非小细胞肺癌患者驱动基因与静脉血栓栓塞症的研究进展

癌症相关静脉血栓栓塞症（venous thromboembolic disease，VTE）是恶性肿瘤患者的常见死因之一，也是肺癌常见的并发症。目前研究显示非小细胞肺癌（non-small cell lung cancer，NSCLC）患者的驱动基因状态与VTE发生风险有关，常见的驱动基因主要包括EGFR、ALK、ROS1及KRAS等，因此检测患者的驱动基因状态对早期筛选VTE高危人群具有重要意义。本文就NSCLC患者驱动基因状态与VTE关系的研究进展作一综述。     

肿瘤患者VTE风险评估模型的研究进展

静脉血栓栓塞（venous thromboembolism,VTE）已经成为肿瘤患者最常见的并发症,且成为除肿瘤患者外第二大死因。肿瘤本身是一种存在血栓和出血双风险并存的状态,对患者能够进行有效风险评估筛查的模型显得尤为关键。只有能在对肿瘤患者进行精准的风险分层,低风险患者能够不进行血栓预防或仅进行机械预防降低治疗成本和出血风险,高风险患者预防血栓中获益。本文对目前肿瘤并发相关VTE的情况、当前VTE风险评估模型的对比、风险模型的建立及未来发展方向进行探讨,旨在提高对相关VTE风险评估模型的的认识,并对风险模型的建立和发展提出理论支持。      

恶性淋巴瘤血栓形成的研究进展

静脉血栓栓塞（venous thrombolism,VTE）是恶性肿瘤患者第二致死原因,并且癌症患者是血栓栓塞的高发人群,其预防和治疗是非常重要的。肿瘤患者发生VTE的风险较非肿瘤患者至少增加7倍,而血液系统肿瘤并发VTE的概率则较非肿瘤患者增加28倍,严重影响了恶性淋巴瘤患者的预后和生活质量。恶性淋巴瘤患者并发VTE的机制和危险因素尚未明确,VTE的发生与组织因子、微粒以及基因的单核苷酸多态性相关。为了降低VTE发生率,预测可能发生VTE的高危患者是非常重要的,这些患者将会从血栓预防中受益,因此临床上急需一种简单有效的VTE风险评估模型,联合检测外周血中生物标记物可提高VTE诊断率。由于淋巴瘤患者发生出血的风险较高,导致血栓的治疗更加复杂。本文就恶性淋巴瘤患者发生VTE的流行病学、发病机制、预防和治疗的最新研究做一综述。      

非小细胞肺癌中EGFR和K-ras基因突变与蛋白表达相关性的研究

背景与目的：当前表皮生长因子受体（epidermal growth factor receptor,EGFR）基因靶向治疗已成为晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）治疗的研究的热点之一。本研究旨在探讨NSCLC患者中EGFR基因和K-ras（Kirsten rat sarcoma viral oncogene）基因突变的情况,分析其与蛋白表达的相关性及对吉非替尼（gefitinib）治疗的指导意义。方法：收集200例NSCLC患者新鲜组织,采用基因测序法检测EGFR及K-ras基因突变的状态;同时采用免疫组织化学法检测EGFR和K-ras蛋白的表达。结果：200例患者中,EGFR基因突变率为33%,主要发生在19号和21号外显子;K-ras基因突变率为5.5%,主要位于第12密码子;不存在同时携带有EGFR和K-ras两种基因突变的病例。腺癌尤其是含细支气管肺泡癌（bronchioloalveolar carcinoma,BAC）病理分型的患者、非吸烟患者和女性患者EGFR突变率较高。EGFR蛋白表达阳性率为16%,与总的EGFR突变无关（P〉0.05）,但与19号外显子突变具有统计学意义（P〈0.05）。K-ras蛋白表达阳性率为52.5%,与K-ras基因突变无关（P〉0.05）。15例携带有EGFR基因突变的NSCLC患者服用吉非替尼,12例（其中8例为EGFR蛋白表达阴性）有效。结论：EGFR蛋白表达与EGFR基因19号外显子突变具有一定相关性;联合检测EGFR和K-ras基因突变可用来筛选对EGFR酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）治疗敏感的人群,并预测吉非替尼治疗晚期NSCLC的疗效及预后。     

