血管生成与恶性血液病

血管生成与恶性血液病的关系近年备受关注。本文就血管生成的定义，恶性血液病骨髓血管生成程度，血管生成与恶性血液病的发生发展、疾病活动性、生存期及临床疗效间的关系，具抗血管生成作用的药物沙利度胺治疗恶性血液病的临床疗效作一综述，提出抗血管生成疗法有望成为恶性血液病的一种新型治疗策略。     

恶性血液病患者骨髓微血管密度与凝血酶敏感蛋白-1的表达及意义

目的探讨恶性血液病患者骨髓微血管密度（MVD）和凝血酶敏感蛋白．1（TSP-1）的表达及意义。方法选择恶性血液病患者48例（观察组），其中急性白血病（AL）23例、慢性粒细胞白血病（CML）10例、多发性骨髓瘤（MM）15例；正常对照组20例。利用sP免疫组化法检测观察组治疗前后及对照组骨髓组织标本中MVD、TSP-1的表达情况。结果①恶性血液病在不同疾病的同一阶段比较，骨髓MVD、TSP-1表达均元统计学差异（P均〉0．05）。②初诊组与未缓解组的骨髓MVD值高于对照组及缓解组（P均〈0．01），TSP-1阳性率低于对照组及缓解组（P均〈0.01）。③相关性分析显示，MVD、TSP-1与年龄、性别、血细胞计数等无显著相关性（P〉0．05）。结论MVD是分析恶性血液病病情的独立指标，TSP-1是血管生成负性调节分子，联合检测有助于更准确地评价病情及疗效，指导临床治疗。     

血清唾液酸检测在血液疾病诊治中的应用价值

目的:探讨血清唾液酸(SA)在血液疾病中的临床诊断、疗效监测及预后评判的价值。方法:收集2009-05-2012-05健康体检者40例、血液系统良性疾病45例及恶性血液疾病211例,分别检测各组血清SA水平,并对恶性血液病组中211例患者进行治疗前、后SA检测,比较三组之间及恶性血液病治疗前后血清SA水平变化。结果:良性血液病组、恶性血液病组、对照组之间比较差异有统计学意义(P0.05),对照组与良性血液病组之间比较差异无统计学意义(P0.05),恶性血液病组与其他两组比较,均差异有统计学意义(均P0.05),良性血液病组内比较差异无统计学意义(P0.05),恶性血液病组内比较差异无统计学意义(P0.05);恶性血液病组标准治疗后病情缓解者,血清SA水平显著降低(P0.05),而病情恶性时其水平显著升高(P0.05)。结论:血清SA检测在恶性血液疾病诊断、疗效观察、预后评价等方面有重要的参考价值。     

骨髓检查在临床诊断中的价值：附722例分析

目的 :探讨骨髓像对临床 ,尤其是血液病诊断的意义。方法 :结合 72 2例骨髓穿刺检查结果进行回顾性分析 ,其中 2 10例进行了骨髓活检。结果 :对各类型白血病、多发性骨髓瘤、骨髓转移癌、部分恶性组织细胞病及疟疾可确诊。可协助增生性贫血、再障等疾病的诊断及与某些疾病的鉴别诊断。结论 :骨髓检查、周围血检查及临床资料对诊断血液系统疾病、感染性疾病是重要的     

反应停治疗恶性血液病的研究进展

血管生成在实体瘤的发生、发展中的重要作用已被证实 ,且抗血管生成治疗实体瘤也取得了令人满意的效果。近年来 ,血液系统恶性疾病的发生、发展和预后与血管新生的密切关系 ,已成为人们关注的热点之一。曾因致畸作用而被禁用的反应停 (ｔｈａｌｉｄｏｍｉｄｅ)具有明显的抗血管生成作用 ,目前已用于多种恶性血液病的治疗 ,特别是对难治性多发性骨髓瘤 (ＭＭ )的治疗取得了令人鼓舞的结果。本文就其抗肿瘤机制及在ＭＭ等恶性血液病中的应用等方面的研究进展作一综述。1　反应停的历史反应停于 195 3年在前西德首先合成 ,2 0世纪 5 0年代后期…     

鞘氨醇激酶信号途径与血液肿瘤

血液系统恶性肿瘤的发生发展与骨髓造血微环境密切相关。骨髓微环境包括微血管系统、神经成分、间质细胞、细胞基质以及分泌的各种细胞因子。骨髓微环境通过不同的细胞信号途径调节血液肿瘤细胞的增殖、分化、凋亡及耐药等生物学特性。目前，已经证明多种信号通路及重要信号传递分子的异常调节（如生长因子受体、MAPK、PI3K、Akt等）与白血病、多发性骨髓瘤等恶性血液疾病密切相关。部分信号分子已经成为治疗恶性血液肿瘤的靶点。本文将介绍鞘氨醇激酶信号通路与恶性血液肿瘤的关系。     

