Prognostic significance of vascular endothelial growth factor immunoexpression in the context of adverse standard prognostic factors in multiple myeloma

Ribas, Christian; Colleoni, Gisele W. B.; Silva, Maria Regina Regis; Carregoza, Maria José; Bordin, José Orlando

doi:10.1111/j.1600-0609.2004.00314.x

Cited by 30 publications

(16 citation statements)

References 30 publications

(35 reference statements)

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“…We identified VEGF immunoreactivity in 79.7% bone marrow biopsy specimens. These data are in accordance with the results of previous immunohistochemical studies in myeloma patients [18][19][20][21][22][23]. Nevertheless, there are conflicting data regarding correlation between VEGF expression and clinicopathological parameters.…”

Section: Discussionsupporting

confidence: 95%

“…Nevertheless, there are conflicting data regarding correlation between VEGF expression and clinicopathological parameters. Some authors have found association between VEGF expression and proliferative activity [20], plasmablast morphology, low hemoglobin, and high grade of angiogenesis [21]. On the contrary, we did not find significant correlation between VEGF expression and selected clinicopathological parameters, which is in accordance with the results of Choi et al [18].…”

Section: Discussionsupporting

confidence: 88%

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Expression of VEGF and microvessel density in patients with multiple myeloma: clinical and prognostic significance

Marković

Marisavljević

Čemerikić³

et al. 2008

Med Oncol

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The conflicting data are reported on the clinical significance of VEGF deregulation and intensity of angiogenesis in multiple myeloma. The aim of this study was to evaluate the incidence and prognostic significance of VEGF expression and microvessel density (MVD) in multiple myeloma, as well as the relationship of their expression with selected clinical data, histological features, and proliferative activity of myeloma cells. We analyzed bone marrow biopsy specimens obtained from 59 patients with newly diagnosed multiple myeloma. Expression of VEGF and MVD was analyzed using standard immunohistochemical method (antibodies against VEGF and CD34, respectively) on B5-fixed and routinely processed paraffin-embedded bone marrow specimens. MVD was estimated by counting the number of microvessels in three "hot spots" at 400x magnification. VEGF immunoreactivity was estimated on the basis of intensity and percentage of positive plasma cells. VEGF was expressed in 47/59 (79.7%) specimens. There was no significant correlation between VEGF overexpression and age, clinical stage, the extent of osteolytic lesions, type of monoclonal protein, hemoglobin concentration, platelet count, serum concentration of creatinine, calcium, and albumins, the extent of bone marrow infiltration, histological grade, and proliferative activity index (measured with Ki-67 immunoreactivity). No significant difference was observed regarding the overall survival between VEGF-positive and VEGF-negative patients (29 vs. 34 months, P = 0.8). Median MVD was 15, ranging from 1 to 89 microvessels per three "hot spots". There was significant correlation between MVD and histological grade, the extent of bone marrow infiltration, and proliferative activity. Significant difference was observed regarding the overall survival between patients with low MVD (<15) and patients with high MVD (> or = 15) (46 vs. 22 months, P = 0.009; univariate analysis). The results of this study did not reveal clinical significance of VEGF overexpression in multiple myeloma. On the contrary, the extent of bone marrow angiogenesis is an indicator of biological potency of malignant clone and a predictor of poor survival in newly diagnosed myeloma.

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Section: Discussionsupporting

confidence: 95%

Section: Discussionsupporting

confidence: 88%

Expression of VEGF and microvessel density in patients with multiple myeloma: clinical and prognostic significance

Marković

Marisavljević

Čemerikić³

et al. 2008

Med Oncol

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“…That is probably the reason why VEGF and bFGF levels have been found to be increased in MM patients and correlate with survival. 17,18,32,33 In our cohort of patients with refractory/relapsed MM, serum levels of both VEGF and bFGF were increased in comparison with the values among normal controls. In addition, MVD values were also increased in this cohort of patients compared to controls who had NHL with no bone marrow involvement, confirming the role of angiogenesis in myeloma biology.…”