肿瘤患者静脉血栓栓塞症的风险评估模型及其应用

静脉血栓栓塞症（VTE）是肿瘤患者常见的并发症和死亡原因。多项研究显示，有效的VTE风险评估模型和恰当的预防性抗凝治疗可以降低肿瘤患者的血栓发生风险。但哪些肿瘤患者需要进行预防性抗凝治疗，需要有效的VTE风险评估模型，对肿瘤患者进行VTE风险分层。对血栓高危人群，在排除抗凝禁忌证后进行预防性抗凝。但肿瘤疾病存在复杂性，不同的病理类型和分期，VTE风险和特点不同，而目前专门针对肿瘤患者的VTE风险评估模型仍然有限，本文将对肿瘤患者的VTE风险评估模型的现状及其应用进行综述。     

肿瘤与静脉血栓栓塞症

 肿瘤患者有较高的静脉血栓发生率。研究发现,静脉血栓栓塞症（VTE）可增加肿瘤患者的死亡风险。VTE的发生机制与组织因子（TF）及癌促凝物质（CP）等因素密切相关。患者相关性因素、肿瘤相关性因素及治疗相关性因素均可导致患者VTE发生率增加。应重视对患者危险因素进行评估,对高危患者及早进行预防性抗凝治疗,在诊断VTE后应立即进行急性期治疗及慢性期维持治疗。     

非小细胞肺癌组织中表皮生长因子受体基因突变与拷贝数之间的相关性以及与患者临床病理特征之间的关系

目的 研究中国非小细胞肺癌(NSCLC)患者组织中表皮生长因子受体(EGFR)基因状态,分析EGFR基因突变与拷贝数之间的相关性以及与NSCLC患者临床病理特征之间的关系。方法 应用实时荧光定量PCR法检测118例NSCLC组织中EGFR基因的突变状态,同时采用荧光原位杂交(FISH)技术检测EGFR基因拷贝数。分析EGFR基因突变与拷贝数之间的相关性,探讨EGFR基因状态与NSCLC患者临床病理特征之间的关系。结果118例NSCLC组织中,EGFR基因的突变率为41.5％,其中腺癌为50.0％,鳞癌为5.0％。EGFR基因FISH阳性率为70.3％,其中29例为基因扩增,54例为高度多体性;腺癌FISH阳性率为78.1％,鳞癌为35.0％。EGFR基因突变与EGFR基因高拷贝数主要存在于腺癌、晚期、女性和不吸烟的患者,EGFR基因突变与EGFR基因拷贝数之间有显著的相关性。结论在中国NSCLC患者中,腺癌、晚期、女性、不吸烟的患者EGFR基因突变率和FISH阳性率较高,且二者具有显著的相关性;联合检测EGFR基因拷贝数和基因突变可能更有利于NSCLC靶向药物的筛选。     

肺腺癌中表皮生长因子受体基因突变与拷贝数的检测分析

目的检测肺腺癌组织中表皮生长因子受体（EGFR）19、21外显子基因突变和拷贝数,分析EGFR基因突变和拷贝数变化的相关性。方法应用荧光定量PCR技术和荧光原位杂交（FISH）技术分别检测58例肺腺癌患者肿瘤组织中的EGFR基因突变和基因扩增,用X^2检验进行数据分析。结果58例肺腺癌患者组织中,EGFR19、21外显子突变率为43．1％（25／58）,其中2例存在两种类型的突变。EGFR基因拷贝数增加阳性率为51．7％（30／58）,包括8例扩增,22例高多体扩增。不同分化程度的肺腺癌组织间,扩增阳性率差异无统计学意义（P〉0．05）,低分化癌的突变率低于高、中分化癌（P〈O．05）。EGFR基因突变与EGFR基因拷贝数之间显著相关（P〈0．01）。结论肺腺癌组织具有较高的EGFR基因突变率和扩增阳性率;联合检测EGFR基因拷贝数和基因突变,更有利于靶向药物的筛选。     

淋巴瘤患者静脉血栓栓塞症的研究进展

血液恶性肿瘤患者易发生出凝血障碍，以急性白血病为代表，其中淋巴瘤出凝血障碍发生率也较高，凝血异常所致静脉血栓栓塞（VTE）是其死亡主要原因之一。淋巴瘤血栓栓塞症在非霍奇金淋巴瘤中发生率明显高于霍奇金淋巴瘤，VTE的发生可形成凝血瀑布从而促进肿瘤生长，提示患者疾病进展及病情恶化。淋巴瘤VTE发生的危险因素及相关特点可作为临床早期用药干预的依据从而改善患者预后，极大提高患者的生活质量。     

