高危急性髓系白血病异基因造血干细胞移植后复发的防治

急性髓系白血病（AML）是一组高度异质性的克隆性疾病,化学药物治疗和造血干细胞移植均为治疗AML的方法。对于高危AML患者而言,异基因造血干细胞移植为治疗该疾病的有效手段,但部分AML患者造血干细胞移植后仍可能面临疾病复发的问题,大多数复发患者再行化学药物治疗、二次移植等的效果不佳,是导致患者异基因造血干细胞移植后死亡的主要原因。因此,加强对异基因造血干细胞移植后AML患者的随访,并采取一些合适的手段预防移植后复发显得尤为重要。本文就高危AML患者异基因造血干细胞移植后复发的监测、药物治疗和细胞治疗进行综述,以期为改善高危AML患者异基因造血干细胞移植预后提供参考。     

造血干细胞移植治疗多发性骨髓瘤(附视频)

自体造血干细胞移植治疗多发性骨髓瘤(MM)始于20世纪80年代。多个历史对照和随机临床研究显示自体造血干细胞移植较传统化疗可提高治疗的反应率、完全缓解率、无事件存活率和/或总存活率,而治疗反应程度与生存相关。由此自体造血干细胞移植在欧美国家已成为年轻、适合移植(年龄≤65岁、肾功能正常和一般状况良好)MM患者的一线标准治疗方法。双次移植有可能进一步提高治疗反应率、无事件存活率和/或总存活率。免疫调节药物沙利度胺及其衍生物来那度胺和蛋白酶体抑制剂硼替佐米等新型抗骨髓瘤药物的发展提高了治疗的反应率和缓解率。目前新药并不能替代自体造血干细胞移植;这些药物运用于移植前后的整体治疗策略进一步提高了移植疗效。尽管如此,MM仍然是难以治愈的疾病。异基因造血干细胞移植有治愈MM的可能,但因清髓性预处理的高死亡率限制了其应用。近年来,联合移植即自体造血干细胞移植后进行减低剂量预处理的异基因造血干细胞移植的研究结果初步显示了其疗效和可行性。     

用于异基因移植的造血干细胞来源

造血干细胞移植(hcmatopoiedc stem cell transplantation，HSCT)的临床应用已有近50年的历史，目前已成为治疗多种良恶性血液病、实体肿瘤、遗传性疾病和重症自身免疫性疾病等的有效手段。本文试就异基因造血干细胞移植中应用的不同来源造血干细胞(hematopoietic stemcell，HSC)的特点及其对移植效果的影响作一评述。     

慢性移植物抗宿主病的研究进展

异基因造血干细胞移植是目前治疗造血系统恶性肿瘤的重要手段，但移植后的相关并发症严重影响了其治疗效果。目前，在异基因造血干细胞移植后与慢性移植物抗宿主病（cGVHD）相关的死亡率约占非复发性死亡的54％。但对cGVHD发生的机制尚不明确。随着国内外学者研究的不断深入，关于cGVHD的发生机理正逐渐得到揭示，一些新的治疗措施也取得了较理想的效果，这给造血干细胞移植及cGVHD患者带来新的希望。     

非亲缘脐血造血干细胞移植治疗儿童非霍奇金淋巴瘤1例报道

目的观察非亲缘异基因脐血造血干细胞移植治疗儿童非霍奇金淋巴瘤的临床效果。方法 1例5岁非霍奇金淋巴瘤（Ⅳ期）患儿接受了高剂量放化疗联合非亲缘异基因脐血造血干细胞移植的治疗。结果静脉输注脐血后无异常反应。白细胞植入时间为移植后17d,血小板植入时间为移植后25d。移植后出现Ⅰ度急性移植物抗宿主病（GVHD）,分别于24d、40d采集患者外周血,经短串联重复序列GeneScan方法分析判定供者造血干细胞在患者体内存活。患儿移植后43d出院,随访至2010年6月,已无病存活67个月,至今状况良好,无复发、无并发症、无慢性GVHD发生。结论大剂量化疗联合非亲缘异基因脐血造血干细胞移植治疗非霍奇金淋巴瘤儿童患者的移植效果较好,并发症较少。     

