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

Angiogenesis is a complex process involved in the proliferation and metastasis of malignant tumours, and partly triggered by the secretion of various angiogenic factors by tumour cells or cells in the stromal environment. We investigated the correlation between bone marrow angiogenesis, estimated as microvessel density (MVD), and interleukin-6 (IL-6), basic fibroblastic growth factor (bFGF), hepatocyte growth factor (HGF) and syndecan-1 in 67 patients with newly diagnosed multiple myeloma, and evaluated the prognostic value of these parameters. Circulating levels of IL-6, bFGF, HGF and syndecan-1 were significantly higher in patients than in controls. Moreover, in patients, bone marrow levels of bFGF, HGF and syndecan-1 were higher than peripheral blood levels. Positive correlations were found between MVD and syndecan-1 blood levels (r = 0.33, P = 0.017), syndecan-1 bone marrow levels (r = 0.49, P = 0.046) and HGF blood levels (r = 0.36, P = 0.008) respectively. High MVD and high blood levels of IL-6, HGF and syndecan-1 were predictive of a shorter survival. In a multivariate survival analysis MVD and blood levels of IL-6 retained independent prognostic significance, while in a survival analysis without MVD the peripheral blood levels of HGF and syndecan-1 were strong independent prognostic factors.     

Bone marrow angiogenesis in multiple myeloma and its correlation with clinicopathological factors

Increased angiogenesis has been found to be an adverse prognostic factor in solid tumors but evidences show that angiogenesis also plays an important role in hematological malignancies including multiple myeloma (MM). In this report we studied the various angiogenesis parameters like microvessel density (MVD) and total vascular area (TVA), on bone marrow biopsies in 50 newly diagnosed cases of MM. The aim was to study bone marrow angiogenesis in MM using light microscopy (MVD-A) and computerized image analyzer (MVD-B and TVA) and correlate it with clinical features, laboratory findings, histological features, and response to treatment on follow-up. Bone marrow biopsies of test cases (n = 50) were immunohistochemically stained with CD34 for visualization of microvessels. MVD-A (range 8–80; mean 50.4; SD 17.5), MVD-B (5.2–33.2; mean 16.3; SD 5.1), and TVA in percentage (range 0.42–7.20; mean 2.8; SD 1.5) were measured. Ten age- and sex-matched controls were studied and their parameters were taken as grade I. There was a significant correlation between these angiogenesis parameters (MVD-A vs MVD-B, Pearson’s correlation coefficient (pcc) = 0.724; MVD-A vs TVA, pcc = 0.370; MVD-B vs TVA, pcc = 0.406). The angiogenesis was significantly higher in cases as compared to controls. Patients with residual disease had a higher MVD as compared to the complete responders. High tumor burden and diffuse pattern of infiltration were also associated with grade III MVD and TVA. Hence, it can be concluded that angiogenesis correlates with other histological features associated with prognosis and is also a good predictor for complete response in patients with multiple myeloma.     

急性白血病患者骨髓MVD与血清 VEGF水平的研究

目的：探讨急性白血病(AL)骨髓血管新生的状态及意义。方法：应用改良的GMA塑料包埋骨髓病理切片进行免疫组化染色检测AL患者治疗前后骨髓微血管密度(MVD)，应用ELISA方法检测AL患者治疗前后血清血管内皮生长因子(VEGF)的浓度。结果：AL患者治疗前骨髓MVD明显增加，化疗缓解后骨髓MVD降至正常水平，复发者骨髓MVD再次升高至化疗前水平；AL患者治疗前血清VEGF水平比正常对照明显升高，化疗缓解的患者VEGF水平仍然较高。结论：骨髓血管新生在AL发生过程中有着重要的作用，血清VEGF水平能够在一定程度上解释白血病骨髓血管新生现象。     

Comparison of microvessel density before and after peripheral blood stem cell transplantation in multiple myeloma patients and its clinical implications: multicenter trial