肿瘤细胞减灭加腹腔热灌注化疗术后静脉血栓栓塞症的预防

  目的  评估行肿瘤细胞减灭术（cytoreductive surgery，CRS）加腹腔热灌注化疗（hyperthermic intraperitoneal chemotherapy，HIPEC）治疗的腹膜癌患者静脉血栓栓塞症（venous thromboembolism，VTE）发生风险，研究术后早期主/被动活动联合间歇充气加压按摩对VTE的预防效果。  方法  对2015年5月至2016年8月武汉大学中南医院肿瘤科收治的120例胃肠道及妇科肿瘤等来源的腹膜癌患者行CRS+HIPEC治疗，使用Caprini血栓风险评估模型评价VTE风险，所有患者采取早期肢体主/被动活动及间歇充气加压按摩治疗，记录分析VTE相关事件。  结果  患者中位Carprini评分为12（10~16）分，均为VTE极高危组，在3个月的随访中仅1例患者发生深静脉血栓，经药物治疗后痊愈。  结论  腹膜癌患者VTE风险极高，术后早期足背曲/跖曲及扩胸等主/被动运动联合间歇充气加压按摩，可有效预防VTE。      

The NCCN Clinical Practice Guidelines on Venous Thromboembolic Disease: strategies for improving VTE prophylaxis in hospitalized cancer patients

The risk for venous thromboembolism (VTE) is high in hospitalized cancer patients, and is associated with an elevated risk for recurrent thrombosis, bleeding complications, and use of health care resources. Thromboembolism is the second leading cause of death in hospitalized cancer patients. Thromboprophylaxis with unfractionated heparin or low-molecular-weight heparins has been clinically proven to reduce the risk for VTE and improve outcomes. However, VTE prophylaxis continues to be underprescribed in cancer patients. Recognizing the clinical burden of VTE in cancer patients, the National Comprehensive Cancer Network (NCCN) recently released guidelines for VTE prevention and management. These NCCN guidelines recommend evidence-based prophylactic anticoagulant therapy for all patients admitted to hospital with a diagnosis of cancer who do not have contraindications to anticoagulant use. However, there continue to be barriers to the implementation of clinical practice guidelines and appropriate use of VTE prophylaxis. Multifaceted active educational and electronic interventions are necessary to raise awareness and reduce the burden of cancer-associated thrombosis and its attendant consequences.     

恶性肿瘤合并静脉血栓栓塞症1例诊治分析

静脉血栓栓塞症（VTE）在肿瘤患者中的发病率是非肿瘤患者的6~7倍，并且是肿瘤患者第二常见的致死原因，同时其发病率呈逐年上升趋势。因此，肿瘤患者合并VTE的早期诊断、早期治疗尤为重要。现介绍1例天津医科大学肿瘤医院介入治疗肿瘤科收治的胰腺癌合并下肢深静脉血栓形成患者的诊治经验及多学科讨论，以提高临床工作中对肿瘤患者合并VTE的重视，并注重多学科间的协作治疗。      

Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants

Anticoagulation for cancer-associated venous thromboembolism (VTE) can be challenging due to complications—including bleeding and potential drug–drug interactions with chemotherapy—associated with vitamin K antagonists and inconvenience of low-molecular-weight heparin (LMWH). Direct oral anticoagulants (DOACs) could partially overcome these issues, but until recently there were no large clinical trials assessing their efficacy and safety in cancer patients. This review summarizes clinical treatment guidelines, prior clinical and real-world evidence for anticoagulant choice, recent clinical trials assessing DOACs for cancer-associated VTE (i.e. Hokusai-VTE Cancer, SELECT-D, CARAVAGGIO, and ADAM VTE), and special considerations for DOAC use. Based on established data, clinical guidelines recommend patients with cancer-associated VTE receive LMWH treatment of at least 3–6 months. Nevertheless, LMWH is underused and associated with poor compliance and persistence in these patients relative to oral anticoagulants. Clinical data supporting DOAC use in cancer patients are becoming available. In Hokusai-VTE Cancer, edoxaban was noninferior to dalteparin for the composite of recurrent VTE and major bleeding (12.8% versus 13.5%), with numerically lower recurrent VTE (7.9% versus 11.3%) and significantly higher major bleeding (6.9% versus 4.0%); only patients with gastrointestinal cancer had significantly higher risk of bleeding with edoxaban. In SELECT-D, rivaroxaban had numerically lower VTE recurrence (4% versus 11%), comparable major bleeding (6% versus 4%), and numerically higher clinically relevant nonmajor bleeding (13% versus 4%) versus dalteparin. Most bleeding events were gastrointestinal or urologic; patients with esophageal/gastroesophageal cancer had higher rates of major bleeding with rivaroxaban (36% versus 11%). For comparison of apixaban versus dalteparin, CARAVAGGIO is ongoing, and preliminary results from ADAM VTE are favorable. This review concludes that DOACs appear to be reasonable alternatives to LMWH for treatment of cancer-associated VTE. In patients with gastrointestinal cancer, DOAC use should be considered on a case-by-case basis with consideration of the relative risks and benefits.     

