硼替佐米对多发性骨髓瘤干细胞的作用研究

目的:探讨硼替佐米对多发性骨髓瘤干细胞的作用?方法:本实验采用人多发性骨髓瘤细胞系KMS-11及OCI-MY5常规体外培养,随机设定空白组和硼替佐米干预处理后的实验组,通过流式细胞仪利用肿瘤干细胞外排Hoechst33342染料的特性来分析比较侧群细胞的比例?结果:硼替佐米作用后侧群细胞比例明显上升(P < 0.05)?结论:硼替佐米主要的作用靶点是非侧群细胞,为硼替佐米的序贯治疗提供了客观依据?     

造血干细胞移植治疗多发性骨髓瘤的研究进展

多发性骨髓瘤（MM）是浆细胞恶性克隆性疾病,造血干细胞移植治疗MM患者的疗效明显优于传统化疗,是初治MM患者的标准治疗方案。造血干细胞移植包括自体干细胞移值、异基因造血干细胞移植（包括清髓性异基因造血干细胞移植及非清髓异基因造血干细胞移植）。本文就造血干细胞移植治疗MM的疗效、预后因素、预处理方案、移植时机及二次移植等问题的研究进展进行了阐述。     

造血干细胞移植治疗多发性骨髓瘤的研究进展

多发性骨髓瘤(MM)是浆细胞恶性克隆性疾病,造血干细胞移植治疗MM患者的疗效明显优于传统化疗,是初治MM患者的标准治疗方案。造血干细胞移植包括自体干细胞移值、异基因造血干细胞移植(包括清髓性异基因造血干细胞移植及非清髓异基因造血干细胞移植)。本文就造血干细胞移植治疗MM的疗效、预后因素、预处理方案、移植时机及二次移植等问题的研究进展进行了阐述。     

血液肿瘤干细胞研究进展

肿瘤的复发和难以根治一直困扰着人们。近年来肿瘤干细胞（CSC）的发现及相关的研究越来越引起人们重视,2004年5月7日还在加拿大召开了由白血病淋巴瘤协会主办的肿瘤干细胞会议。目前认为可能大多数的恶性肿瘤都起源于一小群肿瘤干细胞,在乳腺癌和脑瘤中已经证实了有肿瘤干细胞的存在,而研究最多的当属白血病干细胞（LSC）。这群数量极少的细胞常常处于静止期,对放化疗不敏感,但却有着干细胞样的自我更新能力,维持着肿瘤的发生发展。对干细胞加深认识有助于深刻了解肿瘤的起源,找到更有效治疗肿瘤的方法。作者就血液肿瘤方面的干细胞研究情况作一综述。     

多发性骨髓瘤遗传学研究进展

多发性骨髓瘤(MM)是一种不可治愈的疾病，其完全缓解率低，预后不佳。了解MM的细胞遗传学特征，从遗传学方面对多发性骨髓瘤进行分类，研究不同亚型多发性骨髓瘤对治疗的反应及预后，对于多发性骨髓瘤具有重要意义。本文就此方面的进展作一综述。     

自体造血干细胞移植治疗多发性骨髓瘤的研究进展

同传统化疗相比,大剂量化疗后的自体造血干细胞移植能够使多发性骨髓瘤患者完全缓解(CR)率明显增加,生存率提高,逐渐成为65岁以下初始多发性骨髓瘤患者的标准化一线治疗方法,但存在较高的复发风险。序贯式二次移植能够弥补其不足,尤其对未达到CR或很好部分缓解者,其无事件生存期及总生存期均明显优于单次移植。     

多发性骨髓瘤的诊治思路

多发性骨髓瘤为发生于B淋巴细胞的恶性浆细胞病。好发于中老年，但近年其发病率有增高及发病年龄有提前的趋势。     

多发性骨髓瘤的CAR-T治疗研究进展

多发性骨髓瘤(MM)是一种几乎无法治愈的浆细胞恶性肿瘤.嵌合抗原受体(CAR)是结合抗原识别域和T细胞信号域的融合蛋白,通过基因工程表达CAR的T细胞(即CAR-T)可以特异性地识别和结合肿瘤细胞抗原,激活的T细胞会杀死肿瘤细胞.CAR-T免疫治疗为MM的治疗提供了新思路.目前MM的治疗靶点包括B细胞成熟抗原、CD19...     