福达拉滨、环磷酰胺、美罗华方案进行预处理的非清髓性异基因干细胞移植治疗复发的滤泡性淋巴瘤

异基因造血干细胞移植是治疗滤泡性淋巴瘤的有效方法,大量研究显示接受异基因造血干细胞移植患者的复发率显著低于接受自体造血干细胞移植的患者.非清髓性异基因造血干细胞移植利用其移植物抗淋巴瘤的免疫作用以达到治疗滤泡性淋巴瘤的目的,但是此策略长期的疗效和毒性仍不明确.本项前瞻性研究分析并评价了非清髓性异基因干细胞移植治疗复发的滤泡性淋巴瘤的8年经验.     

自体骨髓间充质干细胞与造血干细胞共移植治疗恶性血液病患者的护理

目的 探讨自体骨髓间充质干细胞(MSCs)与造血干细胞共移植治疗恶性血液病患者的护理.方法 从无骨髓浸润的恶性血液病患者本人骨髓中分离、培养间充质干细胞.经放化疗等预处理后,与造血干细胞共移植治疗恶性血液病患者5例,并对其进行全程共移植护理.结果 在移植过程中5例患者均未出现感染,无移植并发症.自体骨髓间充质干细胞和造血干细胞输注过程中未见明显不良反应.移植后造血功能恢复,中性粒细胞≥0.5×109/L的中位时间为9.4(8～11)d,血小板≥20×109/L的中位时间为12.2(10～14)d.结论 自体骨髓闻充质干细胞与适血干细胞共移植治疗恶性血液病安全性好,不良反应小;做好移植护理是减少感染和并发症的重要措施.     

自体骨髓间充质干细胞与造血干细胞共移植治疗恶性血液病患者的护理

目的探讨自体骨髓间充质干细胞（MSCs）与造血干细胞共移植治疗恶性血液病患者的护理。方法从无骨髓浸润的恶性血液病患者本人骨髓中分离、培养间充质干细胞,经放化疗等预处理后。与造血干细胞共移植治疗恶性血液病患者5例。并对其进行全程共移植护理。结果在移植过程中5例患者均未出现感染,无移植并发症。自体骨髓间充质干细胞和造血干细胞输注过程中未见明显不良反应。移植后造血功能恢复,中性粒细胞≥0．5×10^9／L的中位时间为9．4（8～11）d,血小板≥20×10^9／L的中住时间为12．2（10～14）d。结论自体骨髓间充质干细胞与造血干细胞共移植治疗恶性血液病安全性好,不良反应小;做好移植护理是减少感染和并发症的重要措施。     

布地奈德治疗造血干细胞移植后肠道急性移植物抗宿主病四例

急性移植物抗宿主病(aGVHD)是异基因造血干细胞移植后的主要并发症，肠道aGVHD主要表现为腹泻，严重者可出现血便、腹痛和肠梗阻，是影响移植效果的重要因素。布地奈德是一种肠道吸收率低的糖皮质激素类药物，临床多用于治疗支气管哮喘及结肠炎所致的腹泻。我们将布地奈德用于4例异基因造血干细胞移植后肠道aGVHD的治疗，观察其治疗效果，现报道如下。     

造血干细胞移植后远期并发症的危险因素及筛查

造血干细胞移植后的远期并发症是指造血干细胞移植3个月后发生的并发症。这些并发症的危险因素包括预处理方案、慢性移植物抗宿主病及其治疗、感染、移植前的治疗、移植前的合并症等。     

Renal transplantation after myeloablative and non-myeloablative hematopoietic cell transplantation from the same donor

Hematopoietic cell transplantation is a key treatment to prolong patient survival for many hematological disorders. Renal impairment is well recognized as a significant complication of hematopoietic cell transplantation, which can progress to end-stage renal disease. Herein, we report our experience of two patients who underwent renal transplantation from the same donor who provided cells for the preceding hematopoietic cell transplantation. One patient had undergone peripheral blood stem cell transplantation with a non-myeloablative conditioning regimen, whereas the other had received bone marrow transplantation with a myeloablative regimen. Chronic immunosuppressive therapy was not needed in either one to maintain the kidney graft function. Not only bone marrow transplantation with a myeloablative conditioning regimen, but also peripheral blood stem cell transplantation with a non-myeloablative regimen can confer immunological tolerance.     

