间充质干细胞治疗糖皮质激素耐药性慢性移植物抗宿主病临床疗效观察

Objective To assess whether treatment with mesenchymal stem cells (MSCs) is an effective adjunct therapy for refractory extensive chronic graft-versus-host disease (GVHD) resistant to conventional therapy. Methods 12 patients with steroid-resistant extensive chronic GVHD were treated with MSCs. One patient received one dose, 10 received two doses, and the remaining three doses. The MSCs were obtained from HI,A-identical sibling donors (n = 14), haploidentical donors (n = 2), unrelated mismatched donor (n = 1) and third-party HLA-mismatched donors (n = 7). Of the 11 patients treated with multiple infusions, 5 received cells derived from two donors. The median first dose of MSCs was 1.0 (0. 4-2. 1) × 106/kg , the median second dose was 1.2(0. 8-1.9) × 106/kg , and the third dose in one patient was 1.1 × 106/kg. Meanwhile the proportion of CD3+ ,CD4+,CD8+ ,CD19+,CD4+ CD25+ ,FOXP3+,FOXP3+CD4+ and FOXP3+ CD25+ was determined with double fluorescent-labeled antibodies and flow cytometry before and 4 weeks after the MSCs infusion. Results No patients had side-effects during or immediately after the infusions of MSCs. After a treatment course of one to three doses, 3 patients had complete response(CR), 6 showed partial response(PR) and 3 did not respond; the total effective rate was 75% (9/12). Complete resolution was seen in the involvement of skin (3/12), lung (1/3), joints (1/5), liver (3/10), oralcavity (4/12) and eye (2/7). Response rate was not related to donor HLA-match. 3 CR patients discontinued all of the immunosuppressive agents without relapse 100 to 292 days after the MSC infusion and 6 PR patients taped all immunosuppressive agents after 60 to 79 days. Mean follow-up period was 1152(795-1914) days, leukemia free survival rate was 91.7% (11/12) and the overall survival rate was 75% (9/12). The ratio of CD4/CD8 and the proportion of regulatory T cells were significantly higher than that before MSCs treatment. Conclusion Third-party MSCs were as effective as HLA-identical or haploidentical cells. This finding has practical implications and suggests that third-party cells can be prepared and stored frozen to be used for steroid-resistant extensive chronic GVHD therapy. It is concluded that MSCs may prevent the lethal cGVHD after allogeneic hematopoietic stem cell transplantation and raise the survival rate by increasing the ratio of CD4/CD8 and proportion of regulatory T cells in vivo.     

黏膜相关淋巴样组织淋巴瘤易位蛋白功能及其在血液肿瘤中对核因子-κB信号通路的调节作用

在机体适应性免疫反应中,黏膜相关淋巴样组织淋巴瘤易位蛋白(MALT)1是抗原诱导的核因子-κB信号通路激活的关键因子,其蛋白酶活性的激活可增强机体免疫反应.近年来,相关研究结果表明,MALT1的蛋白酶活性对MALT1依赖性淋巴瘤[活化B细胞样亚型弥漫大B细胞淋巴瘤(ABC-DLBCL)与MALT淋巴瘤]细胞生存及增殖是必需的;亦有文献报道,MALT1与急性T淋巴细胞白血病(T-ALL)、急性B淋巴细胞白血病(B-ALL)的发生相关,且在骨髓瘤细胞株中过表达.笔者拟就MALT1的功能、对核因子-κB信号通路的调节作用及其与血液系统肿瘤的关系进行综述.     

恶性血液病的表观遗传学研究进展

表观遗传学是研究可遗传的、基因DNA序列不发生改变的基因表达调控的一门新学科.近年来,诸多研究结果均表明,表观遗传学异常改变在恶性血液病的发生、发展过程中起着十分重要的作用.相关基因异常甲基化是骨髓增生异常综合征(MDS)发生、发展的重要因素之一,并且与MDS患者的预后相关;微小RNA (miRNA)的异常甲基化与急性髓细胞白血病(AML)相关;zeste基因增强子同源物(EZH)2基因通过突变、缺失或过表达,甲基化下游靶基因调控其转录水平,从而与淋巴瘤等多种恶性血液病相关.针对表观遗传学异常改变的治疗方案给恶性血液病的免疫治疗赋予更广的内涵.笔者拟就表观遗传学异常改变在恶性血液病中的最薪研究进展,以及针对表观遗传学异常改变的免疫治疗方案的相关研究与应用前景进行综述.     

