DKK1在多发性骨髓瘤中的表达及临床意义

目的检测多发性骨髓瘤治疗前及治疗后血清中DKK1的表达水平,分析其临床意义及与治疗的相关性。方法通过ELISA法检测25例多发性骨髓瘤患者治疗前及治疗后血清中DKK1的表达水平,并以23例健康成年人为对照组。结果①Ⅱ/Ⅲ期初治多发性骨髓瘤患者血清DKK1水平高于I期患者[(13.26±11.85)ng/mLVS(3.03±0.93)ng/mL]](P=0.011),并高于健康对照组[(2.83±1.75)ng/mL](P<0.001)。②治疗有效者治疗后血清DKK1水平较治疗前显著降低[(12.93±11.22)ng/mLVS(7.01±3.14)ng/mL,P<0.001],在传统治疗组及新药治疗组均有显著差异(P分别为0.018,0.028)。③难治复发多发性骨髓瘤患者血浆DKK1水平治疗前后无显著差异[(7.57±6.38)ng/mLv(s6.98±4.60)ng/mL,P=0.441]。结论多发性骨髓瘤DKK1表达水平增加并与疾病分期有关,疾病缓解后DKK1水平下降。     

IL-33水平与多发性骨髓瘤相关性分析

目的通过检测多发性骨髓瘤患者血清中IL-33水平,探讨两者之间的相关性。方法选取2012年1月—2013年1月间37例多发性骨髓瘤患者,50例健康对照者作为研究对象,应用ELISA方法检测所有研究对象血清中IL-33水平,并进行统计学分析。结果两组研究对象IL-33检出率无显著差异,但MM患者IL-33水平与健康对照者相比显著降低,具有统计学差异（P〈0.05）,且IL-33水平与MM分期呈负相关。结论 IL-33水平降低可能通过调节细胞免疫的变化而促进多发性骨髓瘤的进展,维持T细胞亚群平衡可能有助于骨髓瘤疾病的治疗。     

A novel drug of elotuzumab for treatment of refractory/relapsed multiple myeloma: a meta-analysis of eight trials

Elotuzumab was approved by the US FDA in 2015 as a new drug for the treatment of multiple myeloma (MM), and it became a new choice for MM patients. The drug is the first immunostimulatory drug to treat MM and used to treat recurrent/refractory multiple myeloma (R/RMM) in combination with lenalidomide and dexamethasone. Therefore, we collected the reports from existing clinical trials to analyze the efficacy of the drug in clinical applications to better evaluate the effects of the drug on R/RMM. The search strategy used “elotuzumab” and “multiple myeloma” as keywords to search from the database of Cochrane, Embase, PubMed and Medline. The heterogeneity among the studies was assessed using the Cochrane χ² test, and its extent was evaluated using I² statistics. A P value of less than 0.05 was considered as statistically significant. All meta-analyses were conducted with R Software 3.3.2. We identified eight prospective studies consisting of 608 MM patients. The meta-analysis showed that the overall response rate (ORR) was 63%, 162 patients (26.6%) achieved a very good partial response rate (VGPR), and 34 patients (5.59%) achieved complete response rate (CR). The most common adverse effects of the drug included anemia, lymphopenia, thrombocytopenia, neutropenia and fatigue. Therefore, elotuzumab combination regimens offered clinical benefits to R/RMM patients, and such a combination therapy was a suitable option for continuous treatment for R/RMM patients.     