恶性血液病患者血清和骨髓透明质酸测定及其临床意义

应用放免法测定43例恶性血液病、37例良性血液病和23例健康人血清、骨髓液HA。结果表明：恶性血液病患者血清和骨髓液HA显著高于良性血液病（P＜0.01）及健康人（P＜0．01）。骨髓液HA分别是血清的2～2．5倍。若以血清HA＞185μg／L为标准，则血清HA对恶性血液病诊断的敏感性为81．6％。血清和骨髓液HA在急性白血病完全缓解时下降，复发时又升高。观察血清和骨髓液HA变化，对鉴别良、恶性血液病、判断急性白血病病情及估计预后有一定意义。     

血液系统疾病

973943恶性血液病患者血清和骨髓透明质酸测足及其临床意义/王景昌…//临床内科杂志一1,,?,1魂·442.中国医学文摘·内科学]997年第18卷第5期(3)一156~157 恶性血液病组43例血清和骨髓液透明质酸(HA)显著高于良性血液病组37例和健康人组23例,均尸<0.01。骨髓液HA分别是血清的2一2.5倍。以血清HA>185pg/L(放免法)为标准,诊断恶性血液病的敏感性为81.6写。血清和骨髓液HA在急性白血病完全缓解时下降,复发时又升高口认为测定血清和骨髓液HA并进行动态观察,对鉴别良、恶性血液病.判断急性白血病病情及估计预后都有较重要意义。表2参4(杨尤…     

重组人粒细胞集落刺激因子在老年人恶性血液病治疗中的临床应用

老年恶性血液病患者多数具有体质差、伴有其他系统疾病、骨髓增生低等特点,对化疗的耐受力低、易发生感染.我们对本科收治的老年恶性血液病患者在化疗同时应用重组人粒细胞集落刺激因子(rhG-CSF),取得较好的疗效,现报告分析如下.     

鞘氨醇激酶信号途径与血液肿瘤

血液系统恶性肿瘤的发生发展与骨髓造血微环境密切相关。骨髓微环境包括微血管系统、神经成分、间质细胞、细胞基质以及分泌的各种细胞因子。骨髓微环境通过不同的细胞信号途径调节血液肿瘤细胞的增殖、分化、凋亡及耐药等生物学特性。目前,已经证明多种信号通路及重要信号传递分子的异常调节(如生长因子受体、MAPK、PI3K、Akt等)与白血病、多发性骨髓瘤等恶性血液疾病密切相关。部分信号分子已经成为治疗恶性血液肿瘤的靶点。本文将介绍鞘氨醇激酶信号通路与恶性血液肿瘤的关系。1细胞内鞘氨醇代谢与信号传导磷脂类物质是细胞膜的主要…     

Angiogenesis in hematologic malignancies

Angiogenesis, defined as the blood vessel generation from preexisting blood vessels, was found to play an important role in the progression of solid tumors. In addition, bone marrow-derived endothelial precursor cells may contribute to tumor angiogenesis. Recently angiogenesis induction was described in several hematologic neoplasms as leukemia, lymphoma, myelodysplastic syndrome and multiple myeloma (MM). Clinical angiogenesis research also termed as angiodiagnosis has established the prognostic relevance of markers of angiogenesis e.g., microvessel density and circulating levels of angiogenic peptides. Development of antiangiogenic treatment for hematologic neoplasms has recently been sparked by the success of Thalidomide (Thal) which has antiangiogenic properties in MM. Antiangiogenic treatment strategies are now being tested in clinical trials on several types of hematologic neoplasms.     

Targeting the vascular endothelial growth factor in hematologic malignancies

There exists increasing evidence that apart from solid tumors, angiogenic growth factors also play important roles in the development and/or maintenance of hematolymphoid malignancies. Thus, in these cancers, angiogenesis and bone marrow microvessel density often correlate with prognosis and disease burden. Several reports speculated on the role of angiogenesis and the resulting possible therapeutic options in hematologic malignancies. The most prominent angiogenic factor, vascular endothelial growth factor (VEGF), is expressed in a number of established leukemic cell lines as well as in freshly isolated human leukemias and lymphomas, and several human leukemias express VEGF receptor 1 and/or VEGF receptor 2. VEGF/VEGF‐receptor interactions are also involved in proliferation, migration, and survival of leukemic cells by autocrine and paracrine mechanisms. As a consequence, a possible drugable effect by inhibiting VEGF signaling in different hematologic malignancies has been discussed. This review focuses on angiogenesis‐independent effects of VEGF on survival and proliferation of leukemic or lymphoma cells and on possible therapeutic approaches using anti‐VEGF/VEGF‐receptor therapies to inhibit proliferation or induce apoptosis of malignant cells in hematologic diseases.     

