri ◽  
Morie A. Gertz
Keyword(s):  
Light Chain ◽  
Plasma Cells ◽  
Treatment Options ◽  
Organ Damage ◽  
Major Effect ◽  
Response To Treatment ◽  
Al Amyloidosis ◽  
Prognostic Effect ◽  
Amyloid Light Chain ◽  
Immunoglobulin Light Chain Amyloidosis

Immunoglobulin amyloid light-chain (AL) amyloidosis is the most common form of systemic amyloidosis, where the culprit amyloidogenic protein is immunoglobulin light chains produced by marrow clonal plasma cells. AL amyloidosis is an infrequent disease, and since presentation is variable and often nonspecific, diagnosis is often delayed. This results in cumulative organ damage and has a negative prognostic effect. AL amyloidosis can also be challenging on the diagnostic level, especially when demonstration of Congo red-positive tissue is not readily obtained. Since as many as 31 known amyloidogenic proteins have been identified to date, determination of the amyloid type is required. While several typing methods are available, mass spectrometry has become the gold standard for amyloid typing. Upon confirming the diagnosis of amyloidosis, a pursuit for organ involvement is essential, with a focus on heart involvement, even in the absence of suggestive symptoms for involvement, as this has both prognostic and treatment implications. Details regarding initial treatment options, including stem cell transplantation, are provided in this review. AL amyloidosis management requires a multidisciplinary approach with careful patient monitoring, as organ impairment has a major effect on morbidity and treatment tolerability until a response to treatment is achieved and recovery emerges.

Correlation between serum levels of free light chain and phenotype of plasma cells in bone marrow in primary AL amyloidosis

Amyloid ◽  
2005 ◽  
Vol 12 (1) ◽  
pp. 33-40 ◽  
Author(s):  
Yasuhiro Shimojima ◽  
Masayuki Matsuda ◽  
Takahisa Gono ◽  
Wataru Ishii ◽  
Tomohisa Fushimi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Light Chain ◽  
Plasma Cells ◽  
Serum Levels ◽  
Free Light Chain ◽  
Al Amyloidosis

scholarly journals Inflammation Response Cytokines IFN-γ and IL-10 Regulate Monocyte Subset Differentiation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3586-3586
Author(s):  
Hui Zhong ◽  
Weili Bao ◽  
Yunfeng Liu ◽  
Karina Yazdanbakhsh
Keyword(s):  
Flow Cytometry ◽  
Inflammatory Response ◽  
Inflammatory Disease ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Response To Treatment ◽  
Monocyte Subset ◽  
Monocyte Differentiation ◽  
Ifn Γ

