儿童朗格汉斯细胞组织细胞增生症的BRAF-V600E基因突变及临床意义

目的 探讨儿童朗格汉斯细胞组织细胞增生症（LCH）的BRAF-V600E基因突变的意义。方法 采用实时荧光定量PCR技术检测26例儿童LCH患儿石蜡包埋组织样本中的BRAF-V600E基因突变情况,并回顾性分析BRAF-V600E基因突变与临床特征及预后的关系。结果 25例患儿接受正规化疗,2年总生存率（OS）及无事件生存率（EFS）分别为100%、88%。70%（18/26）的病理标本来自骨组织,BRAF-V600E基因突变阳性率达50%（13/26）。BRAF-V600E基因突变与LCH患儿年龄、性别、受累器官、临床分类、早期治疗效果、复发情况以及2年OS及EFS均无相关性（P > 0.05）,但与LCH的临床分组相关（P < 0.05）。结论 LCH患儿总体生存率较高,BRAF-V600E基因突变发生率高,BRAF-V600E基因突变与LCH临床分组相关。     

两种方案治疗182例郎格汉斯细胞组织细胞增生症的历史对照研究

目的：比较复旦大学附属儿科医院（我院）CHFU-LCH 2006方案（简称2006方案）和CHFU-LCH 2012方案（简称2012方案）治疗郎格汉斯细胞组织细胞增生症（LCH）患儿的疗效和不良反应。方法：2006年1月1日至2012年11月31日在我院接受2006方案治疗的LCH初治患儿纳入2006组, 2012年12月1日至2015年12月31日在我院接受2012方案治疗的LCH初治患儿纳入2012组。两组均经病理确诊LCH,排除治疗6周内自动终止治疗者。每组进一步分为单系统LCH（SS-LCH）和多系统LCH（MS-LCH）亚组。所有患儿随访至2017年3月31日。治疗有效为无活动性病变或活动性病变好转。以Kaplan-Meier法计算5年预计总生存率（OS）和无病生存率（EFS）。不良反应根据WHO急性和亚急性毒性反应分级标准分为0~4级。比较两组治疗6和12周有效率,恶化、复发和死亡情况,5年预计OS、EFS和不良反应发生情况。结果：96例患儿进入2006组,男64例,女32例,中位年龄3.4岁,中位随访时间6.9年;86例患儿进入2012组,男59例,女27例,中位年龄2.9岁,中位随访时间4.0年。两组性别、诊断年龄、临床分型和危险器官受累（RO+）情况差异无统计学意义。①2006组和2012组比较,SS-LCH、MS-LCH亚组治疗6、12周,有效率和复发率差异均无统计学意义。②2006组和2012组MS-LCH亚组分别有4例和5例退出方案,转入其他挽救方案,分别有5例和4例死亡。③两组MS-LCH患儿共93例,其中＜2岁5年预计EFS和OS均明显低于≥2岁患儿［EFS：（41.9±8.1）% vs（ 62.6±7.5）%,OS：（80.8±6.2）% vs （98.0±2.0）%］,P均＜0.05;RO+患儿5年预计EFS和OS低于RO-患儿［EFS：（37.4±8.0）% vs （66.0±7.3）%,OS：（80.4±6.3）% vs （98.0±2.0）%］,P均＜0.05;RO-患儿＜2岁和≥2岁5年预计EFS和OS差异无统计学意义;6周治疗无效患儿5年预计EFS 低于6周治疗有效患儿［（33.1±7.9）% vs （70.8±7.2）%］,P＜0.05。④2006组和2012组SS-LCH亚组5年预计EFS分别为（84.8±5.3）%和（86.7±5.6）%,5年预计OS均为100%;MS-LCH亚组5年预计EFS分别为（50.0±7.1）%和（53.2±10.0）%, 5年预计OS分别为（90.0±4.1）%和（90.6±4.5）%;差异均无统计学意义。⑤2006组MS-LCH亚组化疗相关3/4级不良反应发生率（50.0%,25/50）高于2012组（23.3%,10/43）,P=0.008 0。结论：CHFU-LCH 2012方案与2006方案疗效未发现有差别,化疗相关严重不良反应较轻,MS-LCH的5年EFS仍不满意。RO+和治疗6周反应情况是MS-LCH的重要预后影响因素。     

