组蛋白去乙酰化酶抑制剂对多发性骨髓瘤细胞的杀伤机制及临床应用现状

多发性骨髓瘤（multiple myeloma,MM）是恶性浆细胞瘤,至今无法治愈。在过去的20年中,蛋白酶体抑制剂（proteasome in? hibitors,PIs）硼替佐米和免疫调节剂（immunomodulatory drug,IMiD）来那度胺显著改善了MM患者的预后,延长了MM患者的生存时间。组蛋白去乙酰化酶抑制剂（histone deacetylase inhibitors,HDACis）具有较好的抗MM活性,可以显著提高MM患者治疗的总有效率（overall response rate,ORR）,延长MM患者的无进展生存期（progression free survival,PFS）和总生存期（overall survival,OS）。而对既往应用IMiD或PIs耐药的患者,HDACis仍能取得较好的疗效。本文就HDACis作用于MM细胞的杀伤机制以及临床中对MM的治疗效果进行综述。      

曲妥珠单克隆抗体治疗乳腺癌研究进展

研究证实,原发性乳腺癌患者中有25％～30％的患者HER-2过表达,该亚组乳腺癌患者的预后较差。尽管1991年开始的NSABPB-11试验已经证实蒽环类药物能够提高HER-2阳性乳腺癌患者的无瘤生存期（disease free survival,DFS）、无远处转移生存期（distant disease free survival,DDFS）和总生存期（overallsurvival,OS）,但其作用仍然有限。     

靶向治疗对多发性骨髓瘤患者疗效及生存的影响

目的 探讨分子靶向治疗（沙利度胺、来那度胺或硼替佐米）对多发性骨髓瘤（MM）患者疗效及生存的影响.方法 回顾性分析217例自1989年至2013年上海交通大学附属第一人民医院血液科收治的MM患者治疗情况,对比不同时期诊治患者的生存情况,分析治疗措施的改进对患者疗效及生存的影响.结果 基于靶向治疗的普及从1998年后开始,1998年之后确诊的MM患者较之前确诊患者的生存期有显著改善.共有75例患者在初始治疗中接受了沙利度胺或硼替佐米治疗,其疗效优于接受MP、VAD等传统方案的患者.在复发、进展阶段中接受靶向治疗的患者有49例,其疗效较传统方案占优.共有16例患者接受了自体或异基因造血干细胞移植,其中接受自体及异基因双移植的有4例,其疗效及生存期较其他未接受移植治疗的患者占优.结论 分子靶向治疗的应用提高了MM的疗效,并进一步使患者的生存时间得到延长.     

多发性骨髓瘤移植治疗进展

多发性骨髓瘤（MM）是浆细胞恶性增殖性疾病，大剂量化疗结合自体造血干细胞移植（AHSCH）可明显延长患者的生存期，对于年轻患者，异基因干细胞移植提供了一个可能治愈的方法，非清髓性移植治疗因可能减少治疗相关死亡率、提高疗效、减少复发，目前正在研究中。移植后应用干扰素能明显改善部分缓解患者的生存期，对于移植后复发特别是伴有髓外复发者，反应停是很好的治疗药物。     

造血干细胞移植治疗多发性骨髓瘤的研究进展

 【摘要】　造血干细胞移植（HSCT）是治疗多发性骨髓瘤（MM）的一线方案。自体造血干细胞移植（auto-HSCT）可提高患者缓解率,延长生存期。首次auto-HSCT后,未获得非常好的部分缓解及以上疗效的患者,可行二次auto-HSCT进一步改善疗效。异基因造血干细胞移植（allo-HSCT）具有治愈MM的潜能,但移植相关死亡率高,患者生存并未获益。减低剂量的allo-HSCT相关死亡率低,但复发率高,也未显示出生存优势。序贯auto-HSCT及allo-HSCT也未使患者生存明显获益。总结近期HSCT的研究进展。     