单倍体相合造血干细胞移植联合间充质干细胞输注治疗异染性脑白质营养不良

目的探讨单倍体相合造血干细胞移植联合间充质干细胞输注治疗异染性脑白质营养不良的疗效。方法 7岁患儿,采用单倍体相合造血干细胞移植联合间充质干细胞输注的方法,经氟达拉滨、马利兰、环磷酰胺和抗人胸腺细胞球蛋白方案进行预处理,供者应用G-CSF动员和联合免疫抑制剂(包括环胞菌素A、氨甲喋呤、霉酚酸酯、CD25单抗)预防移植物抗宿主病。造血重建后,每周输注脐带来源的间充质干细胞1次,连续4周。结果患儿造血重建迅速,11 d时中性粒细胞0.5×109/L、血小板20×109/L;14 d时血白细胞芳基硫酸酯酶A水平明显上升;28 d时达正常水平。患者无急性GVHD发生。移植后1个月经植入证据检测,证实为完全供者造血,神经系统症状逐渐恢复。结论单倍体相合造血干细胞移植,联合间充质干细胞输注,治疗异染性脑白质营养不良,安全、有效,血白细胞芳基硫酸酯酶A水平回升迅速。这种新型疗法可能是治疗缺乏HLA全相合供者的异染性脑白质营养不良疾病患者的可靠选择。     

Tolerance to vascularized kidney grafts in canine mixed hematopoietic chimeras

BACKGROUND: Recent progress in allogeneic hematopoietic stem cell transplantation provides new methods for reliable engraftment with nonlethal conditioning regimens. These techniques have been successfully applied in the treatment of both malignant and nonmalignant diseases, but have not been fully exploited for their potential to tolerize recipients for organ transplantation. These studies were undertaken to test whether the tolerance of host immune cells toward donor hematopoietic cells in mixed hematopoietic chimeras extends to include a vascularized organ, the kidney. METHODS: Using nonmyeloablative doses of total body irradiation, a short course of immunosuppression, and hematopoietic stem cells from marrow or peripheral blood sources, five dog lymphocyte antigen-identical canines were made to become stable mixed hematopoietic chimeras with no development of graft-versus-host disease or posttransplant lymphoproliferative disorder. Subsequently, renal transplantations were performed between stem cell donor and recipient littermates, and no additional immunosuppressive therapy was given after stem cell transplantation. RESULTS: All mixed chimeric dogs demonstrate different, but stable, levels of donor peripheral blood lymphocyte and granulocyte chimerism. With follow-up of longer than 1 year, all of the mixed chimeric dogs (five/five) have excellent renal function with normal serum creatinines (<1.5 mg/dl) and no pathological evidence of rejection on biopsies. CONCLUSIONS: In a major histocompatibility-matched model, minor antigen differences between donor and recipient are not sufficient to induce a host immune response to a vascularized kidney transplant in mixed hematopoietic chimeras.     