Bone marrow angiogenesis has been reported to increase in several hematologic malignant diseases, including multiple myeloma. Because high-dose chemotherapy combined with autologous stem cell transplantation (SCT) improves the response rate, event-free survival, and overall survival in patients with multiple myeloma (MM), we studied the changes in bone marrow microvessel density (MVD) in 21 patients who underwent high-dose chemotherapy combined with autologous SCT to determine whether there was persistently increased angiogenesis at the time of response. Bone marrow biopsy specimens were obtained before and after SCT for each patient and immunostained with anti-CD34 antibodies for the identification of microvascular endothelial cells. The mean value of MVD in 21 MM patients at initial diagnosis was 46.0 +/- 24.0 and in healthy controls was 26.8 +/- 8.54 (P = .046). The mean MVD at initial diagnosis was 46.0 +/- 24.0 compared with 29.0 +/- 12.5 after achievement of response with SCT, and there was a statistically significant difference (P = .004). Sixteen of 21 patients (76.2%) had decreased MVD after SCT, and 5 patients were found to have a greater than 50% decrease in MVD after SCT. However, there was no difference in overall survival between the patient group with decreased MVD after SCT and that without decreased MVD (P = .9370). These results suggest that angiogenesis plays an important role in MM. In addition, the persistence of MVD at the time of response indicates continuous stimulus of microvessels by minimal residual disease even after SCT.     

Bone marrow angiogenesis and its correlation with other disease characteristics in multiple myeloma in stage I versus stage II-III

PURPOSE: We studied bone marrow angiogenesis in different stages of multiple myeloma according to the Durie and Salmon classification and its correlations with other disease characteristics. METHODS: Sixty-five immunohistochemical CD34-stained, paraffin-embedded bone marrow biopsies of multiple myeloma patients and 12 controls were studied. The mean number of microvessels per area in each sample was determined as the microvessel density (MVD). In addition, plasma cell infiltration of the bone marrow, serum beta2-microglobulin, immunoglobulin levels, C-reactive protein, and serum calcium concentration were measured in 22 patients with stage I multiple myeloma and in 43 patients in stage II-III. RESULTS: In myeloma patients, the bone marrow MVD was significantly higher than in controls (P<0.001). In 43 patients with stage II-III multiple myeloma, MVD was significantly higher than in 22 patients with stage I (median MVD 46 and 21 vessels/mm(2), respectively, P=0.005). Additionally, in stage II-III the bone marrow MVD correlated positively with the bone marrow plasma cell infiltration (r=0.55, P<0.001) and the serum beta2-microglobulin level (r=0.53, P<0.001), while in stage I patients no correlation could be found. CONCLUSIONS: Angiogenesis is significantly increased in stage II-III myeloma in comparison to stage I. In stages II-III, bone marrow angiogenesis is correlated with plasma cell infiltration and serum beta2-microglobulin levels.     

Prognostic value of bone marrow angiogenesis in multiple myeloma: use of light microscopy as well as computerized image analyzer in the assessment of microvessel density and total vascular area in multiple myeloma and its correlation with various clinical, histological, and laboratory parameters