NSCLC根治术后pN2期患者不同放化疗模式的疗效分析

目的 ：比较序贯放化疗（Sequential radiochemotherapy，SCRT）与同步放化疗（Concurrent chemoradiotherapy,CCRT）在非小细胞肺癌（non small cell lung cancer,NSCLC）根治术后pN2期患者辅助治疗中的价值。方法 ：选取2012年1月～2017年12月期间，在四川省肿瘤医院行肺癌根治术后pN2期NSCLC患者92例，据放化疗方式不同分为SCRT组（n=54）和CCRT组（n=38），比较两组副反应,无局部复发生存期（local recurrence free survival,LRFS）、无远处转移生存期（distant metastasis free survival,DMFS）、无病生存期（disease free survival,DFS）、总生存（overall survival,OS）及1年、2年、3年生存率。结果： 两组患者在一般资料、病理类型、病理T分期、淋巴结状态等方面差异无统计学意义。CCRT组白细胞减少发生率较SCRT组高，差异有统计学意义（P＜0.05），放射性食管炎、放射性肺炎等副反应发生率在两组间差异无统计学意义（P＞0.05）。SCRT组的中位DMFS、DFS优于CCRT组，两组的中位LRFS及CCRT组的中位OS暂未达到，但差异均未达到统计学意义（P＞0.05）。结论： 对于根治术后pN2期NSCLC，SCRT与CCRT均是有效的治疗方式，但SCRT的安全性更佳，且SCRT的DMFS、DFS有优于CCRT的趋势，SCRT及CCRT的价值有待于进一步探索。     

多发性骨髓瘤的治疗现状

 多发性骨髓瘤（MM）的治疗取得了突破性进展。20世纪90年代开始,应用造血干细胞移植治疗MM明显提高了疗效,中位总生存期达到5年。近年来,随着多种靶位治疗药物（沙利度胺、硼替佐米、雷利度胺）的临床应用,使得各类型骨髓瘤的预后有了显著改善,据统计中位总生存期又提升了50 %。临床资料最新估计,65岁以下患者中位生存期约为10年,老年患者约5～6年。目前正在研制的新药物必将进一步提高患者的疗效。     

17号染色体缺失与乳酸脱氢酶相关性研究及其对多发性骨髓瘤预后的影响

目的：分析del（17p13）（TP53）与多发性骨髓瘤患者临床资料的关系及其对预后的影响。方法：收集56例初诊多发性骨髓瘤患者临床资料,并对其骨髓标本行荧光原位杂交（ fluorescence in situ hybridization, FISH）检测。统计软件采用SPSS 19.0,研究del（17p13）与临床基本资料间的关系使用卡方检验,与实验室检查指标间的关系使用t检验。生存分析使用Kaplan-Meier法。结果：初诊多发性骨髓瘤（ multiple myeloma, MM）患者del（17p13）缺失的检出率为21.43%。Del（17p13）与乳酸脱氢酶（ lactate dehydrogenase,LDH）水平相关联（ P＝0.034）,与性别、年龄、分型、D-S分期、ISS分期、血小板、白蛋白、球蛋白、β2微球蛋白、尿素氮、血肌酐、血钙、骨髓瘤细胞比例无关。Del（17p13）患者的无进展生存期（ progression free survival,PFS）及总生存期（overall survival,OS）均较未缺失者显著缩短（P﹤0.05）。结论：本研究发现del（17p13）与部分临床特征相关,del（17p13）的MM患者预后不良。     