全程化疗药物标识在恶性血液病患者中的应用及效果评价

目的 探讨全程化疗药物标识在降低恶性血液病化疗患者护理风险中的应用效果。 方法 成立静脉治疗专科护理小组,建立并应用全程化疗药物标识,对护士进行给药资质培训。 应用前后比较护士化疗药物配置时间、取药正确率及患者与家属的满意度。 结果 化疗标识应用后,护士一次性完成化疗药物配置时间由（ 17.24±5.94 ） s 下降到（ 8.85±2.74 ） s （ P＜0.05 ）,取药不正确率由 7.5% 下降到 1.0% （ P＜0.05 ）,患者满意度明显提高（ P＜0.01 ）。 结论 建立全程化疗药物标识,可有效促进规范化、科学化和系统化管理,提高工作效率,提高护理质量和患者的满意度,降低化疗护理风险,保障患者安全。     

双特异性抗体在血液肿瘤治疗中的研究进展

免疫治疗作为一种新的肿瘤治疗方法,其基础和临床研究已有大量文献报道.双特异性抗体(BsAb)作为含有2种特异性抗原结合位点的人工抗体,可诱导效应细胞靶向杀伤肿瘤细胞,具有良好的临床应用前景,如抗CD3/抗CD19 BsAb和抗CD33/抗CD3 BsAb等,目前已成为免疫治疗血液肿瘤的研究热点之一.笔者拟就基础及临床试验2个方面介绍BsAb在血液肿瘤治疗中的研究进展,旨在进一步探讨BsAb在血液肿瘤的应用潜能.     

交替半身照射治疗恶性血液病的初步临床研究

目的　评价交替半身照射 (AHBI)治疗恶性血液病的疗效。方法　采用AHBI治疗 17例恶性血液病患者。先给予大剂量化疗 ,然后分别对上、下半身照射 6～ 9Gy。上半身照射在停用大剂量化疗中位时间 14 (12～ 2 2 )d进行 ,上、下半身照射中位间隔时间为 2 3(7～ 34)d。同时选择同期行自体造血干细胞移植 (AHSCT)的 14例急性淋巴细胞白血病 (ALL)患者作为对照组。结果　 17例AHBI治疗的患者均获得造血恢复。完全缓解期进行AHBI治疗患者的 3年无病生存 (DFS)率为(5 2 .38± 13.4 7) % ,最长生存期为 14 4 6d ,中位随访时间为 92 7(4 2 8～ 14 4 6 )d ,无一例发生治疗相关死亡。其中 11例ALL患者 3年DFS率为 (4 7.73± 17.5 5 ) % ;AHSCT组 3年DFS率为 (5 3.88±14 .0 8) % ,移植相关死亡率为 14 %。两组ALL患者的 3年DFS率相比无显著性差异 (P >0 .0 5 )。结论　AHBI可作为恶性血液病的一种治疗手段。     

Pleiotropy within gene variants associated with nonalcoholic fatty liver disease and traits of the hematopoietic system

Genome-wide association studies of complex diseases, including nonalcoholic fatty liver disease (NAFLD), have demonstrated that a large number of variants are implicated in the susceptibility of multiple traits — a phenomenon known as pleiotropy that is increasingly being explored through phenome-wide association studies. We focused on the analysis of pleiotropy within variants associated with hematologic traits and NAFLD. We used information retrieved from large public National Health and Nutrition Examination Surveys, Genome-wide association studies, and phenome-wide association studies based on the general population and explored whether variants associated with NAFLD also present associations with blood cell-related traits. Next, we applied systems biology approaches to assess the potential biological connection/s between genes that predispose affected individuals to NAFLD and nonalcoholic steatohepatitis, and genes that modulate hematological-related traits—specifically platelet count. We reasoned that this analysis would allow the identification of potential molecular mediators that link NAFLD with platelets. Genes associated with platelet count are most highly expressed in the liver, followed by the pancreas, heart, and muscle. Conversely, genes associated with NAFLD presented high expression levels in the brain, lung, spleen, and colon. Functional mapping, gene prioritization, and functional analysis of the most significant loci (P < 1 × 10^-8) revealed that loci involved in the genetic modulation of platelet count presented significant enrichment in metabolic and energy balance pathways. In conclusion, variants in genes influencing NAFLD exhibit pleiotropic associations with hematologic traits, particularly platelet count. Likewise, significant enrichment of related genes with variants influencing platelet traits was noted in metabolic-related pathways. Hence, this approach yields novel mechanistic insights into NAFLD pathogenesis.     

