Murine 5T multiple myeloma cells induce angiogenesis in vitro and in vivo

Multiple myeloma is a B cell malignancy. Recently, it has been demonstrated that bone marrow samples of patients with multiple myeloma display an enhanced angiogenesis. The mechanisms involved seem to be multiple and complex. We here demonstrate that the murine 5T multiple myeloma models are able to induce angiogenesis in vitro by using a rat aortic ring assay and in vivo by determining the microvessel density. The rat aortic rings cultured in 5T multiple myeloma conditioned medium exhibit a higher number of longer and more branched microvessels than the rings cultured in control medium. In bone marrow samples from 5T multiple myeloma diseased mice, a statistically significant increase of the microvessel density was observed when compared to bone marrow samples from age-matched controls. The angiogenic phenotype of both 5T multiple myeloma cells could be related, at least in part, to their capacity to produce vascular endothelial growth factor. These data clearly demonstrate that the 5T multiple myeloma models are good models to study angiogenesis in multiple myeloma and will allow to unravel the mechanisms of neovascularisation, as well as to test new putative inhibitors of angiogenesis.     

多发性骨髓瘤患者OPN、CD44v6的表达与病情进展的关系

背景与目的:骨桥蛋白(osteopontin,OPN)与其受体--CD44受体和整合素受体结合后,参与骨重建、骨质重吸收、血管重塑、癌细胞浸润和转移等过程.为此本研究检测了多发性骨髓瘤(multiple myeloma,MM)患者的OPN和变异的CD44受体(CD44v6)水平,以探讨其与MM病情进展的关系.方法:32例MM患者,分为A组(包括初发和复发病例)和B组(化疗后病情稳定)2组,同时收集外伤骨折或非肿瘤良性贫血患者15例作为对照.采用酶链免疫吸附试验(ELISA)分别检测了患者和对照组的单个核细胞及骨髓基质细胞(bone marrow mononuclear eells,BMSCs)培养上清液的0PN、CD44v6水平并进行相关分析.结果:A组(19例)患者的0PN表达水平显著高于B组(13例)和对照组患者(P<0.05).对A组中的14例患者和B组中的10例患者进行了CD44v6水平检测,其结果A组的CD44v6表达水平显著高于B组和对照组患者(P<0.05),B组的CD44v6水平显著高于对照组(P<0.05);0PN水平与CD44v6(r=0.52,P=0.000)、恶性浆细胞数(r=0.74,P=0.000)、M蛋白水平(r=0.53,P=0.014)、血β2-MG水平(r=0.62,P=0.002)均呈正相关.结论:0PN和CD44v6水平升高与删的发生和病情进展有关;可能与MM的肿瘤负荷、疾病阶段和肿瘤浸润有关.     

多发性骨髓瘤综合治疗现状与进展

多发性骨髓瘤（MM）是浆细胞克隆增生性恶性肿瘤,其治疗效果较差,迄今仍视为不可治愈的疾病。近年来着眼于MM细胞内信号通路、骨髓微环境及二者的相互作用,MM的治疗有了很大进展。该文综述了MM的化学治疗、造血干细胞移植、生物治疗、支持治疗及免疫治疗现状及其进展。     

冒烟型骨髓瘤的研究进展

第21届欧洲血液学会年会在多发性骨髓瘤的基础研究、疾病诊治方面都取得了令人振奋的进展.年会上特别将冒烟型骨髓瘤作为一个专题来讲解,从其定义到进展的高危因素以及当前对冒烟型骨髓瘤理念的转变作了详细的阐述.     

多发性骨髓瘤的治疗

Multiple Myeloma(MM)is characterised by the accumulation of malignanat plasma cells in the bone marrow producing a monocolonal immungoglobulin.The standard conventiona therapy in the combination of melphalan and prednisone resulting in a response rate of 40%-60% and in a median survival time of approximately 3 years.In order to improve the therapeutic efficacy va rious combination regimens have been tested.Most randomized trials have frailed to show a significant improvement in survival time when combination chemotherapy is used instead of melphalan with or without prednisone.The benefit of maintenance therapy with interferon-alpha has been demonstrated.The toxicity of interferon-alpha,which may reduce the quality of life,should be considered.Recently,myeloma-treatment has been modified.High-dose chemotherapy accompaniced by hematopoietic stem-cell support via autologous transplant is recommended up to the age of 65-70 years.First results from a French study comparing single versus double autologous transplantaiton have shown a benefit in terms of event-free survival for the sequential approach.Vaccinations as an adoptive immuntherapy to treat minimal residual dsease are umder way.The mortality rate of allogeneic transplantation of hemaatopoietic stem cells has been reduced in the last 5 years.The use of reduced conditioning regimens or the partial depletion of T cells in peripheral blood stem cell transplants in an effort to decrease transplant related mortality are promising approaches.Thalidomide and its derivates are a new class of agents with independent anti-tumour activity in MM.Encouraging results with this antiangiogenic therapy in phase Ⅱ trials have been reported.Supportive therapies,such as the treatment of anaemia with erythropoietin,the management of renal failure and the use of bisphosphonates,improve the life quality of MM patients.     