BCD方案不同疗程数对于初治多发性骨髓瘤的疗效影响

  目的  分析2、4、6个疗程以硼替佐米（bortezomib）为基础的3药联合诱导, 包括硼替佐米、环磷酰胺（cyclophosphamide）、地塞米松（dexamethasone）即BCD方案3药联合治疗初治多发性骨髓瘤（multiple myeloma, MM）的疗效。  方法  回顾性分析2014年1月1日至2016年7月30日北京大学人民医院初诊MM一线采用BCD的3药方案治疗≥ 2个疗程、随访资料完整、不合并髓外浆细胞瘤及淀粉样变性的70例患者的临床资料。统计单纯接受2、4、6个疗程患者疾病治疗疗效。  结果  70例患者中, 男女比为36: 34。中位年龄为58.4（33~81）岁, ISS分期Ⅰ、Ⅱ、Ⅱ期分别为16、18、36例。单纯接受2、4、6个疗程BCD患者分别为14、20、36例。仅接受2个疗程组中完全缓解（complete response, CR）、≥非常好的部分缓解（very good partial response, VGPR）、≥部分缓解（partial response, PR）比例分别为14.28%、42.86%和71.42%;仅接受4个疗程组中CR、≥ VGPR、≥ PR比例分别为30.00%、60.00%和80.00%;仅接受6个疗程组中CR、≥ VGPR、≥ PR比例分别为38.89%、75.00%和83.33%。中位随访时间为15.37（2~32）个月, 预估中位无进展生存期（median progression free survival, mPFS）为21.96（95%CI:19.26~24.70）个月。3组无进展生存期（progression free survival, PFS）差异无统计学意义（P=0.700）。  结论  BCD方案3药联合治疗中, 最大疗效发生在4个疗程及以后。随着诱导疗程数的进一步增加, 疾病缓解程度增加, 但总体缓解率提高不明显。一线诱导治疗初诊MM可采用BCD方案4个疗程及以上。      

晚期黑素瘤过继免疫治疗的Ⅱ期临床研究

目的：观察化疗联合细胞因子诱导的杀伤细胞（cytokine induced killer,CIK）治疗转移性恶性黑素瘤（metastatic melanoma,MM）的疗效及其安全性。方法：53例MM患者接受福莫司汀100mg/m2,第1～5天;氮烯咪胺400mg/d,第2～6天;CIK第7、14、和16天;每28d为1个周期的联合治疗,每2个周期评价疗效。结果：34例可评价患者中完全缓解（com-plete response,CR）1例（2.9%）,部分缓解（partial response,PR）7例（20.6%）,总有效率（overall response,ORR）为23.5%;疾病稳定（stable disease,SD）14例（44%）,临床获益率（clinical benefit rate,CBR）67.5%;中位无进展生存期（progressionfree survival,PFS）8个月;中位总生存期（overall survival,OS）11个月;乳酸脱氢酶（lactate dehydrogenase,LDH）正常者的OS长于升高者;有效或稳定患者的PFS和OS长于疾病进展（progression disease,PD）患者。不良反应中G3＋G4血小板减少41%,白细胞减少23.5%;发生2例超敏反应。无治疗相关死亡。结论：化疗联合CIK治疗MM患者耐受性尚好,有效率高于常规化疗,可延长LDH升高和疗效评价未PD患者的生存时间,但仍有待Ⅲ期临床研究进一步验证。     

Maintenance therapy with thalidomide improves overall survival after autologous hematopoietic progenitor cell transplantation for multiple myeloma

