甲磺酸伊马替尼联合VDLD化疗方案治疗急性淋巴细胞白血病患儿的长期随访研究

目的探究甲磺酸伊马替尼联合VDLD化疗方案治疗急性淋巴细胞白血病(ALL)患儿的应用价值。方法选取2015年5月~2018年6月收治的74例ALL患儿,按照治疗方案不同分组。对照组(37例)实施VDLD方案治疗,联合组(37例)实施甲磺酸伊马替尼+VDLD化疗方案治疗。对比两组疗效、不良反应发生率、随访1年无复发生存率(RFS)及治疗前、治疗2个疗程后血清B淋巴细胞刺激因子(BAFF)、增殖诱导配体(APRIL)水平。结果联合组总有效率(91.89%)高于对照组(72.97%)(P<0.05);联合组治疗2个疗程后血清BAFF、APRIL水平低于对照组(P<0.05);两组不良反应发生率、随访1年RFS对比无显著差异(P>0.05)。结论甲磺酸伊马替尼联合VDLD化疗方案治疗ALL,疗效确切,能显著降低血清BAFF、APRIL水平,且安全性高。     

胃肠间质瘤的CT诊断及治疗评价

目的:探讨胃肠间质瘤(GIST)的CT表现及分子靶向药物甲磺酸伊马替尼(STI571)对胃肠间质瘤疗效的CT评价。方法:选择经手术及病理证实的胃肠间质瘤病例32例进行回顾性分析。对19例接受STI571治疗者进行定期CT检查随访,观察病灶大小、形态及密度变化,评价药物疗效。结果:32例GIST中,发生于胃部的18例,小肠11例,肠系膜1例,直肠2例。①CT特征:恶性度较高的胃肠间质瘤CT表现为:肿块相对较大,密度不均,肿瘤中央坏死及囊变多见;肿瘤边缘多不光整,可呈分叶状。增强扫描肿瘤呈不均匀强化;少数巨大肿瘤密度较低,极少数可见高密度出血及钙化灶。良性GIST体积较小,密度均匀,肿瘤坏死及囊变少见,病灶边缘光整,增强扫描多呈均匀强化;②19例接受STI571治疗者定期CT检查疗效评价为(肿瘤缩小):疗效达PR(部分缓解)者9例,占47.4%,疗效为SD(疾病稳定)者8例,占42.1%,病灶进展(PD)者2例,占10.5%。术后2年内复发及转移者19例。结论:①螺旋CT扫描是诊断胃肠间质瘤最常用和最有价值的影像检查手段,其定位诊断率达81%以上;②应用CT扫描观察测量病灶变化是评价药物(STI571)治疗胃肠间质瘤疗效最重要和最直接的方法之一;对指导临床治疗具有重要意义。     

甲磺酸伊马替尼治疗国人胃肠间质瘤的临床研究

 目的 观察和评价甲磺酸伊马替尼（Imatinib mesylate）治疗国人胃肠间质瘤（GIST）的有效性和安全性。方法 2002年8月至2004年12月，在本院通过病理形态学及免疫组化确诊的GIST共52例，其中36例应用伊马替尼治疗，用法为伊马替尼400mg，口服，1／日。参照WHO实体瘤客观疗效标准观察和判定疗效，NCI-CTC2．0版抗癌药的毒性标准观察和判定毒性。结果 伊马替尼治疗的36例患者中，包括新辅助治疗和姑息治疗在内可以评价疗效的有28例，用药后获得部分缓解为14例（50％），疾病稳定10例（35．7％），疾病进展4例（14．3％）；即有效率（RR）为50％，疾病控制率（DCR）达到85．7％。36例均可进行毒性评价，除了1例因胃部GIST合并脾脏B细胞型非霍奇金淋巴瘤，姑息切除术后口服格列卫同时进行CHOP方案化疗，结果 发生了Ⅲ级骨髓抑制外，其他35例中毒副反应均为Ⅰ～Ⅱ级，而且大多数毒性可以控制或恢复正常。结论 与国外文献报道一致，甲磺酸伊马替尼治疗国人GIST安全高效，耐受性好。     