We studied the prognostic value of parameters of angiogenesis on bone marrow biopsies in newly diagnosed multiple myeloma (MM) patients. Angiogenesis parameters studied were the microvessel count done manually on light microscopy (MVD-A), microvessel count done by using computerized image analyzer (MVD-B), and total vascular area (TVA) measured by computerized image analyzer. One hundred ten newly diagnosed cases of MM treated at Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, were analyzed with respect to clinical features, laboratory findings, histological features, angiogenesis parameters, and responses to the treatment on follow-up. Twenty age- and sex-matched controls were studied for comparing with angiogenesis of the test cases. Bone marrow microvessels were examined using immunohistochemical staining for CD34. MVD-A (range 4.9-85.2; mean 28.2; SD 19.4), MVD-B (range 2.0-26.9; mean 11.7; SD 5.9), and TVA measured in percentage (range 0.1-17.1; mean 2.4; SD 2.5) were measured for test cases (n = 110). Grading of angiogenesis parameters of the test cases were done; such that angiogenesis parameters of controls (taken as baseline) were grade I. There was a statistically highly significant correlation between (MVD-A vs MVD-B, pcc = 0.92; MVD-A vs TVA, pcc = 0.78; MVD-B vs TVA, pcc = 0.76). The myeloma cases had significantly higher angiogenesis parameters when compared with controls (Kruskall-Wallis test, P < 0.001). "Complete responders" (n = 38/110) had significant lower angiogenesis (Mann-Whitney U test, P < 0.001) than "nonresponders" (n = 72/110). On treatment follow-up "rapid disease progressors" had the highest levels of angiogenesis (mean rank for MVD-A = 84.7, MVD-B = 82.1, and TVA = 81.1). On multivariate (logistic regression) analysis, factors found to have independent prognostic significance in complete responders (adjusted odd ratio (95% CI, P value)] were: (a) MVD-B grade I [0.134 (0.10-0.16, P < 0.001)], (b) clinical substage A [0.163 (0.12-0.19, P = 0.008)], (c) Bartl's histological stage II & I [0.262 (0.2-0.32, P = 0.021)], (d) MVD-A grade I [0.28 (0.22-0.36, P = 0.03)], (e) beta2 microglobulin levels less than 3,400 ng/dl [0.31 (0.23-0.42, P = 0.04)]. Kaplan-Meier survival analysis for myeloma-related death (n = 16) shows a mean survival time (in months) of 24.75; SE = 3; 95% CI = 21-28. We conclude that MVD (particularly MVD-B) is a very good predictor for the complete response in patients of MM and should be done routinely on bone marrow biopsies.     

Microvessel density,a surrogate marker of angiogenesis,is significantly related to survival in multiple myeloma patients

We evaluated microvessel density (MVD) in bone marrow biopsies (BM) from multiple myeloma (MM) patients after staining with anti-CD34 and anti-CD105 antibodies (mAbs). The anti-CD105 mAb was significantly more sensitive than the anti-CD34 mAb in visualizing blood vessels both in controls and MM samples. MVD was significantly higher in MM than in controls with both anti-CD34 and anti-CD105 mAbs. Patients with low CD34+ MVD survived longer than patients with higher MVD (P = 0.01), whereas there was no difference in survival between patients with low and high CD105+ MVD. Multivariate analysis confirmed the independent significant association between CD34+ MVD and survival (P = 0.001).     

Deficient IFNα production in hairy cell leukemia

Summary Since the application of low doses of IFN-alpha is necessary to maintain remissions in Hairy Cell Leukemia (HCL) it is of interest whether peripheral blood mononuclear cells (MNC) of HCL patients can be induced in vitro to produce IFN-alpha. 9 patients suffering from advanced HCL were included in the study. The diagnoses were confirmed by characteristic findings in peripheral blood and bone marrow biopsies. For IFN treatment we initially used natural IFN-alpha (Bioferon) and switched later to recombinant IFN-alpha₂ (Boehringer). MNC of 5 patients before IFN therapy and of 6 patients during IFN therapy (2–47 weeks) were induced by phythemagglutinin (PHA), Corynebacterium parvum (C.p.), and sendai virus (SV). PHA is known to induce IFN-gamma. Both, C.p. and SV induced IFN-alpha but no IFN-gamma in MNC of healthy controls and of IFN treated breast cancer patients. In HCL patients normal antiviral activities could be induced by PHA. Zero or only low antiviral activities could be induced in MNC from 9 patients tested on 22 occasions. It is concluded that MNC from patients with advanced HCL can be induced to produce IFN-gamma but no IFN-alpha. Since IFN-alpha but not IFN-gamma is produced by monocytes it is likely that reduced numbers of monocytes which were found in our HCL patients before and during IFN treatment account for the described deficiency of IFN-alpha production.     

