来那度胺致多发性骨髓瘤患者静脉血栓形成的机制

来那度胺是一种新型的免疫调节药物,已被广泛应用于治疗多发性骨髓瘤,但其所致静脉血栓形成的副作用也越来越明显。当单独使用来那度胺治疗多发性骨髓瘤时,患者静脉血栓的发生率比较低,而其与地塞米松、化疗药物等联合使用治疗多发性骨髓瘤时,静脉血栓的发生率明显高于单独使用。来那度胺致多发性骨髓瘤患者静脉血栓形成的机制目前尚未完全阐明,国内外研究显示,其主要与内皮细胞功能紊乱、组织因子与磷脂酰丝氨酸暴露增加及体内的高凝状态相关。本文主要就来那度胺致多发性骨髓瘤患者静脉血栓形成的机制进行了简要综述。     

多发性骨髓瘤中NF-κB作用机制研究

多发性骨髓瘤(multiple myeloma,MM)是浆细胞异常增生的恶性肿瘤,其发病机制比较复杂。研究表明,活化NF-κB具有多种生物学功能,它既能调节细胞因子;影响细胞周期,又与血管发生有关,并且与多发性骨髓瘤治疗密切相关。该文就NF-κB在多发性骨髓瘤中的作用机制做一综述。     

STAT3信号通路在多发性骨髓瘤中的调控机制及作用

多发性骨髓瘤(multiple myeloma,MM)是一种肿瘤性浆细胞疾病,其特征在于骨髓微环境中恶性浆细胞的克隆性增殖,分泌单克隆免疫球蛋白以及相关的器官功能障碍.近年来,由于自体干细胞移植的引入,以及来那度胺和硼替佐米等药物的应用改变了骨髓瘤的传统治疗方法,延长了总生存期.尽管取得了显著的治疗进展但目前仍无法治愈...     

DNA甲基化与多发性骨髓瘤

DNA甲基化是目前肿瘤领域研究中研究最多的表观遗传学机制之一.主要发生在DNA的CpG岛.DNA的甲基化通过甲基转移酶(DNA methyltransfeases,DNMTs)完成.DNA甲基化在多种肿瘤的发生、发展中都起到了重要的作用.大量研究发现,甲基化与多发性骨髓瘤的发生、发展及诊断治疗等有密切关系.深入探讨多发性骨髓瘤(MM)相关的甲基化可为MM发病机制的研究及治疗提供新的思路.     

Daratumumab靶向治疗多发性骨髓瘤的研究进展

多发性骨髓瘤(multiple myeloma,MM)是以骨髓中浆细胞异常增殖为特征的恶性克隆性疾病。尽管近年来MM的治疗有了很大的进展,但其依旧是不可治愈的疾病。Daratumumab(DARA)是一种人源化抗CD38单克隆抗体,具有广谱杀伤活性。相关研究证实DARA可以通过多种途径诱导MM细胞的快速死亡。现就CD38分子及DARA作为单药或者联合其他药物治疗复发性、难治性MM患者的临床前实验和临床试验进行综述,以期说明DARA诱导MM细胞死亡的机制及DARA治疗复发性、难治性MM患者的有效性及安全性,为DARA治疗复发性、难治性MM患者提出新的研究思路。     

CD56、CD117表达水平与来那度胺治疗多发性骨髓瘤疗效的相关性分析

目的:探讨CD56、CD117的表达水平与来那度胺治疗多发性骨髓瘤疗效的相关性,为预测来那度胺治疗多发性骨髓瘤的疗效提供参考依据。方法:将我院2016年12月至2019年3月收治的多发性骨髓瘤患者64例,均给予来那度胺联合小剂量地塞米松治疗,所有患者根据疗效分为完全缓解(CR)、非常好的部分缓解(VGPR)、部分缓解(PR)、疾病稳定(SD)、疾病进展(PD),并且采用门诊、电话、住院等随访方式定期随访。采用流式细胞仪测定所有患者入院治疗前一天的CD56、CD117的表达水平,分析CD56、CD117表达与患者病理特征以及来那度胺疗效的相关性。结果:CD56、CD117的表达水平与多发性骨髓瘤患者的轻链分型、M蛋白分型、临床分型显著相关,与性别无关。来那度胺治疗多发性骨髓瘤的64例患者中,有效例数53例,总有效率为83%;其有效组患者中,CD56、CD117的阳性率分别为56.6%、35.8%,显著高于无效组患者(18.2%、9.1%)(P<0.05)。结论:多发性骨髓瘤患者CD56、CD117均呈现高表达的状态,其表达与患者的临床分期、M蛋白类型、轻链重链类型及来那度胺治疗的疗效有显著相关性。     

