骨髓非清除性异基因干细胞移植的基础与临床研究

造血干细胞移植 (ＨＳＣＴ)技术的发展使部分疾病有了根治的希望 ,但是应用可耐受的最大的骨髓清除性治疗通常不可能根治最后的肿瘤细胞 ,大多数患者可能复发。因此 ,复发仍是恶性疾病成功治疗的最大障碍。并且不可避免地会产生许多严重并发症 ,造成较高的移植相关死亡[1] 。骨髓非清除性 (ｎｏｎｍｙｅｌｏａｂｌａｔｉｖｅ )ＨＳＣＴ这一新策略 ,使用低毒性、小剂量、非去髓性的预处理方案 ,目的是提供足够的免疫抑制剂来达到异基因外周血干细胞移植或骨髓移植物的植入 ,由此产生一种免疫性移植物抗肿瘤 (ＧＶＴ)效应[2 ] 。1　清除性与非…     

非清髓异基因造血干细胞移植——造血干细胞移植的新方向

简述了国内外刚刚开展的非清髓异基因造血干细胞移植（NAST）的主要研究进展和研究方向。对NAST的概念、预处理方案、移植物抗宿主病预防、移植物抗白血病效应及临床应用等问题作了讨论和介绍。并提出NAST是对传统异基因造血干细胞移植理论和观念的发展及更新,为血液病、恶性肿瘤及免疫、遗传性疾病的治疗开辟了新路径。并建议加强对NAST有关问题的协作研究。     

供者同后造血干细胞输注在非清髓异基因造血干细胞移植中的应用

为探讨供者造血干细胞输注 (DSI)在非清髓异基因外周血干细胞移植 (NAPBSCT)中的作用 ,6例NAPBSCT患者分别在移植后 +7～ +90天进行DSI治疗 ,共输注单个核细胞 (MNC) (0 .6～ 7.6 )× 10 8/kg ,CD34 + 细胞 (0 .3～ 3.4)× 10 6/kg ,CD3+ 细胞 (0 .3～ 5 .1)× 10 8/kg。 6例中 5例有明显促进植入的作用 ,其中 3例由嵌合体转为完全性植入。 4例有较明确的移植物抗白血病效应 (GVL) ,均未见造血抑制等并发症。初步结果表明 ,DSI能促进NAPBSCT后供者嵌合体的增加 ,有利于NAPBSCT后供者细胞植入并具较好的GVL效应 ,而且并发症少 ,在NAPBSCT中具有较好的应用前景。     

造血干细胞移植中干细胞来源的多元化

异基因造血干细胞移植（Allo—HSCT）是治疗血液系统恶性疾病和部分非恶性疾病的有效方法,有时甚至是惟一可以治愈该病的手段,在血液系统疾病的治疗中占有重要地位。过去由于供者来源所限,只有少部分患者从中受益,更多患者因为没有配型相合的同胞供者而失去了移植的机会。独生子女时代的来临使供者来源越趋困难。令人鼓舞的是,随着HSCT技术体系的不断完善,临床用于移植的造血干细胞来源呈现了多元化的局面。目前用于HSCT的造血干细胞主要有以下几种：     

非清髓异基因造血干细胞移植治疗骨髓增生异常综合征的疗效观察

目的探讨非清髓异基因造血干细胞移植(NST)治疗骨髓增生异常综合征(MDS)的疗效。方法 14例有血缘相关HLA相合的MDS患者接受NST治疗。骨髓增生异常综合征-难治性贫血(MDS-RA)患者非清髓预处理方案为:氟达拉滨(Flud)+环磷酰胺(CTX)+抗人胸腺细胞免疫球蛋白(ATG);骨髓异常综合征-难治性贫血伴原始细胞过多(MDSRAEB)患者非清髓预处理方案为:在MDS-RA患者非清髓预处理方案基础上加用马利兰(Bu)。移植物抗宿主病(GVHD)预防采用环孢素(CSA)联合霉酚酸酯(MMF)。结果 13例患者造血均获得快速重建,1例造血未恢复。中性粒细胞在术后第9～12天恢复到0.5×109/L以上,12例患者血小板在术后第11～21天恢复到30×109/L以上。14例中12例完全植入,2例混合嵌合植入,其中1例经过二次移植后达到完全植入,另1例在移植后2个月发生移植排斥,移植后70d因脑出血死亡。1例发生急性Ⅱ度肠道GVHD,经静脉给予他克莫司(FK506)和甲泼尼龙治疗后病情控制,但患者在后期应用FK506治疗过程中出现癫痫持续发作,经多种抗癫痫药物治疗未见好转,家属放弃治疗自动出院后死亡。14例中未见慢性GVHD和间质性肺炎发生。随访36～133个月,11例患者现无病存活,其中10例存活60个月以上,3例死亡。结论 NST治疗MDS安全可行,可为治愈MDS提供新手段。     