Survivin在多发性骨髓瘤中的表达及其与VEGF的相关性

目的研究Survivin在多发性骨髓瘤（MM）中的表达及其与血管内皮生长因子（vascular endothelial growth factor,VEGF）之间的相关性。方法采用RT-PCR和Western blot法检测骨髓瘤细胞系RPMI8226及28例MM患者（其中初治16例、复发,难治12例）,6例正常人骨髓细胞中Survivin和VEGF mRNA、蛋白质表达水平。结果骨髓瘤细胞系RPMI8226高表达Survivin和VEGF。Survivin mRNA在正常人、初治和难治／复发MM患者骨髓细胞中阳性率分别为19．8％、77．3％和80．2％,表达水平（Survivin与内参比）分别为0．07±0．03、0．37±0．12和1．2±0．31,MM患者表达率和表达水平显著高于正常人（P〈0．01）,而难治／复发MM组表达水平高于初治组（P〈0．05）。在初治和难治／复发MM组Survivin蛋白阳性率分别为43．8％和61％（P〉0．05）,难治,复发MM组表达水平明显高于初治组。VEGF在MM中的表达变化与Survivin呈相同趋势。结论Survivin和VEGF参与了MM的发病且与疾病进展有关,两者间存在协同关系。     

Alterations in human circulating and bone marrow mononuclear cell polyamine levels in hematologic malignancies as a consequence of difluoromethylornithine administration

Summary The effect of administering increasing intravenous doses of difluoromethylornithine on human tumor cell polyamine levels was determined in patients with hematologic malignancies. Difluoromethylornithine from 5.5. to 64 gm/m² per day was administered to nine patients with refractory acute leukemia or multiple myeloma. Putrescine, spermidine, and spermine levels were determined on a daily basis in the circulating mononuclear cells and on a weekly basis in the mononuclear cells of the bone marrow. Tumor cell putrescine levels declined in 5 patients, spermidine levels declined in 4 patients, and spermine levels declined in 3 patients. Alterations in the polyamine levels of the bone marrow mononuclear cells paralleled those occuring in the peripheral blood mononuclear cells in the patients with leukemia. Seven to ten days of DFMO treatment were required for mononuclear cell polyamine levels to decrease. The higher drug doses were not significantly more effective than the lower doses in bringing about a decline in tumor cell polyamine levels, either with respect to treatment time required for onset of response or with respect to the ultimate extent of response.Abbreviations DFMO Difluoromethylornithine - ODC ornithine decarboxylase - AML Acute Myeloge-nous Leukemia - MM Multiple Myeloma - WBC Mononuclear White Blood Cell - MGBG methylglyoxal bis(guanylhydrazone) Recipient of NIH Posdoctoral Fellowship NRSA AMO7331.     

HIV-1 integrase inhibitor raltegravir promotes DNA damage-induced apoptosis in multiple myeloma

Raltegravir, the first integrase inhibitor approved for the treatment of HIV infection, has been implicated as a promising potential in cancer treatment. Therefore, the present study aimed to investigate the repurposing of raltegravir as an anticancer agent and its mechanism of action in multiple myeloma (MM). Human MM cell lines (RPMI-8226, NCI H929, and U266) and normal peripheral blood mononuclear cells (PBMCs) were cultured with different concentrations of raltegravir for 48 and 72 h. Cell viability and apoptosis were then measured by MTT and Annexin V/PI assays, respectively. Protein levels of cleaved PARP, Bcl-2, Beclin-1, and phosphorylation of histone H2AX were detected by Western blotting. In addition, the mRNA levels of V(D)J recombination and DNA repair genes were analyzed using qPCR. Raltegravir treatment for 72 h significantly decreased cell viability, increased apoptosis, and DNA damage in MM cells while having minimum toxicity on cell viability of normal PBMCs approximately from 200 nM (0.2 μM; p < .01 for U66 and p < .0001 for NCI H929 and RPMI 8226 cells). Furthermore, raltegravir treatment altered the mRNA levels of V(D)J recombination and DNA repair genes. We report for the first time that treatment with raltegravir is associated with decreased cell viability, apoptosis induction, DNA damage accumulation, and alteration of mRNA expression of genes involved in V(D)J recombination and DNA repair in MM cell lines, all of which show its potential for anti-myeloma effects. Hence, raltegravir may significantly impact the treatment of MM, and further studies are required to confirm its efficacy and mechanism of action in more detail in patient-derived myeloma cells and in-vivo models.     