多发性骨髓瘤信号通路靶向治疗

多发性骨髓瘤(multiple myeloma,MM)发病机理十分复杂,寻找有效的治疗方法仍是世界性的难题。以往的研究表明,MM细胞的存活、增殖、迁移及耐药性与多种信号通路有着密切的联系。最近的研究不断发现与MM细胞扩散和生存密切相关的信号通路新分子靶点,并据此提出了针对性的治疗方案,使MM的治疗逐步改善。本文根据以往的研究成果以及最新的研究动态,对已知的MM靶向治疗通路及相关药物做一综述。     

多发性骨髓瘤的生长调控机制

多发性骨髓瘤（Multiple myeloma,MM）是一种目前仍无法治愈的血液系统恶性肿瘤。其发生、发展与细胞因子、体内微环境以及癌基因产物等多种作用因素密切相关。本文将分别阐述影响MM细胞生存和生长的控制因子及其作用机制。     

多发性骨髓瘤与白细胞介素-6

白细胞介素-6是多发性骨髓瘤(multiple myeloma,MM)瘤细胞生长和生存的关键因子,也是MM患者发病的主要因子。IL-6/IL-6R系统通过不同通路影响多发性骨髓瘤瘤细胞生长并导致患者骨损害、类风湿性关节炎等一系列并发症。针对IL-6/IL-6R系统的治疗方法将给MM的治疗带来重大的进展。     

多发性骨髓瘤相关microRNA的研究进展

microRNA(miRNA)是一种内源性非编码的单链小分子RNA,长度约19~24个核苷酸,通过靶向结合mRNA的3′非翻译区域(3′UTR)区域,抑制翻译或者降解靶标mRNA而调节基因的表达.miRNA参与一些重要的生理、病理学过程,包括细胞增殖、分化、生长和凋亡等.大量研究发现,miRNA与多发性骨髓瘤(multiplemyeloma,MM)的发生、发展及诊断治疗等有着密切关系.深入探讨MM相关miRNA的调节机制和功能等,可为MM发病机制的研究及诊治提供新的思路.     

The role of bone morphogenetic proteins in myeloma cell survival

Multiple myeloma is characterized by slowly growing clones of malignant plasma cells in the bone marrow. The malignant state is frequently accompanied by osteolytic bone disease due to a disturbed balance between osteoblasts and osteoclasts. Bone morphogenetic proteins (BMPs) are present in the bone marrow and are important for several aspects of myeloma pathogenesis including growth and survival of tumor cells, bone homeostasis, and anemia. Among cancer cells, myeloma cells are particularly sensitive to growth inhibition and apoptosis induced by BMPs and therefore represent good models to study BMP receptor usage and signaling. Our review highlights and discusses the current knowledge on BMP signaling in myeloma.     

Immunomodulatory drugs improve the immune environment for dendritic cell-based immunotherapy in multiple myeloma patients after autologous stem cell transplantation

Multiple myeloma (MM) is characterized by a malignant proliferation of plasma cells in the bone marrow with associated organ damage. Although the prognosis of MM has improved recently, the disease remains incurable for the large majority of patients. The eradication of residual disease in the bone marrow is a main target on the road toward cure. Immune cells play a role in the control of cancer and can be tools to attack residual MM cells. However, the myeloma-associated immune deficiency is a major hurdle to immunotherapy. We evaluated ex vivo the effects of low doses of the immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide on several immune cell types from MM patients after autologous stem cell transplantation and with low tumor burden. We observed that these drugs increased CD4⁺ and CD8⁺ T-cell proliferation and cytokine production, enhanced the lytic capacity of cytotoxic T lymphocytes and reduced the suppressive effects of regulatory T cells on CD8⁺ T-cell responses. In addition, we found that functional dendritic cells (DCs) can be generated from mononuclear cells from MM patients. The presence of IMiDs improved the quality of antigen-specific T cells induced or expanded by these DCs as evidenced by a higher degree of T-cell polyfunctionality. Our results provide a rationale for the design of early phase clinical studies to assess the efficacy of DC-based immunotherapy in combination with posttransplant maintenance treatment with IMiDs in MM.     