儿童多系统受累朗格罕细胞组织细胞增生症53例临床分析

目的分析多系统受累朗格罕细胞组织细胞增生症(MS-LCH)患儿的临床特征及远期预后,评价改良DAL-HX83/90方案对MS-LCH患儿的疗效。方法回顾性病例分析。研究对象为2011年1月至2019年5月郑州大学第一附属医院儿童医院血液肿瘤科收治的53例MS-LCH患儿,初始化疗采用改良DAL-HX83/90方案,按是否累及危险器官分为无危险器官受累(RO-)组和累及危险器官(RO+)组,RO+组再分为Ⅰ组(仅肺受累)、Ⅱ组(肺外,伴或不伴肺受累),总结临床特征和随访结果,Kaplan-Meier生存分析法计算生存率,Log-Rank检验及Cox比例风险回归模型对年龄、性别、危险器官受累、6周诱导化疗反应进行单因素及多因素预后分析。结果53例MS-LCH患儿中男34例、女19例,发病年龄21月龄(3月龄至13岁),RO-组31例,RO+组22例,其中Ⅰ组12例、Ⅱ组10例。随访时间51(12~144)个月,6周诱导化疗有效率89%(47/53),进展复发率30%(16/53),5年无事件生存率(EFS)为(67±6)%,5年总生存率(OS)为(83±5)%。单因素分析发现6周诱导化疗有效者5年EFS、OS明显高于无效者[(76±6)%比0,(88±4)%比(41±22)%],差异均有统计学意义(χ²=34.743、10.608,均P<0.05)。RO-组5年EFS、OS明显高于RO+组[(80±7)%比(49±10)%,(93±4)%比(70±10)%],差异均有统计学意义(χ²=6.022、4.793,均P<0.05)。Ⅰ组5年EFS明显高于Ⅱ组[(83±10)%比(10±9)%],差异有统计学意义(χ²=9.501,P=0.002),年龄、性别与EFS、OS无明显相关性(均P>0.05)。Cox比例风险回归模型分析发现6周诱导化疗反应是影响EFS(HR=13.114,95%CI 3.759~45.742,P<0.01)、OS(HR=7.748,95%CI 1.542~38.920,P=0.013)的独立危险因素。结论采用改良DAL-HX83/90方案治疗无危险器官受累MS-LCH,患儿多数可获长期生存。但累及肝、脾或造血系统的MS-LCH患儿疾病进展和复发率较高。     

CD20阳性不提示高白细胞计数急性B淋巴细胞白血病患儿预后不良

目的 探讨初诊骨髓白血病细胞CD20表达联合白细胞计数在儿童B系急性淋巴细胞白血病（B-ALL）预后评估中的价值。方法 回顾性分析2008年4月至2015年4月接受CCLG-ALL2008方案治疗的821例初诊B-ALL患儿的临床资料，并随访观察其生存情况。结果 821例患儿中，CD20阴性患儿547例（66.6%），CD20阳性患儿274例（33.4%）。694例白细胞 < 50×10⁹/L（低白细胞计数）的患儿中，CD20阳性、CD20阴性患儿5年无事件生存（EFS）率分别为65.9%±3.2%、77.3%±2.0%（P=0.001），5年总生存（OS）率分别为78.3%±2.9%、87.5%±1.6%（P=0.005）；多因素分析示CD阳性是EFS率、OS率的独立危险因素（分别HR=1.634，P=0.001；HR=1.761，P=0.005）。127例白细胞≥50×10⁹/L（高白细胞计数）的患儿中，CD20阳性、CD20阴性患儿5年EFS率分别为64.3%±7.7%、53.7%±5.5%（P=0.135），5年OS率分别为81.4%±6.4%、58.6%±5.6%（P=0.022）；多因素分析示CD20阳性是OS率的独立保护因素（HR=0.367，P=0.016）。结论 接受CCLG-ALL2008方案治疗的B-ALL患儿中，初诊低白细胞计数、CD20阳性表达者长期预后较差，而初诊高白细胞计数、CD20阳性表达者有较好的生存趋势。     