多发性骨髓瘤患者血清M蛋白分型及相关因素分析

目的对多发性骨髓瘤(MM)患者血清M蛋白分型及相关因素进行分析。方法对104例血清蛋白电泳异常的多发性骨髓瘤患者血清进行免疫固定电泳分型,同时分别检测各型患者血清中的β2-TG、CRP和Cr的含量。结果 104例MM患者血清中IgG-к型有31例;25例IgG-λ型;11例IgA-к型,13例IgA-λ型,5例IgD-λ型和7例к轻链型、12例λ轻链型;MM患者血清中β2-TG、CRP和Cr的含量较正常对照组均明显升高(P<0.05);各型之间β2-TG、CRP和Cr的含量无显著性差异(P>0.05)。结论应用免疫固定电泳对多发性骨髓瘤患者的M蛋白进行分型鉴定特异性好、灵敏度高,是多发性骨髓瘤的诊断和鉴别诊断的重要手段。多发性骨髓瘤患者β2-TG、CRP和Cr的含量明显高于正常人,各型之间β2-TG、CRP和Cr的含量无显著性差异。     

Cooperation between Apo2L/TRAIL and bortezomib in multiple myeloma apoptosis

The proteasome inhibitor bortezomib is currently an important drug for treatment of relapsed and refractory multiple myeloma (MM) and for elderly patients. However, cells from some patients show resistance to bortezomib. We have evaluated the possibility of improving bortezomib therapy with Apo2L/TRAIL, a death ligand that induces apoptosis in MM but not in normal cells. Results indicate that cotreatment with low doses of bortezomib significantly increased apoptosis of MM cells showing partial sensitivity to Apo2L/TRAIL. Bortezomib treatment did not significantly alter plasma membrane amount of DR4 and DR5 but increased Apo2L/TRAIL-induced caspase-8 and caspase-3 activation. Apo2L/TRAIL reverted bortezomib-induced up-regulation of β-catenin, Mcl-1 and FLIP, associated with the enhanced cytotoxicity of combined treatment. More important, some cell lines displaying resistance to bortezomib were sensitive to Apo2L/TRAIL-induced apoptosis. A cell line made resistant by continuous culture of RPMI 8226 cells in the presence of bortezomib (8226/7B) was highly sensitive to Apo2L/TRAIL-induced apoptosis. Moreover, RPMI 8226 cells overexpressing Mcl-1 (8226/Mcl-1) or Bcl-x_L (8226/Bcl-x_L) also showed enhanced resistance to bortezomib, but co-treatment with Apo2L/TRAIL reverted this resistance. These results indicate that Apo2L/TRAIL can cooperate with bortezomib to induce apoptosis in myeloma cells and can be an useful adjunct for MM therapy.     

IgD型与其他类型多发性骨髓瘤实验室检查结果比较分析

目的：探讨临床上较为少见的IgD型多发性骨髓瘤（MM）的实验室特点,分析其与常见型MM患者实验室检查结果的异同。方法选择2009年11月至2013年11月在该院住院治疗的152例MM患者进行骨髓穿刺检查和免疫固定电泳（IFE）、免疫球蛋白（Ig）定量和血脂测定,比较分析IgD型与其他各型MM检测结果的差异。结果 IgD型MM患者原始浆细胞和幼稚浆细胞百分比显著高于IgG型和IgA型,差异有统计学意义（P＜0.05）;IgD型MM患者以λ轻链升高为主（87.5%,7/8）,且轻链比值异常;各型之间血清异常免疫球蛋白检出率比较,差异无统计学意义（P＞0.05）;IgD型患者三酰甘油（TG）、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）和高密度脂蛋白胆固醇（HDL-C）水平与轻链型患者比较,差异无统计学意义（P＞0.05）;与IgG 型和IgA 型患者比较,IgD 型患者各项指标显著升高,差异有统计学意义（P＜0.05）;MM患者血清TC、LDL-C和HDL-C较对照组显著降低,差异有统计学意义（P＜0.05）。结论实验室诊断能够区分IgD型与其他类型MM,避免IgD型MM的漏诊和误诊。     

