Microvessel Density In Bone Marrow Research Articles

Anti-Apoptotic Pathways in Bone Marrow and Megakaryocytes in Myeloproliferative Neoplasia

Objective: Proliferative activity contributes to bone marrow cellularity in myeloproliferative neoplasia (MPN). Megakaryocytes are the most important cells in MPN bone marrow pathology. JAK2^V617F mutation constitutively activates JAK2, pErk (phosphorylating extracellular signal-regulated kinase) and PI3K (phosphatidylinositol 3-kinase)-Akt signaling. Erk is involved in megakaryocyte differentiation, PI3K-Akt inhibits megakaryocyte apoptosis via Bcl-x_L and two downstream effectors (p70S6k and Bnip3). Immunohistochemic expression of phosphorylated Erk, Akt, p70S6k and Bnip3 was studied along with microvessel density (MVD) in MPN bone marrow and megakaryocytes. Methods: 36 essential thrombocythemia (ET), 25 polycythemia vera and 45 primary myelofibrosis patients were analyzed for pErk, pAkt, Bnip3, p70S6k and MVD expression by immunostaining bone marrow biopsy sections followed by automated image analysis. JAK2^V617F was analyzed through real-time PCR in blood samples. Results: pErk and pAkt were significantly higher expressed in MPN megakaryocytes, mainly in ET patients, compared to controls. Bnip3 was higher expressed in bone marrow of control patients and in MPN megakaryocytes. Mainly in ET patients, MPN megakaryocytes showed higher p70S6k expression compared to controls. Conclusion: Increased bone marrow cellularity in MPN patients might be influenced by increased pErk, pAkt and decreased Bnip3 expression. A dominant role for megakaryocytes in ET patients was shown. Increased amounts of megakaryocytes in MPN patients can be due to increased pAkt and p70S6k.

Correlation among DCE‐MRI measurements of bone marrow angiogenesis, microvessel density, and extramedullary disease in patients with multiple myeloma

Correlation among DCE‐MRI measurements of bone marrow angiogenesis, microvessel density, and extramedullary disease in patients with multiple myeloma

Selected Aspects of Angiogensis in Haematological Malignancies

SummaryIt is well established that angiogenesis is necessary in solid tumours development. Interesingly, the role of angiogensis in haematological malignancies has been also recognized. Recent publicationts indicate that microvessel density in bone marrow and angiogenic factors like endoglin, placental growth factor and cyclooxygenase 1 are increased in lymphoproliferative disorders and suggest that angiogensis is a part of pathomechanism of these malignancies. However, it has not been identified how angiogenesis can be involved in progression of haematological disorders. There is a strong need for further investigations in this area, since antiangiogenic therapy is a potential adjunct to conventional therapy of lymphoproliferative disorders.

Bone marrow microvessel density in chronic myeloproliferative disorders: a study of 115 patients with clinicopathological and molecular correlations

Philadelphia-negative chronic myeloproliferative disorders (CMD) include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Angiogenesis is critical in the pathogenesis of PMF. We studied angiogenesis in 115 patients with CMD (23 PV, 24 ET, 46 PMF, 12 post-PV and 10 post-ET myelofibrosis) by assessment of microvessel density (MVD) in bone marrow (BM). Kruskall-Wallis analysis of variance showed that patients with PMF had significantly higher values of MVD than those with PV (P < 0.001), ET (P < 0.001) and controls (P < 0.001). Mann-Whitney U-test demonstrated that patients with PMF at the prefibrotic stage had significantly higher MVD values than those with ET (P = 0.02). Patients with post-PV myelofibrosis showed significantly higher MVD values than those with PV (P < 0.001), as did patients with post-ET myelofibrosis compared with ET (P < 0.001). In patients with CMD, the multivariate generalized linear regression model showed that the JAK2 (V617F) mutational burden (P = 0.01), serum lactate dehydrogenase level (P = 0.003), and anaemia (P < 0.001) independently correlated with MVD. In summary, this study indicates that assessment of BM angiogenesis, as measured by MVD, may be a useful additional tool in the histopathological definition of CMD.