BRAF基因V600E突变在儿童朗格罕细胞组织细胞增生症中的临床意义

目的探讨单中心儿童朗格罕细胞组织细胞增生症(LCH)患者BRAF基因V600E突变情况及其临床意义。方法回顾性分析80例首都医科大学附属北京儿童医院2014年1月—2014年12月期间经病理诊断的LCH患者的临床资料,用二代基因测序的方法检测其病理标本及血浆中BRAF基因V600E突变。采用SPSS 18.0统计软件进行数据分析处理。结果本组研究中病理标本检测BRAF基因F600E突变的阳性率68%,血浆样本检测阳性率59%。其中双阳性42例(53%),双阴性15例(19%)。对血浆或病理阳性患者BRAF基因F600E突变与年龄、性别、临床分组、受累器官、早期治疗反应、复发进行相关性分析,血浆阳性组P值分别为:0.737,0.06,0.718,0.727,0.739,0.879;病理标本阳性组P值分别为:0.303,0.88,0.519,0.728,0.088,0.065,提示差异均无显著性。结论本组儿童LCH患者存在较高的BRAF基因V600E突变,提示部分患者组织细胞呈克隆性生长。该研究未发现BRAF基因F600E突变与LCH患者临床表现、治疗反应和预后的相关性,也许与本研究样本量少有关,仍有待于扩充样本量进一步研究。     

核苷类似物治疗儿童朗格罕细胞组织细胞增生症

朗格罕细胞组织细胞增生症（Langerhans cell histiocytosis，LCH）是一组由朗格罕细胞为主的组织细胞在机体网状内皮系统内广泛增生、浸润为基本特征的疾病，全身各器官、系统均可受累，其中肝、脾、血液系统和肺被认为是受累的危险器官［1］。LCH的异质性很强，单系统和（或）无危险器官受累患儿对常规治疗反应好，个别甚至可自愈，长期生存率在90％以上，而多系统尤其伴危险器官受累的高危患儿对常规化疗反应不佳，成为难治或复发病例，预后不良［2］。近些年，陆续报道了核苷类似物对难治和复发LCH患者的挽救治疗及一线治疗，效果令人振奋。本文就此方面进展进行综述。     

伴口腔颌面部受累的朗格罕细胞组织细胞增生症12例临床分析

目的 探讨伴口腔颌面部受累的朗格罕细胞组织细胞增生症（LCH）的临床特点。方法 回顾性分析2012年9月至2017年9月期间住院治疗的12例伴口腔颌面部受累LCH患儿的临床资料,分析其临床表现、病理学特征、治疗及预后。结果 12例伴口腔颌面部受累的LCH患儿中,8例（67%）伴有多系统受累,7例（58%）伴危险器官受累。受累部位以骨最常见（11例,92%）,主要累及下颌骨（7例）。口腔软组织受累表现为牙龈溃疡或增生（4例）、活动牙齿（5例）、口腔黏膜病变（2例）及结节性病变（1例）。病理检查11例CDla阳性,12例CD207、CD68、S-100、LCA均阳性。治疗以手术联合化疗为主,局灶病变可单纯手术切除。痊愈或好转11例,1例放弃治疗并失访,均未见复发。结论 伴口腔颌面部受累LCH患儿易合并多系统受累及危险器官受累,最常累及下颌骨,并伴有牙龈、口腔黏膜、牙齿受累。治疗以手术联合化疗为主,预后良好,不易复发。     

儿童急性呼吸窘迫综合征预后及其影响因素分析

目的：了解儿童急性呼吸窘迫综合征（ARDS）的预后,探讨影响其预后的相关因素。方法：纳入78 例 ARDS 患儿,追踪确诊后 30 d 内生存状况。结果：（1）78 例 ARDS 患儿中,死亡 51 例,生存 27 例,30 d 生存率为 35%,平均生存 14.4 d,中位生存时间 8 d,确诊 ARDS 后 3 d 内为死亡的高峰期。（2）死亡患儿和生存患儿在年龄、原发病、新生儿肺透明膜病的构成比、小儿危重病例评分（PCIS）、机械通气时间、氧合指数（PaO2/FiO2）、WBC 和受累器官数目方面差异存在统计学意义（P＜0.05或0.01）。Cox多因素分析显示年龄（HR 3.924~3.938）、原发病（HR=1.817）和 PCIS（HR=0.469）是发生死亡的危险因素。结论：ARDS 后 3 d 内是死亡的高危期。年龄、原发致病因素和 PCIS 是影响 ARDS 患儿预后的独立因素。     