ABO血型不合异基因外周血干细胞移植对红系造血重建的影响

为研究ABO血型不合对Allo PBSCT患者造血重建的影响 ,将 2 0例恶性血液病(CML 9例、ALL 8例、难治性NHL 3例 )按统计学配对原则分组 ,ABO血型异同者各 10例 ,两组年龄、性别、诊断、移植前病程、疾病状态、预处理方案、输注的MNC和CD34+ 细胞量及GVHD预防方法均无明显差异(P >0 0 5 )。外周血干细胞经G CSF动员后CS 30 0 0Plus分离 ,移植后定期检查血象和血型抗体滴度。结果显示 ,血型转为供者型的中位数时间 (40 2± 2 5 )天 ,白细胞、血小板达正常水平在两组中无明显差异 (P >0 0 5 ) ,而血红蛋白 <110g/L者在ABO血型不合组明显高于ABO血型相合组 (5 5 %∶2 5 % ,P <0 0 1)。 6例ABO血型主要不合者 3例发生纯红再障。提示供受者ABO血型不合影响红系造血重建 ,主要血型抗原不合时容易发生纯红再障 ,而GVHD及移植相关死亡率与红细胞血型无关     

非清髓异基因外周血造血干细胞移植后供体细胞植入证据的研究

采用染色体荧光原位杂交（FISH）并结合常规染色体和染色体分带等方法,观察并比较了4例血液病人非清髓异基因外周血干细胞移植（NAPBSCT）后的植入情况。结果4例病人均有不同程度的植入,全部形成混合性嵌合体,其中2例转化为完全植入。统计结果分析表明,FISH分析中期分裂相与间期细胞的结果无统计学差异。与常规染色体检测结果相比较,FISH分析中期分裂相或间期细胞的植入率高,但无统计学差异。但FISH具有操作简单、实验周期短、结果敏感可靠等优点,适合用于性别不合的NAPBSCT后植入证据检测。     

异基因造血干细胞移植中真菌感染的预防和护理体会

真菌感染是异基因造血干细胞移植的主要并发症和致死原因之一,积极地预防和科学的护理,早期发现并预防真菌感染已成为移植成功的关键问题之一。我院自1995年以来,共进行异基因造血干细胞移植37例,仅6例发生真菌感染,该6例真菌感染的患者,经积极的治疗和细致的护理均已康复。现将真菌感染的预防和护理体会介绍如下。     

非清髓异基因造血干细胞移植治疗急性白血病的临床研究

采用非清髓预处理（环胞霉素A、环磷酰胺、阿糖胞苷及CD3单克隆抗体或抗淋巴细胞球蛋白）的异基因外周造血干细胞移植治疗急性白血病5例。5例病人均顺利度过造血抑制期并移植成功。2例例经嵌合性植入转为完全植入,另3例为嵌合性植入。5例中2例发生Ⅱ～Ⅲ度GVHD,经治疗后治愈。5例中4例仍无病存活。结果表明,非清髓异基因造血干细胞移植简便安全,并发症少,疗效较好,为急性白血病的治疗提供了新手段。     

异基因造血干细胞移植对肠道菌群的影响

正常情况下,肠道微生物群多样性对维持免疫稳态至关重要,但其组成及其多样性受多种因素干扰。肠道微生物群组成和多样性的改变与许多疾病如肠道移植物抗宿主病（graft-versus-host disease,GVHD）紧密相关。肠道GVHD是异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation,allo HSCT)后并发症之一,明显增加移植相关死亡率。随着高通量测序技术的不断进步,肠道GVHD与菌群多样性的关系得到了验证。然而国内关于如何改善患者预后方面的研究甚少,作者对allo HSCT后患者的肠道菌群与GVHD之间的关系作一综述,进一步总结通过平衡肠道菌群的多种治疗方法,为临床上改善手术预后,降低患者死亡率提供治疗策略。     

HLA不全相合异基因外周血干细胞移植治疗重型再生障碍性贫血

目的探索HLA不全相合异基因外周血干细胞移植治疗重型再生障碍性贫血(SAA)的可行性。方法4例SAA患者接受HLA1~3个位点不合造血干细胞移植。供者给予G-CSF5μg/(kg.d),皮下注射,连续5天,以动员外周血干细胞,在第4、5天采集外周血干细胞。预处理采用氟达拉宾(Flu) CTX ATG TBI组成的新方案。受者应用环孢素A(CsA) 甲氨蝶呤(MTX) 骁悉(MMF) 舒莱预防GVHD。结果4例全部成功植入,中性粒细胞>0.5×109/L的时间平均为15.3(14~16)天,PLT>20×109/L的时间平均为17.5(16~19)天。中位随访时间14个月,仅1例患者发生Ⅱ度急性GVHD。1例因系统性念珠菌病死亡外,其余3例无病生存。结论新的HLA不全相合移植方案耐受性好,可以获得长期稳定的植活,而且不增加GVHD等并发症的发生。     

