EML4-ALK融合介导EGFR-TKI耐药晚期肺腺癌个案报告

表皮生长因子受体（EGFR）基因突变和间变性淋巴瘤激酶（ALK）基因融合的发现显著改变了非小细胞肺癌的治疗模式，并使患者生存显著获益。ALK融合突变是EGFR酪氨酸激酶抑制剂（TKI）耐药的机制之一。我们报告了1例64岁晚期肺腺癌女性患者，其存在EGFR突变，并在EGFR-TKI耐药后发生了ALK融合，通过先后使用EGFR-TKI或ALK-TKI获得了长期生存，为ALK融合介导的EGFR-TKI耐药患者的靶向治疗药物选择提供参考。     

BRAF V600E基因突变与甲状腺乳头状癌远处转移及预后的关系

目的 研究BRAF V600E基因突变能否成为乳头状甲状腺癌（PTC）预后相关分子标志物，从而更有利于PTC的个体化治疗。方法 收集远处转移的高分化乳头状甲状腺癌患者的肿瘤组织标本共30例，运用扩增受阻突变系统（ARMS）法进行BRAF基因检测。结果 BRAF基因突变率为36.67%（11/30），均为V600E突变；BRAF V600E基因突变与患者性别、有无淋巴结转移、远处转移情况、肿瘤病理类型及大小均无明显相关性（P>0.05），而与患者年龄（≥45岁）显著相关（P=0.025）；BRAF突变型患者的无进展生存时间（PFS）更长（P=0.05）。结论 BRAF突变型远处转移高分化乳头状甲状腺癌患者可能预后更好。     

UGT1A1基因多态性对药物代谢和临床作用影响的进展

UGT1A1基因是参与人体代谢循环的重要基因,随着药物基因组学的发展,发现其基因多态性与某些药物代谢水平相关,进而影响疾病的发生、发展及治疗等诸多方面。随着研究进展,UGT1A1的底物在不断扩展,包括胆红素、雌激素、伊立替康及其他一些药物已有研究。研究UGT1A1基因多态性对药物代谢情况的影响,在临床疾病的诊治、预后判断及药物不良反应等方面有重要的指导意义。     

MET扩增非小细胞肺癌患者的临床病理特征及其对克唑替尼的响应分析★

目的 探讨非小细胞肺癌患者MET基因扩增与临床病理特征的相关性，揭示MET扩增与其他驱动基因突变共存患者对克唑替尼的敏感性。方法 回顾性分析252例非小细胞肺癌患者的临床病理资料，采用二代测序法检测常见驱动基因EGFR、ALK、ROS1、RET、HER2、BRAF和MET的突变情况，特定突变患者采用Fish法进行验证；根据患者MET基因扩增情况进行分组，比较各组患者年龄、吸烟史、性别、病理类型、疾病阶段及其他驱动基因突变情况；收集MET扩增与其他驱动基因突变共存患者使用克唑替尼后的预后数据。结果 252例患者中，MET扩增发生率为19.4%（49/252），其中原发MET扩增和继发MET扩增突变率分别为16.2%（33/203）和31.2%（15/48）。MET扩增多见于Ⅲ~Ⅳ期肺癌（P=0.02）、骨转移（P=0.02）及ROS1融合阳性（P=0.02）患者，与年龄、性别、吸烟史、病理学分类无明显相关性（P>0.05）。31例MET扩增阳性患者具有其他驱动基因突变，其中5例患者使用克唑替尼进行治疗。5例使用克唑替尼的患者中，2例是原发MET扩增，3例是继发MET扩增；4例使用克唑替尼获得了较好的效果，1例死于重度感染。总结 MET扩增在本研究人群中的突变率高于文献报道，且多见于临床分期较晚、骨转移、ROS1融合阳性患者。MET扩增与其他驱动基因突变共存的患者也能在一定程度上从克唑替尼中获益。     