多发性骨髓瘤患者Survivin、VEGF表达及其相关性

目的:研究多发性骨髓瘤（MM）患者血清及骨髓Survivin、VEGF表达及意义。方法:酶联免疫法（ELASA）检测60例初诊多发性骨髓瘤患者及30例对照组患者血清Survivin、VEGF表达情况;免疫细胞化学法（SABC法）检测骨髓单个核细胞中Survivin、VEGF阳性率。酶联免疫法（ELASA）检测VAD联合沙利度胺治疗4周期后患者血清Survivin、VEGF水平,与治疗前比较。结果:初诊多发性骨髓瘤患者血清Survivin、VEGF表达水平较对照组明显升高;初诊骨髓瘤患者骨髓单个核细胞Survivin、VEGF阳性率较对照组明显提高;经统计学分析,P＜0.05,差异有统计学意义。治疗后患者,血清Survivin、VEGF在不同疗效组有差异,疗效良好组与疗效较差组差异比较,P＜0.05。骨髓中Survivin与VEGF表达阳性率呈正相关,与疾病疗效呈负相关。结论:Survivin及VEGF在多发性骨髓瘤患者中表达增加,二者表达水平与疾病疗效密切相关。二者存在协同关系,可作为评估疗效、预后指标。     

Obesity and multiple myeloma

An exploratory study was conducted of common clinical conditions as predictors of subsequent cancer in 143,574 outpatients of a health maintenance organization (in California, USA). An association was noted between obesity, diagnosed in 14,388 patients, and the subsequent development of multiple myeloma (MM) in up to 21 years (33 cases observed, 21.3 expected based on the experience of the entire cohort; standardized morbidity ratio=1.55, 95 percent confidence interval [CI]=1.06–2.17). This association was evaluated further in a second cohort of 163,561 multiphasic-checkup examinees followed up for as many as 24 years. Body mass index (BMI) at entry examination was associated positively with the incidence of MM in White men (e.g., relative risk [RR]=1.07, CI=1.01–1.15 per unit increase in BMI; and RR=1.68, CI=0.75–3.78, comparing the highest with lowest quartile). This association was absent in White women, partially confirmed in Black men and women (BMI quartiles two, three, and four showed higher risk than quartile one), and not explained by the presence of diabetes mellitus. The association was reduced or absent with BMI based on reported greatest adult-weight, and in White women was inverse with BMI based on reported lowest adult-weight. Among subjects with more than one checkup, increased risk was associated directly with weight loss among White men and associated inversely with weight gain among Black women. These findings suggest that body build or nutritional status may be involved in the development of MM by mechanisms that are presently unknown. If increased weight is a causal factor, weight loss occurs later after the disease process begins.This research was supported by Grant R35 CA 49761 from the US National Cancer Institute.     

Controversies in multiple myeloma: Evidence-based update

The US Food and Drug Administration (FDA) approved 10 new drugs for the treatment of multiple myeloma (MM) over the last two decades. The influx of new anti-myeloma agents with high efficacy and acceptable tolerability add complexity to the clinical decision-making process. First, treatment of smoldering multiple myeloma (SMM) remains investigational to date, although a randomized trial showed a survival gain in high-risk patients receiving lenalidomide. Second, in newly diagnosed MM, the majority of contemporary induction regimens have been studied in single-arm trials or compared to an older regimen, which complicates evidence-based treatment selection. Third, the role of consolidation chemotherapy followed by autologous stem cell transplant (ASCT) needs to be revisited in the context of highly effective agents, as newer regimens— such as carfilzomib, lenalidomide, and dexamethasone—are able to achieve extremely deep responses equivalent to or exceeding those seen after conventional induction and ASCT. Fourth, risks and benefits of maintenance therapy should also be redefined and individualized, as long-term survival and safety data accumulate. Here we selected four clinical settings where controversies exist, reviewed evidences behind conflicting treatment strategies, and asked myeloma experts to discuss evidence-based recommendations.     