STR typing of skin swabs from individuals after an allogeneic hematopoietic stem cell transplantation

One of the pre-requisites for forensic DNA analysis is the fact that all nucleated cells of a person carry the same genetic information. However, this is not the case for individuals who have received an allogeneic hematopoietic stem cell or bone marrow transplantation, as all new cells formed by the bone marrow no longer show the genetic information of the recipient but that of the donor, while all other cells still carry the original information before transplantation. Thus, STR typing of a blood sample after successful transplantation yields a DNA profile that differs from the recipient’s original profile and corresponds to the donor genotype instead. Evidence from a routine case suggests that transplanted individuals may show donor alleles in skin swabs, as well. In order to examine this issue more closely, various skin swabs from 28 patients who have received an allogeneic hematopoietic stem cell transplantation were examined in this study. Swabs from the right and left palm, the back of the hand, one of the two upper arms, and the neck were collected from each person. Ninety-one of the 140 resulting swabs delivered useful results. All of those samples showed mixtures of recipient and donor DNA with different mixture ratios and the proportions of donor and recipient alleles revealed inter- and intra-individual differences. Those results were discussed with respect to graft versus host disease.

     

同种异基因造血干细胞移植术后巨细胞病毒感染的有效防治

目的：巨细胞病毒（CMV）感染和巨细胞病毒疾病是异基因造干细胞移植(allo-HSCT)术后的主要并发症,如发现和处理不及时则病死率高。我院对70例异基因造血干细胞移植者于移植后进行巨细胞病毒血症监测,以指导CMV感染防治,方法：采用CMVpp^65单克隆抗体免疫组化法监测。结果：移植后CMV抗原血症见于94．3％（66／70）患者。61．4％（43／70）发展为CMV疾病。其中35例为CMV相关性间质性肺炎（CMV－IP）。随讠－24个月,25例（25／70,35．7％）,病故,其中CMV疾病相关性死亡率为19例（19／25,765）,巨细胞病毒感染和急性移植物抗宿主病（GVHD）之间密切相关。CMV疾病伴Ⅲ-Ⅳ度急性GVHD或慢性GVHD者占CMV疾病例数的54．3％（19／43）。症状前治疗组与CMV疾病组比较显示,CMV疾病组的CMV疾病发生率,继发细菌、真菌感染,严重GVHD发生率以及死亡率均显著高于症状前治疗组（P＜0．001）,随讠－24个月,CMV疾病组的总体生存率仅为31．3％（10／32）而症状前治疗组为93．8％（30／32）。结论：HSCT后CMV感染和CMV疾病常见,于CMV疾病之前的症状前期及时进行抗CMV治疗多可挽救患者生命,急取较好的临床转归。     

Imaging of complications of hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation is increasingly used for treatment of malignant and nonmalignant disorders, genetic and immunologic disorders, and solid tumors. Although advances in immunosuppressive therapy and management of infections have improved long-term survival, transplant recipients remain at risk for a multitude of complications, many of which are serious and life threatening. Posttransplant complications may be classified either according to the organ system or according to the timeframe following transplantation. Complications may involve the chest, abdominopelvic organs, the central nervous system, or musculoskeletal tissues. This article reviews the various clinical and radiologic findings of key complications following hematopoietic stem cell transplantation and the pertinent differentiating factors.     

Impact of stem cell source on allogeneic stem cell transplantation outcome in hematological malignancies