自体造血干细胞移植治疗多发性骨髓瘤新进展

<正>大剂量化疗联合自体造血干细胞移植(autologous stem cell transplantation,ASCT)是治疗恶性血液系统疾病的一种重要手段。多发性骨髓瘤(multiple myeloma,MM)患者采用传统方案化疗,其完全缓解率(CRR)和很好的部分缓解率(VGPR)均很低;而基于大剂量化疗再联合ASCT,CRR及患者的无进展生存时间(PFS)得到明显提高[1]。对于年龄小于65岁的年轻MM     

MAC方案作预处理ASCT治疗老年多发性骨髓瘤

目的：探讨采用自体外周血干细胞移植（简称ＡＳＣＴ）治疗老年多发性骨髓瘤（简称ＭＭ）疗效及安全性。方法：采用大剂量马法兰联合阿糖胞苷和环磷酰胺作预处理，大剂量阿糖胞苷结合Ｇ－ＣＳＦ作动员剂。结果：２例患者均顺利渡过危险期。主要副作用是骨髓抑制、胃肠道反应及口腔溃疡等。生存期分别为２４月和１２月，移植后缓解时间分别为１６月和５月。结论：ＡＳＣＴ采用ＭＡＣ方案作预处理疗效好、安全性高，其不良反应是可耐受的     

新药硼替佐米条件下的自体造血干细胞移植治疗多发性骨髓瘤

目的了解新药硼替佐米(Bor)治疗条件下自体造血干细胞移植(AHCT)治疗多发性骨髓瘤(MM)的安全性及疗效。方法回顾性分析我科2008年3月-2010年4月18例符合条件MM患者进行AHCT的安全性与疗效。结果 18例AHCT预处理方案:大剂量马法兰(HDM)8例,Bor联合HDM(Bor-HDM)10例。8例诱导治疗和移植预处理方案均应用Bor治疗,8例诱导治疗时应用Bor而移植预处理方案未应用,2例诱导治疗未应用而移植预处理应用Bor。HDM和Bor-HDM组移植中恶心、呕吐、厌食、腹泻、口腔黏膜炎及发热均无统计学差异(P>0.1)。移植后粒系重建中位时间HDM组12d,Bor-HDM组13d(P>0.1);血小板重建中位时间HDM组16.5d,Bor-HDM组18d(P>0.1)。移植后14例接受反应停维持治疗。随访25(14-39)月,11例出现疾病进展,进展时间6-25月;HDM组进展4例,Bor-HDM进展6例(P>0.1)。AHCT后2年无疾病进展生存率为(44.2±12)%。结论新药硼替佐米治疗条件下MM进行AHCT安全、易行,但移植后仍易出现疾病进展。     

骨髓瘤细胞可诱导骨髓间充质干细胞的基因表达谱发生暂时和 (或)长期性改变

目的:正常骨髓间充质干细胞(mesenchymal stem cell,MSC)在与骨髓瘤细胞相互作用过程中,MSC的全基因表达谱的改变目前尚未有报道,本研究就对此进行研究并进一步探索多发性骨髓瘤的发病机制。方法:正常人骨髓MSC与骨髓瘤细胞株在Transwell共培养体系培养前后,用全基因表达芯片检测MSC全基因mRNA的表达谱,比较正常MSC在与骨髓瘤细胞共培养(MC组)或共培养后去除骨髓瘤细胞后继续单独培养的MSC(MA组),和MSC单独培养的对照组(MK组)基因表达谱的变化。结果:MC组与MK组相比较,在所有分析的10 000个基因中共发现837个差异基因(837/10 000,8.37%),其中有472个基因表达上调(472/837,56.39%),365个基因表达下调(365/837,43.61%)。而MA组与MK组相比较,共发现367个差异基因,其中有218个基因表达上调(218/367,59.40%),149个基因表达下调(149/367,40.60%)。从芯片结果中筛选出MMP1、FGFR2、ANGPTL4、MFAP5、TGM2、STC1、CCL7和IL-32这8个基因,经定量PCR验证后的结果与基因芯片结果相一致。结论:骨髓瘤细胞可以诱导正常骨髓MSC多种基因表达改变,并且有些改变即使在骨髓MSC脱离骨髓瘤细胞后仍可存在;此外,初步筛选到8个差异表达基因,其中7个基因在多发性骨髓瘤发病机制中的作用既往未见报道,有待今后进一步研究。     

