异基因造血干细胞移植治疗43例慢性粒细胞白血病疗效分析

目的:评价采用一种新预处理方案行异基因造血干细胞移植(allo-HSCT)治疗慢性粒细胞白血病(CML)患者的疗效。方法:2005年1月-2008年12月对43例CML患者进行allo-HSCT,采用白消安加环磷酰胺联合氟达拉滨、阿糖胞苷(Bu/Cy/Flu/Ara-C)为预处理方案,具体剂量为Bu3.2mg·kg-1·d-1静点(iv)或4mg·kg-1·d-1口服(po)2～4d、Cy50mg·kg-1·d-1×2、Flu30mg·m-2·d-1×3、Ara-C2g·m-2·d-1×3。移植方式为HLA相合或半相合亲缘供者造血干细胞移植,其中外周血干细胞移植(PBSCT)16例,骨髓移植(BMT)26例,骨髓加外周血干细胞移植1例。结果:所有患者均获造血重建,发生Ⅱ～Ⅳ度急性移植物抗宿主病(aGVHD)12例(27.9%),慢性GVHD(cGVHD)19例(45.2%),移植相关死亡(TRM)9例(20.9%),细胞遗传学或血液学复发6例(14.0%),其中4例复发后采用格列卫与DLI联合的挽救治疗获得稳定的分子生物学缓解;总体无病生存率(DFS)为(72.0±7.0)%,其中CP1和非CP1期移植患者D...     

母供子单倍体与无关供体异基因造血干细胞移植治疗恶性血液病临床对照研究

目的比较母供子单倍体异基因造血干细胞移植(allogeneichematopoieticstemcelltransplantation,Allo-HSCT)和无关供体Allo-HSCT治疗恶性血液病安全性及疗效。方法同期对照研究于2002年6月至2005年1月对苏州大学附属第一医院的18例母供子单倍体Allo-HSCT(A组)和10例无关供体Allo-HSCT(B组)的临床结果。供者动员方案:重组人粒细胞集落刺激因子(G-CSF)300μg,每日2次,5d后采集造血干细胞。预处理方案:髓系白血病采用改良白消安与环磷酰胺(Bu/Cy)方案,急性淋巴细胞白血病及非霍奇金淋巴瘤患者以一次全身照射(TBI)代替Bu。移植物抗宿主病(GVHD)预防,A组:环孢素A(CsA) 短程甲氨蝶呤(MTX) 霉酚酸酯(MMF) 胸腺细胞球蛋白(ATG);B组:CsA 短程MTX MMF。结果两组均顺利完成预处理并获造血重建。A、B两组达到ANC≥0·5×109/L、Plt≥20×109/L的时间差异无显著性(P>0·05);Ⅰ~Ⅱ度及Ⅲ~Ⅳ度aGVHD累积发生率分别为61·1%对40·0%及27·8%对30·0%(P>0·05),差异均无显著性;cGVHD及广泛型cCVHD累积发生率分别为58·8%对20·0%,17·6%对20·0%(P>0·05),差异亦无显著性。A、B两组累积存活率(49·8%对58·3%,P>0·05)差异均无显著性。结论初步研究表明,单倍体及无关供体Allo-HSCT治疗恶性血液病的安全性及有效性相当,母供体单倍体Allo-HSCT值得探索。     