伴t(8;21)/AML1-ETO阳性的儿童急性髓系白血病的临床特点及预后研究

目的分析伴t(8;21)/AML1-ETO阳性的儿童急性髓系白血病（AML）的临床特点、生物学特征及预后。方法对伴t(8;21)/AML1-ETO阳性的55例AML患儿的临床资料进行回顾性分析,采用Kaplan-Meier 曲线评估患儿的无事件生存（EFS）率、无病生存(DFS)率和总生存(OS)率,COX回归模型评估预后因素。结果①55例伴t(8;21)/AML1-ETO阳性患儿中,4例放弃治疗,4例化疗1疗程后失访,47例患儿进行了双诱导方案化疗,1疗程、2疗程完全缓解率分别为71%和94%,复发10例（21%）,47例患儿的5年EFS率、DFS率、OS率分别为（56.1±7.9）%、（59.8±8.1）%、（72.0±8.1）%。②多因素分析显示年龄是影响患儿预后的独立危险因素,年龄越大出现事故或死亡的风险性越大（P<0.05）。③缓解后继续巩固强化规范化疗的患儿（n=27）5年OS率明显高于不规范化疗的患儿（n=13）［（47.5±17.1）% vs （38.9±17.3）%,P<0.01］。结论伴t (8;21)/AML1-ETO阳性儿童AML是一类具有高度异质性的疾病,其治疗完全缓解率高,远期疗效好,年龄是决定远期疗效的重要因素之一,完全缓解后进行巩固强化规范化疗疗效较好。     

早期B细胞因子1基因异常在儿童急性B淋巴细胞白血病中的意义

目的 了解早期B细胞因子1（EBF1）基因异常在急性B淋巴细胞白血病（B-ALL）患儿中的发生情况,并进一步分析EBF1基因异常与B-ALL患儿预后的相关性。方法　应用多重连接探针扩增（MLPA）技术检测2008年4月至2013年4月中国医学科学院北京协和医学院血液病医院血液学研究所儿童血液病诊疗中心初诊的B-ALL 195例患儿EBF1基因异常情况。根据有无EBF1基因缺失将所有B-ALL患儿分为EBF1缺失组和非EBF1缺失组。结果　195例中15例（7.7%）发生EBF1缺失。两组初诊各项临床特征差异无统计学意义（P＞0.05）。Kaplan-Meier法分析显示EBF1缺失组无病生存率（DFS）及无事件生存率（EFS）明显低于非EBF1缺失组［（59.5±14.8）% vs. （85.5±3.2）%;（55.6±14.3）% vs. （84.2±2.9）%; P均＜0.05］。但两组总生存率（OS）差异无统计学意义［（86.7±8.8）% vs. （91.9±2.1）%, P＞0.05］。Cox法分析显示在排除多项影响因素后, EBF1缺失仍为影响患儿DFS及EFS的不利因素（P＜0.05）。结论　部分B-ALL患儿初诊时伴EBF1基因缺失,EBF1缺失为B-ALL患儿DFS及EFS的独立危险因素。     

Treatment of Langerhans cell histiocytosis with a modified risk‐adapted protocol—experience from a tertiary cancer institute in India

Background

Involvement of risk‐organs (RO+) in Langerhans cell histiocytosis (LCH) and inadequate early response identifies patients at high risk for relapse and mortality requiring intensive salvage therapy including stem cell transplant, adding cost and toxicity. To mitigate this, we used a standard induction, augmented with metronomic etoposide, and prolonged maintenance—similarly augmented for RO+, and retrospectively analyzed its impact.

Procedure

LCH patients from 2009 through 2014 were included. Patients received standard vinblastine and prednisolone therapy weekly till week 25 for RO+. Single site (SS) and multisystem (MS) without risk organ involvement (RO?) received 3‐weekly pulses from week 13 till week 25. Maintenance was 3‐weekly vinblastine and 5‐day prednisolone pulses, daily 6‐mercaptopurine (60 mg/m²) and weekly methotrexate (15 mg/m²) for 18 and 9 months for RO+ and MSRO?, respectively. RO+ also received oral etoposide (50 mg/m²) for 21 of every 28‐day cycle for the first year.