硼替佐米用于3例初治多发性骨髓瘤的诱导化疗及自体干细胞移植预处理

目的探讨硼替佐米应用于初治多发性骨髓瘤患者的诱导化疗及自体外周血造血干细胞移植预处理方案的可行性和效果。方法对3例初治多发性骨髓瘤患者给予PAD（硼替佐米＋表柔比星＋地塞米松）方案化疗4疗程,后进行PMD（硼替佐米＋马法兰＋地塞米松）方案预处理的自体外周血造血干细胞移植。动员方案为环磷酰胺＋硼替佐米＋地塞米松联合G-CSF 5-10μg/（kg.d）。结果3例患者在4疗程PAD方案化疗后达VGPR,干细胞采集顺利,移植后造血功能顺利重建,移植后中性粒细胞和血小板临床植入的时间分别为14、16、16d和25、29、22d。结论万珂应用于初治多发性骨髓瘤患者的诱导治疗及自体外周血造血干细胞移植的预处理,安全有效,值得临床进一步研究探索。     

Modified conditioning regimen busulfan-cyclophosphamide followed by allogeneic stem cell transplantation in patients with multiple myeloma

Background Allogeneic stem cell transplantation is a potential curative approach in patients with multiple myeloma. The very high transplant related mortality associated with standard allogeneic stem cell transplantation is currently the major limitation to wider use of this potentially curative treatment modality. The challenge for clinical investigators is to reduce the incidence of post-transplant complications for patients receiving autologous hematopoietic stem cell transplantion for multiple myeloma. In this study the toxicity and efficacy of modified myeloablative conditioning regimen followed by allogeneic stem cell transplantation was investigated in patients with multiple myeloma. Methods The conditioning regimen consisted of hydroxyurea, cytarabine, busulfan, cyclophosphamide, and semustine. Ten patients underwent allogeneic transplantation among them hydroxyurea （40 mg/kg） was administered twice on day -10 and cytarabine （2 g/ms） was given on day -9, busulfan was administered orally in four divided doses daily for 3 days （days -8 to -6）. The dose of busulfan was 12 mg/kg in the protocol followed by cyclophosphamide intravenously over 1 hour on days -5 and -4 （1.8 g/m^2）, and with semustine （Me-CCNU） 250 mg/m^2 on day -3. Results Chimerism data were available on all patients and all patients achieved full donor chimerism without graft failure. Six patients had not acute graft-versus-host disease （GVHD, 36.4%; 95% CI： 13.9%-38.6%）. Two patients （18.2%） developed grade Ⅰ acute GVHD （95% CI： 10.9%-35.9%） and grade Ⅱ acute GVHD occurred in one patient （9.1%; 95% Cl. 8.4%-32.3%）. Severe grade IVa GVHD was seen in one patient, who died from acute GVHD. The incidence of chronic GVHD was 22.2% （95% Cl： 11.7%-36.7%）, among them one died of severe grade IV GVHD and one developed multiorgan failure on day ＋170; the treatment-related mortality was 22.0% （95% Cl： 10.3%-34.1%）. The overall 4-year survival rate was 67.8% （95% Cl： 16.3%-46.7%）. The estimated 4-year progression-free survival rate was 58.5% （95% CI： 13.7%-41.8%）. The 4-year complete remission was 72.7% （95% CI： 27.8%-49.6%）. One patient relapsed after 4 months and achived the complete remission after receiving the donor lymphocyte infusion. Conclusions Modified conditioning regimen busulfan-cyclophosphamide with peripheral blood stem cells＋bone marrow cells transplantation result in a low incidence of severe GVHD with a relatively low treatment-related mortality, high complete remission rates and a long-term survival.     

Sequential treatment with bortezomib plus dexamethasone followed by autologous hematopoietic stem cell transplantation in patients with multiple myeloma

Background  Whether the sequential treatment with bortezomib plus dexamethasone (BD) followed by autologous hematopoietic stem cell transplantation (ASCT) could extend the overall survival period in multiple myeloma patients is still not clear. Few large case studies about this therapeutics in multiple myeloma were reported in China. Our purpose was to assess the efficacy and adverse effects of sequential treatment with BD chemotherapy and ASCT in patients with multiple myeloma.

Methods  Fifty-three patients with newly diagnosed or relapsed/refractory multiple myeloma received BD as induction therapy before ASCT. Stem-cell mobilization was undertaken with cyclophosphamide 3–5 g/m² plus granulocyte colony-stimulating factor 300 µg/d. Target yield was 2.0×10⁶ CD34⁺ cells/kg. Conditioning for ASCT consisted of melphalan 200 mg/m². Thalidomide and/or α-interferon was used as post-transplantation maintenance treatment.