减低剂量预处理对异基因造血干细胞移植治疗恶性血液病疗效观察

目的:探讨应用减低剂量的氟达拉宾、白消安和环磷酰胺(FBC)方案预处理对异基因造血干细胞移植(alloHSCT)治疗恶性血液病疗效的影响。方法:19例恶性血液病患者移植前进行减低剂量的FBC预处理。采用磷酸氟达拉宾(Flud)30mg/m2·d-1静脉滴注5d。白消安(Bu)0.6mg/kg、4次/d,共3d。环磷酰胺(CTX)30mg/kg·d-1静脉滴注,共2d,随后施行HLA配型的同胞或父亲供者的造血干细胞移植。术后采用环孢素及霉酚酸酯预防移植物抗宿主病(GVHD)。结果:全部患者的造血功能均获得快速重建。白细胞升至1.0×109/L以上,中位时间为(11.4±4.6)d。中性粒细胞升至0.5×109/L以上,中位时间为(11.9±6.7)d;血小板升至20×109/L以上,中位时间为(12.2±3.5)d。供者细胞完全植入15例,混合嵌合性植入4例,1例出现宿主排斥移植物(HVG)反应,进行供者淋巴细胞输注(DLI)2次后,达到完全供者嵌合。11例出现急性GVHD(57.89%),7例出现慢性GVHD(36.83%),2例HLA配型不完全相合者死于急性GVHD。结论:减毒的FBC预处理方案allo-HSCT治疗恶性血液病疗效肯定,并发症少,是治疗恶性血液病的有效方法。     

氟达拉滨联合静脉马利兰的预处理方案治疗髓系恶性血液病的临床研究

目的:评价氟达拉滨(Flu)联合静脉马利兰(Bu)的预处理方案在髓系恶性血液病患者异基因造血干细胞移植(allo-HSCT)中的疗效及静脉Bu的最佳剂量。方法:45例接受allo-HSCT的髓系恶性血液病患者,预处理方案主要采用Bu3.2mg·kg-1.d-1×2～4d,Cy40～50mg/kg×2d,Flu30mg.m-2.d-1×3d,Ara-C2g.m-2.d-1×3d,无关供者移植同时加用兔抗人血清免疫球蛋白(ATG)2.5mg/kg×4d。按静脉Bu用量进一步分为2d组17例,3d组18例,4d组10例。结果:预处理过程无严重不良事件发生,无肝静脉闭塞病(VOD)发生,Ⅱ～Ⅳ度急性移植物抗宿主病(aGVHD)9例(20%),100d移植相关死亡(TRM)1例(2.2%),3年TRM15例(33.3%),3年累计复发3例(6.7%),3年无病生存率(DFS)和3年总体生存率(OS)分别为(60.5±7.5)%和(62.2±7.2)%。与Bu2d组和3d组比较,4d组患者的慢性GVHD的发生率显著增高,TRM有增高趋势;OS显著降低,DFS有降低趋势。结论:Flu联合静脉Bu的预处理方案治疗髓系恶性血液...     

含全身照射预处理方案行HLA不相合非去T造血干细胞移植治疗白血病8例临床分析

目的探讨采用全身照射(TBI)预处理方案行人类白细胞抗原(HLA)配型不相合亲缘供者非去T异基因造血干细胞移植(allo-HSCT)治疗白血病的疗效。方法2002年4月至2007年1月北京大学血液病研究所8例采用TBI预处理方案行HLA不合非去T亲缘供者allo-HSCT的白血病患者,其中急性髓性白血病(AML)3例,急性淋巴细胞性白血病(ALL)4例,慢性粒细胞白血病1例;预处理方案采用TBI加环磷酰胺(CY)方案4例,TBI加氟达拉滨(FLU)方案4例;干细胞来源包括骨髓和外周血造血干细胞移植6例,外周血造血干细胞移植(PBSCT)2例;移植物抗宿主病(GVHD)预防采用经典的环孢素A(CsA) 霉酚酸酯(MMF) 短程甲氨蝶呤(MTX)方案。结果8例供者采集单个核细胞(MNC)中位数为7.39(6.27~12.46)×108/kg,粒细胞植入中位时间11(11~13)d,血小板植入中位时间13(11~21)d。5例发生Ⅰ~Ⅱ度急性GVHD,2例出现慢性广泛性GVHD,无严重急性GVHD或因GVHD死亡病例。中位随访时间9(3~53)个月,除1例复发存活外,其余病例无病存活。结论对于HLA不相合异基因造血干细胞移植,TBI方案是一种比较安全、有效的非去T预处理方案,对于高危和二次移植患者同样有效。     