Novel biologically based therapeutic strategies in myeloma

Multiple myeloma remains incurable despite advances in conventional chemotherapy and wider applicability of high dose chemotherapy with single and/or tandem autologous peripheral blood stem cell transplantation. Although a complete remission rate of 41% and an event-free survival of 43 months have been reported after tandem transplantation, it is highly unlikely that further improvements in the outcome of multiple myeloma will be achieved by escalating cytotoxic chemotherapy alone. Novel biologically based therapies are therefore urgently required. Targeted therapeutic approaches based on: identification of genetic abnormalities in malignant plasma cells; interrupting growth of myeloma cells; triggering apoptotic signaling cascades in tumor cells; modulating growth and survival of multiple myeloma cells in the bone marrow microenvironment, i.e. angiogenesis and cytokine networks; enhancing allogeneic and autologous antimyeloma immunity; and characterizing newer myeloma antigens for serotherapy are under development. These therapies offer great promise, used alone/or in combination with conventional treatment approaches, to improve the outcome in this disease in newly diagnosed/refractory or relapsed patients with multiple myeloma.     

Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis

Objective To assess the risk of venous thromboembolism in women using hormone replacement therapy by study design, characteristics of the therapy and venous thromboembolism, and clinical background.Design Systematic review and meta-analysis.Data sources Medline.Studies reviewed Eight observational studies and nine randomised controlled trials.Inclusion criteria Studies on hormone replacement therapy that reported venous thromboembolism.Review measures Homogeneity between studies was analysed using χ² and I² statistics. Overall risk of venous thromboembolism was assessed from a fixed effects or random effects model.Results Meta-analysis of observational studies showed that oral oestrogen but not transdermal oestrogen increased the risk of venous thromboembolism. Compared with non-users of oestrogen, the odds ratio of first time venous thromboembolism in current users of oral oestrogen was 2.5 (95% confidence interval 1.9 to 3.4) and in current users of transdermal oestrogen was 1.2 (0.9 to 1.7). Past users of oral oestrogen had a similar risk of venous thromboembolism to never users. The risk of venous thromboembolism in women using oral oestrogen was higher in the first year of treatment (4.0, 2.9 to 5.7) compared with treatment for more than one year (2.1, 1.3 to 3.8; P<0.05). No noticeable difference in the risk of venous thromboembolism was observed between unopposed oral oestrogen (2.2, 1.6 to 3.0) and opposed oral oestrogen (2.6, 2.0 to 3.2). Results from nine randomised controlled trials confirmed the increased risk of venous thromboembolism among women using oral oestrogen (2.1, 1.4 to 3.1). The combination of oral oestrogen and thrombogenic mutations or obesity further enhanced the risk of venous thromboembolism, whereas transdermal oestrogen did not seem to confer additional risk in women at high risk of venous thromboembolism.Conclusion Oral oestrogen increases the risk of venous thromboembolism, especially during the first year of treatment. Transdermal oestrogen may be safer with respect to thrombotic risk. More data are required to investigate differences in risk across the wide variety of hormone regimens, especially the different types of progestogens.     

Role of osteoblast suppression in multiple myeloma

Multiple myeloma is the most common form of plasma cell dyscrasia and virtually all cases of myeloma exhibit osteolytic lesions, which result in bone pain, pathological fractures, spinal cord compression, and hypercalcaemia. Malignant plasma cells disrupt the delicate balance between bone formation and bone resorption, which ultimately leads to the debilitating osteolytic lesions. This review focuses principally on mechanisms of osteoblast inhibition by malignant plasma cells with emphasis placed on our experimental findings, which support a model for abnormal Wnt signaling in osteoblast suppression. We describe how excessive amounts of soluble Wnt inhibitors secreted by malignant plasma cells in multiple myeloma could promote osteolytic lesions, tumor growth, suppress hematopoiesis, prevent proper engraftment, and expansion of transplanted stem cells. Finally, we detail current therapies shown to disrupt the interaction between the myeloma cell and the microenvironment, leading to activation of osteoblasts.