难治性儿童朗格汉斯组织细胞增生症的治疗进展

难治性朗格汉斯组织细胞增生症(Langerhans cell histiocytosis,LCH)是指具有多脏器浸润尤其是具有危险器官(骨髓、肝、脾)浸润和初治治疗失败的LCH病例,预后极差,及时有效的治疗是患者存活的关键.目前有单药克拉屈滨(2-chlorodeoxyadenosine,2-CdA)、2-CdA联合大剂量阿糖胞苷、消炎痛、造血干细胞移植、靶向治疗等多种二线治疗方案.该文就近年儿童难治性LCH的相关治疗方案进展进行综述.     

中剂量阿糖胞苷治疗儿童难治性高危朗格罕细胞组织细胞增生症的效果及安全性分析

目的分析中剂量阿糖胞苷治疗儿童难治性危险器官受累朗格罕细胞组织细胞增生症(LCH)的效果、安全性及远期预后。方法回顾性分析2013年1月至2016年12月北京儿童医院血液病中心收治的多系统危险器官受累、一线治疗失败且选用中剂量阿糖胞苷[250 mg/(m2·次), 2次/d]治疗的17例LCH患儿临床资料。患儿共接受2种治疗方案:在长春地辛和地塞米松的基础上, 方案A为中剂量阿糖胞苷联合克拉屈滨, 方案B为单纯中剂量阿糖胞苷。分析两种方案的治疗效果、安全性及预后。结果 17例LCH患儿中男11例、女6例, 诊断年龄2.1(1.6, 2.7)岁。10例患儿接受了方案A治疗, 所有患儿在诱导治疗8个疗程后评估疾病好转, 疾病活动评分(DAS)从治疗前的5.5(3.0, 9.0)分下降至1.0(0, 2.3)分。7例患儿接受了方案B治疗, 6例患儿在诱导治疗8个疗程后评估疾病好转, DAS从治疗前的4.0(2.0, 4.0)分下降至1.0(0, 2.0)分。A组及B组患儿分别随访6.2(4.9, 7.2)年及5.2(3.7, 5.8)年。A组及B组患儿5年总体生存率均为100.0%, 5年无...     

替莫唑胺联合托泊替康治疗儿童难治性/复发神经母细胞瘤6例临床分析

目的观察替莫唑胺(TMZ)联合托泊替康(TOPO)即TOTEM方案治疗儿童难治性/复发神经母细胞瘤(NB)的疗效。方法 6例难治性/复发NB患儿,分别给予替莫唑胺150 mg/(m~2·d),d1-5,口服;托泊替康0.75 mg/(m~2·d),d1-5,静脉点滴,每3周为一个化疗周期,每个患儿共接受8~10个周期的化疗。治疗中监测血常规、肝功、肾功、心脏功能等;每2个化疗周期行CT或MRI等影像学检查,同时结合骨髓受累病例中微小残留检测结果,进行疗效估。结果 6例NB患儿接受共53个周期TOTEM方案化疗,3例患儿临床达到完全缓解,2例患儿为部分缓解,1例患儿因疾病进展,放弃治疗,本组病人平均随诊时间为15个月,随访1年时4例存活。化疗期间不良反应主要表现为:5例出现Ⅲ°~Ⅳ°骨髓抑制,3例出现Ⅱ°~Ⅲ°恶心、呕吐、厌食,但整个治疗中无化疗相关性死亡病例发生。结论难治性/复发NB患儿对TOTEM方案表现较理想的治疗反应和顺应性,但远期疗效尚待进一步观察,可作为目前治疗儿童难治性/复发NB的选择之一。     

三氧化二砷对急性早幼粒细胞白血病患儿的肝脏毒性

目的 研究治疗剂量三氧化二砷(As2O3)对急性早幼粒细胞白血病(APL)患儿的肝脏毒性.方法 对41例APL患儿静脉滴注As2O3注射液,同时进行肝脏毒性监测:肝功能的动态变化、分析影响因素并观察治疗反应.结果 1.肝脏损害的发生率:发生轻度肝损害8例(19.5%),中度肝损害2例(4.9%),未见重度损害.9例(21.9%)ALT升高,10例(24.4%)AST升高,5例(12.2%)γ谷氨酰转肽酶(γ-GT)升高,多在1～3周发生,第4周以后恢复正常.2.肝功能变化:诱导缓解期所有病例的总蛋白、清蛋白、清蛋白与球蛋白比例、总胆红素、前清蛋白和胆碱酯酶均未见动态性差异变化;ALT在第1周开始明显增高,但恢复较快,持续到第3周恢复正常;AST在第1周开始与γ-GT同时明显增高,持续到第4周恢复正常.3.肝功能损害的影响因素:未见患者的年龄、性别、发病时间、有无肝大和肝功能异常、是否存在DIC与肝毒性的发生存在关系;初诊时血常规及LDH与肝毒性的发生亦未见显著性差异;为了达到完全缓解而应用蒽环类药物者,未见肝毒性增加;短期内As2O3的蓄积量变化与肝毒性的发生未见显著性差异;发生分化综合征者,肝毒性的发生率增多.4.治疗反应:暂时停用As2O3,给予保肝治疗后肝功能恢复,未见因肝衰竭而死亡者.结论 常规剂量As2O3治疗小儿APL肝毒性较轻,且短暂,存在一过性肝功能损害,诱导缓解期第1-3周是重点监测时期,应注意分化综合征发生时可能加重肝毒性.As2O3累积量的变化对小儿肝脏功能近期影响不大,但应动态观察肝功能的变化.     