ROS在小白菊内酯诱导MM细胞凋亡中的作用

目的研究倍半萜内酯小白菊内酯(parthenolide,PL)对多发性骨髓瘤原代细胞和细胞株诱导的凋亡作用及其机制。方法以多发性骨髓瘤原代细胞及细胞株为研究对象,利用台盼蓝染色检测细胞存活率,用DAPI染色法检测细胞凋亡率,流式细胞仪检测反应氧(ROS)和线粒体膜电位水平变化。结果2.5μmol.L-1PL引起多发性骨髓瘤(multi-ple myeloma,MM)细胞明显凋亡及线粒体膜电位下降,而正常淋巴细胞在同等条件下不受影响。用2.5μmol.L-1PL作用10 h后,KMM-1和MM1S细胞ROS水平明显增加。用自由基清除剂L-N-乙酰半胱氨酸(L-NAC)预处理可抑制ROS的产生,对两种细胞存活率、凋亡率无影响。用还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶抑制剂二亚苯基烟碱氯化物(diphenylene iodonium chloride,DPI)预处理KMM-1和MM1S,可明显抑制PL介导的ROS的产生,并对两种细胞凋亡率无影响。结论PL诱导多发性骨髓瘤细胞凋亡,而正常淋巴细胞在同等条件下不受影响。PL的凋亡活性是通过引起MM细胞氧化应激而介导的,并进一步推测NADPH氧化活性与PL介导的MM细胞ROS的产生相关。     

多发性骨髓瘤患者血清IL-10、IL-12和sFas水平及其临床意义

目的 研究多发性骨髓瘤(MM)患者血清白细胞介素10(IL-10)、白细胞介素12(IL-12)和可溶性Fas(sFas)水平及其在MM发病机制中的作用.方法 采用酶联免疫夹心(ELISA)法检测15例MM患者和20例正常人血清IL-10、IL-12和sFas水平.结果 与正常组比较,MM患者IL-10和sFas水平明显升高(P＜0.01);IL-12水平有下降趋势,但无显著性差异(p＞0.05).结论 IL-10、IL-12和sFas参与MM的免疫病理生理过程.检测上述三种细胞因子水平变化,为MM患者监测病情、疗效判断及免疫治疗提供较为客观指标.     

Expression of proliferating cell nuclear antigen (PCNA) in multiple myeloma: its relationship to bone marrow microvessel density and other factors of disease activity

The expression of proliferating cell nuclear antigen (PCNA) was studied in plasma cells in bone marrow biopsies from patients with multiple myeloma (MM) using a double immunostaining method. In the same samples, microvessel density (MVD), after staining with anti-CD34 antibodies, was determined before and after chemotherapy. The correlation of PCNA expression and MVD with other myeloma parameters (clinical stage, bone marrow plasma cell infiltration and serum interleukin-6 (IL-6)) was also investigated. The study population included 51 newly diagnosed MM patients, 15 patients in plateau phase after treatment and 15 normal controls. Pretreatment mean +/- SE values of PCNA, MVD, plasma cell infiltration and serum IL-6 were significantly higher than post treatment values and controls. Pretreatment PCNA expression correlated significantly with bone marrow MVD (p<0.05) plasma cell infiltration (p<0.01) and IL-6 (p<0.01). These findings show that the proliferative activity of plasma cells is related to the angiogenic activity in the bone marrow of multiple myeloma patients. Both PCNA and MVD correlate with markers of disease activity thus may provide additional information when included in the initial evaluation of myeloma bone marrow biopsies.     