Absence of Clinical Prognostic Value of Vascular Endothelial Growth Factor and Microvessel Density in Multiple Myeloma

Vascular endothelial growth factor (VEGF) is considered a potent stimulator of angiogenesis. In multiple myeloma (MM), it has been reported that bone marrow angiogenesis parallels tumor progression and correlates with a poor prognosis. To investigate the role of angiogenesis in MM, we investigated VEGF expression and microvessel density (MVD) in the bone marrow of 75 MM patients by immunohistochemical methods. VEGF expression was observed in 87.3% (62 of 71) of patients. MVD was 69.42 +/- 9.67 (mean +/- SE) compared with the normal control values of 26.81 +/- 2.85. MVD values were 73.98 +/- 11.27 and 36.04 +/- 6.99 in the VEGF-positive and VEGF-negative groups, respectively. The MVD of patients in the VEGF-positive group was significantly higher than in the VEGF-negative group (P = .045). However, there were no significant differences in various clinical parameters, such as age, sex, hemoglobin, platelet count, serum levels of albumin, calcium, creatinine, and beta2-microglobulin, and bone marrow plasma cell percentage, between the VEGF-positive and VEGF-negative groups. Multivariate analysis revealed that age, hemoglobin, platelet count, serum levels of albumin and creatinine, and bone marrow plasma cell percentage were correlated with overall survival, whereas VEGF expression or MVD was not. In conclusion, our results suggest that VEGF is highly expressed and that MVD is increased in MM, indicating that angiogenesis may play a role in MM. Although MVD in the bone marrow of the VEGF-positive group is significantly higher compared with the VEGF-negative group (P = .045), VEGF is not correlated with overall survival. Further studies that include other angiogenic factors are needed to determine the functional role of angiogenesis in MM.     

Increased angiogenesis in bone marrow of children with acute lymphoblastic leukaemia has no prognostic significance

The importance of angiogenesis for the growth and viability of solid tumours has been established. Similarly, prognostic information may be gained from the extent of angiogenesis in these tumours. Haematopoietic malignancies should have equal requirements for angiogenesis and important prognostic information may be derived from quantification of bone marrow angiogenic activity. We retrospectively investigated 82 bone marrow trephine biopsies from 41 children with acute lymphoblastic leukaemia (ALL) at diagnosis and following treatment. Nine normal bone marrow trephines from age-matched children were also analysed as controls. The microvessels were stained immunohistochemically with anti-Factor VIII-related antigen (antivWF) and antithrombomodulin (anti-THR). Angiogenesis was quantified manually by two independent observers and was highly reproducible (Pearson's r = 0.91). Staining with anti-vWF and anti-THR was highly specific for microvessels and thetwo stains closely correlated (r = 0.68). Microvessel densities (MVD) at presentation were significantly increased in the majority of patients in comparison with controls (P < 0.0001) and MVD dropped towards normal in remission (P < 0.0001). Of interest, the difference in total vessel counts between leukaemic and normal/remission marrows was contributed solely by small microvessels. There was no significant difference in MVD at presentation or remission from children in poor prognostic groups or those who subsequently relapsed. Similarly, we could not find an association with age, sex, cytogenetic abnormality or disease phenotype.     