Results

Fifty consecutive patients were analyzed. Median age was 36 months (4–189 months). SS, MSRO?, and RO+ were 29 (58%), 12 (24%), and nine (18%), respectively. Four were lost to follow‐up and excluded from further evaluation. On response evaluation at week 6, 24 (52%) had no active disease (NAD), 17 (37%) had AD‐better (where AD is active disease), and one (2%) had AD‐worse. In RO+, eight (66.6%) had AD‐better and three (25%) had NAD. Forty‐five patients had NAD by week 12. Three patients relapsed. With median follow‐up of 39 months (8–84), 5‐year event free survival was 85.6% (RO? and SS), and 100% for RO+. One patient's death in remission from unrelated causes resulted in overall survival of 97%.

Conclusions

RO+LCH receiving oral etoposide augmented induction and maintenance had early and durable responses. Prolonging maintenance lowered reactivation rates in RO+ and RO?LCH, resulting in excellent survival.

     

Pulmonary Langerhans cell histiocytosis: a variable disease in childhood

BACKGROUND: Pulmonary Langerhans cell histiocytosis (PLCH) is rare in childhood but occurs most commonly in children with multisystem (MS) LCH. In adults, by contrast, the lung is the most common and usually the sole organ affected. This retrospective study describes the clinical manifestation, course, and outcome of PLCH in children consecutively diagnosed at two Canadian institutions. PROCEDURE: The medical records of children (<18 years of age) consecutively diagnosed with LCH at the two institutions, were examined to ascertain the demographic details, pathological diagnosis, and organs involved. Further clinical details including, the clinical manifestation, details of therapy, course of lung disease, and clinical outcome were extracted for patients with PLCH. Initial and follow-up lung radiographs and CT scans were re-reviewed. RESULTS: Of the 178 patients with LCH, 40 (22.5%) presented with MS disease. Thirteen (7.3%) had PLCH, seven at initial diagnosis, and six at the time of disease progression. The median age was 10.1 months and mean was 11.9 months at diagnosis of PLCH. Lung involvement was always in the context of MS LCH, and half of the patients had no respiratory symptoms. Disease-free survival was around 70%, with a mean follow-up duration of 7 years. Of the four patients who died, three had other risk-organ involvement. Five of the nine surviving patients have had complete radiological resolution of PLCH. CONCLUSION: PLCH is seen in less than 10% of childhood LCH, but more than 30% of MS LCH. About half of children with PLCH may be asymptomatic, and the prognosis appears to depend on the presence or absence of other risk-organ involvement. The MS PLCH found in children appears to be a different disease from the single system (SS) PLCH seen in adults.     

Langerhans cell histiocytosis in neonates

BACKGROUND: To study the incidence, clinical patterns, course, and outcome of neonatal Langerhans cell histiocytosis (LCH). PROCEDURE: Retrospective analysis of the data of the Austrian/German/Swiss/Netherlands LCH Study Group. The incidence of neonatal LCH was estimated with the data from the population-based German Childhood Cancer Registry. RESULTS: The estimated incidence of neonatal LCH (LCH diagnosed within 28 days after birth) in the population-based registry was 1-2/1,000,000. In 61/1,069 trial patients (6%), the first disease manifestations were observed in the neonatal period. However, in only 20 of them, the diagnosis was established within this period. There was a preponderance of multisystem (MS)-LCH 36/61 (59%). Cutaneous changes were the most common initial manifestation in both, single-system (SS)-LCH (92%), and MS-LCH (86%). In 72% of the MS-LCH patients, risk organs (ROs) were involved at diagnosis as well. The probability of survival at 5 years was 94% in SS-LCH and 57% in MS-LCH, which is significantly lower than in older age groups. CONCLUSIONS: In contrast to the available literature, neonatal LCH is characterized by a clear predominance of MS-LCH. Cutaneous changes are the most common initial manifestation in neonates with both SS-LCH and MS-LCH. Prompt evaluation of disease extent upon diagnosis is mandatory for risk-adapted treatment. The disease course is unpredictable upon diagnosis. Close monitoring for disease progression is mandatory if isolated cutaneous LCH is managed by the "wait and see" approach. Neonates with MS-LCH, especially those with RO involvement at diagnosis, have less favorable prognosis compared to infants and older children, and need systemic therapy.     

