格列卫治疗一例以咳嗽、发热为首发表现的特发性嗜酸粒细胞增多综合征及文献复习

目的 提高临床医师对特发性嗜酸粒细胞增多综合征的认识.方法 分析一例特发性嗜酸粒细胞增多综合征患者的临床资料及诊治经过,并复习相关文献.结果 患者,男,27岁,因“咳嗽伴畏寒发热1周,痰中带血1d”入院.多次复查血常规提示血嗜酸粒细胞增高,肺部CT提示双侧胸腔积液,心包积液,诊断为特发性嗜酸粒细胞增多综合征,给予甲基泼尼松龙治疗无效,后行血清FIP1L1/PDGFRα融合基因检测,结果提示阳性,改格列卫治疗,复查血常规提示血嗜酸粒细胞恢复正常.结论特发性嗜酸粒细胞增多综合征比较少见,临床表现不典型,故临床医师应提高对本病的认识.     

七例FIPL1-PDGFRα阴性高嗜酸性粒细胞综合征临床分析

目的探讨FIPL1-PDGFRα阴性高嗜酸性粒细胞综合征患者的临床特征。方法对7例FIPL1-PDGFRα阴性高嗜酸性粒细胞综合征患者的病史、临床表现和实验室检查结果以及治疗进行综合分析。结果FIPL1-PDGFRα阴性高嗜酸性粒细胞综合征的诊断需要排除反应性和继发性因素,分为克隆性和特发性。临床表现为外周血嗜酸性粒细胞增高和受累器官相应症状。以激素作为一线治疗。结论不明原因嗜酸性粒细胞明显升高伴个或多个器官损害的患者应警惕高嗜酸性粒细胞综合征。FIPL1-PDGFRα阴性的高嗜酸性粒细胞综合征足量使用激素可取得较好疗效。     

原发性嗜酸性粒细胞增多症的诊断分型与治疗进展

原发性嗜酸性粒细胞增多症(HES)是一类少见的异质性疾病,近年来随着对FIP1L1-PDGFRα(简称F/P)融合基因等特异性分子学特性的深入研究,人们对HES诊断分型和临床治疗手段进一步提高,新的酪氨酸激酶抑制剂的临床应用也使HES疗效显著改善.     

并殖吸虫病临床表现及误诊分析

目的:探讨并殖吸虫病的临床表现、治疗及误诊情况,提高对本病的认识,减少误诊率。方法:分析80例并殖吸虫病的临床类型、实验室检查结果、诊治方法及误诊情况。结果:临床分型依次为胸肺型55例(68.8%);皮肤型18例(22.5%);腹型4例(5%);其他3例(3.7%)。临床误诊49例,占61.3%,多被误诊为肺结核、结核性胸膜炎、慢性支气管炎,其次为肺肿瘤、嗜酸性粒细胞增多症、结核性心包炎及颅脑肿瘤等。所有患者肺吸虫抗体检测均为阳性,90%患者白细胞及嗜酸性粒细胞升高,白细胞数为(10.91±4.99)×109/L,嗜酸性粒细胞计数为(1.65±2.07)×109/L,嗜酸性粒细胞百分比为(39.40±19.17)%,经吡喹酮驱虫治疗后嗜酸性粒细胞百分比下降至(9.20±10.17)%,且全部患者治愈。结论:并殖吸虫病临床表现复杂多变,临床误诊率高,提高对本病的认识,保持高度的警惕性,是减少误诊的关键。如能及时诊断和治疗,预后良好。     

特发性嗜酸粒细胞增多综合征研究进展

特发性嗜酸粒细胞增多综合征是一种以嗜酸粒细胞增多伴靶器官损害为特征的异源性疾病,既往以排除性诊断和防治靶器官损害为主,新近研究显示酪氨酸激酶抑制剂伊马替尼可使部分患者获得完拿血液学缓解,并由此发现一由染色体缺失形成的融合基因FIPILI—PDGFRα。现将已有对特发性嗜酸粒细胞增多综合征的认识及FIPILI—PDGFRα对特发性嗜酸粒细胞增多综合,正诊断分类及治疗的意义作一综述。     