伊马替尼抑制脂多糖诱导的巨噬细胞炎症表型

【目的】探讨伊马替尼（Ima）在体外对脂多糖（LPS）诱导的RAW264.7巨噬细胞炎症表型的影响。【方法】RAW264.7细胞在LPS（0.1μg/mL）或/和Ima（1μmol/L,5μmol/L）处理后,通过Q-PCR方法检测细胞因子IL-1β、IL-10、CCL2、iNOS、TNF-α和Arg1的mRNA表达变化;采用Western Blot检测iNOS蛋白表达变化以及NF-κB和MAPK信号通路活化情况;利用ELISA法检测细胞上清IL-1β、CCL2、IL-10和TNFα的蛋白表达情况。【结果】与对照组相比较,LPS刺激8h后,RAW264.7细胞内的炎症指标IL-1β、CCL2、iNOS和TNF-α的mRNA水平显著升高（P<0.001）以及抗炎指标IL-10的mRNA水平也明显升高（P<0.001）;LPS刺激24h后,细胞上清中IL-1β、IL-10、CCL2和TNF-α的蛋白水平显著上升（P<0.001）,细胞内iNOS蛋白表达以及p65,p38,ERK和AKT的磷酸化水平显著增加。和LPS组相比,Ima提前处理后,IL-1β、CCL2、iNOS和TNF-α的mRNA及蛋白水平显著下降（P<0.01,P<0.001）而IL-10的mRNA及蛋白水平显著升高（P<0.001）,这种抑制作用具有剂量依赖性。Ima的预处理抑制了LPS诱导的p65,p38,ERK和AKT磷酸化。单独用Ima处理RAW264.7细胞后,细胞的功能状态未见明显的改变。【结论】伊马替尼可抑制LPS诱导的巨噬细胞炎症表型,这种作用与抑制NF-κB和MAPK信号通路的过度激活有关。     

A Phase II Study of CLAG Regimen Combined With Imatinib Mesylate for Relapsed or Refractory Acute Myeloid Leukemia

IntroductionNo standard salvage chemotherapy regimen is available for relapsed or refractory (RR) acute myeloid leukemia (AML). Preclinical data have suggested synergy in vitro between cytarabine and imatinib mesylate (IM) on AML cell growth inhibition. After demonstrating the safety and feasibility in a phase I study, we conducted a phase II clinical study of CLAG (cladribine, cytarabine, granulocyte colony-stimulating factor) regimen combined with IM for patients with RR-AML.Patients and MethodsWe performed a single-institution 2-stage phase II study. The primary endpoint was the remission rate measured using the standard AML response criteria. The secondary endpoints included overall survival (OS) and progression-free survival (PFS).ResultsFrom August 2009 to April 2011, 38 patients were treated at the Moffitt Cancer Center. Their median age was 62 years (range, 26-79 years). Of the 38 patients, 7 (18%) had refractory AML, 19 (50%) had early relapse, and 12 (32%) had late relapse. At the original diagnosis, only 2 patients had favorable risk factors, 18 had intermediate risk, and 16 had poor risk; for 2 patients, the karyotype was missing. The overall response rate for all 38 evaluable patients was 37%. The median OS was 11.1 months (95% CI, 4.8-13.4 months), the median PFS was 4.9 months (95% CI, 1.6-11.7 months). Among the responders, 8 of 14 patients subsequently underwent allogeneic hematopoietic cell transplantation.ConclusionCLAG plus IM was well tolerated, with encouraging signs of activity in patients with poor-risk AML.     