低剂量ATG用于父母HLA 10/10相合造血干细胞移植患者的临床分析

目的:探讨父母HLA 10/10相合不去除T细胞的外周血造血干细胞移植治疗恶性血液病的植入情况、疗效和相关并发症。方法:预处理采用改良的Bu/Cy方案,用低剂量的兔抗人T淋巴细胞球蛋白、环孢素A、吗替麦考酚酯和短程甲氨蝶呤预防移植物抗宿主病(GVHD)。回输G-CSF动员的外周血干细胞,输注单个核细胞中位数为7.830(7.320~10.004)×108/kg,CD34+细胞中位数为4.59(3.68~5.32)×106/kg。结果:4例患者均达完全供者植入,粒系植入时间为16(11~16)d,血小板植入时间为22(11~29)d。发生Ⅱ度急性GVHD1例,发生率25%。发生慢性GVHD 3例,广泛型1例。中位随访267(178~1903)d,死亡1例(非复发死亡),复发1例(为高危患者),无复发存活2例。结论:低剂量ATG用于父母HLA 10/10相合供者异基因造血干细胞移植治疗高危恶性血液病是比较安全、有效的方案。     

静脉滴注白消安和氟达拉滨预处理方案行异基因造血干细胞移植治疗髓系血液病疗效观察

目的探讨静脉滴注白消安(Bu)和氟达拉滨(Flu)作为预处理方案,进行异基因造血干细胞移植治疗髓系血液病的疗效。方法选取2003年10月至2005年4月成都军区昆明总医院血液科髓系血液病患者9例,其中急性非淋巴细胞白血病(ANLL)3例,慢性粒细胞白血病(CML)5例,骨髓增生异常综合征(MDS)1例,均进行同胞白细胞抗原(HLA)全相合异基因造血干细胞移植。预处理方案采用移植前第6天至移植前第3天静脉滴注白消安3.2mg/(kg.d),共4d;移植前第6天至移植前第2天静脉滴注氟达拉滨30mg/(m2.d),共5d。环孢素A和霉酚酸酯(骁悉)联合应用预防移植物抗宿主病(GVHD)。结果9例患者均成功植入,中性粒细胞>0.5×109/L的平均时间为12d;血小板(PLT)>20×109/L的平均时间为14d。中位观察时间为31个月。除轻微胃肠道反应外,无严重的预处理相关毒性,移植后1个月检测证实均为供者型完全植入。发生急性GVHD2例,慢性GVHD1例。9例患者中8例无病存活。结论静脉滴注Bu/Flu预处理方案,移植相关毒性小,治疗髓系血液病安全有效。     

非清髓单倍体造血干细胞移植联合格列卫治疗慢性粒细胞白血病

目的:探讨格列卫联合非清髓性单倍体造血干细胞移植在治疗慢性粒细胞白血病(CML)中的作用。方法:4例CML患者,采用移植前、后口服格列卫,以环磷酰胺、阿糖胞苷、抗胸腺细胞球蛋白、赛尼派、环胞素A等作非清髓性预处理的单倍体异基因外周血造血干细胞移植。结果:移植过程顺利,4例患者均植入成功,嵌合性植入。中性粒细胞>0.5×109/L天数,16(10~21)d;血小板>20×109/L天数,10(4~15)d。3例发生Ⅰ~Ⅱ度皮肤急性移植物抗宿主病(GVHD),1例发生Ⅳ度皮肤慢性GVHD。1例+27d死于肺部感染并多脏器功能衰竭,1例死于Ⅳ度皮肤慢性GVHD并发感染。2例无病存活(随访16个月仍健在),且Ph+染色体,bcr-abl融合基因转阴。结论:非清髓单倍体造血干细胞移植联合格列卫治疗CML,具有降低移植前白血病细胞负荷,抑制残留白血病细胞增殖,促进供者完全嵌合状态的转变,增强抗移植物白血病(GVL)效应的作用,是一种有效的治疗方法,值得进一步临床研究。     