Predictive value of microvascular density for response to anlotinib in advanced NSCLC

Nonsmall cell lung cancer (NSCLC) is the most common type of lung cancer. This study aimed to categorize the microvessels in advanced NSCLC and determine the relationship between intratumoral microvascular density (MVD) and the efficacy of anlotinib for NSCLC.The clinical data of 68 patients receiving anlotinib as third-line treatment or beyond for advanced NSCLC were retrospectively collected. Microvessels were stained for CD31 and CD34 by using immunohistochemical staining and were classified as undifferentiated (CD31+ CD34−) and differentiated vessels (CD31+ CD34+). The relationship between MVD and anlotinib efficacy and patient prognosis was analyzed.Patients were divided into the high or low MVD groups according to the median MVD of differentiated (9.4 vessels/field) and undifferentiated microvessels (6.5 vessels/field). There were significantly more patients with high undifferentiated-vessel MVD in the disease control group than in the disease progression group (72.7% vs 16.7%, P < .001). Patients with high undifferentiated-vessel MVD had significantly longer median progression-free survival than those with low undifferentiated-vessel MVD (7.1 vs 3.7 months, P < .001).Anlotinib as third- or beyond line therapy is safe and effective for advanced NSCLC. Patients with a higher density of undifferentiated microvessels have better response to anlotinib and longer progression-free survival.     

Decrease of bone marrow angiogenesis in myeloma patients achieving a remission after chemotherapy

The impact of angiogenesis is well known for the growth and viability of solid tumors. Fewer studies have been published relating angiogenesis to clinical or pathological parameters in hematological malignancies. In this report, we have estimated the bone marrow microvessel density (MVD) before and after conventional-dose or high-dose chemotherapy with autologous stem cell transplantation. Immunohistochemical CD34-stained paraffin-embedded bone marrow biopsies of 21 patients with stage III multiple myeloma were studied. Microvessels were counted at 400x magnification, and the mean number of vessels per area in each sample was noted as the MVD. The median MVD of all patients was 53.1 vessels/mm2 (range 15.5-174.7 vessels/mm2) before treatment and 29.3 vessels/mm2 (range 0-221.1 vessels/mm2) after chemotherapy. The post-treatment MVD in the two groups of patients with and without remission was significantly different (p=0.001), whereas the pretreatment MVD was not. Responders but not nonresponders showed a significant decrease of MVD after therapy in comparison to their pretreatment levels. The progression-free survival in patients who achieved a reduction in MVD after chemotherapy was significantly longer than in patients without a decrease in MVD (P=0.006). Furthermore, we compared the MVD of patients after achievement of a remission to MVD of 15 untreated stage I myeloma patients. The MVD of patients in remission was not statistically different from the MVD in stage I myeloma. These results underscore the impact of angiogenesis in myeloma and give the first report that effective chemotherapy is accompanied by a significant decrease in bone marrow angiogenesis in this disease.     

The significance of minimal residual disease in hairy cell leukaemia treated with deoxycoformycin: a long-term follow-up study

We investigated the clinical significance and long-term follow-up of detecting minimal residual disease (MRD) in hairy cell leukaemia (HCL) in complete remission (CR) after treatment with deoxycoformycin (DCF). MRD was assessed in 23 patients by immunophenotyping peripheral blood and bone marrow frozen sections using a panel of antibodies, CD11c, CD25, CD103 and HC2, which detect hairy cells. 31 cases with active HCL were used as controls. 10/23 patients (43%) had MRD in bone marrow (seven), blood (one) or both sites (two) which was not detected on haematoxylin–eosin bone marrow sections nor by immunohistochemistry on paraffin sections in six cases tested. Sequential studies in four cases did not show changes in the amount of MRD. At a median follow-up of 72 months (range 15–108), 5/23 (22%) patients have relapsed with a median time of 59 months (range 15–105). MRD was detected in three of the five patients who relapsed. In the two patients with negative MRD, one relapsed with an abdominal mass and the other was a late relapse at 84 months. MRD was also documented in 7/18 patients who continued in clinical CR for a median of 80 months (range 63–98). There were no statistical differences in disease-free survival between MRD⁺ and MRD⁻ patients ( P   =  0.8). Our findings indicate that relapse after long-term remission achieved with DCF cannot be predicted when MRD is detected by sensitive methods. A search for other parameters such as proliferative rate of the residual cells or chest and abdominal CT scan might identify patients with a higher probability of disease recurrence.     