Section: Discussionmentioning

confidence: 92%

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

Hatjiharissi

Terpos

Papaioannou

et al. 2004

Hematological Oncology

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The aim of the study was the evaluation of anti-angiogenic activity of the combination of intermediate doses of thalidomide and dexamethasone in patients with refractory/relapsed myeloma. Twenty-five patients were included in the study. Microvessel density (MVD) was evaluated in marrow biopsies before and after treatment. Serum levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), tumor necrosis factor-alpha (TNF-alpha), which have angiogenic potential and interleukin-6 (IL-6), IL-1beta, soluble IL-6 receptor (sIL-6R), and transforming growth factor-beta (TGF-beta) which are involved in the disease biology, were measured before treatment and then every 2 weeks for 8 weeks. Pretreatment levels of MVD, VEGF, b-FGF, IL-6, sIL-6R were increased in the patients compared to controls. The overall response rate to therapy was 72%. The administration of the combined regimen produced a significant reduction in MVD in responders. However, an increase in serum levels of VEGF, b-FGF, IL-6, sIL-6R was observed post-treatment in responders. In contrast, serum levels of TNF-alpha, TGF-beta, IL-1beta did not differ between patients and controls and remained unchanged during the study. These results suggest that the combination of thalidomide plus dexamethasone is an effective treatment for myeloma reducing MVD marrow levels but not serum levels of angiogenic cytokines or cytokines implicated in myeloma biology.

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“…High expression of VEGF in myeloma cells or increased serum VEGF levels in patients with myeloma is linked with aggressive disease and resistance to chemotherapy, suggesting that the VEGF pathway may be a critical therapeutic target [20,21]. VEGF is also expressed in Hodgkin lymphomas [22] and increased serum levels in these patients have been reported [23].…”

Section: Discussionmentioning

confidence: 95%

Phosphorylated VEGFR2/KDR receptors are widely expressed in B‐cell non‐Hodgkin's lymphomas and correlate with hypoxia inducible factor activation

Giatromanolaki

Koukourakis

Pezzella

et al. 2008

Hematological Oncology

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The expression of hypoxia inducible factors (HIF) 1alpha and 2alpha, of vascular endothelial growth factor (VEGF) and of the phosphorylated form of its receptor VEGFR2 (pVEGFR2/KDR) were investigated immunohistochemically in a series of 146 B-cell non-Hodgkin's lymphomas and 48 normal lymph nodes. These proteins were significantly up-regulated in neoplastic lymphocytes and a significantly higher expression of HIF1alpha (p = 0.05), VEGF (p = 0.02) and pVEGFR2/KDR (p = 0.007) was recorded in diffuse large B-cell lymphomas(DLBCL) compared to follicular lymphomas (FL). A strong statistical association of pVEGFR2/KDR expression with high HIF1alpha, HIF2alpha and VEGF was noted in both DLBCL and FL. HIF1alpha andHIF2alpha were linked with VEGF expression but no association between HIF1alpha and HIF2alpha was noted. Vascular density was significantly higher in the lymphoma compared to normal tissue, but there was no association with any of the examined parameters. It is concluded that the VEGF/receptor pathway is active in more than half of NHLs and particularly in DLBCL. The intimate correlation of VEGF production with the presence of phosphorylated VEGF-receptors strongly supports the concept of an autocrine pathway. The strong association of HIFalphas with the expression of VEGF and pVEGFR2/KDR found in the study provide strong evidence on the role of HIFalphas inthe activation of angiogenic and VEGF-autocrine pathways that may be critical therapeutic targets for HIF-inhibitors or other anti-angiogenic agents.

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Prognostic significance of vascular endothelial growth factor immunoexpression in the context of adverse standard prognostic factors in multiple myeloma

Cited by 30 publications

References 30 publications

Expression of VEGF and microvessel density in patients with multiple myeloma: clinical and prognostic significance

Expression of VEGF and microvessel density in patients with multiple myeloma: clinical and prognostic significance

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

Phosphorylated VEGFR2/KDR receptors are widely expressed in B‐cell non‐Hodgkin's lymphomas and correlate with hypoxia inducible factor activation

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