供者用粒细胞集落刺激因子单倍体骨髓移植的临床研究

目的探讨供者用粒细胞集落刺激因子(G-CSF)和受者联合应用多种免疫抑制剂治疗的单倍体骨髓移植在降低重症移植物抗宿主病(GVHD)和改善无病生存的疗效.方法单倍体骨髓移植治疗白血病13例(单倍体移植组),移植后结果和连续完成的13例白血病HLA匹配异基因移植 (相合移植组) 相比较,单倍体移植方法是供者应用G-CSF 250 μg/d,连用7 d后采髓, 受者GVHD预防除环孢素A(CSA)和甲氨蝶呤(MTX)外,在移植前4～1 d用抗胸腺细胞球蛋白(ATG) 5 mg*kg-1*d-1, 移植后7 d始加服霉酚酸酯(MMF).结果单倍体移植组植入物CD+34细胞中位数6.1×106/kg,是相合移植组输入CD+34细胞中位数2.5×106/kg的2倍多(P＜0.01),单倍体移植组和相合移植组植入物CD+3细胞中位数分别是50.5×106/kg和47.0×106/kg(P＞0.05).移植后无1例发生植入失败,两组造血重建速度无差异(P＞0.05),所有患者经骨髓植活直接证据检测证实为完全供者造血.单倍体移植组发生急性Ⅱ～Ⅳ GVHD 5例(38.5%),可评价的8例中7例发生慢性GVHD(87.5%),为局限性慢性GVHD,这与相合移植组差异无显著性 (P＞0.05).单倍体移植组中位随访453 d(180～690),移植相关死亡5例,无复发死亡病例,剩余8例无病存活(61.5%).相合移植组中位随访510 d(220～810),移植相关死亡2例,复发死亡2例,9例无病存活(69.2%),通过比较两组差异无显著性(P＞0.05).结论本研究单倍体骨髓移植治疗白血病是一种安全和有效方法,在降低重症急性GVHD 及改善无病生存方面和HLA相合同胞供者移植相当.     

以静脉注射和口服白消安为预处理行HLA半相合造血干细胞移植治疗恶性血液病的比较

目的:比较以静脉注射和口服白消安(Bu)为预处理方案行亲属间HLA半相合外周血造血干细胞移植在造血重建、移植物抗宿主病(GVHD)、预处理相关毒性及并发症和疗效的差异,观察白消安注射液(ivBu)的疗效和安全性.方法:20例恶性血液病患者中,10例采用静脉注射Bu为预处理方案(ivBu组),10例采用口服Bu为预处理方案(口服Bu组),回顾性分析2组移植后造血重建、GVHD、预处理相关毒性及并发症和疗效情况.结果:ivBu组和口服Bu组移植后均获造血功能重建,2组中性粒细胞绝对值≥0.5×109/L的中位时间均为14 d(P>0.05),血小板计数≥20×109/L的中位时间分别为12和13 d(P>0.05),ivBu组急性GVHD发生率为10.0%,低于口服Bu组(50.0%)(P>0.05),慢性GVHD的发生率在2组中分别为20.0%和60.0%(P>0.05),2组在预处理相关毒性及并发症方面差异无统计学意义(P>0.05),ivBu组1例因间质性肺炎死亡,2组分别有1例和2例复发,余16例无病生存.结论:ivBu组和口服Bu组在造血重建、GVHD、预处理相关毒性及并发症等的差异均无统计学意义,以ivBu为主的预处理方案治疗血液病是安全有效的.     