Feasibility and obstacles in home chemotherapy for malignant lymphoma

Home care has become a treatment option for cancer patients; however, medical practice at patients' homes has been expected mainly for terminal care in Japan. Most physicians believe that it is difficult to treat patients with hematologic malignancy at home because they frequently develop complications requiring urgent interventions. We herein report the case of an 80-year-old patient with advanced follicular lymphoma who safely received aggressive chemotherapy at home and finally died due to disease progression at the hospital. Home chemotherapy can be a feasible and potentially novel treatment option for some patients with hematologic malignancy, although the clinical course of the present patient suggested that patient selection is critical for the safe operation of home chemotherapy and that it is important to educate families on how to evaluate patients' conditions and how to cope with aggravation and admission arrangements in back-up hospitals.     

间充质干细胞治疗糖皮质激素耐药性慢性移植物抗宿主病临床疗效观察

Objective To assess whether treatment with mesenchymal stem cells (MSCs) is an effective adjunct therapy for refractory extensive chronic graft-versus-host disease (GVHD) resistant to conventional therapy. Methods 12 patients with steroid-resistant extensive chronic GVHD were treated with MSCs. One patient received one dose, 10 received two doses, and the remaining three doses. The MSCs were obtained from HI,A-identical sibling donors (n = 14), haploidentical donors (n = 2), unrelated mismatched donor (n = 1) and third-party HLA-mismatched donors (n = 7). Of the 11 patients treated with multiple infusions, 5 received cells derived from two donors. The median first dose of MSCs was 1.0 (0. 4-2. 1) × 106/kg , the median second dose was 1.2(0. 8-1.9) × 106/kg , and the third dose in one patient was 1.1 × 106/kg. Meanwhile the proportion of CD3+ ,CD4+,CD8+ ,CD19+,CD4+ CD25+ ,FOXP3+,FOXP3+CD4+ and FOXP3+ CD25+ was determined with double fluorescent-labeled antibodies and flow cytometry before and 4 weeks after the MSCs infusion. Results No patients had side-effects during or immediately after the infusions of MSCs. After a treatment course of one to three doses, 3 patients had complete response(CR), 6 showed partial response(PR) and 3 did not respond; the total effective rate was 75% (9/12). Complete resolution was seen in the involvement of skin (3/12), lung (1/3), joints (1/5), liver (3/10), oralcavity (4/12) and eye (2/7). Response rate was not related to donor HLA-match. 3 CR patients discontinued all of the immunosuppressive agents without relapse 100 to 292 days after the MSC infusion and 6 PR patients taped all immunosuppressive agents after 60 to 79 days. Mean follow-up period was 1152(795-1914) days, leukemia free survival rate was 91.7% (11/12) and the overall survival rate was 75% (9/12). The ratio of CD4/CD8 and the proportion of regulatory T cells were significantly higher than that before MSCs treatment. Conclusion Third-party MSCs were as effective as HLA-identical or haploidentical cells. This finding has practical implications and suggests that third-party cells can be prepared and stored frozen to be used for steroid-resistant extensive chronic GVHD therapy. It is concluded that MSCs may prevent the lethal cGVHD after allogeneic hematopoietic stem cell transplantation and raise the survival rate by increasing the ratio of CD4/CD8 and proportion of regulatory T cells in vivo.     

恶性血液病中急腹症手术治疗的探讨

为探讨恶性血液病并发急腹症时的手术治疗问题，对１４例患者的资料进行分析。原发病有急性白血病，非霍奇金淋巴瘤，多发性骨髓瘤，恶性组织细胞病及骨髓增生异常综合征并难治性贫血，其中１３例处于进展期，并发症为急性阑尾炎，急性胰腺炎，急性胆囊炎，小肠穿孔继发腹膜炎，小肠低位梗阻，原发性腹膜炎及回讯肠综合征。