BACKGROUND: High-dose chemotherapy with autologous hematopoietic progenitor cell (HPC) transplantation improves survival for patients with multiple myeloma (MM); however, most patients develop recurrent disease after undergoing transplantation, and new treatment approaches are needed. The objective of this retrospective review of autologous HPC transplantation for patients with MM was to evaluate the impact of conditioning regimens and posttransplantation therapy on survival. METHODS: The authors reviewed 112 patients with MM who received autologous HPC grafts at their institution. Between June 1992 and August 2001, 54 patients received busulfan, cyclophosphamide, and etoposide (Bu/Cy/VP-16), and 58 patients received high-dose melphalan (MEL-200) followed by autologous HPC transplantation. After transplantation, 36 patients received thalidomide for maintenance or salvage therapy, and 76 patients received no posttransplantation thalidomide. RESULTS: At a median follow-up of 58 months, the median survival was 54 months. There was no statistically significant difference noted with regard to response to conditioning regimen, progression-free survival, or overall survival between the Bu/Cy/VP-16 and MEL-200 cohorts. Patients who received thalidomide after transplantation had improved median survival (65.5 months) compared with patients who did not receive thalidomide (44.5 months; P = .09). When they were separated according to reasons for thalidomide use, patients who received thalidomide as maintenance had improved overall survival compared with patients who received thalidomide as salvage (65 months vs. 54 months; P = .05). CONCLUSIONS: Combination chemotherapy provided no advantage over high-dose melphalan in patients with MM who underwent autologous HPC transplantation. The posttransplantation use of thalidomide seemed to improve the survival of patients compared with historical controls from the prethalidomide era. Further prospective trials are underway to confirm the benefit of thalidomide in the posttransplantation setting.     

多发性骨髓瘤的信号通路及其靶向治疗的研究进展

多发性骨髓瘤（multiple myeloma,MM）是一种常见的血液系统恶性肿瘤。目前,广泛认可的治疗方法包括蛋白酶体抑制剂、化疗、免疫调节剂、干细胞移植和单克隆抗体治疗。随着新的治疗选择以及创新诊断方法的应用,患者生存期显著延长,但由于复发、耐药性的存在,它仍然是一种不可治愈的疾病。MM细胞的生长和存活依赖于肿瘤微环境中的细胞和非细胞成分,如骨髓基质细胞、内皮细胞和细胞因子,这种相互作用的累积效应使MM细胞内多种信号转导途径异常激活,最终导致MM细胞的增殖、存活、迁移和耐药性发生改变。探究这些信号通路与 MM 发病以及疾病进展之间的关系,寻找针对信号通路的新治疗靶点,是阐明MM发病机制以及治疗MM患者最有效的方法之一。目前针对信号通路的靶向治疗药物部分已在临床应用中取得成效,但部分仍处于基础研究。未来,针对信号通路的靶向治疗将是MM患者治愈的关键。本文就近年来MM的信号通路及其靶向治疗的研究进展进行综述。     

多发性骨髓瘤的新药研发与治疗现状

近20年来，多发性骨髓瘤（multiple myeloma，MM）治疗领域出现了划时代的进步。随着免疫调节剂（immunomodulatory drugs，IMiDs）、蛋白酶体抑制剂（proteasome inhibitors，PIs）的出现和普及，患者的治疗疗效明显提高，生存期显著延长，上述两类药物以及自体造血干细胞移植（autologous stem cell transplantation，ASCT）已成为MM治疗的基石。同时，新的药物仍在不断涌现。如新一代的IMiDs、PIs，抗体类药物及其衍生药物及小分子靶向性治疗药物，还出现了嵌合抗原受体T细胞免疫治疗（chimeric antigen receptor T-cell immunotherapy，CAR-T）等手段。上述治疗在MM中均显示出良好的前景。本文旨在对MM领域新药的研发和应用进行综述。      