伴t(5;12)(q31;p13),FIP1L1/PDGFRα阴性慢性嗜酸细胞白血病一例并文献复习

目的 提高对慢性嗜酸细胞白血病(CEL)的认识水平.方法 报告1例伴t(5;12)(q31;p13),FIP1样基因1(FIP1L1)血小板衍化生长因子(PDGFRα)(-)CEL的诊治过程.外周血及胸腔积液细胞的免疫表型采用流式细胞术(FCM)分析,染色体采用G显带分析,FIP1L1/PDGFRα融合基因表达采用RT-PCR技术检测,骨髓、肺及脾组织行常规病理学检查.结果 1例16岁女性患者严重贫血、发热、脾大、血小板减少、嗜酸细胞显著增高,持续22个月.骨髓嗜酸细胞浸润伴纤维化改变;肺和脾组织均呈嗜酸细胞浸润,伴脾栓塞.克隆性染色体异常为t(5;12)(q31;p13),不表达FIP1L1/PDGFRα融合基因.外周血及胸腔积液细胞中除大量嗜酸细胞外,CD3-、CD4-、CD8+异常T淋巴细胞分别占淋巴细胞总数的5.43%和1.66%.患者对羟基脲、泼尼松、干扰素和甲磺酸伊马替尼(400 ms/d共40 d)治疗无效,小剂量阿糖胞苷、米托蒽醌、长春新碱、环磷酰胺、甲氨蝶呤、泼尼松等联合化疗仅有短期效果.患者最终死于心、肺、肝、肾多脏器功能衰竭.结论 本例FIP1L1/PDGFRα(-)CEL符合WHO诊断标准,对多种药物及甲磺酸伊马替尼治疗无效,应在疾病早期尽早争取造血干细胞移植.CD3-、CD4-、CD8+克隆性T细胞异常与CEL发病的关系值得关注.     

糖皮质激素对嗜酸性粒细胞阳性AECOPD患者临床疗效观察

目的观察糖皮质激素对嗜酸性粒细胞阳性的慢性阻塞性肺疾病急性加重期(AECOPD)患者的临床疗效。方法将60例符合AECOPD诊断的患者,根据外周血嗜酸性粒细胞百分比分成嗜酸性粒细胞阳性组(≥2%) 33例,嗜酸性粒细胞阴性组(2%) 27例。两组在常规治疗基础上第1～5天给予注射用甲泼尼龙琥珀酸钠40 mg,1次/d。于入院第1天及第7天测定C反应蛋白(CRP)及白细胞介素-8(IL-8),并于入院后第7天评估临床疗效。结果嗜酸性粒细胞阳性组CRP及IL-8水平下降较嗜酸性粒细胞阴性组更明显。嗜酸性粒细胞阳性组治愈21例,好转10例,无效2例;嗜酸性粒细胞阴性组分别为12例、6例和9例。嗜酸性粒细胞阳性组临床疗效优于嗜酸性粒细胞阴性组(P 0. 05)。结论嗜酸性粒细胞阳性组对糖皮质激素反应效果较阴性组好,在临床中可以考虑对嗜酸性粒细胞阳性AECOPD患者使用糖皮质激素。     

融合基因蛋白靶点药物--依马替尼治疗恶性血液病的临床研究

依马替尼(格列卫,STI571)是继全反式维甲酸成功治疗白血病之后又一个被公认的基因产物的靶向药物。目前,已明确对表达bcr/abl融合基因、Ckit或CD117及FIP1L1/PDGFR-α融合基因的肿瘤细胞具有很好的治疗作用。自美国食品药品管理局(FDA)批准用于临床4年来,其研究进展取得了丰硕的成果。以下将我们的研究并结合当前的临床研究进展介绍如下。1作用机制研究表明,95%的慢性粒细胞白血病(CML)患者bcr/abl阳性,成人急性淋巴细胞白血病(ALL)和急性髓细胞白血病(AML)中伴有Ph染色体阳性者分别为30%和15%左右,在原发性高嗜酸粒细胞增多症(…     

肺癌合并血嗜酸性粒细胞增多临床特点

目的 探讨肺癌合并血嗜酸性粒细胞增多的临床特点及意义.方法 结合我院收治的1例肺癌合并嗜酸性粒细胞增多的临床资料及国外文献报道的实体肿瘤合并嗜酸性粒细胞增多的病例报道进行综合分析.结果 患者男,80岁,表现为右侧胸痛,呈持续性钝痛,胸部CT示右肺上叶后段厚壁空洞,伴邻近骨质破坏,右肺动脉及右主支气管受侵,右侧少量胸腔积液.血嗜酸性粒细胞增多,比例为0.169,绝对值2.15×109/L,痰及支气管灌洗液中嗜酸性粒细胞比例也明显增高.CT引导下穿刺活检显示为鳞癌.患者发现合并嗜酸性粒细胞时,肺癌已有转移,预后差,与文献报道一致.结论 肺癌等恶性肿瘤通过分泌嗜酸性粒细胞克隆刺激因子引发血嗜酸性粒细胞增多,为较少见的副癌综合征,提示肿瘤已有转移,预后差.     