Angiogenesis in Hematologic Malignancies and Its Clinical Implications

Angiogenesis is defined as a neoformation of blood vessels of capillary origin. Hematopoiesis is closely linked with angiogenesis, for they share a common ancestor, the hemangioblast. Although it is well established that growth in solid tumors is dependent on angiogenesis, its role in hematologic malignancies has not yet been clarified. In this review, the direct evidence, ie, increased microvessel density, and the indirect evidence, ie, elevated level of angiogenic factors or overexpression of messenger RNA or protein of angiogenic factors, for and against the role of angiogenesis in the development and progression of hematologic malignancies are presented.     

Evaluation and clinical correlations of bone marrow angiogenesis in myelofibrosis with myeloid metaplasia

Recent observations have underscored the biologic relevance of intratumoral angiogenesis and its potential impact on prognosis. Increased bone marrow angiogenesis has been demonstrated in a variety of hematologic disorders, including multiple myeloma. The extent and prognostic significance of bone marrow angiogenesis in 114 patients with myelofibrosis with myeloid metaplasia (MMM) was investigated. A control group of 44 patients without bone marrow disease, 15 patients with polycythemia vera, and 17 patients with essential thrombocythemia was also studied. Bone marrow microvessel density was assessed by a semiquantitative method, visual microvessel grading, and 2 separate quantitative methods, visual count and computerized image analysis. Angiogenesis estimation by all 3 methods was highly comparable. On visual microvessel grading, a grade 3 or 4 increase in bone marrow angiogenesis was demonstrated in 70% of patients with MMM, 33% of patients with polycythemia vera, 12% of patients with essential thrombocythemia, and 0% of normal controls. In a multivariate analysis, increased angiogenesis in MMM correlated significantly with increased spleen size and was found to be a significant and independent risk factor for overall survival. Increases in marrow angiogenesis correlated with hypercellularity and megakaryocyte clumping. In contrast, these 2 features were inversely proportional to reticulin fibrosis, whereas increases in marrow angiogenesis were independent of reticulin fibrosis. These preliminary findings suggest that neo-angiogenesis is an integral component of the bone marrow stromal reaction in MMM and may provide useful prognostic information and a rationale for the therapeutic investigation of anti-angiogenic agents.     

Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia

The importance of angiogenesis for the progressive growth and viability of solid tumors is well established. In contrast, only few data are available for hematologic neoplasms. To investigate the role of angiogenesis in acute myeloid leukemia (AML), bone marrow biopsies from 62 adults with newly diagnosed, untreated AML (day 0) were evaluated. Further studies were done after the completion of remission induction chemotherapy (day 16 of induction chemotherapy, n = 21; complete remission, n = 20). Microvessels were scored in at least 3 areas (x500 field, 0.126 mm(2)) of the highest microvessel density in representative sections of each bone marrow specimen using immunohistochemistry for von Willebrand factor and thrombomodulin. Microvessel counts were significantly higher in patients with AML (n = 62) compared with control patients (n = 22): median (interquartile range) 24.0 (21.0-27.8)/x500 field vs 11.2 (10. 0-12.0)/x500 field, respectively (P <.001). On day 16 of induction chemotherapy, microvessel density was reduced by 60% (44-66) (P <. 001) in hypoplastic marrows without residual blasts, in contrast to only 17% (0-37) reduction in hypoplastic marrows with >/= 5% residual blasts (P <.001 for the difference between both groups). Bone marrow biopsies taken at the time of complete remission displayed a microvessel density in the same range as the controls. In conclusion, there is evidence of increased microvessel density in the bone marrow of patients with AML, which supports the hypothesis of an important role of angiogenesis in AML. Furthermore, these findings suggest that antiangiogenic therapy might constitute a novel strategy for the treatment of AML. (Blood. 2000;95:2637-2644)     

Angiogenesis and antiangiogenic therapy in hematologic malignancies

Angiogenesis, the generation of new blood capillaries from preexisting blood vessels, is tightly regulated in the adult organism. Although many of the initial studies were performed on solid tumors, increasing evidence indicates that angiogenesis also plays an important role in hematologic malignancies. Overexpression of angiogenic factors in particular VEGF and bFGF in most hematologic malignancies may explain the increased angiogenesis found in these malignancies and correlate with poor prognosis as well as decreased overall survival. In this review, we focus on the current literature of angiogenesis and antiangiogenic therapy in hematologic malignancies, and finally describe advances and potential challenges in antiangiogenic treatment in hematologic malignancies.     

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.     