多发性骨髓瘤44例临床分析

目的:探讨多发性骨髓瘤的临床特点。方法:回顾性分析西安交大二院血液科2001年～2006年收治的44例多发性骨髓瘤患者的临床资料。结果:发病中位年龄为58.23岁,首发症状为骨痛(40%),乏力(16.3%)。血清β2-MG,CRP升高者及血清白蛋白水平降低者中位生存期与上述三值正常者相比均有显著性差异。结论:生存分析显示β2微球蛋白和C反应蛋白与疾病预后相关。     

Isoprenoid pathway related cascade in multiple myeloma

This study assessed the changes in the isoprenoid pathway and its metabolites digoxin, dolichol and ubiquinone in multiple myeloma. The following parameters were assessed: isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition and free radical metabolism. There was elevation in plasma HMG CoA reductase activity, serum digoxin and dolichol and a reduction in RBC membrane Na+ - K+ ATPase activity, and serum ubiquinone levels. Serum tryptophan, serotonin, nicotine, strychnine and quinolinic acid were elevated while tyrosine, dopamine, noradrenaline and morphine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions, the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins and serum glycolipids were elevated. The RBC membrane glycosaminoglycans, hexose and fucose residues of glycoproteins, cholesterol and phospholipids were reduced. The activity of all free radical scavenging enzymes, concentration of glutathione, iron binding capacity and ceruloplasmin decreased significantly while the concentration of lipid peroxidation products and NO increased. Hyperdigoxinemia related altered intracellular Ca++ mediated oncogene activation, dolichol induced altered glycoconjugate metabolism and ubiquinone deficiency related mitochondrial dysfunction can contribute to the pathogenesis of multiple myeloma. The biochemical findings reported could be the cause or the consequence of multiple myeloma.     

The neural cell adhesion molecule NCAM in multiple myeloma

The Neural Cell Adhesion Molecule NCAM is a membrane glycoprotein and belongs to the immunoglobulin superfamily. It is expressed on neural cells as well as on various neuroendocrine tumors and can be detected in sera of patients with small cell lung cancer. Its role is attributed to tumor invasion and formation of metastases. Malignant plasma cells and a subset of plasma cells from patients with monoclonal gammopathy exhibit surface expression of NCAM whereas normal plasma cells do not express NCAM. Expression as measured by flow cytometry using anti-CD56 antibodies does not seem to correlate with clinical course, however leukemic myelomas and myeloma cell lines tend to loose NCAM surface expression.

An isoform of NCAM which is rich in polysialic acids and characteristic for embryonal NCAM (eNCAM) has been shown to be elevated in sera of patients with multiple myeloma using a chemiluminescence immunoassay. Patients with progressive myeloma tend to have high serum NCAM levels above the normal range of 20 U/ml. Analysis of 125 myeloma patients suggest that serum NCAM is a valuable parameter for tumor progression rather than tumor mass. Increase in serum NCAM may be associated with loss of adhesive function.     

Vincristine and oral etoposide in refractory multiple myeloma

A total of 15 patients with refractory multiple myeloma (MM; 4 primary unresponsive and 11 relapsed and resistant to re-induction/salvage therapy) received i.v. vincristine on day 1 and oral etoposide daily for 4 days, the treatment being repeated at 3-weekly intervals. The patients were re-assessed after three cycles of chemotherapy, and non-responders received no further therapy. There was no complete or partial response. A minimal response was seen in two patients, and two others showed stable disease. None of the responses was sustained, and all patients eventually had progressive disease. It is concluded that combination chemotherapy with vincristine and oral etoposide given by this schedule is unlikely to be of any value in refractory myeloma.     

早期死亡的多发性骨髓瘤患者临床分析

目的：探讨新药时代早期死亡的多发性骨髓瘤（multiple myeloma,MM）患者的临床特点。方法：回顾性分析2009年1 月至2015年12月北京朝阳医院京西院区收治的188 例多发性骨髓瘤患者的临床资料,早期死亡定义为确诊后1 年内各种原因所致的死亡。结果：1）早期死亡率10.1% ;中位年龄67（40～84）岁;IgG 型8 例,非IgG 型11例;DS分期均为Ⅲ期,伴肾功能不全10例;ISS分期Ⅱ期4 例,Ⅲ期15例;伴髓外浸润（EMP ）6 例;10例遗传学高危;5 例乳酸脱氢酶升高;3 例淀粉样变性;2 例浆细胞白血病;体能状态评分（KPS）20～80分,中位评分70分;16例使用含硼替佐米的方案化疗,3 例使用CADT 方案化疗。2）可评价疗效的13例,总反应率（orerallresponserate,ORR ）46.2%（6/ 13）,接近完全缓解率（CR+nCR）7.7%（1/ 13）;3）中位生存3（1～11.5）个月,继发浆细胞白血病的2 例生存期不到2 个月;4）19例患者中死于疾病进展8 例（42.1%）,死于严重感染8 例（42.1%）,死于血栓事件3例。结论：遗传学高危、LDH 高、伴EMP 、继发淀粉样变性、高龄、体能状态差以及治疗期间严重并发症是导致MM患者早期死亡的重要原因。新药时代需探索高危MM的个体化治疗,降低MM的早期死亡率,使更多的MM患者获益。     