自体造血干细胞移植治疗多发性骨髓瘤的疗效及预后影响因素分析

目的:探讨自体造血干细胞移植治疗多发性骨髓瘤（MM）的疗效和影响MM患者预后的因素。方法:回顾性分析我院2012年01月至2019年12月37例接受自体造血干细胞移植的MM患者的临床资料,中位随访时间为55（1～91）个月。对37例患者的反应深度、无进展生存时间（PFS）、总生存时间（OS）和影响预后的相关因素进行分析。结果:移植后3月内疗效达到完全缓解率和深度缓解率均优于移植前（P＜0.01,P＜0.05）,移植前后总有效率（ORR）比较无统计学意义（P＞0.05）。患者3年、5年OS率为97.0%、81.4%;3年、5年PFS率为62.7%、51.0%;中位PFS和OS均未获得。单因素分析结果表明移植后3月内疗效获得深度缓解较未获得患者无论是OS 还是PFS均较优 (P均＜0.01);诱导化疗后获得深度缓解可明显延长OS（P＜0.05）;DS分期Ⅰ-Ⅱ期、mSMART3.0危险分层标危患者相比DS分期Ⅲ期、高危患者PFS均有明显优势(P＜0.05)。Cox 多因素回归分析显示,移植后3月内疗效达深度缓解是PFS和OS的独立预后因素,mSMART3.0危险分层也是PFS的独立预后因素。结论:自体造血干细胞移植可以提高 MM 患者的反应深度。移植前后疗效、DS分期和mSMART3.0危险分层均可影响MM患者生存率。移植后3月内疗效达深度缓解是PFS 和OS的独立预后因素,mSMART3.0危险分层也是PFS的独立预后因素。     

多发性骨髓瘤的维持治疗:有最佳药物或药物组合吗?

多发性骨髓瘤(MM)是一种常见的血液系统恶性肿瘤,新药的应用及自体造血干细胞移植等显著提高了MM的反应率,但由于无法根除微小残留病,患者最终难免复发.维持治疗有望保持甚至提高缓解深度,进而延长MM患者的无进展生存和总生存时间.     

Molecular remission after allogeneic or autologous transplantation of hematopoietic stem cells for multiple myeloma.

PURPOSE: To assess the clinical relevance of minimal residual disease (MRD) in patients with multiple myeloma (MM), 50 patients were monitored while they were in complete clinical remission (CCR) after autologous or allogeneic stem-cell transplantation. PATIENTS AND METHODS: Stringent molecular monitoring using clonal markers based on rearranged immunoglobulin heavy-chain genes was performed in 44 of 50 MM patients in CCR. Molecular clinical remission (MCR) was defined as more than one consecutive negative polymerase chain reaction (PCR) test result. RESULTS: Twelve (27%) of 44 molecularly monitored patients achieved MCR; four of the 12 became PCR-positive, and one of these four relapsed. In comparison with patients who did not achieve MCR, patients who achieved MCR had a significantly lower relapse rate (41% v 16%; P <.05) and longer relapse-free survival (35 v 110 months; P <.005). Fourteen of 26 patients in CCR who had received allografts were evaluated on a molecular basis: seven (50%) of the 14 achieved MCR and did not relapse; one of the seven remaining patients relapsed. Thirty of 47 patients in CCR who received autografts were evaluated on a molecular basis: five (16%) of the 30 achieved MCR; two of these five became PCR-negative, and one of these two relapsed. Ten of the 25 remaining patients later relapsed. For these nonrandomized groups, the higher MCR rate after allograft procedures was statistically significant (P <.01; Fisher's exact test). CONCLUSION: MCR can be obtained in a relatively high proportion of MM patients who have achieved CCR after undergoing allograft procedures and in a smaller fraction of patients after undergoing autograft procedures. In approximately one fourth of MM patients who achieve CCR after transplantation, it may be possible to keep the disease burden constantly below the PCR threshold. Because MCR was associated with prolonged relapse-free survival, these patients could have a relatively favorable clinical outcome.     

Second autologous transplantation for multiple myeloma patients relapsing after the first autograft -- a pilot study for the evaluation of experimental maintenance therapies. Report of the prospective non-randomized pilot study of the Czech Myeloma Group