不同类型吉兰-巴雷综合征预后及疗效比较

目的 分析比较不同亚型吉兰-巴雷综合征（GBS）患者的预后及不同药物治疗的临床疗效。方法 收集2014年1月至2016年9月在安徽医科大学第一附属医院住院治疗的72例GBS患者的临床资料及肌电图检查结果,依据肌电图的表现分为髓鞘型21例,轴索型27例,髓鞘+轴索型24例。神经功能缺损程度应用Hughes量表进行评定,比较3种不同亚型GBS预后情况。对存在轴索损害的GBS患者分别给予丙种球蛋白、激素及两者联合治疗,比较3种不同治疗方案治疗后的短期效果。结果 依据肌电图结果结合临床表现区分出髓鞘型、轴索型、髓鞘+轴索型。轴索型、髓鞘+轴索型患者神经功能修复较差,Hughes评分分别为：入院时2.37（0～4）分、2.42（0～4）分,出院时1.92（0～4）分、1.88（0-4）分,髓鞘型患者Hughes评分入院时1.38（0～4）分、出院时0.71（0～2）分,与髓鞘型比较,差异有统计学意义（P< 0.05）,而轴索型与髓鞘+轴索型患者比较,差异无统计学意义（P> 0.05）。丙种球蛋白、激素及丙种球蛋白+激素联合使用对存在轴索损害的GBS患者临床疗效,差异无统计学意义（P> 0.05）。结论 患者的预后与轴索是否受损密切相关,存在轴索受损的患者,预后较差,但无论应用丙种球蛋白、激素、还是丙种球蛋白+激素治疗,均有疗效。     

靶向联合化疗与常规化疗治疗表皮生长因子受体基因突变肺腺癌患者的临床效果

目的 探讨靶向联合化疗治疗表皮生长因子受体（EGFR）基因突变晚期肺腺癌患者的临床疗效及靶向联合化疗对EGFR基因不同突变位点患者的疗效差别。方法 选择安徽省胸科医院2016年1~12月收治确诊的64例EGFR基因检测阳性的Ⅲb/IV期肺腺癌患者,使用随机数字表方法分为靶向联合化疗组（33例）与常规化疗组（31例）,同时对靶向联合化疗组患者按照其基因突变位点不同分为3个亚组（19外显子突变组、21外显子突变组、20外显子突变组）。靶向联合化疗组患者采用EGFR受体酪氨酸抑制剂靶向治疗联合培美曲塞+卡铂/顺铂治疗,常规化疗组患者采用培美曲塞+卡铂/顺铂治疗。比较两治疗组患者的近期及远期疗效,并对靶向联合化疗组不同位点远期疗效进行数据分析。结果 靶向联合化疗组的中位无进展生存期高于常规化疗组,两组差异有统计学意义（P<0.05）,两组患者总体疗效和不良反应总发生率相似,差异无统计学意义（P>0.05）。靶向联合化疗组中,不同外显子突变的肺腺癌患者之间靶向联合化疗的生存期相似,差异无统计学意义（P>0.05）。结论 EGFR基因突变晚期肺腺癌患者接受靶向联合化疗能延长无进展生存时间,且不良反应未见增加。不同位点基因突变患者接受靶向联合化疗的临床效果无明显差别。     

CYP2C19基因指导冠心病患者经皮冠状动脉介入术后抗血小板药合理应用

目的 探索CYP2C19基因指导冠心病患者经皮冠状动脉介入（PCI）术后抗血小板药物的合理使用。方法 利用医院管理信息系统,收集2015年12月至2016年12月在心内科住院的冠心病患者2 836例,从中选取符合标准的CYP2C19 IM和PM基因型患者480例,根据患者是否根据基因型改变治疗方案,将患者分为常规剂量氯吡格雷组（常规治疗组）、氯吡格雷剂量加倍组和替格瑞洛组,观察各组患者血小板聚集抑制率和1年内主要不良心血管（MACE）及出血事件发生率。结果 最终入选468例患者,替格瑞洛组和剂量加倍组的血小板聚集抑制率均高于常规治疗组（P<0.05）,且替格瑞洛组又明显高于剂量加倍组（P<0.05）。MACE事件发生率方面,各组患者均是再发心肌梗死发生率最高,且替格瑞洛组及剂量加倍组明显低于常规治疗组（P<0.017）,其余MACE各事件及出血发生率各组之间无差异性（P>0.017）。结论 CYP2C19基因指导下冠心病患者PCI术后抗血小板治疗临床效果较好,临床应根据患者基因特点进行个体化合理用药。     