Results  The BD chemotherapy before transplantation was effective in 86.7% of the 53 patients, including 22.6% with complete remission (CR), 39.6% with near complete remission (nCR), and 24.5% with partial remission (PR). The best effect was achieved after two treatment courses. Most bortezomib-related adverse effects were classes 1–2. All patients were successfully mobilized after BD for autologous peripheral blood stem cell transplantation. The ASCT was effective in 96.3% of patients, including 49.1% with CR, 32.1% with nCR, and 15.1% with PR. The CR rate was significantly increased (49.1% vs. 22.6%, P <0.05) by sequential ASCT. Within 27 (range, 6–53) months of follow-up, the efficacy of ASCT was maintained in 29 patients and further enhanced by post-transplantation maintenance treatment in four patients. Eleven patients died after transplantation. Among the patients undergoing BD/ASCT treatment, overall survival (OS) was significantly better in newly diagnosed patients in comparison to relapsed/refractory patients (P=0.046).

Conclusions  BD chemotherapy can be used as an induction therapy prior to ASCT in patients with multiple myeloma. Its rate of effectiveness is high and it alleviates symptoms quickly without affecting peripheral blood stem cell collection. The majority of adverse effects are mild (tolerable). Sequential BD with ASCT is the preferred option for transplant patients. First-line ASCT could prolong survival of newly diagnosed patients rather than delayed ASCT.

     

Clinical effects of autologous stem cell transplantation as consolidation treatment in 70 multiple myeloma patients: a case-controlled study

Background  Autologous stem cell transplantation (ASCT) is a part of the standard induction therapy of multiple myeloma (MM). This case-controlled clinical trial aimed to further evaluate the therapeutic effects of ASCT as a consolidation therapy for MM and discuss factors influencing the prognosis.

Methods  Clinical data of 70 patients diagnosed as MM who received ASCT as a consolidation therapy in our hospital between October 1998 and August 2010 were analyzed retrospectively (ASCT group). Other 70 MM patients receiving routine chemotherapy without ASCT (non-ASCT group) during the same period were used as controls. Differences in the degree and duration of remission, progression-free survival (PFS) and overall survival (OS) were compared to explore factors that may influence the prognosis.

Results  The median follow-up period was 38 months (range 1–128 months). The complete response (CR) rate of ASCT group increased from 27.1% (19/70) before ASCT to 51.4% (36/70) after ASCT. The median PFS of ASCT group was significantly higher than non-ASCT group (45 months vs. 25 months, P <0.001). The median OS of ASCT group was also significantly higher (55 months vs. 30 months, P=0.016). Single-factor analysis showed that International Staging System (ISS) stage, very good partial response (VGPR) or better outcome were significantly correlated with PFS and OS (P <0.001). Multi-factor analysis showed that whether or not VGPR or better outcome was achieved were independent factors influencing the disease prognosis.

Conclusion  Used as a consolidation therapy, ASCT can achieve better responses and higher OS and PFS of MM patients.

     

人宫颈癌组织和Hela细胞株中SP细胞水平和生物学特性的比较研究

目的：比较宫颈癌组织和Hela细胞株中多种恶性肿瘤的侧群（SP）细胞的含量和生物学特性。方法采用Altra流式细胞仪分选出宫颈癌组织原代培养6代细胞和Hela细胞株中SP细胞,检测两种细胞的表面标记和细胞周期增殖状况。结果宫颈癌组织和Hela细胞株中SP细胞水平分别为（1．62±0．48）％和（2．70±0．59）％,Hela细胞株中SP的水平明显高于宫颈癌组织,差异有统计学意义（P＜0．05）。宫颈癌组织和Hela细胞株SP细胞的生物学标记（ABCG2、CD133、CD43、P63、Ki‐67、MDR）表达率分别为：ABCG2（78．59±5．42）％vs．（80．17±3．60）％,CD133（51．55±6．29）％vs．（52．87±4．96）％,CD43（69．73±5．70）％vs．（70．68±5．44）％,P63（47．56±6．92）％vs．（48．06±5．28）％,Ki‐67（14．69±1．69）％vs．（15．33±1．38）％,MDR（58．36±11．12）％vs．（58．24±5．32）％,表达差异均无统计学意义（P＞0．05）。各细胞周期时相分布分别为：G0/G1期（94．70±1．76）％vs．（95．10±1．59）％,S期（3．25±0．99）％vs．（2．92±0．84）％,G2/M期（2．05±1．10）％vs．（1．98±0．95）％,凋亡率（4．06±0．64）％vs．（3．92±0．59）％,坏死率（1．00±0．38）％vs．（1．12±0．31）％,表达差异均无统计学意义（P＞0．05）。宫颈癌组织和Hela细胞株两组SP细胞在生物学标记和细胞周期增殖状况的表达差异均无统计学意义（P＞0．05）。结论宫颈癌组织和Hela细胞株中都存在SP细胞且含量不同,他们均具有肿瘤干细胞的生物学特性。