Sources of human hematopoietic stem cells for transplantation—a review

Transplantation of hematopoietic stem cells provides a means of replacing a defective hematopoietic system in patients with a wide range of malignant and nonmalignant disorders that affect the blood forming tissue. The same procedure has also allowed dose-escalation of standard chemotherapy and radiotherapy in the treatment of malignant disease of nonhematological origin. Until recently, bone marrow has been the sole source of hematopoietic stem cells, but limitations of conventional bone marrow transplantation have stimulated a search for alternative sources and uses of stem cells. Fetal tissues (especially liver) are a recognized source of transplantable stem cells and offer the great advantage of reduced immunogenicity, potentially removing the problems of tissue type matching. Umbilical cord blood is also a rich source of stem cells and, although it contains alloreactive cells, it is readily available without special ethical constraints. Both fetal tissue and cord blood suffer the disadvantages of limited numbers of stem cells per donation, and there is much interest in the development of technologies for the safe and reliable expansion and/or pooling of stem and progenitor cells. The observation that small numbers of stem cells are found in the peripheral blood of adults has led to the exploitation of the blood as a further source of stem cells. The ability to mobilize these cells from the medullary compartment into the periphery by the use of chemotherapy and/or recombinant hematopoietic growth factors has enabled the collection of sufficient numbers of cells for transplantation purposes. All of these advances are increasing the options and the range of choices available to clinicians and patients in the arena of hematopoietic stem cell transplantation.     

第三方脐血细胞辅助输注对小鼠单倍型造血干细胞移植后造血重建的影响

目的分析以脐血细胞作为第三方细胞辅助输注对小鼠单倍型造血干细胞移植后造血重建的影响。 方法以CB6/F1雄性小鼠为供鼠,以BALB/C小鼠为受鼠。受鼠经Co60全身照射清髓后回输供鼠干细胞,建立单倍型造血干细胞移植模型。将40只受鼠分为对照组和实验组,每组各20只,对照组受鼠回输供鼠干细胞,实验组受鼠回输供鼠干细胞＋脐血单个核细胞。于移植后＋7 d、＋14 d、＋21 d、＋28 d和＋50 d对存活受鼠进行断尾采血,检测白细胞、血红蛋白和血小板,分析造血重建情况。处死小鼠时取外周血1 mL,采用荧光原位杂交技术检测Y染色体比例,计算嵌合率。两组受鼠各时间点白细胞、血红蛋白及血小板检测结果采用成组t检验进行比较,嵌合率采用卡方检验进行比较。P<0.05为差异有统计学意义。 结果移植后＋14 d实验组和对照组白细胞数量分别为(8.4±2.6)×10⁹/L和(3.8±1.0)×10⁹/L,差异有统计学意义(t＝6.968,P<0.05);其他时间点两组白细胞数量差异无统计学意义。移植后两组受鼠各时间点血红蛋白检测结果差异均无统计学意义。移植后＋7 d实验组和对照组血小板数量分别为(125±40)×10⁹/L和(64±15)×10⁹/L,移植后＋14 d分别为(282±47)×10⁹/L和(163±41)×10⁹/L,差异均有统计学意义(t＝6.366和8.093,P均<0.05);其他时间点两组血小板数量差异无统计学意义。 结论使用脐血细胞作为第三方细胞辅助输注后,可促进单倍型造血干细胞移植受鼠早期白细胞和血小板较快恢复。     

Treatment of a Pediatric Case of Severe Hemorrhagic Cystitis: Case Report and Review of Literature

Hemorrhagic cystitis is one of the complications of allogeneic hematopoietic stem cell transplantation. Treatment of hemorrhagic cystitis is difficult, especially in pediatric patients. A pediatric case of severe hemorrhagic cystitis after hematopoietic stem cell transplantation was treated in our hospital with arterial embolization combined with corticosteroid therapy because the conventional therapy was invalid for him. After the treatment, hemorrhagic cystitis was cured. During follow-up, the patient was in stable condition, with normal urine, blood cells returned to normal, bone marrow was in complete remission state, and disease-free survival for more than 8 months. Selective bladder arterial embolism followed by corticosteroid therapy successfully treated the patient.     