EGFR突变肺癌脑膜转移奥希替尼加量治疗1例

非小细胞肺癌（NSCLC）脑膜转移患者的生存期短,治疗方法有限。奥希替尼是第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）,可高效抑制EGFR敏感突变和EGFR T790M耐药突变,同时对EGFR突变的NSCLC软脑膜转移患者也有很好的疗效。本文报道1例奥希替尼加量至160 mg·d^-1治疗EGFR突变肺腺癌脑膜转移,为临床治疗NSCLC难治性软脑膜转移提供参考。     

注射用紫杉醇（白蛋白结合型）联合放疗治疗不同分子亚型老年乳腺浸润性小叶癌的效果及预后影响因素分析

目的 探讨注射用紫杉醇（白蛋白结合型）联合放疗治疗不同分子亚型老年乳腺浸润性小叶癌患者的临床效果及预后的影响因素。方法 选择2016—2017年于邯郸市中心医院和河北医科大学第四医院就诊的晚期乳腺浸润性小叶癌患者200例进行前瞻性研究。按随机数字表法将患者随机分为对照组和试验组，每组100例，根据分子亚型又将两组分别分为Luminal A型、Luminal B型、HER-2过表达型和三阴型。对照组采用每天1次，每次1.8～2.0 Gy的常规分割放疗方案，每周照射5 d，共放疗25～28次。试验组放疗方式同对照组，在放疗期间给予注射用紫杉醇（白蛋白结合型），剂量为260 mg·m^-2，静脉滴注30 min，每3周给药1次，至放疗结束。分析比较两组患者近期疗效、治疗后1年乳房外形评级情况、5年无病生存率及复发率，记录治疗期间不良反应发生情况。结果 试验组三阴型、HER-2过表达型、Luminal B型、Luminal A型患者的总有效率（RR，60.00%、53.85%、83.33%、88.10%）均显著高于对照组同亚型的RR（10.00%、14.29%、62.50%、73.17%），差异显著（P<0.05）；试验组三阴型、HER-2过表达型、Luminal B型、Luminal A型患者的肿瘤控制率（DCR，80.00%、84.62%、93.33%、100.00%）均显著高于对照组同亚型的DCR（20.00%、50.00%、81.25%、92.68%），差异显著（P<0.05）。试验组三阴型、HER-2过表达型、Luminal B型、Luminal A型患者治疗后1年乳房外形优良率均高于对照组同亚型（P<0.05）。不同的年龄、临床近期疗效、分子分型、治疗措施的乳腺癌患者，其5年无病生存率比较差异均有统计学意义（P<0.05）。Logistics回归分析结果显示，65～70岁为5年无病生存的保护性因素，分子分型、治疗措施为5年无病生存的独立影响因素。试验组与对照组的胃肠道不良反应发生率分别为45.26%、41.24%（P>0.05），试验组与对照组的血液学异常不良反应发生率分别为56.84%、53.61%（P>0.05）。结论 注射用紫杉醇（白蛋白结合型）联合放疗能有效提升不同分子亚型老年乳腺浸润性小叶癌患者的近期疗效，改善治疗后1年乳房外形评级，提高患者5年无病生存率，安全性较高。而影响患者预后的主要因素为年龄、分子分型、治疗措施，临床上应考虑采取有效措施来改善预后。     

血脂异常患者ApoE和SLCO1B1基因多态性与阿托伐他汀调脂治疗后血脂和肝功能的相关性

目的 研究血脂异常患者载脂蛋白（ApoE）、有机阴离子转运蛋白家族成员1B1（SLCO1B1）基因多态性与阿托伐他汀调脂治疗后血脂、肝功能的相关性。方法 选取2020年1月—2023年9月就诊于沧州市人民医院的128例高脂血症患者,阿托伐他汀治疗至少4周,检测ApoE、SLCO1B1基因和血脂、肝功能指标,分析其因型与调脂疗效、肝功能指标关系。结果 阿托伐他汀治疗后,ApoE基因表型E2组三酰甘油（TG）、高密度脂蛋白胆固醇（HDL-C）水平均较治疗前改善,E3组总胆固醇（TC）、HDL-C、低密度脂蛋白胆固醇（LDL-C）水平均较治疗前改善,E4组HDL-C水平均较治疗前改善,差异有统计学意义（P＜0.05）。治疗后,ApoE基因表型各组丙氨酸转氨酶（ALT）差异无统计学意义,仅E3组谷氨酰转移酶（GGT）差异有统计学意义（P＜0.05）。阿托伐他汀治疗后,SLCO1B1基因表型I型的TC、TG、HDL-C、LDL-C均较治疗前改善,Ⅱ型HDL-C较治疗前改善,差异有统计学意义（P＜0.05）。治疗后,SLCO1B1基因表型各组ALT、GGT差异无统计学意义。结论 临床使用阿托伐他汀时,可检测ApoE、SLCO1B1基因多态性评估降脂疗效,实现阿托伐他汀个体化用药。     