Immunohistologic analysis of zygapophyseal joints in patients with ankylosing spondylitis

Zygapophyseal joints of the spine are often affected in ankylosing spondylitis (AS). In this study, we undertook a systematic immunohistologic evaluation of the immunopathology of the zygapophyseal joints in patients with advanced AS. We obtained zygapophyseal joints from 16 AS patients undergoing polysegmental correction of kyphosis and from 10 non-AS controls (at autopsy). Immunohistologic analysis of the bone marrow was performed by analyzing the number of infiltrating T cells (CD3, CD4, CD8), B cells (CD20), osteoclasts (CD68), bone marrow macrophages (CD68), and microvessel density (CD34) per high-power field. Zygapophyseal joints from 6 of 16 AS patients, but from none of the controls, exhibited 2 or more CD3+ T cell aggregates, signifying persistent inflammation. Interstitial CD4+ and CD8+ T cells were significantly more frequent in AS patients compared with non-AS controls (P = 0.002 and P = 0.049, respectively). While there was no clear difference between the number of CD20+ B cells in AS patients overall compared with controls, there was a significant difference when persistently inflamed joints from patients with AS were compared with joints without active inflammation from patients with AS or joints from controls (both P = 0.03). Microvessel density in bone marrow from AS patients with active inflammation was significantly higher than that in bone marrow from controls. This immunohistologic study of bone marrow from zygapophyseal joints demonstrates persistent inflammation in the spine of patients with AS, including those with longstanding disease. The findings of increased numbers of T cells and B cells and neoangiogenesis suggest that these features play a role in the pathogenesis of AS.

Bone Marrow Microcirculation Parameter Amplitude A of Contrast-Enhanced Dynamic MRI Is a Prognostic Factor for Progressive Multiple Myeloma for Patients with Low Beta2-Microglobulin.

Introduction: We have previously shown that contrast-enhanced dynamic magnetic resonance imaging (dMRI) microcirculation parameters Amplitude A and distribution rate constant kep are significantly increased in patients with multiple myeloma (MM) compared to healthy controls and correlate with osteolytic bone involvement. Furthermore an elevated Amplitude A is associated with a high plasmacell-infiltration and increased microvessel density in bone marrow. We now evaluated the prognostic value of changes in microcirculation of bone marrow as detected by dMRI for overall (OAS) and event free survival (EFS) in patients with MM.Methods: Between 1999 and 2001 62 patients with progressive MM requiring chemotherapy according to international standards (6 newly diagnosed patients, 56 patients with relapse or refractory disease) were investigated with dMRI of the lumbar spine. OAS and EFS were updated for all patients in February 2005. The estimated median follow up was 4.5 years. All patients underwent standardized dMRI with high temporal resolution (T1w-turboFLASH) before start of therapy. The contrast uptake was quantified using a two compartment model with the output parameters Amplitude A and distribution constant rate kep reflecting bone marrow microcirculation. To examine the prognostic value of the findings of dMRI we used the Proportional Hazards model as proposed by Cox.Results: We recorded a correlation with borderline significance (p-value 0.1) between Amplitude A and EFS. We did not find a correlation of dMRI parameters with OAS. The multivariable analysis of Beta2-Microglobulin, age, Lactat Dehydrogenase (LDH) and Albumin revealed Beta2-Microglobulin as the only statistically significant prognostic factor for EFS in this group of patients. When patients were classified according to high or low Beta2-Microglobulin, Amplitude A was able to provide significant additional information characterizing EFS. Patients with low Beta2-Microglobulin and increased Amplitude A had significant shorter EFS than patients with low Beta2-Microglobulin and low Amplitude A.Conclusion: Our investigations indicate that dMRI parameter Amplitude A which reflects the increased bone marrow microcirculation and angiogenesis is a novel prognostic factor for progressive multiple myeloma in patients with low Beta2-Microglobulin. So a more precise differentiation of patients may be possible through dMRI. The prognostic impact of dMRI for newly diagnosed myeloma patients and patients with monoclonal gammopathie with undetermined signifikance will now be evaluated in a prospective study.