Carcinoma of donor origin after allogeneic peripheral blood stem cell transplantation

Secondary cancers developing after allogeneic hematopoietic stem cell transplantation generally originate from recipient-derived cells. In this study, we analyzed the tumor cell origin of 5 epithelial malignant tumors (esophageal squamous cell carcinoma, lung adenocarcinoma, gastric adenocarcinoma, pharyngeal squamous cell carcinoma, and thyroid papillary carcinoma) that developed after allogeneic peripheral blood stem cell transplantation using anti-AE1/3 immunofluorescence with fluorescence in situ hybridization analysis for sex chromosomes and/or short-tandem repeat microsatellite analysis of laser-microdissected tumor cells. The results revealed that 1 of these 5 cancers was derived from donor cells. In this case, transfused pluripotent cells, which include both mesenchymal stem cells and hematopoietic stem cells, might have given rise to epithelial malignant cells. Our observations suggest that transfused peripheral blood cells may be involved in the development of cancers after allogeneic peripheral blood stem cell transplantation.     

Reconstruction of the Hematopoietic System After Stem Cell Transplantation

The practice of hematopoietic stem cell transplantation to rescue patients from the myeloablative effects of chemo- or radiotherapy, or to replace defective hematopoiesis, is based on the assumption that hematopoietic stem cells in the graft have sufficient proliferative potential to supply mature blood cells for the remainder of the recipient’s lifespan. However, the mechanism(s) whereby this is achieved are not well understood. Here we address the reconstruction of the hematopoietic system by considering the effects of stem cell and progenitor cell renewal and differentiation. We conclude that stem cell self-renewal is necessary for hematological recovery and that infused committed progenitor cells (CFU-GM) may contribute to the neutrophil count in the early posttransplant period.     

单倍体造血干细胞联合脐带间充质干细胞移植对再生障碍性贫血的临床观察及其促进造血机制的初步疗效研究

目的 探讨单倍体造血干细胞联合脐带间充质干细胞移植治疗再生障碍性贫血的初步疗效。方法 选取2012年12月至2014年12月间我院收治的5例再生障碍性贫血患者为研究对象,给予患者单倍体造血干细胞联合脐带间充质干细胞移植治疗。术后观察患者回输的MNC、CD34+细胞数,GVHD发生率,血象恢复时间,SDF-1α、G-CSF、IL-6、GM-CSF、TPO、IL-11、SCF等细胞因子变化情况,以及骨髓有核细胞磷酸化ERK1/2蛋白改善情况,并统计并发症发生情况。结果 5例患者均获得造血重建,移植后血小板恢复时间平均为15 d,血细胞恢复时间平均为10.4 d。3例患者发生Ⅲ度a GVHD,3例患者发生局限性c GVHD,经治疗后均好转,4例患者恢复良好,1例患者术后73 d死于真菌性肺炎。移植后患者血清SDF-1α、G-CSF、IL-6、GM-CSF、TPO以及SCF水平明显改善(P<0.05);治疗后骨髓有核细胞磷酸化ERK1/2蛋白明显高于治疗前(P<0.05);1例患者EB病毒血症,2例出血性膀胱炎,2例真菌性肺炎。结论 单倍体造血干细胞联合脐带间充质干细胞移植治疗再生障碍性贫血疗效显著,能够明显改善患者骨髓造血微环境,安全且并发症低,值得进一步开展临床应用研究。     

狼疮肾炎并发肺部曲霉菌感染及脑膜炎一例暨文献复习

目的 通过报道1例典型的狼疮肾炎（LN）患者并发侵袭性真菌感染（IFI）的病例,并复习相关文献以期为临床提供早期诊治系统性红斑狼疮（SLE）患者并发IFI的依据和经验。 方法 描述患者发病及诊治经过,同时系统地回顾相关文献,分析总结SLE患者并发IFI的诊断方法、常见致病菌及易感因素。 结果 通过应用IFI诊断指南可以早期诊断SLE患者并发IFI,同时有效排除呼吸道定植等非侵袭性真菌感染,早期治疗,有利于提高该疾病的诊断率和治愈率。SLE患者并发IFI最常见的致病菌是隐球菌和曲霉菌,不是常见的白色念珠菌。SLE患者并发IFI的易感因素是狼疮活动和免疫抑制剂的应用。 结论 IFI 诊断指南对SLE并发IFI的诊断和治疗具有指导意义。SLE并发IFI的常见致病菌是隐球菌和曲霉菌,易感因素是狼疮活动和免疫抑制剂的应用。