The variant form of hairy-cell leukaemia

Hairy-cell leukaemia-variant (HCL-variant) is a rare B-cell disorder which accounts for 10% of HCL cases. It affects elderly or middle-aged males. The main features are splenomegaly, lymphocytosis and cytopenias without monocytopenia. The circulating cells have a morphology intermediate between prolymphocytes and hairy cells. The immunophenotype shows a mature B-cell phenotype with expression of the B-cell antigens CD11c and CD103-but unlike typical HCL the cells are CD25- and HC2-negative. The histology of bone marrow and spleen shows a pattern of infiltration similar to that in HCL. There is no recurrent chromosomal abnormality but complex karyotypes and monoallelic p53 deletion by fluorescence in situ hybridization are common. Patients are resistant to alkylating agents and interferon-alpha (IFN-alpha) and only half achieve partial responses to pentostatin and/or cladribine. Splenectomy results in long-lasting partial responses in over two-thirds of the patients and is a good palliative treatment. Despite the lack of response to most therapies, the clinical course of HCL-variant is chronic. The median survival is 9 years and 42% of patients die of unrelated causes. Transformation to large cell is seen in 6% of patients. The inferior survival in HCL-variant compared with typical HCL cases may reflect the chemotherapy resistance.     

Angiogenesis occurs in hairy cell leukaemia (HCL) and in NOD/SCID mice transplanted with the HCL line Bonna-12

Microvessel density (MVD), a surrogate marker for angiogenesis, was evaluated by anti-CD34 and CD105 monoclonal antibodies (Abs), and found to be increased in the bone marrow (BM) of hairy cell leukaemia (HCL) patients and in a preclinical model of non-obese diabetic/severe combined immunodeficient mice transplanted with the HCL line Bonna-12. The anti-CD105 Ab was significantly more sensitive than anti-CD34 Ab in identifying blood vessels. The BM tumour burden significantly decreased in patients treated with interferon-alpha, but the mean value of MVD remained unchanged. These data suggest that angiogenesis may be involved in the pathogenesis of HCL.     

Prognostic significance of Fas (CD95/APO-1) positivity in patients with primary nodal diffuse large B-cell lymphoma

Fas (CD95/APO-1) is a protein that is mainly related to apoptosis of lymphoid cells. The increment of Fas expression is associated with long-term survival in various malignancies. However, there are limited studies regarding the effect of Fas expression on the course and prognosis of non-Hodgkin's lymphoma. The aim of this study was to investigate the significance of immunohistochemical Fas expression on the prognosis of nodal diffuse large B-cell lymphoma. A total of 63 patients with primary nodal diffuse large B-cell lymphoma diagnosed in the Erciyes University Department of Hematology between 1990 and 2003 were included in the study. The median age of the patients was 55 years old (range 19-102 years old). The median follow-up period was 19 months (2-132 months). Histopathological sections were stained immunohistochemically and evaluated by light microscopy for Fas, bcl-2, and p53. Clinical and laboratory parameters including Fas, bcl-2, and p53 positivity, age, sex, performance status, clinical stage, presence of B symptoms, bone marrow involvement, extranodal involvement, and lactic dehydrogenase levels were evaluated to compare overall survival. Complete remission was obtained in 28 patients (44.4%) after first-line chemotherapy. Fas positivity, male gender, good performance status, clinical stage I-II, absence of B symptoms, normal lactic dehydrogenase value, and absence of bone marrow involvement were favorable prognostic factors for complete remission in statistical analysis. Multivariate analysis revealed that positive Fas expression and ECOG performance status were independent prognostic factors for overall survival. Also, Fas-positive patients had significantly prolonged progression-free survival. Immunohistochemical Fas positivity was a favorable prognostic factor for complete remission and overall and progression-free survival in primary nodal diffuse large B-cell lymphoma.     