Clinical characteristics and treatment outcome in a large multicentre observational cohort of PDGFRA exon 18 mutated gastrointestinal stromal tumour patients

PurposePatients, platelet-derived growth factor receptor alpha (PDGFRA) D842V-mutated gastrointestinal stromal tumours (GISTs) are known for their insensitivity to imatinib. However, in clinical practice responses have been observed in some patients. We describe the natural history and treatment outcomes in a cohort of PDGFRA exon 18 mutated GIST patients.Patients and methodsA retrospective cohort study was conducted in PDGFRA exon 18 mutation GIST patients treated in six expert centres in the Netherlands and the United States. Two independent radiologists assessed radiological response to imatinib according to Choi's criteria in all patients with measurable disease treated with imatinib in neo-adjuvant or palliative intent.ResultsSeventy-one patients with PDGFRA exon 18 mutation were identified of whom 48 patients (69%) had a D842V mutation. Twenty-two (45.8%) D842V-mutated GIST patients received imatinib treatment, 16 had measurable disease. Fourteen out of the 23 (60.9%) patients with non-D842V mutations received imatinib treatment, eight had measurable disease. Two out of 16 (12.5%) D842V-mutated GIST patients had partial response, 3 patients (18.8%) had stable disease and 9 patients (56.3%) had progressive disease as best response. Two patients did not have follow-up computed tomography scans to assess response. Six out of 8 (75%) patients with non-D842V exon 18 mutations had partial response and two (25%) had stable disease as best response.ConclusionPatients with D842V-mutated GISTs can occasionally respond to imatinib. In the absence of better therapeutic options, imatinib should therefore not be universally withheld in patients with this mutation.     

Chronische myeloproliferative Erkrankungen

Zusammenfassung Die chronischen myeloproliferativen Erkrankungen (CMPE) sind neoplastische Erkrankungen der hämatopoetischen Stammzelle. Sie umfassen die chronische myeloische Leukämie (CML), die Polycythaemia vera, die essentielle Thrombozythämie, die primäre Osteomyelofibrose und Übergangsformen innerhalb dieser Erkrankungen sowie zwischen den CMPE und den Myelodysplasien. Hauptziele der Initialdiagnostik sind die genaue Klassifizierung der Erkrankung, die Erfassung von Risiko- und Prognosefaktoren sowie die Charakterisierung des malignen Klons mittels Zytogenetik und molekulargenetischer Methoden. Herkömmliche Therapeutika für alle CMPE sind Hydroxyurea und Interferon-. Bei der CML führt die gezielte Hemmung der BCR-ABL-Tyrosinkinase mit Imatinib klinisch zu hohen Ansprechraten. Die bisher einzige kurative Therapie für alle Entitäten ist die allogene Stammzelltransplantation. Bei der CML sollte die Indikation auf der Basis der neueren Risikoscores gestellt werden. Bei den BCR-ABL-negativen CMPE ist sie nur bei ungünstigem Krankheitsverlauf in Erwägung zu ziehen.

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In vitro inhibitory effects of imatinib mesylate on stromal cells and hematopoietic progenitors from bone marrow

Imatinib mesylate (IM) is used to treat chronic myeloid leukemia (CML) because it selectively inhibits tyrosine kinase, which is a hallmark of CML oncogenesis. Recent studies have shown that IM inhibits the growth of several non-malignant hematopoietic and fibroblast cells from bone marrow (BM). The aim of the present study was to evaluate the effects of IM on stromal and hematopoietic progenitor cells, specifically in the colony-forming units of granulocyte/macrophage (CFU-GM), using BM cultures from 108 1.5- to 2-month-old healthy Swiss mice. The results showed that low concentrations of IM (1.25 µM) reduced the growth of CFU-GM in clonogenic assays. In culture assays with stromal cells, fibroblast proliferation and α-SMA expression by immunocytochemistry analysis were also reduced in a concentration-dependent manner, with a survival rate of approximately 50% with a dose of 2.5 µM. Cell viability and morphology were analyzed using MTT and staining with acrydine orange/ethidium bromide. Most cells were found to be viable after treatment with 5 µM IM, although there was gradual growth inhibition of fibroblastic cells while the number of round cells (macrophage-like cells) increased. At higher concentrations (15 µM), the majority of cells were apoptotic and cell growth ceased completely. Oil red staining revealed the presence of adipocytes only in untreated cells (control). Cell cycle analysis of stromal cells by flow cytometry showed a blockade at the G₀/G₁ phases in groups treated with 5-15 µM. These results suggest that IM differentially inhibits the survival of different types of BM cells since toxic effects were achieved.