特发性嗜酸性粒细胞增多综合征肾脏损害的临床病理分析

目的:分析特发性嗜酸性粒细胞增多综合征(IHES)伴肾脏损害患者的临床病理特征、治疗及预后。方法:回顾性分析IHES肾脏损害患者的临床表现,探讨其肾脏损害的临床、病理、治疗及预后特点。结果:18例患者,男性13例、女性5例,发病中位年龄36岁(9~67岁)。临床表现为多系统受累,均有肾脏受累,其次是皮肤(27.8%)、肺脏(27.8%)、胃肠道(27.8%)、神经(11.1%)。血嗜酸粒细胞均明显升高(1 670~15 100/μl)。肾损害表现为肾病综合征12例(66.7%)、尿检异常4例(22.2%)、急性肾损伤2例(11.1%)、慢性肾功能不全共6例(33.3%)。15例行肾活检,病理表现为膜增生样病变3例、足细胞病3例、系膜增生性病变2例、IgA肾病2例、膜性肾病2例、慢性间质性肾炎2例、局灶节段性硬化症1例;11例肾间质见嗜酸性粒细胞浸润,3例肾小球见嗜酸性粒细胞浸润;免疫荧光检查:12例见免疫球蛋白、补体沉积。应用糖皮质激素或联合免疫抑制剂治疗后血嗜酸粒细胞均下降;15例随访患者中,14例尿蛋白下降或转阴、肾功能恢复或稳定,停激素后8例嗜酸性粒细胞增加,1例尿蛋白增加,1例进展至终末期肾病。结论:IHES可发生肾脏损害,以肾病综合征为主要表现,病理类型多种多样,肾间质多数可见嗜酸性粒细胞浸润。多数患者经激素治疗后预后较好。     

The FIP1L1-PDGFRalpha kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia

PURPOSE OF REVIEW: The idiopathic hypereosinophilic syndrome is a rare hematologic disorder characterized by sustained unexplained eosinophilia with associated end-organ damage and by a striking male predominance. The first insights into the molecular etiology of this heterogeneous disease were obtained from a "bedside-to-bench" approach. Successful empiric treatment of patients with the hypereosinophilic syndrome with the selective tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis) ultimately led to the discovery of the FIP1L1-PDGFRalpha fusion kinase in about half of the hypereosinophilic syndrome cases. RECENT FINDINGS: The FIP1L1-PDGFRA fusion gene is generated by a cryptic interstitial chromosomal deletion, del(4)(q12q12), which indicates that these cases are clonal hematopoietic malignancies and should be reclassified as chronic eosinophilic leukemias based on current World Health Organization recommendations. In addition, the FIP1L1-PDGFRA fusion gene was also identified in cases with systemic mast cell disease. In vitro and in vivo studies confirmed that FIP1L1-PDGFRalpha is a therapeutic target of imatinib, forming a rational basis for the treatment of FIP1L1-PDGFRA positive chronic eosinophilic leukemia and mastocytosis with imatinib. Similar to BCR-ABL-positive leukemias, resistance to imatinib due to point mutations in the PDGFRalpha kinase domain may develop. We have explored strategies to circumvent resistance to imatinib using alternative tyrosine kinase inhibitors such as PKC412. SUMMARY: The discovery of the FIP1L1-PDGFRA fusion gene in the hypereosinophilic syndrome is an example of the power of clinical translational research and identifies interstitial chromosomal deletion as a novel mechanism to generate oncogenic tyrosine kinase fusion genes.     

The EOL-1 cell line as an in vitro model for the study of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia

We recently identified the chimeric kinase FIP1L1-platelet-derived growth factor receptor alpha (PDGFRalpha) as a cause of the hypereosinophilic syndrome and of chronic eosinophilic leukemia. To investigate the role of FIP1L1-PDGFRA in the pathogenesis of acute leukemia, we screened 87 leukemia cell lines for the presence of FIP1L1-PDGFRA. One cell line, EOL-1, expressed the FIP1L1-PDGFRA fusion. Three structurally divergent kinase inhibitors--imatinib (STI-571), PKC412, and SU5614--inhibited the growth of EOL-1 cells. These results indicate that the fusion of FIP1L1 to PDGFRA occurs rarely in leukemia cell lines, but they identify EOL-1 as an in vitro model for the study of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia and for the analysis of small molecule inhibitors of FIP1L1-PDGFRalpha.     