BACKGROUND: High-dose chemotherapy followed by autologous stem cell transplantation (AT) is accepted as first-line therapy for patients with multiple myeloma (MM), with very good tolerance and low mortality (2-3%). STUDY DESIGN: We tested repeated transplantation with different experimental maintenance therapies in patients with MM relapsing/progressing after first AT. Results were compared using intra-individual analyses, therefore inter-individual differences are excluded (T2 model). PATIENTS AND METHODS: Between January 1997 and January 2003, 32 patients with relapsing/progressing MM after first AT were included in the pilot study, median follow-up was 75.2 months. They received the following experimental therapies: IL-2-activated PBSC (10 pts), pamidronate (4 pts), thalidomide (15 pts), consolidation chemotherapy CED (3 pts). RESULTS: Sensitivity to C-VAD reinduction chemotherapy (4 cycles) was 50%, response to the second AT compared to the first was better in 7, the same in 16 and worse in 9 patients. Toxicity of the first and second transplantation was similar and usually did not exceed grade II (SWOG). Transplant-related mortality was 3% (1/32). Event-free survival after second AT (EFS II) is known in 22 patients; 7 have achieved prolongation of EFS II versus EFS I. In the whole group median EFS I was 15.7 months, median EFS II was 12.9 months, median overall survival (OS) was 79.1 months; 20/32 patients were alive at the time of analysis. CONCLUSIONS: Repeated AT is a feasible and successful strategy in treatment of relapsing MM; response to second AT and toxicity were acceptable and similar to the first AT in our assessment.     

多发性骨髓瘤干细胞移植治疗进展

多发性骨髓瘤(MM)是浆细胞恶性克隆性疾病,尽管常规化疗和放疗可使部分患者病情缓解,但不能使患者治愈.大剂量化疗联合造血干细胞移植提高了患者的完全缓解率、无瘤生存率和总生存率,使MM的疗效取得了突破性的进展.     

Understanding biology to tackle the disease: Multiple myeloma from bench to bedside,and back

Answer questions and earn CME/CNE Multiple myeloma (MM) is a cancer of antibody‐producing plasma cells. The pathognomonic laboratory finding is a monoclonal immunoglobulin or free light chain in the serum and/or urine in association with bone marrow infiltration by malignant plasma cells. MM develops from a premalignant condition, monoclonal gammopathy of undetermined significance (MGUS), often via an intermediate stage termed smoldering multiple myeloma (SMM), which differs from active myeloma by the absence of disease‐related end‐organ damage. Unlike MGUS and SMM, active MM requires therapy. Over the past 6 decades, major advancements in the care of MM patients have occurred, in particular, the introduction of novel agents (ie, proteasome inhibitors, immunomodulatory agents) and the implementation of hematopoietic stem cell transplantation in suitable candidates. The effectiveness and good tolerability of novel agents allowed for their combined use in induction, consolidation, and maintenance therapy, resulting in deeper and more sustained clinical response and extended progression‐free and overall survival. Previously a rapidly lethal cancer with few therapeutic options, MM is the hematologic cancer with the most novel US Food and Drug Administration‐approved drugs in the past 15 years. These advances have resulted in more frequent long‐term remissions, transforming MM into a chronic illness for many patients. CA Cancer J Clin 2014;64:422–444. © 2014 American Cancer Society.     

自体外周血造血干细胞移植治疗多发性骨髓瘤16例临床疗效观察

目的:评价自体外周血造血干细胞移植(autologousperipheralbloodstemcelltransplantation,APBSCT)治疗多发性骨髓瘤的临床疗效。方法:16例确诊多发性骨髓瘤患者接受APBSCT,其中2例接受了二次移植,1例接受CD34+细胞筛选后的自体外周血造血干细胞移植。移植后继续常规化疗,13例患者给予α-干扰素维持治疗。结果:APBSCT可延长多发性骨髓瘤患者的无瘤生存率及总生存率,该组患者3年、5年无瘤生存率分别为18.75%±9.75%、0,平均无瘤生存时间为24.8个月。3年、5年总生存率分别为41.25%±12.72%、18.33%±10.77%,平均总生存时间为37.4个月。本组移植患者的CR率高,达76.92%,接近国外报道。而且,移植后造血重建快,移植相关并发症少。结论:APBSCT是治疗多发性骨髓瘤、改善其预后的重要手段。