Tumour angiogenesis and mast cell density in the prognostic assessment of colorectal carcinomas

BACKGROUND: Tumour angiogenesis is essential for the growth, invasion and metastasis of solid tumours. There are several lines of evidence that the mast cells play an important role in tumour angiogenesis. AIMS: The study focused to determine the correlation between the microvessel and mast cell densities, and to evaluate whether tumour angiogenesis and mast cell density could predict recurrence following curative surgery in patients with colorectal carcinomas. PATIENTS: Microvessel and mast cell densities were investigated in tumour specimens from 60 patients with colorectal carcinoma. METHODS: Microvessels were stained by immunohistochemical method using a monoclonal antibody anti-CD34. The routine Giemsa blue staining method was used to assess the mast cells. Microvessels and mast cells were counted in a x400 field. RESULTS: The mean microvessel and mast cell counts were higher in patients with recurrence compared with those patients who were disease-free for at least 24 months (p<0.001). The Spearman's correlation coefficient revealed a significant correlation between mast cell and microvessel counts in colorectal carcinomas (r=0.684; p<0.001). Kaplan-Meier plots of survival showed that the high microvessel (>28) and mast cell (>6) counts correlated with a shorter disease-free survival (p=0.0003 and p=0.0013, respectively). Multivariate analysis showed that the depth of penetration (T4 versus T2) (p=0.004), liver metastasis (p=0.04) and microvessel density (p=0.003) were independent predictors of recurrence. In multivariate analysis, mast cell density did not reach significance. CONCLUSIONS: Our results suggest that the microvessel density of the primary tumour may be an important independent predictor of tumour recurrence and time to recurrence in colorectal carcinomas. The significant correlation between mast cell and microvessel counts suggest that the mast cells may have a role in tumour progression via promoting angiogenesis.     

Angiogenesis in advanced colorectal adenocarcinoma with special reference to tumoral invasion

BACKGROUND: Angiogenesis is a crucial step in tumor growth and progression. Its quantification by microvessel counting has a prognostic value in several types of malignancies and recently has been appraised in gastrointestinal tumors. AIM: To assess the prognostic significance of microvessel quantification in colorectal carcinomas, studying its association with hematogenous metastases, survival and clinicopathological variables such as size, histologic differentiation and depth of tumoral invasion. PATIENTS/METHODS: Forty eight patients with colorectal adenocarcinoma were included in this study. Histologic sections of invasion tumoral margin (4 microns) were analyzed and endothelined microvessels were immunostained with monoclonal mouse Von Willebrand Factor (anti-FVIII). The microvessel count was performed from the identification of the area with increased microvessel density--hot spots--and results of the mean in five of these fields. RESULTS: The cut-off microvessel count was 14 microvessels/0.785 mm2, which divided the sample into hypovascular and hypervascular groups. While 2/8 (25%) tumors with muscularis propria invasion were classified as hypervascular, 11/15 (73%) tumors with serosa or perivisceral fat were classified as hypervascular. However, a non-significant statistical association was found between the angiogenesis quantification, hematogenous metastases, survival and clinicopathological variables such as size and histologic differentiation of the tumor. CONCLUSIONS: The findings of significantly increase of microvessel count in conformity with tumoral invasion depth supports the hypothesis that tumor progression might be related to angiogenesis. Although angiogenesis is an important step in the tumoral growth and during the metastatization process, other factors can be implicated.     

The importance of angiogenesis markers in the outcome of patients with diffuse large B cell lymphoma: a retrospective study of 97 patients

Purpose The role of angiogenesis has been extensively evaluated in solid tumors and more recently in hematologic malignancies. Several surrogate markers of angiogenesis including tumor VEGF, VEGF receptors, and microvessel density have correlated with outcome in some lymphoma studies. This is a single institution retrospective study evaluating the role of angiogenesis markers in the clinical outcome of patients with diffuse large B cell lymphoma (DLBCL). Patients and methods A total of 97 patients with DLBCL diagnosed and managed at Indiana University between 1993 and 2001 were included. Archived tumor samples were stained for VEGF-A, VEGF-C, VEGF-R1, and CD31 and graded as negative or positive (1+, 2+, 3+). The relationship between the expression of these markers and the international prognostic variables as well as the progression free survival (PFS) and the overall survival (OS) was evaluated. Results VEGF-A, VEGF-C, VEGF-R1 were expressed in 77, 98, and 18% of tumors, respectively. VEGF-A negative patients had an improved OS compared to VEGF-A (1+) (P = 0.0502). VEGF-C correlated with both LDH (r = 0.28, P = 0.0502) and IPI score (r = 0.25, P = 0.013). VEGF-R1 negative patients had a superior survival compared to those with VEGF-R1 (2+) (P = 0.0154). Conclusions The presence of tumor associated angiogenesis may alter the outcome of patients with DLBCL and could be a prognostic factor. Further clinical studies are needed to correlate the degree of angiogenesis with response to anti-angiogenesis agents. Supported in part by funds from Indiana University Cancer Center, Indianapolis, IN, USA.