Response to imatinib mesylate in patients with hypereosinophilic syndrome

Idiopathic hypereosinophilic syndrome (HES) is a rare disorder characterized by unexplained, persistent hypereosinophilia associated with multiple organ dysfunctions. The cause of HES is unknown and shows clinical heterogeneity. FIP1L1-PDGFRA fusion is a clonal marker for the diagnosis and treatment of HES. We prospectively studied 78 patients with chronic eosinophilia. In all cases, the most salient clinical and biological characteristics as well as the response to the therapy were analyzed. In addition, we performed conventional cytogenetics and fluorescent in situ hybridization (FISH) with three BACs covering the FIP1-like-1 (FIP1L1)/platelet-derived growth factor receptor-α gene (PDGFRA) fusion. Nineteen of 78 patients (24?%) presented criteria of HES. The majority of patients were male (18) with median age of 49?years (range 19-84?years). FIP1L1-PDGFRA fusion was found in eight patients. Patients with FIP1L1-PDGFRA fusion presented with more bone marrow eosinophils and peripheral blood eosinophilia as well as anemia, leukocytosis and thrombocytopenia. Using of low-dose imatinib mesylate (100?mg/day) a hematological and molecular remission in all patients displaying the FIP1L1-PDGFRA fusion gene was observed. Therefore, imatinib may be effective for use in the treatment of chronic eosinophilic leukemia, and patients should be treated before tissue damage.     

Cough and hypereosinophilia due to FIP1L1-PDGFRA fusion gene with tyrosine kinase activity.

Eosinophil-associated conditions, such as asthma and eosinophilic bronchitis, have been associated with chronic persistent cough, usually responding to corticosteroid therapy. This case study reports a case of persistent cough associated with gastro-oesophageal reflux (GOR) and hypereosinophilia. Treatment of GOR with proton pump inhibitors and fundoplication did not control the cough. However, high dose prednisolone, but not inhaled corticosteroids, did. The presence of the FIP1L1-PDGFRA fusion gene in myeloid cells was confirmed by fluorescence in situ hybridisation analysis using CHIC2 deletion as a surrogate marker. The cough and other disease features were subsequently suppressed by the tyrosine kinase inhibitor, imatinib. This is the first case of persistent cough caused by hypereosinophilic syndrome characterised by FIP1L1-PDGFRA fusion gene and aberrant tyrosine kinase activity.     

Clinical Features of Hypereosinophilic Syndrome: FIP1L1-PDGFRA Fusion Gene—Positive Disease is a Distinct Clinical Entity with Myeloproliferative Features and a Poor Response to Corticosteroid

We conducted a retrospective analysis of the clinical features of 20 patients with severe eosinophilia at our institution, including 10 cases of hypereosinophilic syndrome (HES) (5 definite and 5 probable cases) and 10 cases of other eosinophilic disorders. Of the 20 patients, 14 initially received prednisolone treatment, which resulted in rapid improvement and normalization of eosinophilia within 8 weeks; however, 2 patients with splenomegaly showed poor control of eosinophilia in response to corticosteroid treatment. In addition, the FIP1L1-PDGFRA fusion gene was detected only in these 2 cases. One of the FIP1L1-PDGFRA - positive HES cases featured bone marrow fibrosis. Treatment of this patient with imatinib mesylate resulted in a dramatic improvement of eosinophilia, organomegaly, and the bone marrow fibrosis. Taken together, our data and previous reports suggest that FIP1L1-PDGFRA - positive HES is a distinct clinical entity with myeloproliferative features and showing a poor response to corticosteroid treatment.     

A single weekly dose of imatinib is sufficient to induce and maintain remission of chronic eosinophilic leukaemia in FIP1L1-PDGFRA-expressing patients

Hypereosinophilic syndrome (HES) is defined as chronic, unexplained hypereosinophilia with organ involvement. A subset of HES patients presents an interstitial deletion in chromosome 4q12, which leads to the expression of an imatinib-responsive fusion gene, FIP1L1-PDGFRA. These patients are diagnosed as chronic eosinophilic leukaemia (CEL). We treated seven CEL and HES patients, six of which expressed FIP1L1-PDGFRA , with imatinib using initial daily doses ranging from 100 to 400 mg. In a remission maintenance phase, the patients were treated with imatinib once weekly. All imatinib-treated patients achieved a complete haematological remission (CHR), and five of the six patients with FIP1L1-PDGFRA expression exhibited molecular remission. The decreased imatinib doses were as follows: 200 mg/week in three patients, 100 mg/week in two patients and 100 mg/d in the remaining two patients. For remission maintenance, imatinib doses were set at 100 mg/week in five patients and 200 mg/week in two patients. At a median follow-up of 30 months all patients remained in CHR and FIP1L1-PDGFRA expression was undetectable in five of the six FIP1L1-PDGFRA -expressing patients. These data suggest that a single weekly dose of imatinib is sufficient to maintain remission in FIP1L1-PDGFRA - positive CEL patients.     