儿童急性白血病肝功能损害及临床意义

为了研究白血病化疗过程中肝功能损害的病因，测定了56例急性白血病化疗前后肝功能，并提出了药物性肝脏损害及白血病细胞肝脏浸润的诊断方法。56例患儿中36例（64．3％）有肝功能受损，其中29例43例次发生药物性肝脏损害，白血病肝浸润9例，2例肝浸润时均无骨髓、中枢等复发证据。4例发生病毒性肝炎。对不同类型肝损害进行治疗，各种肝脏损害恢复时间平均为：药物性8．1天，白血病肝浸润7天，病毒性肝炎30天。结果表明：急淋患儿在诱导及强化治疗过程中易发生药物性肝炎，左旋门冬酰氨酶是引起药物性肝炎最主要药物，其次是6-巯基嘌呤、甲氨喋呤；肝脏可能是急淋白血病的庇护所，环磷酰胺试验治疗对肝脏浸润早期诊断具有重要诊断价值。     

万古霉素治疗儿童革兰阳性球菌重症肺炎血药浓度与疗效分析

目的分析万古霉素血药浓度分布特点及其与革兰阳性球菌重症肺炎疗效的关系。方法回顾性分析2012年10月-2014年10月使用万古霉素治疗的59例革兰阳性球菌重症肺炎患儿万古霉素血药浓度值,分析其与临床生化指标、疾病状态的相关性;并分析临床因素对万古霉素疗效的影响。结果 40~60 mg/(kg·d)给药方案的治疗有效率高于40 mg/(kg·d),差异有统计学意义(89.47%对46.15%,P=0.004),而60 mg/(kg·d)治疗有效率未进一步提高。合并非青紫型先天性心脏病患儿的血药谷浓度高于无先天性心脏病患儿,差异有统计学意义(12.12 mg/L对7.76 mg/L,P=0.008)。用药前急性肝功能受损、中重度贫血可能是万古霉素治疗革兰阳性球菌重症肺炎疗效不佳的危险因素,差异有统计学意义(P0.05)。结论万古霉素治疗革兰阳性球菌重症肺炎推荐选择40~60 mg/(kg·d)给药方案;合并非青紫型先天性心脏病,用药前急性肝功能受损、中重度贫血可能影响药物浓度和治疗效果。     

儿童急性白血病肝功能损害及临床意义

为了研究白血病化疗过程中肝功能损害的病因，测定了５６例急性白血病化疗前后肝功能，提高了药物性肝脏损害及白血病细胞肝脏浸润的诊断方法。５６例患儿中３６例有肝功能受损，其中２９例４３例次发生药物性肝脏损害，白血病肝浸润９例，２例肝浸润时均无骨髓、中枢等复发证据。４例发生病毒性肝炎。对不同类型肝损害进行治疗，各种肝脏损害恢复时间平均为：药物性８．１天，白血病肝浸润７天，病毒性肝炎３０天。结果表明：急淋患     

联合肝脏离断和门静脉结扎二步肝切除术在儿童肝肿瘤治疗中的应用

联合肝脏离断和门静脉结扎的二步肝切除(associated liver partition and portal vein ligation for staged hepatectomy,ALPPS)手术方案具有短期内残肝体积迅速增大的特点,在预估残肝体积(future liver remnant,FLR)不足的成人肝肿瘤手术中已获得推广。儿童肝脏肿瘤往往体积相对较大,尤其是肝母细胞瘤常侵犯多个肝段,或占据肝脏中央解剖部位,存在根治性肝切除术导致FLR不足的情况,有实施这一术式的价值。目前ALPPS在儿童肝脏肿瘤中的应用尚处于起步阶段。一般认为,术前评估FLR30%的病例可考虑实施本术式;术前应对患儿肝体积、肝功能以及肿瘤的可切除性进行精准评估;两次手术间隔时间以7~14 d为宜。手术并发症主要包括肝功能不足、出血和胆漏。关于儿童肝肿瘤中该术式的临床疗效评估尚待进一步总结。     