Circulating monocytes comprise of a heterogeneous and functionally-diverse cell population which based on surface markers can be divided into three subsets: classical (CMo), intermediate (IMo), and non-classical monocytes/patrolling monocytes (PMo). The frequency/number, gene expression profile and activity of IMo and PMo significantly change in a variety of inflammatory diseases with the changes associated with disease risk and severity as well as response to treatment. While it is believed that CMo differentiate into IMo and that IMo further differentiate into PMo, there is paucity of data on the mechanisms that alter CMo to IMo/PMo differentiation profiles in these conditions. In addition, factors which induce human and mouse IMo and PMo differentiation have yet to be identified. To screen cytokine/chemokine candidates affecting IMo/PMo differentiation, human monocytes were isolated from healthy donors (HD) and cultured with candidates (22 cytokines/chemokines) for 3 days. On day 3, IMo/PMo marker expression was examined by flow cytometry focusing on candidate molecules that led to increased expression of markers (CD16, CX3CR1, CD11c, HO-1, HLA-DR) whose levels are normally found to be higher in IMo/PMo and to decrease in expression of markers (CD14, CD36, CCR2) which are expressed at higher level in CMo as measured by mean fluorescence intension (MFI). We found that of all molecules tested, only two , IFN-γ and IL-10, had significant effects: IFN-γ (10ng/ml) increased expression of CX3CR1 (20 fold), CD16 (60%), HLADR (15%) and inhibited CD36 (42% inhibition) and CD14 expression (45% inhibition) while IL-10 (10ng/ml) increased CD16 (3.3 fold), CD11c (45%), HO-1 (59%) and CX3CR1 (6 fold) expression and inhibited CCR2 (60% inhibition) expression. These data suggest that IFN-γ and IL-10, two key cytokines involved in sterile and infectious inflammation, induce IMo and PMo differentiation. To test whether the effect of IFN-γ and IL-10 in human in vitro cultures can be replicated in vivo, wildtype B6 mice were I.V. injected with IFN-γ or IL-10 for 3 days: IFN-γ, IL-10, or the same volume of PBS. The frequencies of monocyte subsets in blood (gated on CD45+Ly6G-CD11bhighCD115+ for total monocyte population and CMo/IMo/PMo based on Ly6C expression level) on day 4 were analyzed by flow cytometry. We found that IFN-γ (2.5μg/injection/mice twice/day) significantly increased IMo frequencies (from 12% to 35%) but decreased PMo frequencies (from 38% to 26%) while IL-10 (0.25μg/injection/mice twice/day) significantly induced PMo differentiation (from 38% to 63%) without effect on IMo frequencies. The data suggest that IFN-γ increases IMo frequency by simultaneously inducing CMo differentiation into IMo and inhibiting IMo differentiation into PMo. We have previously reported lower PMo frequency in patients with sickle cell disease (SCD), considered an inflammatory disease with altered immune profiles. To test whether altered differentiation programming of IMo/PMo may contribute to reduced PMo frequency in SCD, we analyzed the frequency of CMo/IMo/PMo at baseline and after IFN-γ or IL-10 injection to mimic an inflammatory response in AA mice (expressing normal human hemoglobin) and SS mice (expressing human SCD hemoglobin). We found significantly lower IMo frequency before treatment (AA vs SS:15.0% vs 9.2%) but also lower induction of IMo following IFN-γ treatment in SS mice (18%) relative to AA mice (35%), suggesting that IFN-γ inhibition of IMo differentiation into PMo in SCD is impaired. Furthermore, IL-10 was less effective in inducing PMo in SS as compared to AA mice (SS vs AA: 40% vs 60%). These data suggest that IFN-γ or IL-10-mediated monocyte differentiation in SCD is altered. Altogether, these data have unraveled a novel role for IFN-γ or IL-10, two key cytokines known to be induced during an inflammatory response, in monocyte differentiation, and suggest that IMo/PMo differentiation in a chronic inflammatory disease such as SCD may be defective due to altered response to IFN-γ and IL-10, opening up the potential for identification of novel therapeutic targets for IMo/PMo associated diseases including SCD. Disclosures No relevant conflicts of interest to declare.

Comparison Of Hevylite™ Assay and Plasma Cell Immunophenotyping For Response Evaluation and Residual Disease Characterisation In IgA Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5319-5319
Author(s):  
Daniela Lakomy ◽  
Stephanie Lemaire-Ewing ◽  
Cedric Rossi ◽  
Jessica Borgeot ◽  
Jean-Noël Bastie ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Binding Site ◽  
Plasma Cell ◽  
Light Chain ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Response To Treatment ◽  
Response Evaluation ◽  
Bone Marrow Plasma

Abstract Introduction The evaluation of multiple myeloma response to treatment as defined by international guidelines is currently based on morphologic examination of bone marrow plasma cells, serum protein electrophoresis (SPEP), immunofixation electrophoresis (IFE) and serum free light chain assay. For several years new tools are available as bone marrow plasma cell immunophenotyping and the HevyliteTM assay. HevyliteTM IgA assay provides an automated evaluation of serum heavy/light chain ratio (HLC) of the involved and uninvolved immunoglobulin (Ig) (i.e. IgAΚ/IgAλ). This is particularly interesting in IgA myeloma where the use of SPEP is limited due to a frequent comigration of monoclonal IgA with other proteins. We therefore compared the IgA quantification by Hevylite™ assay and the bone marrow plasma cell immunophenotyping for response evaluation and residual disease characterisation in IgA myeloma. Methods Hevylite™ assay, SPEP, IFE were performed in eleven IgA myeloma patients at different times: after induction chemotherapy, after the consolidation phase and after autologous stem-cell transplantation (ASCT). In the same time, minimal residual disease (MRD) assessment was performed on bone marrrow by multiparameter flow cytometry (MFC). Hevylite™ assay was performed on a Binding Site SPAplus analyser (Hevylite, Binding Site, Birmingham, UK) following the manufacturer recommendations. SPE and IFE were realized on Sebia Hydrasys analyser (Sebia, Evry, France) and results were read by two experienced biologists. Results 1. We found a perfect agreement between the IFE and immunophenotyping results at each time of evaluation, for positive results as for negative results. 2. The SPEP was contributive only in two patients and in these cases it was less sensitive than IFE. In the other patients, the monoclonal IgA migrated in beta region and/or as multiple bands, making the quantitative estimation difficult. 3. In all patients, when MRD by MFC was undetectable and IFE was negative, the HLC ratio was normal. 4. In 3 patients, HLC ratio was consistent with the IFE and MRD by MFC at each time of evaluation. Nevertheless, in 8 patients out of 11, while HLC ratio became normal, MRD by MFC and IFE were still positive. In all cases, the normalization of HLC ratio was followed, at the next step of evaluation, by the normalization of MFC and IFE. 5. In 5 patients, the normalization of HLC ratio occurred before ASCT, while IFE and MRD by MFC were still positive. Nevertheless, after ASCT, IFE and MRD by MFC became also negative, in accordance with the HLC ratio (Table 1). Conclusions During the evaluation of response to treatment of IgA myeloma, we observed a normalization of HLC ratio (Hevylite™ IgA assay) preceding the normalization of MRD by MFC and IFE. This could be explained by the fact that IFE and immunophenotyping provide very sensitive information but only on the monoclonal component. HLC ratio reflects the balance between the monoclonal and polyclonal Igs of involved and uninvolved isotype. A normalization of HLC ratio can be interpreted as an increasing polyclonal Ig proportion parallel with a decreasing monoclonal Ig proportion and may reflect the reconstitution of polyclonal plasma cells. If confirmed by other studies and long term follow-up, HLC ratio could be a non-invasive predictive marker of a good response in IgA myeloma. Disclosures: No relevant conflicts of interest to declare.