Investigational FMS-like tyrosine kinase 3 inhibitors in treatment of acute myeloid leukemia

Introduction: Outcomes for the majority of patients with acute myeloid leukemia (AML) remain poor. Over the past decade, significant progress has been made in the understanding of the cytogenetic and molecular determinants of AML pathogenesis. One such advance is the identification of recurring mutations in the FMS-like tyrosine kinase 3 gene (FLT3). Currently, this marker, which appears in approximately one-third of all AML patients, not only signifies a poorer prognosis but also identifies an important target for therapy. FLT3 inhibitors have now undergone clinical evaluation in Phase I, II and III clinical trials, as both single agents and in combination with chemotherapeutics. Unfortunately, to date, none of the FLT3 inhibitors have gained FDA approval for the treatment of patients with AML. Yet, several promising FLT3 inhibitors are being evaluated in all phases of drug development.

Areas covered: This review aims to highlight the agents furthest along in their development. It also focuses on those FLT3 inhibitors that are being evaluated in combination with other anti-leukemia agents.

Expert opinion: The authors believe that the field of research for FLT3 inhibitors remains promising, despite the historically poor prognosis of this subgroup of patients with AML. The most promising areas of research will likely be the elucidation of the mechanisms of resistance to FLT3 inhibitors, and development of potent FLT3 inhibitors alone or in combination with hypomethylating agents, cytotoxic chemotherapy or with other targeted agents.     

Genetic mutations in epigenetic modifiers as therapeutic targets in acute myeloid leukemia

Introduction: Despite enormous insights into the molecular mechanisms of acute myeloid leukemia (AML) pathophysiology, this disease is still fatal in the majority of patients, highlighting the urgent need for novel biomarkers useful in AML prognosis and therapy.

Areas covered: The advent of modern sequencing technologies has allowed the identification of genetic mutations in genes encoding for specific enzymes involved in the epigenetic regulation of gene expression. The authors review recent data demonstrating the involvement of mutations in genes encoding for epigenetic players and their complex combination with somatic genetic mutations in the pathogenesis of AML. They also discuss the prognostic and therapeutic implications of these findings.

Expert opinion: Current clinical and preclinical studies are underscoring the importance of targeting epigenetic modifiers as new biomarkers for a better prognostic risk stratification and therapeutic evaluation of intermediate-risk patients. Combining data from traditional and modern methodologies will allow a definition of the complex networks of epigenetic changes and molecular interactions between candidate epitargets and key regulators of hematopoiesis. It will thus be possible to achieve an overview of potential aberrant mechanisms driving leukemogenesis in different classes of AML patients. Such an improved approach could pave the way towards ‘personalized’ therapies.     

成人急性髓系白血病治疗现状及新药研究进展

急性髓系白血病（Acute myeloid leukemia, AML）是一类高度异质性疾病,过去常规诱导化疗和各类支持治疗为主,但随着二代测序等技术应用以来,AML药物迅速发展。本文从细胞毒药物、小分子靶向药物以及免疫靶向药物等方面,系统概述AML的致病机制,以及临床研究中较为前沿的各类新型药物（如FLT3抑制剂Midostaurin、IDH抑制剂AG-221和CPX-351等）的研究进展,旨在为AML的新药研发提供参考。     

Targeted therapy in acute myeloid leukaemia: current status and future directions

Background: The limit of acceptable toxicity for standard chemotherapeutic drugs used in acute myeloid leukaemia (AML) therapy has been reached. New therapeutic strategies are therefore needed. Objective: This review summarizes development in new strategies, and gives an overview of the clinical status on new drugs for non-promyelocytic AML in adults. Methods: Information was principally gathered from the databases ClinicalTrials.gov and PubMed.gov. Results/conclusion: The major improvements in AML treatment during the last two decades has not been the introduction of new therapeutic agents, but rather the more optimal use of well-known drugs (e.g., high-dose cytarabine therapy, the use of ATRA in maintenance therapy of acute promyelocytic leukaemia) and improvement in the diagnosis and treatment of potentially life-threatening complications in patients treated with allogeneic stem cell transplantation. However, further investigations based on specific targeted therapy and stratification of patients according to knowledge of the individual disease and health status will probably be necessary in future studies of new targeted therapy.     