多发性骨髓瘤骨髓病理检测血管内皮生长因子的表达情况

目的：探讨多发性骨髓瘤（MM）骨髓病理中,血管内皮生长因子（VEGF）的表达情况。方法应用石蜡包埋的方法,经过免疫组化的相关方法对10例缺铁性贫血（对照组）的患者和40例MM患者（ MM组）骨髓活检组织,检测血管内皮生长因子（ VEGF）的表达情况。结果在本次研究中,VEGF在MM组和对照组的表达率比较,差异有统计学意义（ P ＜0忖．05）。 VEGF在多发性骨髓瘤不同分期中存在明显差异（ P ＜0．05）。结论在多发性骨髓瘤中,骨髓病理检测VEGF对于多发性骨髓瘤的诊断有重要意义,同时对于疾病的分期更有临床价值,VEGF在MM的发生、发展及预后有重要意义。     

多发性骨髓瘤伴浆细胞瘤的诊治进展

目的:综述多发性骨髓瘤伴髓外浆细胞瘤的诊治进展。方法 :收集近年国内外发表的相关文章并对多发性骨髓瘤(MM)合并髓外浆细胞病(EMD)的发病情况、预后及治疗进展进行分析。结果与结论:根据病例研究MM诊断时EMD的发生率为7%¹8%,复发时可达6%18%,复发时可达6%²0%。发生髓外进展的患者预后较差,生存期短。目前对于MM伴髓外病变的治疗没有明确的最佳方案。髓内病变稳定而出现单个髓外浆细胞瘤的患者可行放疗,MM系统复发并出现髓外病变的患者应行化疗。年轻患者进行大剂量治疗加自体干细胞移植可克服髓外病变带来的不利预后的影响。单药沙利度胺治疗EMD无反应,但与其他药物联合化疗可能有效。可能有效的一线治疗方案为含硼替佐米方案和含来那度胺的联合化疗方案,如果可能随后进行自体造血干细胞移植(ASCT)。     

多发性骨髓瘤患者联合酞胺哌啶酮治疗的疗效分析

目的探讨低剂量酞胺哌啶酮联合VAD方案治疗多发性骨髓瘤(MM)的疗效及安全性。方法选择我院收治的MM患者53例,进行酞胺哌啶酮联合VAD方案治疗,4个疗程后进行整体评估。观察治疗前后骨髓增生情况以及骨髓瘤细胞数量,血红蛋白、β_2-微球蛋白、卡氏评分等各项检测指标的变化,分析患者的不良反应。结果 53例患者的总有效率为83.02%,治疗后患者血红蛋白、卡氏评分显著高于治疗前,差异有统计学意义(血红蛋白:t=7.465,P=0.000;卡氏评分:t=12.082,P=0.000)。骨髓浆细胞百分比、β_2-微球蛋白、肌酐、血清球蛋白显著低于治疗前,差异有统计学意义(骨髓浆细胞:t=22.747,P=0.000;β_2-微球蛋白:t=14.442,P=0.000;肌酐:t=2.928,P=0.004;血清球蛋白:t=20.894,P=0.000)。25例轻度嗜睡(47.17%)、6例头晕(11.32%)、38例便秘(71.70%)、30例四肢麻木(56.60%)。25例轻度纳差(47.17%),13例轻度恶心呕吐(24.53%),但均可耐受。结论低剂量酞胺哌啶酮联合VAD方案治疗MM疗效显著,且不良反应少、耐受性好、给药方便,值得临床推广。     