Thalidomide for the Treatment of Acute Myeloid Leukemia

In analogy to solid neoplasms, accumulating data suggest the requirement of angiogenesis also for the development and progression of hematopoietic malignancies including acute myeloid leukemia (AML). Inhibition of increased microvessel density in bone marrow (BM) might be a promising target for pharmacological interventions aimed at reducing disease activity. Among the putative inhibitors of angiogenesis, thalidomide has demonstrated a considerable efficacy in myelodysplastic syndromes (MDS) and AML with overall response rates up to 56% and 25%, respectively. Responders experienced hematologic improvements with increased hemoglobin and platelet counts resulting in temporary transfusion independence. In AML, partial responses—defined as reduction of the leukemic blast cell infiltration of at least 50% in BM—occurred in four of 20 patients after one month of thalidomide administration in a previous phase I/II study. Additionally, we observed a long-term response in one AML patient of more than 20 months, meanwhile fulfilling the criteria of complete remission. The decrease in leukemic blast infiltration in BM of responders was accompanied by a significant reduction of the microvessel density. Overall adverse events caused by the drug consisted mainly of fatigue, constipation, skin rash and polyneuropathy with a tolerable dose of 200–400 mg p.o. per day.In conclusion, thalidomide as a single agent has significant anti-leukemic activity with some evidence for anti-angiogenic effects in BM, although the precise mechanism of action remains to be elucidated.

Thalidomide for the Treatment of Acute Myeloid Leukemia

In analogy to solid neoplasms, accumulating data suggest the requirement of angiogenesis also for the development and progression of hematopoietic malignancies including acute myeloid leukemia (AML). Inhibition of increased microvessel density in bone marrow (BM) might be a promising target for pharmacological interventions aimed at reducing disease activity. Among the putative inhibitors of angiogenesis, thalidomide has demonstrated a considerable efficacy in myelodysplastic syndromes (MDS) and AML with overall response rates up to 56% and 25%, respectively. Responders experienced hematologic improvements with increased hemoglobin and platelet counts resulting in temporary transfusion independence. In AML, partial responses—defined as reduction of the leukemic blast cell infiltration of at least 50% in BM—occurred in four of 20 patients after one month of thalidomide administration in a previous phase I/II study. Additionally, we observed a long-term response in one AML patient of more than 20 months, meanwhile fulfilling the criteria of complete remission. The decrease in leukemic blast infiltration in BM of responders was accompanied by a significant reduction of the microvessel density. Overall adverse events caused by the drug consisted mainly of fatigue, constipation, skin rash and polyneuropathy with a tolerable dose of 200–400 mg p.o. per day.In conclusion, thalidomide as a single agent has significant anti-leukemic activity with some evidence for anti-angiogenic effects in BM, although the precise mechanism of action remains to be elucidated.

Stable remission after administration of the receptor tyrosine kinase inhibitor SU5416 in a patient with refractory acute myeloid leukemia

AbstractThe small molecule receptor tyrosine kinase (RTK) inhibitor SU5416 targets the vascular endothelial growth factor receptor 2 and the stem cell factor receptor c-kit. Herein is described the successful treatment of a 65-year-old woman with SU5416, in second relapse of acute myeloid leukemia (AML) and refractory toward standard chemotherapy regimens. After 12 weeks of treatment with SU5416, the blast cell counts (blood and bone marrow) decreased to undetectable levels and the peripheral blood cell counts normalized with the exception of the platelet count (50-80 × 109/L [50-80 × 103/μL]). The duration of the remission is longer than 4 months during maintenance therapy with SU5416. Microvessel density in the patient's bone marrow dropped from 33.4 to 12.3 microvessels/×500-field 8 weeks after SU5416 administration and remains in the normal range. This is the first report of a stable remission achieved after administration of the RTK inhibitor SU5416 in a patient with AML relapse.

Clinical significance of microvessel density in multiple myeloma patients.

To investigate the role of angiogenesis in multiple myeloma (MM), bone marrow biopsy from 75 adults with newly diagnosed, untreated MM were evaluated. Microvessels were scored in at least 3 areas ( x 200 fields) of the highest microvessel density in representative sections of each bone marrow specimen using immunohistochemistry for CD34. Prognostic variables were also evaluated for the overall survival. Microvessel counts were significantly higher in patients with MM (n=69.42+/-9.67), compared with control (n=26.81+/-2.85). Microvessel density had a weak correlation with percentage of bone marrow plasma cells. By univariate analysis, age, beta2-microglobulin, serum albumin, serum creatinine, serum calcium, hemoglobin, platelet count, and bone marrow plasma cell percentage were correlated with survival. By multivariate analysis, age, serum albumin, serum creatinine, hemoglobin, platelet count and bone marrow plasma cell percentage were correlated with overall survival, whereas microvessel density was not. In summary, microvessel density in bone marrow of MM is significantly increased compared to control, but was not correlated with overall survival. Further studies regarding angiogeneic molecules are needed to determine the functional role of angiogenesis in MM.