急性髓细胞白血病FLT3-ITD基因的表达及临床意义

目的 通过对初诊急性髓细胞白血病(acute myeloid leukemia,AML)患者进行FLT3 -ITD基因突变检测,探讨FLT3-ITD基因突变与AML临床特征的相关性,为AML的临床分层治疗、分子靶向治疗及预后判断提供理论依据.方法 采用实时定量聚合酶链反应(RT-PCB)检测60例初治AML患者和10例对照组患者骨髓FLT3-ITD基因突变.结果 60例初治AML患者突变阳性率为25.0％( 15/60),10例对照组患者骨髓均未检测到该突变;依据法美英协作组(FAB)分型标准备亚型FLT3 -ITD突变率不同,其中以M3、M5型突变率较高;60例初治AML中,28例老年AML组与32例非老年AML组FLT3-ITD基因表达水平比较,差异有统计学意义(P＜0.05);FLT3-ITD阳性组患者具有外周血白细胞数、骨髓白血病细胞比例高的临床特点,并且FLT3-ITD阳性组化疗后完全缓解率(CR)低于FLT3-ITD阴性组(P＜0.05).结论 FLT3-ITD基因突变在AML患者中存在一定的突变率,且多见于M3、M5型患者,FLT3-ITD阳性患者具有外周血白细胞数、骨髓白血病细胞比例高,CR低的临床特点.     

New approaches for pediatric rhabdomyosarcoma drug discovery: targeting combinatorial signaling

Introduction: Rhabdomyosarcomas (RMS) are rare heterogeneous pediatric tumors that are treated by surgery, chemotherapy and irradiation. New therapeutic approaches are needed, especially in the advanced stages to target the pro-oncogenic signals. Exploring the molecular interactions of the regulatory signals and their roles in the developmental aspects of different subtypes of RMS is essential to identify potential targets and develop new therapeutic drugs.

Areas covered: Insights into different drug discovery approaches are discussed with specific emphasis on gene expression profiling, fusion protein, role of small interfering RNA (siRNA)- and microRNA (miRNA)-based discovery approaches, targeting cancer stem cells, and in vitro and in vivo model systems. Targeting some overexpressed signals along with the possibilities of combination therapy of validated drug targets is discussed. Additionally, methods to overcome the limitations of discovery-based research are briefly discussed.

Expert opinion: Due to drug resistance, ineffective therapy in advanced stages and relapse, there is a demand to explore new drug targets and discovery approaches. Implementing miRNA-based profiling would reveal the extent of miR-based regulation, various biomarkers and potential targets in RMS. A suitable combination of innovative techniques and the use of model systems might assist the identification and validation of novel targets and drug discovery methods. Combining specific drugs along with type-specific target inhibition of overexpressed mRNAs through siRNA approaches would enable the development of personalized therapy.     

Durable efficacity and remission after treatment with imatinib mesylate for FIP1L1-PDGFRA transcript negative associated eosinophilic cardiomyopathy

Introduction

The cardiac involvement in hypereosinophilia remains a major cause of morbidity and mortality. Recent advances have identified new molecular mechanisms responsible for the expansion of the eosinophilic lineage, allowing a better classification of the different forms of Hypereosinophilic syndrome (HES) and especially targeted therapy. Since the discovery of the involvement of deregulated tyrosine kinases in the pathophysiology of these diseases, and particularly the identification of the fusion gene FIP1L1–PDGFRA, new molecules inhibiting specifically this signaling pathway (imatinib) were individualized, leading to dramatic therapeutic benefits in proliferative forms of HES considered before that of very poor prognosis.