多发性骨髓瘤118例临床特征调查及治疗无效的影响因素分析

目的 调查多发性骨髓瘤（MM）病人的临床特征并分析其治疗无效的影响因素。方法 选取石家庄市人民医院2012年1月至2020年3月收治的118例的MM病人，统计病人性别、年龄、血常规、血肌酐、血钙离子、乳酸脱氢酶（LDH）、血清白蛋白、病理类型等临床特征。根据治疗效果将其分为有效组和无效组，采用logistic多元回归分析探讨病人治疗无效的影响因素。结果 MM病人中男性占比高于女性，平均年龄49.52岁，身体质量指数>25 kg/m2、血肌酐、血钙离子、LDH水平升高、贫血、骨骼损害、合并淀粉样变、白蛋白水平降低、修订的国际分期体系（R-ISS）分期Ⅰ期、免疫球蛋白G型（IgG型）、轻链型、免疫球蛋白A型（IgA型）、国际骨髓瘤工作组（IMWG）10%～50%、<10%占比高；MM病人治疗无效率为40.68%(48/118)，且治疗无效病人年龄[（58.75±10.18）岁，（43.19±5.63）岁]、血肌酐水平升高[38(79.17%),33(47.14%)]、血钙离子水平升高[35(72.92%),30(42.86%)]、血清LDH水平升高[36(75.00%),31(...     

碱性成纤维细胞生长因子检测对多发性骨髓瘤的临床意义

目的探讨碱性成纤维细胞生长因子(bFGF)在多发性骨髓瘤(MM)中的表达及其临床意义。方法应用酶联免疫法(ELISA)检测41例MM不同时期的血清bFGF的水平,观察其与MM临床分期、肿瘤量分级、治疗效果和骨损评分的关系,并与正常对照组比较。结果MM患者血清中的bFGF水平(70.53±21.88)pg/L较正常人水平(22.96±7.13)pg/L明显升高(P<0.01);MMⅢ期患者的bFGF血清水平(78.14±40.52)pg/L显著高于Ⅰ期(39.28±21.53)pg/L及Ⅱ期的水平(47.05±24.87)pg/L(P<0.05),而Ⅰ、Ⅱ期之间差异无显著性(P>0.05);不同肿瘤量分级的MM患者间血清bFGF的水平有显著性差异(P<0.05);MM治疗完全缓解者血清bFGF的水平比治疗前明显降低(P<0.01),而部分缓解及未缓解者,血清bFGF的水平治疗前后比较差异无显著性差异(P>0.05);不同骨损评分组间bFGF的水平无显著性差异(P>0.05)。结论血清bFGF的检测对了解MM的疾病严重程度及疗效观察有一定临床价值。     

Model-based pharmacokinetic analysis of elotuzumab in patients with relapsed/refractory multiple myeloma

Elotuzumab is a humanized immunoglobulin G1 monoclonal antibody in development for the treatment of patients with multiple myeloma who have received one or more prior therapies. In this work, 6958 elotuzumab serum concentrations from 375 patients enrolled in four Phase 1 to 3 clinical trials were used to analyze the pharmacokinetics (PK) of elotuzumab. A population PK model with parallel linear and Michaelis–Menten elimination from the central compartment and limited-capacity target-mediated elimination from the peripheral compartment described the elotuzumab concentration–time course. Clearance of elotuzumab increased with increasing body weight and weight-based dosing generated uniform exposures across a range of body weights. Coadministration of lenalidomide/dexamethasone background therapy decreased elotuzumab nonspecific clearance by 35 %. Target-mediated elimination of elotuzumab increased with increasing baseline serum M-protein, resulting in lower exposure in patients with high baseline serum M-protein concentration. Age, race, sex, renal and hepatic function, Eastern Cooperative Oncology Group performance status, lactate dehydrogenase, albumin and β₂-microglobulin had less than 20 % effect on model parameters and are unlikely to have clinically meaningful effects. Impact of anti-drug antibodies (ADAs) on the PK of elotuzumab was assessed as an ad hoc analysis. In the majority of ADA-positive patients, immunogenicity started early, was transient and resolved by 2–4 months. Since the majority of patients had ADAs detected early, this resulted in a corresponding transient increase in nonspecific clearance at these time points. Nonspecific clearance appeared to return to baseline at later time points when ADAs were no longer detected.