A randomized trial of treatment for multisystem Langerhans' cell histiocytosis

OBJECTIVE: To compare 2 active agents, vinblastine and etoposide, in the treatment of multisystem Langerhans' cell histiocytosis (LCH) in an international randomized study. STUDY DESIGN: One hundred forty-three untreated patients were randomly assigned to receive 24 weeks of vinblastine (6 mg/m(2), given intravenously every week) or etoposide (150 mg/m(2)/d, given intravenously for 3 days every 3 weeks), and a single initial dose of corticosteroids. RESULTS: Vinblastine and etoposide were equivalent (P > or = .2) in all respects: response at week 6 (57% and 49%); response at the last evaluation (58% and 69%); toxicity (47% and 58%); and probability of survival (76% and 83%) [corrected], of disease reactivation (61% and 55%), and of developing permanent consequences (39% and 51%) including diabetes insipidus (22% and 23%). LCH reactivations were usually mild, as was toxicity. All children > or = 2 years old without risk organ involvement (liver, lungs, hematopoietic system, or spleen) survived. With such involvement, lack of rapid (within 6 weeks) response was identified as a new prognostic indicator, predicting a high (66%) mortality rate. CONCLUSIONS: Vinblastine and etoposide, with one dose of corticosteroids, are equally effective treatments for multisystem LCH, but patients who do not respond within 6 weeks are at increased risk for treatment failure and may require different therapy.     

Clinical Characteristics and Treatment Outcome of Langerhans Cell Histiocytosis: 22 Years’ Experience of 154 Patients at a Single Center

Langerhans cell histiocytosis (LCH) is a rare disease of unknown etiology. Large studies by single institutions have been infrequent because of the rarity of the disease and the diversity of clinical manifestations. In this study, the clinical characteristics, prognostic factors, and treatment outcomes were analyzed. Medical records were analyzed retrospectively for the 154 patients diagnosed and treated with LCH at Seoul National University Children's Hospital from January 1986 to December 2007. A total of 154 patients were evaluated. One hundred and six patients (68.8%) had single system disease, 48 patients (31.2%) had multisystem disease. Twenty-nine patients (18.8%) had risk organ involvement. Twenty-nine patients (18.8%) relapsed and the overall survival (OS) of the total study population was 97.1% with a median follow-up period of 7.0 years. Patients less than 4 years old, with involvement more than 2 organs and with risk organ involvement showed lower progression free survival (PFS) (P = .001, <.001, and <.001, respectively). Estimated 10-year PFS of patients with and without risk organ involvement were 52.6% and 83.8%, respectively. Patients with single system LCH had excellent prognosis showing 89.6% of PFS and 100% of OS. Patients with multisystem LCH also had a high survival rate, although the incidences of relapse remain to be solved. A new strategy to decrease the incidence of relapse is needed.     

82例朗格罕斯细胞组织细胞增生症临床分析

目的 分析82例郎格汉斯细胞组织细胞增生症（LCH）患儿的治疗效果,旨在了解LCH的长期预后.方法 收集2001年6月-2011年5月我院收治的初治LCH患儿,其中2001年6月-2005年12月发病者按改良DAL-HX 83/90方案治疗,设为DAL-HX 83/90组,共27例;2006年1月-2011年5月发病者按LCH-Ⅲ方案治疗,设为LCH-Ⅲ组,共55例.所有患儿均按国际组织细胞协会疗效标准评价疗效.结果 82例患儿化疗结束后总有效率为87％,其中DAL-HX83/90组治疗总有效率为82％,LCH-Ⅲ组治疗总有效率为89％,两者比较差异无显著性（P=0.54）.82例患儿5年无事件生存率（EFS）为82％,5年总生存率（OS）为95％.DAL-HX 83/90组和LCH-Ⅲ组患儿复发率分别为22％和16％ （x2=0.12,P=0.73）,3年EFS分别为78％和84％（x2=0.14,P=0.71）.结论 采用改良DAL-HX 83/90方案和LCH-Ⅲ方案的近、远期疗效相仿,均可获得与国外研究近似的有效率和生存率.对有高危脏器累及、复发难治LCH患儿的治疗,仍是目前临床难题.