Case report

We report here the dramatic effectiveness of imatinib used as second line therapy for dilated cardiomyopathy revealing a hypereosinophilic syndrome in a patient in whom the search for FIP1-L1-PDGFRA fusion gene was negative.

Conclusion

If hypereosinophilia has varied clinical and morphological outcome, its clinical consequences, particularly on heart function, are sometimes dreadful, and are not correlated either with blood eosinophil levels or with a specific etiology. We report here a case of HES lacking the FIP1-L1-PDGFRA fusion gene showing that despite the absence of this molecular defect, imatinib mesylate may have therapeutic interest in those cases of HES resistant to first line therapies.     

靶向干预SETDB1对急性髓系白血病的治疗作用

目的 探究组蛋白甲基转移酶SETDB1在急性髓系白血病(acute myeloid leukemia,AML)恶性进展中的作用及干扰SETDB1对AML的治疗效果。方法 基于TCGA、GTEx、TARGET数据库,分析SETDB1在不同肿瘤的表达情况,并对比分析在AML骨髓细胞和正常骨髓细胞中的表达情况,进一步分析SETDB1的表达与AML患者不同风险分层、不同FAB(French-American-British)分型及微小残留病灶(minimalresidualdisease,MRD)的相关性;对SETDB1高/低表达患者进行基因富集分析。通过RT-qPCR考察shRNA序列对SETDB1的沉默效率;通过台盼蓝染色法考察沉默SETDB1对AML细胞的增殖及活力的影响;通过检测细胞表面抗原CD11b、CD14的比例、细胞核形态和氯化硝基四氮唑蓝(NBT)还原能力考察沉默SETDB1对AML细胞的分化治疗作用。结果 与其他肿瘤相比,SETDB1在AML中显著高表达,且在AML中的表达水平显著高于正常骨髓细胞。SETDB1在AML高风险患者中、MRD残留患者中也显著高表达。沉默SETDB...     

Suppression of farnesyltransferase activity in acute myeloid leukemia and myelodysplastic syndrome: current understanding and recommended use of tipifarnib

Importance of the field: Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) incidence in the United States increases with age. Given the progressive ageing of the general population, incidence of these diseases is likely to continue to rise in the future. There is an acute need for therapeutic developments because of the poor prognosis of these diseases. Since the knowledge of molecular genetics in AML and MDS has expanded recently, targeted therapeutics should offer an exciting new frontier for advancement. Of all the targeted inhibitors developed, tipifarnib represents one of the few compounds with some activity as a single agent.

Areas covered in this review: Described in this review are the molecular targets of tipifarnib, safety and tolerability of the drug, chemistry, and clinical efficacy in AML.

What the reader will gain: The reader will gain a thorough understanding of tipifarnib as it relates to the current and future use of the drug in AML.

Take home message: The future of tipifarnib, along with other molecularly-targeted drugs, lies in achieving a better understanding of leukemia biology and harnessing the activity of this agent using predictive biomarkers for improved patient selection.     

Gilteritinib for the treatment of relapsed and/or refractory FLT3-mutated acute myeloid leukemia

ABSTRACT

Introduction: The receptor tyrosine kinase FLT3 is the most commonly mutated gene in acute myeloid leukemia (AML). FLT3-internal tandem duplication mutations are associated with an increased risk of relapse, and a number of small molecule inhibitors of FLT3 have been developed. The highly potent and selective FLT3 kinase inhibitor gilteritinib is the first tyrosine kinase inhibitor approved as monotherapy for the treatment of relapsed and/or refractory FLT3-mutated AML.

Areas covered: We review the biology and prognostic significance of FLT3 mutations in AML and discuss the pharmacology, clinical efficacy, and toxicity profile of gilteritinib. We also summarize important differences among the various FLT3 inhibitors that are currently approved or under development and highlight areas of ongoing research.

Expert opinion: Gilteritinib has been shown to improve survival compared to salvage chemotherapy in relapsed and/or refractory FLT3-mutated AML. Gilteritinib is orally available with a favorable toxicity profile and as such is quickly becoming the standard of care for this patient population. Ongoing clinical trials are evaluating gilteritinib in combination with frontline chemotherapy, in combination with other agents such as venetoclax and azacitidine for patients who are ineligible for standard induction therapy, and as a maintenance agent.