The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management

Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) comprise a spectrum of indolent to aggressive diseases characterized by unexplained, persistent hypereosinophilia. These disorders have eluded a unique molecular explanation, and therapy has primarily been oriented toward palliation of symptoms related to organ involvement. Recent reports indicate that HES and CEL are imatinib-responsive malignancies, with rapid and complete hematologic remissions observed at lower doses than used in chronic myelogenous leukemia (CML). These BCR-ABL-negative cases lack activating mutations or abnormal fusions involving other known target genes of imatinib, implicating a novel tyrosine kinase in their pathogenesis. A bedside-to-benchtop translational research effort led to the identification of a constitutively activated fusion tyrosine kinase on chromosome 4q12, derived from an interstitial deletion, that fuses the platelet-derived growth factor receptor-alpha gene (PDGFRA) to an uncharacterized human gene FIP1-like-1 (FIP1L1). However, not all HES and CEL patients respond to imatinib, suggesting disease heterogeneity. Furthermore, approximately 40% of responding patients lack the FIP1L1-PDGFRA fusion, suggesting genetic heterogeneity. This review examines the current state of knowledge of HES and CEL and the implications of the FIP1L1-PDGFRA discovery on their diagnosis, classification, and management.     

FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia

A novel oncogenic mutation (FIP1L1-PDGFRA), which results in a constitutively activated platelet-derived growth factor receptor-alpha (PDGFRA), has been invariably associated with a primary eosinophilic disorder. The current study examines both the prevalence and the associated clinicopathologic features of this mutation in a cohort of 89 adult patients presenting with an absolute eosinophil count (AEC) of higher than 1.5 x 10(9)/L. A fluorescence in situ hybridization (FISH)-based strategy was used to detect FIP1L1-PDGFRA in bone marrow cells. None of 8 patients with reactive eosinophilia displayed the abnormality, whereas the incidence of FIP1L1-PDGFRA in the remaining 81 patients with primary eosinophilia was 14% (11 patients). None (0%) of 57 patients with the hypereosinophilic syndrome (HES) but 10 (56%) of 19 patients with systemic mast cell disease associated with eosinophilia (SMCD-eos) carried the specific mutation. The bone marrow mast cell infiltration pattern in FIP1L1-PDGFRA(+) SMCD-eos was distinctly diffuse with loose tumoral aggregates. Treatment with low-dose imatinib (100 mg/d) produced complete and durable responses in all 8 FIP1L1-PDGFRA(+) cases treated. In contrast, only 40% partial response rate was seen in 10 HES cases. FIP1L1-PDGFRA is a relatively infrequent but treatment-relevant mutation in primary eosinophilia that is indicative of an underlying systemic mastocytosis.     

Safety and efficacy of imatinib in chronic eosinophilic leukaemia and hypereosinophilic syndrome: a phase-II study

This study evaluated the efficacy and safety of imatinib in chronic eosinophilic leukaemia (CEL, n = 23) and hypereosinophilic syndrome (HES, n = 13). In CEL with FIP1L1-PDGFRA (n = 16) or various PDGFRB fusion genes (n = 5), complete haematological remission (CHR) was achieved in 95% (20/21) after 3 months. Complete molecular remission (CMR) was seen in 75% (12/16) of cases with FIP1L1-PDGFRA positive CEL by 6 months, and in 87% (13/15) after 12 months. CMR was achieved in three of five PDGFRB fusion positive patients after 3, 9 and 18 months respectively. All patients are currently on imatinib (100 mg; n = 13, 400 mg; n = 8) and no molecular relapse has yet been observed (median 26.7 months; range, 6.9-39.9). Imatinib was less effective in HES and CEL without known molecular aberration (n = 15); CHR was observed in 40% (6/15) of patients, two patients relapsed after 4.8 and 24.5 months. Three patients died due to imatinib-resistant progressive CEL (n = 2) or myocardial infarction (n = 1) unrelated to study treatment. Overall, imatinib was well tolerated with a low incidence of grade III/IV toxicities. These data confirmed the long-term efficacy of imatinib for PDGFR-rearranged CEL patients, and also showed that a minority of HES cases without known molecular aberrations may benefit from imatinib.