Cancer and thrombosis: implications of published guidelines for clinical practice

Cancer is a frequent finding in patients with thrombosis, and thrombosis is much more prevalent in patients with cancer, with important clinical consequences. Thrombosis is the second most common cause of death in cancer patients. Venous thromboembolism (VTE) in cancer is also associated with a high rate of recurrence, bleeding, a requirement for long-term anticoagulation, and worsened quality of life. Risk factors for cancer-associated VTE include particular cancer types, chemotherapy (with or without antiangiogenic agents), the use of erythropoietin-stimulating agents, the presence of central venous catheters, and surgery. Novel risk factors include platelet and leukocyte counts and tissue factor. A risk model for identifying cancer patients at highest risk for VTE has recently been developed. Anticoagulant therapy is safe and efficacious for prophylaxis and treatment of VTE in patients with cancer. Available anticoagulants include warfarin, heparin, and low-molecular weight heparins (LMWHs). LMWHs represent the preferred therapeutic option for VTE prophylaxis and treatment. Their use may be associated with improved survival in cancer, although this issue requires further study. Despite the significant burden imposed by VTE and the availability of effective anticoagulant therapies, many oncology patients do not receive appropriate VTE prophylaxis as recommended by practice guidelines. Improved adherence to guidelines could substantially reduce morbidity, decrease resource use, enhance quality of life, and improve survival in these patients.     

肿瘤并发静脉血栓形成196例临床分析

背景与目的：静脉血栓形成(venous thromboembolism,VTE)是恶性肿瘤患者的第二常见死亡原因。通过了解复旦大学附属肿瘤医院5年间收治的患者VTE的发病情况,分析VTE的相关特点,以提高肿瘤合并VTE的诊断和防治意识,改善患者预后。方法：对复旦大学附属肿瘤医院2009年7月-2014年6月收治的196例肿瘤并发VTE的患者的临床资料进行回顾性分析。分析肿瘤并发VTE的临床特点及发病情况,了解相关因素对VTE发病的影响,了解VTE首发情况。结果：复旦大学附属肿瘤医院5年间共收治肿瘤患者207 514例,其中VTE患者196例,肿瘤并发VTE发生率为0.94‰。腺癌在妇科肿瘤(56.5%)、胃肠道肿瘤(91.7%)、肺癌(71.4%)和胰腺癌(80%)中所占比例较高。单变量Logistic回归分析显示,腺癌为肿瘤患者并发肺栓塞(pulmonary embolism,PE)的高危险因素(OR=0.36,95%CI：0.146~0.885,P=0.026)。化疗大于2次者明显比化疗小于等于2次者VTE的发生率更高(χ²=10.976,P=0.001)。手术组VTE发生率高于非手术组。妇科肿瘤中有大量腹水者的非手术患者并发VTE者(>2 000 mL)更多(34.1% vs 10.7%,P=0.015)。术后和放化疗期间78%~88%的患者因出现深静脉血栓(deep vein thrombosis,DVT)症状发现VTE,而术前检查期间主要是在下肢静脉加压超声(compression venous ultrasonography,CUS)检查发现(59.1%)。复旦大学附属肿瘤医院术后进行物理性预防血栓措施者为15例(13.9%)。结论：复旦大学附属肿瘤医院的肿瘤相关性VTE发生率较其他流行病学调查发生率低。肿瘤患者术后并发VTE的风险明显高于非手术者。腺癌更易并发PE。对于临床无VTE症状的肿瘤患者和大量腹水的妇科肿瘤患者应积极进行VTE的相关检查,术后应更积极采取物理抗栓措施。     