三联疗法治疗幽门螺杆菌感染的疗效

目的用克拉霉素加阿莫西林及奥美拉唑与标准三联疗法(阿莫西林 枸橼酸铋 甲硝唑)对照,三种方案、三种疗程治疗Hp感染儿童,评价其疗效。方法经胃镜检查确诊为慢性胃炎或十二指肠溃疡且Hp呈阳性的患儿204例随机分组,A组治疗方案为阿莫西林50 mg/(kg.d),枸橼酸铋7~8 mg/(kg.d),甲硝唑15~20 mg/(kg.d),疗程6周。B组用药与A组相同,疗程为2周。C组为克拉霉素15 mg/(kg.d),奥美拉唑0.8 mg/(kg.d),阿莫西林50 mg/(kg.d),疗程2周。结果A组Hp根除率73.4%,B组Hp根除率75%,C组Hp根除率92%,B组和C组比较有显著性差异(P<0.05)。结论以克拉霉素、奥美拉唑、阿莫西林三联治疗儿童Hp感染,具有疗程短、疗效高、耐药少、依从性好、Hp根除率高等优点。     

联合阿糖胞苷治疗难治性朗格汉斯细胞组织细胞增生症临床分析

目的 评估联合阿糖胞苷(Ara-C)治疗儿童难治性朗格汉斯细胞组织细胞增生症(LCH)的疗效.方法 回顾分析确诊难治性LCH且采用联合Ara-C化疗患儿的临床资料,评估疗效.结果 共11例难治性LCH患儿,男性6例、女性5例,中位诊断年龄22个月(5～157个月),中位随访时间32个月(17～75个月).所有患儿均为多...     

Nucleoside analogues in the therapy of Langerhans cell histiocytosis: a survey of members of the histiocyte society and review of the literature.

BACKGROUND: Previous reports have suggested activity of the nucleoside analogues 2-chlorodeoxyadenosine (2-CdA) and 2'-deoxycoformycin (2'-DCF) in Langerhans cell histiocytosis (LCH). PROCEDURE: To assess the efficacy of 2-CdA and 2'-DCF as salvage therapy for LCH, a survey of members of the Histiocyte Society and a literature review were undertaken. Twenty-three patients treated with 2-CdA and 4 treated with 2'-DCF were found, age range 2 months to 49 years. RESULTS: All 15 survey patients had multiorgan involvement, and 14 were heavily pretreated. Doses of 2-CdA ranged from 0.1 mg/kg/day continuous infusion for 5-7 days (majority of patients) to 13 mg/m(2)/day for 5 days, for 1-6 courses. One of the 15 patients had an early death, 5 had no response (NR), 3 had partial response (PR), and 6 achieved complete response (CR). Among 8 published patients, 7 achieved stable CR and 1 NR. Among 4 patients treated with 2'-DCF (4 mg/m(2)/week for 8 weeks then q 2 weekly), 2 achieved CR for 16+ and 18+ months and 2 PR for 2 and 5 months. Toxicity consisted mainly of combined myelo- and immunosuppression but no significant infections occurred and there were no toxic deaths. A cumulative thrombocytopenia was noted, which in 1 case took up to 6 months to resolve. Transient gastrointestinal toxicity and elevation of liver enzymes was seen, and 2 patients developed renal tubular acidosis. The peripheral neuropathy reported in adult patients receiving high doses was not seen. CONCLUSIONS: 2-CdA and 2'-DCF appear to have a useful role in LCH and are worthy of prospective trial in patients unresponsive to routine therapy.     

Severe persistent bone marrow failure following therapy with 2-chlorodeoxyadenosine for relapsing juvenile xanthogranuloma of the brain

2-Chlorodeoxyadenosine (2-CdA) has been successfully used in children to treat refractory Langerhans cell histiocytosis and juvenile xanthogranuloma (JXG) as salvage therapy. Although 2-CdA is generally well-tolerated, with temporary myelosuppression as the primary dose-limiting toxicity, prolonged myelosuppressive, and immunosuppressive effects have been reported. We describe an adolescent patient with refractory multiple central nervous system JXG, with the lesion size markedly reduced after treatment with 2-CdA. However, severe transfusion-dependent bone marrow failure developed after five courses of 2-CdA. He underwent successful bone marrow transplantation from his HLA compatible sister with reduced intensity conditioning.     