Effect of allogeneic stem cell transplantation on bone marrow angiogenesis in chronic myelogenous leukemia

Increased bone marrow angiogenesis is a poor prognostic marker in patients with chronic myelogenous leukemia (CML). Allogeneic stem cell transplantation (ASCT) can be curative for patients with CML. Studies in myeloma have shown persistent increased bone marrow microvessel density (MVD) after autologous transplantation. It is not clear if abnormal bone marrow angiogenesis persists following a curative intervention like allogeneic transplantation. We evaluated MVD from bone marrow samples obtained just prior to and at 3-5 months after ASCT in 24 patients with CML. The median MVD pre-transplant was 14 (4-37), with 11 patients having high-grade angiogenesis and 13 having low grade. The median post transplant MVD was 20 (range 5-36), with 12 patients having high-grade angiogenesis and 12 low grade. The median time between biopsies was 4 months (range 1-6 months). The microvessels in the post transplant bone marrow appeared morphologically different with striking dilatation and sinusoidal appearance compared to the pre-transplant marrow. However, there was no significant change in MVD following transplant (P=0.8, paired t-test). Abnormal bone marrow angiogenesis appears to persist in the bone marrow following ASCT for CML, at least in the short term.     

Bone marrow angiogenesis in multiple myeloma: effect of therapy

Recent studies have demonstrated that angiogenesis has a role in haematological malignancies, including multiple myeloma. Multiple myeloma is characterized by inevitable relapse after standard or high-dose chemotherapy. To study the effect of chemotherapy on bone marrow angiogenesis in patients with multiple myeloma, we used two methods to evaluate bone marrow angiogenesis in patients with newly diagnosed multiple myeloma, comparing these findings with those from bone marrow obtained after standard chemotherapy. Before therapy, an increased degree of bone marrow angiogenesis and a high bone marrow plasma cell labelling index (PCLI) were predictive of poorer survival. As estimated by microvessel density (MVD), the median survivals for patients with low-grade, intermediate-grade and high-grade angiogenesis were 77, 30 and 14 months respectively. After therapy, the MVD did not change significantly. However, when patients with at least a partial response were considered separately, they showed a decrease in MVD. Post-therapy PCLI was predictive of survival, but post-therapy MVD was not. There was good correlation between angiogenesis estimated by visual grading and that determined by MVD assessment. We conclude that the degree of bone marrow angiogenesis is a prognostic marker in patients with multiple myeloma and does not decrease significantly after therapy.     

Angiogenesis in chronic myeloproliferative diseases detected by CD34 expression

Increased bone marrow angiogenesis estimated as bone marrow microvessel density (MVD), or as serum angiogenic factor levels and/or immunohistochemical expression of these factors in bone marrow biopsy has been demonstrated in a variety of hematological disorders including chronic myeloproliferative diseases (MPDs). The aim of this study was to investigate the MVD in 25 cases of myelofibrosis with myeloid metaplasia (MMM). MVD was estimated by CD34 immunohistochemical expression in bone marrow biopsies. A control group of 27 patients without bone marrow disease, eight cases of polycythemia vera (PV), 41 cases of essential thrombocythemia (ET) and nine cases of chronic myeloid leukemia (CML) were also studied. Moreover, in cases with MMM, MVD was correlated with clinical, laboratory, histological parameters and the outcome of the patients. Our study confirmed a significantly higher degree of angiogenesis in MMM, PV, ET and CML compared with controls (P < 0.001, P = 0.0007, P < 0.001 and P = 0.0008, respectively). Angiogenesis was higher in MMM than PV, ET and CML cases (P < 0.001, P < 0.001 and P = 0.008). Increased angiogenesis was correlated with hypercatabolic symptoms in MMM patients (P = 0.009). No correlation with other clinicopathological parameters or clinical outcome was found. However, definitive conclusions regarding the prognostic value of increased angiogenesis may require additional follow-up and a larger group of patients.