多发性骨髓瘤误诊3例临床分析

目的：研究多发性骨髓瘤（MM）的临床特征,误诊原因。方法：对我院误诊的3例多发性骨髓瘤病例进行回顾性分析。结果：MM首发症状与临床表现复杂多变,极易误诊、漏诊。结论：对MM的临床表现要综合分析,外周血涂片形态学检查可为临床提供重要参考,骨髓细胞学检查及骨髓活组织检查是确诊的首要方法。完善MM相关检测对避免误诊有重要意义。     

APE1表达增强与多发性骨髓瘤细胞对马法兰耐药的关系研究

目的:探讨脱嘌呤/脱嘧啶核酸内切酶(apurinic/apyri midinic endonucle-ase,APE1)在多发性骨髓瘤(multiple my-eloma,MM)细胞中的表达及其与马法兰耐药的关系。方法:采用双荧光抗体免疫标记法结合激光共聚焦显微镜和免疫细胞化学观察KM3细胞、32例MM患者和10例正常自愿者骨髓标本APE1蛋白定位及表达,并通过免疫细胞化学和West-ern blot检测0~15μmol/L马法兰作用KM3细胞1~2d后APE1表达的变化。结果:APE1和CD38蛋白在MM细胞存在共表达,APE1蛋白表达尤以细胞核周围表达明显;APE1阳性表达在正常对照组、MM初治组和MM复发或难治组间依次增高,P<0·05;马法兰可诱导KM3细胞APE1表达增强,并与其作用时间及剂量成正比。结论:APE1蛋白表达强度与MM疗效有关,且马发兰作用可诱导其表达增强,提示APE1基因表达增强可能在MM对马发兰耐药中起一定作用。肿瘤防治杂志,2005,12(19):1445-1448     

Serum exosomal microRNAs as novel biomarkers for multiple myeloma

Accumulating studies have focused on circulating microRNAs, which might be potential biomarkers for different malignancies. The aim of this study was to investigate the potential of serum exosomal microRNAs to be novel serum biomarkers for smouldering myeloma (SMM) or even multiple myeloma (MM). The levels of serum exosomal microRNAs and serum circulating microRNAs were measured in healthy individuals and patients with SMM (n = 20) or MM (n = 20). Serum exosomal microRNAs and serum circulating microRNAs were extracted from serum, and the expression levels of selected microRNAs were quantified by real‐time polymerase chain reaction (PCR). The levels of serum exosome‐derived miR‐20a‐5p, miR‐103a‐3p, and miR‐4505 were significantly different among patients with MM, patients with SMM, and healthy individuals, while there were differences in the levels of let‐7c‐5p, miR‐185‐5p, and miR‐4741 in patients with MM relative to those in SMM patients or healthy controls. Additionally, a significant correlation was rarely found between the levels of serum and exosomal microRNAs. This study shows that serum exosomal microRNAs can be used independently as novel serum biomarkers for MM.     

Thalidomide: present and future in multiple myeloma

Multiple myeloma continues to be an incurable disease. The understanding of the disease’s pathophysiology has significantly improved over the past few years, partly due to the discovery of the role of immunomodulatory agents and the study of their mechanism of action. Thalidomide, the first of the immunomodulatory family to be used in the management of multiple myeloma, proved not only to be effective in the treatment of multiple myeloma, but also instigated a wide range of in vitro and in vivo studies to define the pathophysiology of the plasma cell dyscrasia. The attention thalidomide has received in the past and recent history has not been without a price. The drug has a side-effect profile that, if managed appropriately, provides the most unique active molecule in the management of the disease, where it maintains the same response rate in newly diagnosed patients as in advanced relapsed/refractory multiple myeloma patients.     

Lenalidomide and its role in the management of multiple myeloma

Treatment of multiple myeloma has changed in recent years. Advances in the understanding of the pathogenesis of the disease and the mechanism of drug resistance have led to the development of novel effective biological treatment agents such as thalidomide and bortezomib. Lenalidomide is an oral analogue of thalidomide that lacks the neurotoxic side effects associated with the parent drug, and has shown significant antimyeloma activity. Lenalidomide has now been approved by the US FDA and the European Medicines Agency for use in combination with dexamethasone in patients with at least one prior therapy. Several trials are testing lenalidomide-based regimens in both newly diagnosed and relapsed patients. This review summarizes the profile of lenalidomide and its current role in the treatment of multiple myeloma.