HIV Triggers Interleukin 21-Mediated Induction of Granzyme B-Secreting B Cells with Regulatory and Antiviral Potential

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1042-1042
Author(s):  
Christof Kaltenmeier ◽  
Ali Gawanbacht ◽  
Stefanie Lindner ◽  
Thamara Beyer ◽  
Georg Haerter ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Hiv Infection ◽  
Cd4 T Cells ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Granzyme B ◽  
Elevated Serum ◽  
Serum Levels ◽  
Cd40 Ligand

Abstract Abstract 1042 Certain regulatory lymphocyte subpopulations including plasmacytoid dendritic cells and regulatory T cells secrete granzyme B (GrB), thereby suppressing T cell expansion. Recently, we found that B cells can also produce GrB and acquire regulatory potential in response to interleukin (IL-)21. Since HIV has been shown to be associated with elevated serum IL-21 levels, we hypothesized that GrB-expressing B cells may be induced during HIV infection. Here, we show that infection of CD4+ T cells with HIV 1 (NL4-3), but not mock infection, induces strong expression of IL-21 without upregulation of CD40 ligand. Importantly, we further demonstrate that such IL-21+CD40Llow T cells induce GrB in cocultured B cells in an IL-21-dependent fashion, rather than supporting their differentiation into plasma cells. In support of these findings, serum levels of both IL-21 and GrB are significantly higher in HIV-infected patients before HAART as compared to healthy controls. Up to 60% of freshly isolated B cells (36.2% ± 12.9%) from patients infected with HIV, but not B cells isolated from healthy individuals, express GrB. Of note, coculture of HIV-infected CD4+ T cells with GrB+ B cells result in GrB transfer, and strongly suppresses both, proliferation of T cells and viral replication as indicated by significantly reduced p24 levels in coculture supernatants. The observed effects are enhanced by IL-21, and reduced by GrB inhibition. In summary, we demonstrate that HIV infection induces IL-21 in CD4+ T cells, thereby indirectly triggering the development of GrB-secreting B cells with antiretroviral properties. GrB-secreting B cells may play a so far unappreciated role in decelerating HIV expansion, particularly in the early phase of infection. On the other hand, induction of GrB in HIV-specific B cells may interfere with their terminal differentiation into plasma cells, which may explain the lack of an efficient anti-HIV humoral immune response in HIV-infected patients. Disclosures: No relevant conflicts of interest to declare.

High Serum Levels of Angiogenic Cytokines in AL Amyloidosis Correlates with Disease Features.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4781-4781
Author(s):  
Efstathios Kastritis ◽  
Evangelos Terpos ◽  
Mihail Mihail ◽  
Konstantinos Anargyrou ◽  
Sossana Delimpassi ◽  
...  
Keyword(s):  
Growth Factor ◽  
Plasma Cells ◽  
Serum Levels ◽  
Vascular Wall ◽  
Serum Markers ◽  
High Serum ◽  
Al Amyloidosis ◽  
Serum Samples ◽  
Angiopoietin 2 ◽  
Angiogenic Cytokines