The immunoneuroendocrine role of melatonin

Abstract: A tight, physiological link between the pineal gland and the immune system is emerging from a series of experimental studies. This link might reflect the evolutionary connection between self-recognition and reproduction. Pinealectomy or other experimental methods which inhibit melatonin synthesis and secretion induce a state of immunodepression which is counteracted by melatonin. In general, melatonin seems to have an immunoenhancing effect that is particularly apparent in immunodepressive states. The negative effect of acute stress or immunosuppressive pharmacological treatments on various immune parameters are counteracted by melatonin. It seems important to note that one of the main targets of melatonin is the thymus, i.e., the central organ of the immune system. The clinical use of melatonin as an immunotherapeutic agent seems promising in primary and secondary immunodeficiencies as well as in cancer immunotherapy. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides as well as by lymphokines and, perhaps, by pituitary hormones. Melatonin-induced-immuno-opioids (MHO) and lymphokines imply the presence of specific binding sites or melatonin receptors on cells of the immune system. On the other hand, lymphokines such as -γ-interferon and interleukin-2 as well as thymic hormones can modulate the synthesis of melatonin in the pineal gland. The pineal gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine network which functions as an unconscious, diffuse sensory organ.     

Response of rat pineal melatonin to calcium, magnesium, and lithium is circadian stage dependent

Abstract: Herein we documented the response of pineal melatonin production to electrolytes known to be effective on pineal function in view of a possible circadian stage dependence. We studied the release of melatonin by perifused rat pineal glands at 2 different circadian stages corresponding to the middle of the light and dark periods, i.e., respectively, 7 and 19 HALO (Hours After Light Onset, L:D = 12:12). The initial efflux rates were, as expected, much higher in the perifusates of glands removed from rats sacrificed during the dark phase than of those removed during the light phase. After 3 hr of perifusion, melatonin release reached similar levels which were found constant up to the 8th hr of perifusion, whatever the circadian stage. Perifusion of the glands with physiological concentrations for the rat of calcium (5.2 mmol/1) and magnesium (1.34 mmol/1) resulted in a stimulatory effect on the pineal glands removed from rats sacrificed in the middle of the dark period (19 HALO), whereas no effects were observed on the pineal glands removed from rats sacrificed during the light (7 HALO). Lithium (0.28 and 0.55 mmol/1) was ineffective on melatonin release in pineal glands removed 7 and 19 HALO. Our results show differences in the initial efflux rates of melatonin and in the response of perifused pineal glands to calcium and magnesium according to the circadian stage.     

Changes in connexin43, the gap junction protein of astrocytes, during development of the rat pineal gland

Abstract: The abundance of gap junctions between rat pineal astrocytes formed by connexin43 (Cx43) was studied during development. Levels and distribution of Cx43 were measured by immunoblotting and indirect immunofluorescence, respectively. The amount of Cx43 in cells located within the gland was low until about the 7th postnatal day and increased to adult values between the 14th and 21st days postpartum. Although astrocytes, recognized by their vimentin immunoreactivity, were scarce before birth, they were abundant by the 7th postnatal day suggesting that the low levels of Cx43 found at this age corresponded to a low expression of this protein. Localization of the immunoreactivity to Cx43 and vimentin showed a close correlation, indicating that mature or immature pineal astrocytes form gap junctions made of Cx43. Since Cx43 levels attained their adult values at about the time the innervation and the functional state of the gland reached maturity (2–3 weeks after birth), it is proposed that astrocyte gap junctions are involved in the function of the adult rat pineal gland.     

Conservative management of perforated duodenal diverticulum： A case report and review of the literature

Duodenal diverticula are a relatively common condition. They are asymptomatic, unless they become complicated, with perforation being the rarest but most severe complication. Surgical treatment is the most frequently performed approach. We report the case of a patient with a perforated duodenal diverticulum, which was diagnosed early and treated conservatively with antibiotics and percutaneous drainage of secondary retroperitoneal abscesses. We suggest this method could be an acceptable option for the management of similar cases, provided that the patient is in good general condition and without septic signs.     