BACKGROUND/AIM: Peripheral blood (PB) is used more frequently as a source of stem cells (SCs) for allogeneic transplantation. However, the influence of cell source on the clinical outcome of SC transplantation is not yet well established. The aim of this study was to compare the results of PBSC transplantation (PBSCT) with bone marrow transplantation (BMT) on the basis of engraftment, frequency and severity of immediate (mucositis, acute Graft versus Host Disease--aGvHD) and delayed (chronic GvHD--cGvHD) complications, as well as transplant-related mortality (TRM), transfusion needs, relapses and overall survival (OS). METHODS: We analyzed 158 patients, women/men ratio 64/94 median age 29 (range 9-57), who underwent allogeneic SC transplantation between 1989 and 2009. All included patients had diseases as follows: acute myeloid leukemia (AML)--39, acute lymphoblastic leukemia (ALL) 47, chronic myeloid leukemia (CML)--32, myelodysplastic syndrome (MDS)--10, Hodgkin's lymphoma (HL)- 2, multiple myeloma (MM) 3, granulocytic sarcoma (GrSa) 3, severe aplastic anemia (sAA)--22. The patients underwent transplantations were divided into two groups: BMT group (74 patients) and PBSCT group (84 patients). Each recipient had HLA identical sibling donor. SCs from bone marrow were collected by multiple aspirations of iliac bone and from PB by one "Large Volume Leukapheresis" (after recombinant human granulocyte colony stimulating factor, rHuG-CSF) application (5-12 microg/kgbm, 5 days). Conditioning regimens were applied according to primary disease, GvHD prophylaxis consisted of combination of a cyclosporine A and methotrexate. Results. Engraftment, according to the count of polymorphonuclear and platelets, were significantly (p < 0.001) faster in the PBSCT vs BMT group. The needs for transfusion support were significantly (P < 0.01) higher in the BMT group. Those patients had more frequently oropharingeal mucositis grade 3/4 (33.3% vs 10.0%, p < 0.05). There were no significant differences in the incidence of aGvHD and cGvHD between the two groups. The patients who underwent PBSCT had more frequently extensive cGvHD in comparison with the BMT group (29.1% vs 11.29%, p < 0.05). SC source (SCS) had no significant influence on the TRM (21.62% vs 23.8%, p = 0.64) and the incidence of relapses (21.6% vs 29.7%, p = 0.32). Finally, the patients treated by BMT hd a significantly better OS (logrank 2.33, p < 0.05). Conclusion. SCs harvesting from PB resulted in improved cell yield, faster engraftment, as well as in a decrease of immediate transplantation related complications with a reduced treatment cost. Allogeneic PBSCT were associated with more frequent extensive cGvHD, while the influence of SCS in TRM and relapses was not observed. Finally, the long-term OS was better in the patients treated by BMT. To verify impact of SC source on transplantation (PBSCT vs BMT) overall efficacy, more larger randomized clinical studies are needed.     

Gastrointestinal complications following hematopoietic stem cell transplantation in children

Gastrointestinal system involvement is one of the principal complications seen in the recipients of hematopoietic stem cell transplantation (HSCT), and it is also a major cause of morbidity and death in these patients. The major gastrointestinal complications include typhlitis (neutropenic enterocolitis), pseudomembranous enterocolitis, viral enteritis, graft-versus-host disease, benign pneumatosis intestinalis, intestinal thrombotic microangiopathy, and post-transplantation lymphoproliferative disease. As these patients present with nonspecific abdominal symptoms, evaluation with using such imaging modalities as ultrasonography and CT is essential in order to assess the extent of gastrointestinal involvement and to diagnose these complications. We present here a pictorial review of the imaging features and other factors involved in the diagnosis of these gastrointestinal complications in pediatric HSCT recipients.     

造血干细胞移植术后肺部并发症的CT表现

造血干细胞移植术后不同肺部并发症具有不同的时间分布特点。早期（术后30d内）多见感染性病变和非感染性病变,以肺水肿、弥漫性肺泡出血以及特发性肺炎综合征为主。中期（术后30~100d）感染性病变多为巨细胞病毒、侵袭性真菌感染,非感染性病变以特发性肺炎综合征、急性移植物抗宿主病、急性放射性肺炎以及肺细胞溶解性血栓为主。后期（术后100d以后）多以非感染性病变为主,慢性移植物抗宿主病最常见。综述早期、中期、晚期不同胸部并发症的CT表现。     

Pediatric hematopoietic stem cell transplantation and the role of imaging

The use of hematopoietic stem cell transplantation (HSCT) in the treatment of children afflicted with many potentially fatal malignant and nonmalignant diseases is well recognized. Although outcomes continue to improve and the utility of HSCT is increasing, HSCT remains a complicated process necessitating support from many medical disciplines, including radiology. Importantly, children who undergo HSCT are at risk for the development of specific complications that are linked to the timeline of transplantation, as well as to the relationship between the underlying diagnoses, severe immune deficiency, cytoreductive regimen, and graft-versus-host reactions. An understanding of the complex interplay of the immune status, therapeutic regimen, and disease allows increased diagnostic accuracy. Successful treatment of these high-risk children requires that radiologists who are involved with their care be familiar with broad concepts, as well as with specific problems that frequently occur following HSCT. In this article, the clinical aspects of pediatric HSCT are summarized, including common complications, and imaging features of these complications are described.     

CT of gastrointestinal complications associated with hematopoietic stem cell transplantation

OBJECTIVE: This article illustrates the characteristic CT findings of bowel damage related to drug toxicity, conditioning regimen, infections, and graft-versus-host disease (GVHD) in patients after hematopoietic stem cell transplantation. CONCLUSION: Although some overlap exists in the CT appearances of the different causes of bowel wall inflammation, the findings are frequently unique enough to suggest a specific diagnosis. Awareness of the specific time of occurrence, intensity of clinical symptoms, preferred localization, and extent of accompanying extraintestinal findings help to distinguish the different pathologic entities.