Abstract Angiogenesis is a crucial step for disease progression in several hematological malignancies, including plasma cell dyscrasias like multiple myeloma (MM). Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are antagonistic ligands for the receptor tyrosine kinase Tie-2. These cytokines are crucial for maturation and stabilization of the vascular wall: Ang-1 binds to Tie-2 and stabilizes the vascular wall, while Ang2- antagonizes Tie-2 binding and induces vessel destabilization, which leads to the angiogenic sprouting in conjunction with onset of angiogenesis. Vascular endothelial growth factor (VEGF), angiogenin and basic fibroblast growth factor (bFGF) are also potent stimulators of both physiological and pathological angiogenesis. However little is known about the role of these molecules in AL amyloidosis and their possible correlations with the features of the disease. Serum levels of Ang-1, Ang-2, VEGF, and VEGF-A (the major angiogenesis component of VEGF), angiogenin, and bFGF were evaluated using ELISA methodology (R&D Systems, Minneapolis, MN, USA, for all, except VEGF-A: Diaclone, Bensancon, France). Serum samples were collected from 62 previously untreated AL amyloidosis patients as well as from 35 age-matched healthy controls and 35 newly diagnosed, untreated, myeloma patients. Microvascular Density (MVD) of the bone marrow (BM) was also measured in 15 AL patients who had both serum and trephine biopsies available. Definition of organ involvement was based on established criteria (Gerrtz et al Am J Hematol 2005). Serum levels of VEGF (p<0.001), angiogenin (p<0.001), Ang-1(p=0.002) and Ang-2 (p<0.001) were significantly higher in AL patients than in controls; however the ang1/ang2 ratio was not different. The levels of Ang-2 (r=0.776, p=0.005), angiogenin (r=0.746, p=0.008) and bFGF ((r=0.743, p=0.009) correlated with MVD in BM biopsies of AL patients while VEGF, VEGF-A and Ang-1 were not. When compared to MM patients, AL patients had significantly higher VEGF levels (p=0.007), angiogenin (p=0.003) and Ang-1(p<0.001) levels but lower angiopoietin-2 levels (p=0.09); thus the Ang-1/Ang-2 ratio was higher in AL compared to MM (p=0.08). Both VEGF and VEGF-A were increased in patients with symptoms of peripheral neuropathy (p=0.016 and 0.029 respectively), while Ang-2 was increased in patients with heart involvement (p=0.03). There were no differences between AL patients with a creatinine ≥2 mg/dl and those with creatinine<2 mg/dl. In patients with BM plasma cells (PCs)>10%, Ang-1 was lower than in those with PCs<10% (p=0.013), while Ang-2 was not different (p=0.170); thus the Ang-1/Ang-2 ratio was lower in patients with BMPCs >10% (p=0.021). There was no correlation among the number of involved organs, a significant predictor of survival in AL amyloidosis, and levels of angiogenic cytokines. In conclusion, serum markers of angiogenesis are significantly higher in AL patients compared to both healthy individuals and MM patients indicating a possible pathogenetic role in some features of the disease and also a possible therapeutic target.

Dysregulation of miRNAs In AL Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4648-4648
Author(s):  
Liangping Weng ◽  
Brain Spencer ◽  
Pam Soo Hoo ◽  
Lawreen Connors ◽  
Carl O'Hara ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Micro Rna ◽  
Chromosome 3 ◽  
Al Amyloidosis ◽  
Stem Loop ◽  
Micro Rnas ◽  
Bone Marrow Plasma ◽  
Apoptosis Gene

Abstract Abstract 4648 Bone marrow plasma cells (BMPC) were purified from aspirates obtained from patients with AL amyloidosis using anti-CD138 immunomagnetic beads, and from controls. Expression levels of micro RNAs (miRNAs) were compared by microarray. The levels of ten miRNAs were found to be increased more than 1.5-fold in BMPC of AL amyloidosis patients. These results were confirmed using stem-loop RT-qPCR for miR-148a, miR-26a, and miR-16, the most highly upregulated miRNAs in the AL samples. miR-16, a micro RNA linked to other hematopoietic diseases, was significantly increased in the AL group at baseline and also in treated patients with persistent monoclonal plasma cells in the bone marrow, but not in patients who achieved a hematologic remission after therapy and normal polyclonal BMPCs. miR-16 can be derived from the miR-16-1/mirR-15a cluster on chromosome 13 or the miR-16-2/miR-15b cluster on chromosome 3. The expression of miR-15b was much higher than miR15a in AL and control BMPC samples; this suggests that miR-16 in plasma cells is mostly derived from chromosome 3. The anti-apoptosis gene BCL-2, a putative target mRNA that can be down-regulated by miR-16, was present in the BMPCs from the AL group despite the elevated levels of miR-16. Our data suggest that miRNAs are dysregulated in clonal plasma cells from AL amyloidosis patients and that abnormal levels of miRNAs may be potential biomarkers for disease. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document