Presence of immunoreactive growth hormone and prolactin in the ovine pineal gland

Abstract: The use of antisera raised against bovine growth hormone (GH) and ovine prolactin (PRL) enabled the detection of related immunoreactive (ir) sequences of proteins in ovine pineal tissue. The isolation of PRL-like ir-material was accomplished using a 0.25 M ammonium sulphate (pH 5.5) extraction followed by ethanol precipitation, whereas the resulting 2.0 M ammonium sulphate (pH 7.0) precipitate contained a GH-like immunoreactivity. Gel chromatography of the GH-like immunoreactivity (Sephadex G-100) indicated the presence of several GH-like fragments ranging in the M_r range of 7,000 to 55,000. Analyses of the PRL-like ir-material found in pineal tissue on HPLC using a TSK 545-DEAE column led to the resolution into a single peak of immunoreactivity. A single peak of activity was also observed following chromatofocusing and hydrophobic interaction chromatography of the ir-peak from the TSK 545-DEAE column. The PRL-like ir-material inhibited the binding of [¹²⁵I]ovine PRL-S14 to anti-ovine PRL antibodies without showing an affinity for binding to anti-rat PRL or anti-bovine GH antibodies. Scatchard analysis of the binding of pineal PRL-like ir-material and pituitary ovine PRL-S14 to liver membranes from day-20 pregnant rats revealed similar affinity constants (K_a of 4.7 ± 0.2 × 10⁹ M^-1). In addition, the replication of Nb 2 Node rat lymphoma cells was stimulated by pineal PRL-like ir-material, an effect known to be specific for lactogenic hormones. The pineal PRL-like immunoreactivity appeared on sodium dodecyl sulfate polyacrylamide gels as a single major band of M_r 24,000. The functional status of PRL-and GH-like ir-material in the ovine pineal remains to be determined, but evidence is presented that the overall protein synthesis rate of the rat pineal responded to circulating concentrations of PRL.     

Microbiology of human immunodeficiency virus anorectal disease

PURPOSE: Individuals who are seropositive for the human immunodeficiency virus are at high risk for opportunistic infection and anorectal disorders. Little prospective information is available regarding anorectal pathogens in these patients. METHODS: One hundred sixty-three HIV-seropositive patients presented to the colorectal clinic between 1989 and 1992. Forty-seven (29 percent) patients were thought to have an infectious process and were prospectively studied using a standardized multiculture protocol. RESULTS: Mean age was 33 (range, 19–59) years. All were male; high-risk behavior accounted for 87 percent of HIV transmissions. Presenting complaints included anorectal pain (79 percent), pus per anum (28 percent), and blood per anum (26 percent). Examination revealed perianal tenderness (60 percent), condyloma (38 percent), perianal ulcers (38 percent), and anal fissures (34 percent). Sixty-six sets of cultures were performed; 28 patients had one set, 15 had two sets, and 4 had three sets. Thirty-two of these 47 patients (68 percent) had positive cultures including herpes (50 percent), cytomegalovirus (25 percent),Neisseria gonorrhoeae (16 percent), chlamydia (16 percent), acidfast bacilli (2 percent), and others (9 percent). Six of 32 patients with positive cultures had more than one organism cultured. Sixteen (50 percent) patients with positive cultures were treated medically, 8 (25 percent) were treated surgically and 8 (25 percent) were treated with both modalities. Sixty-one procedures were performed on 17 patients for condylomata. Eighteen patients had 20 procedures for abscesses, 50 percent of whom had positive cultures for other than common bowel flora; all improved. Fourteen patients underwent 33 procedures for perianal fistulas.Mycobacterium fortuitum was cultured from one patient who required 13 procedures for abscesses and fistulas. Forty-five (96 percent) patients were followed for an average of 12.5 months ±2.9 SEM (range, 1–94 months). Symptoms were improved or resolved in 22 of 32 (69 percent) patients with positive cultures and in 11 of 13 (84 percent) with negative cultures. CONCLUSIONS: Specific pathogens may often be identified in human immunodeficiency virus-seropositive patients with anorectal disorders if aggressively sought. Although patients without specific pathogens identified may be expected to improve with planned empiric treatment, positive identification allows more directed therapy.