Excellent remission rates with limited toxicity in relapsed/refractory Langerhans cell histiocytosis with pulse dexamethasone and lenalidomide in children

Refractory/relapsed Langerhans cell histiocytosis (LCH) has a difficult course with a guarded prognosis. We used a novel protocol including six cycles of pulse dexamethasone and lenalidomide in four children with LCH refractory to first‐line agents and courses of cladribine and cytarabine or single‐agent cladribine. All four children completed the protocol without any significant adverse effects and remain in complete and durable remission 15–18 months posttreatment. The novel protocol we propose for relapsed/refractory LCH is cost‐effective and outpatient‐based with durable remission and minimal toxicity. This is particularly suited for resource‐limited settings.     

多靶点免疫抑制治疗儿童难治性肾病综合征的疗效及安全性

目的探讨应用吗替麦考酚酯联合雷公藤多苷多靶点免疫抑制治疗儿童难治性肾病综合征的疗效及安全性。方法 32例难治性原发性肾病综合征患儿,在综合治疗基础上给予吗替麦考酚酯25 mg/(kg.d)、雷公藤多苷1 mg/(kg.d)口服治疗,同期选取30例应用环磷酰胺冲击治疗和27例只应用吗替麦考酚酯的难治性肾病综合征患儿作为对照。治疗期间严密观察各组不良反应的发生,治疗6个月时分别测定比较患儿的24 h尿蛋白定量、血清白蛋白、血肌酐。结果多靶点免疫抑制组患儿24 h尿蛋白均有下降,其中24例尿蛋白<0.5 g/24 h,血清白蛋白恢复正常,肾功能正常,总有效率为75%,与环磷酰胺冲击组及单独应用吗替麦考酚酯组比较,疗效差异有统计学意义(P<0.05)。多靶点免疫抑制组不良事件发生率与环磷酰胺冲击组及单独应用吗替麦考酚酯组之间的差异无统计学意义(P>0.05)。结论吗替麦考酚酯联合雷公藤多苷多靶点免疫抑制治疗儿童难治性肾病综合征有较好的疗效及安全性。     

Intraocular Langerhans cell histiocytosis in a neonate resulting in bilateral loss of vision

Intraocular involvement in Langerhans cell histiocytosis (LCH) is rare. We describe the case of a neonate with congenital disseminated LCH involving skin, liver, spleen, and intraocular structures including uvea and retina. Early and aggressive treatment according to the LCH-II treatment protocol was administered and resulted in remission of the disease. However, despite close follow-up and additional local treatment, involvement of intraocular structures resulted in severe long-term ophthalmological sequelae including complete bilateral loss of vision.     

Langerhans cell histiocytosis with central nervous system involvement: follow-up by FDG-PET during treatment with cladribine

The prognosis of patients with Langerhans cell histiocytosis (LCH) involving the central nervous system (CNS) is generally poor, despite reports of clinical responses to chemotherapy, surgery, and radiation. We report on a patient with a 20-year history of relapsing multisystem LCH who developed progressive neuropsychiatric symptoms, including diplopia, ataxia, and mental deterioration. There was a regression of lesions in the brain stem and cerebellum following chemotherapy with cladribine (2-CdA) as evidenced by positron emission tomography (PET) scans. In conclusion, our experience is encouraging for the use of cladribine in CNS LCH. PET may be a useful modality for the monitoring of CNS disease activity in LCH and provides additional information in comparison with NMR imaging.     

Langerhans' cell histiocytosis (histiocytosis X): experience at the Children's Hospital of Philadelphia, 1970-1984

Sixty-four patients with biopsy-proven Langerhans' cell histiocytosis (LCH, formerly designated as histiocytosis X) were managed at the Children's Hospital of Philadelphia from 1970 through 1984. Their median age was 3 yr (range, 0.1-22 yr). Thirty-three patients had localized lesions affecting a bone (27) or soft-tissue region (6). Twenty-two patients had multifocal disease affecting bones (17) or soft, nonosseous tissues (5). None of these patients had evidence of dysfunction of liver or lungs, and none had abnormal peripheral blood cell counts. The remaining nine patients had multifocal LCH plus dysfunction of liver or lungs (6) or abnormal blood counts (3). Treatment consisted primarily of surgical excision for patients with localized lesions and of drug therapy with or without irradiation and surgery for those with multifocal disease. Recurrence was infrequent (7%) in those with localized LCH, and all survived. Recurrence was frequent (74%) in those with multifocal LCH but without organ dysfunction or abnormal blood counts, but 21 of the 22 survived. By contrast, only three of the nine patients with organ dysfunction or abnormal blood counts survived. Thus organ dysfunction and abnormal blood counts at diagnosis emerged as the major adverse prognostic factors in children with LCH.