血浆D-二聚体水平与恶性肿瘤患者发生静脉血栓的相关性

目的:观察血浆D-二聚体（D-dimer,D-D）水平对恶性肿瘤患者相关静脉血栓栓塞症（venous thromboembolism,VTE）发生的风险评估效果。方法:回顾性分析2016年1月至2017年1月本院新收住并经病理组织学证实的171例恶性肿瘤患者的临床资料,以初诊3个月内是否发生静脉血栓栓塞症（VTE）分为VTE组（32例）和非VTE组（139例）,比较两组患者、不同临床分期患者、不同治疗方式患者、不同静脉血栓风险分层患者的血浆D-D值水平,采用Logistic多因素回归分析血浆D-D水平对恶性肿瘤患者相关VTE发生的风险评估效果。结果:VTE组的血浆D-D值水平显著高于非VTE组（P＜0.05）,且随着恶性肿瘤临床分期的增加和静脉血栓风险分层的增高,该现象更加显著。Logistic多因素回归分析结果表明,化疗、手术、静脉血栓风险评估和血浆D-D水平是患者发生VTE的独立危险因素（P＜0.05）。结论:恶性肿瘤患者血浆D-D值水平明显升高,且与恶性肿瘤的临床分期和血栓风险分层相关;对恶性肿瘤患者进行血浆D-D值水平的检测,对预防恶性肿瘤患者初诊3个月内VTE的发生具有十分重要的参考意义。     

癌症相关性孤立下肢远端深静脉血栓形成的临床研究进展

静脉血栓栓塞症（venous thromboembolism，VTE）在癌症患者中发病率较高，是导致癌症患者疾病进展或死亡的重要因素。下肢深静脉血栓（deep vein thrombosis，DVT）形成在VTE中占比多、危害大，可分为近端DVT形成（proximal deep vein thrombosis，PDVT）及孤立性下肢远端DVT形成（isolated distal deep vein thrombosis，IDDVT）。PDVT的风险评估及管理策略已有较多研究，然而对约占下肢DVT 50%的IDDVT却鲜有研究，临床工作中对癌症相关性IDDVT的风险评估及管理策略也欠规范，因此本文对癌症相关性孤立下肢远端深静脉血栓形成的临床研究进行综述。      

Primary prevention and treatment of venous thromboembolic events in patients with gastrointestinal cancers - Review

Venous thromboembolism event (VTE) is a common and morbid complication in cancer patients. Patients with gastrointestinal cancers often suffer from symptomatic or incidental splanchnic vein thrombosis, impaired liver function and/or thrombocytopenia. These characteristics require a thorough risk/benefit evaluation for individual patients. Considering the risk factors for the development of VTE and bleeding events in addition to recent study results may be helpful for correct initiation of primary pharmacological prevention and treatment of cancer-associated thrombosis (CAT), preferably with low molecular weight heparins (LMWH). Whereas thromboprophylaxis is most often recommended in hospitalized surgical and non-surgical patients with malignancy, there is less agreement as to its duration. With regard to ambulatory cancer patients, the lack of robust data results in low grade recommendations against routine use of anticoagulant drugs. Anticoagulation with LMWH for the first months is the evidence-based treatment for acute CAT, but duration of secondary prevention and the drug of choice are unclear. Based on published guidelines and literature, this review will focus on prevention and treatment strategies of VTE in patients with gastrointestinal cancers.     

Treatment Algorithm in Cancer-Associated Thrombosis: Updated Canadian Expert Consensus

Patients with cancer-associated thrombosis (CAT) are at high risk of recurrent venous thromboembolism (VTE) and major bleeding complications. Risks vary significantly between individuals based on cancer status, treatment, and other characteristics. To facilitate the evidence-based management of anticoagulant therapy in this patient population, a committee of 11 Canadian clinical experts updated a consensus-based algorithm for the acute and extended treatment of symptomatic and incidental CAT that was developed in 2018. Following a systematic review of the literature, updates to the algorithm were discussed during an online teleconference, and the algorithm was subsequently refined based on feedback from committee members. Clinicians using this treatment algorithm should consider bleeding risk, type of cancer, and drug–drug interactions, as well as patient and clinician preferences, in tailoring anticoagulation for patients with CAT. Anticoagulant therapy should be adapted as the patient’s cancer status and management change over time.