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| 1 | 帕博利珠单抗单用或与放疗联用治疗转移性非小细胞肺癌:两个随机试验的汇总分析显示文摘背景放疗可以提高整个机体对免疫治疗的应答。在Ⅱ期PEMBRO-RT研究和Ⅰ/Ⅱ期MDACC研究中,患有转移性非小细胞肺癌(NSCLC)的患者被随机分配入组,接受免疫治疗(帕博利珠单抗)+放疗联合疗法,或免疫治疗单一疗法。当上述2个研究单独分析时,联合疗法组显示出潜在获益。由于每个研究的样本量较小,缓解率和结局并未显示出统计学意义,然而却有显著的临床获益。因此,本研究进行汇总分析,来判断放疗是否会改善转移性NSCLC患者的免疫治疗应答。方法PEMBRO-RT和MDACC研究纳入标准:患者年龄≥18岁,患有转移性NSCLC,且有≥1处未经放疗照射的病灶,以便进行射野外应答监测。PEMBRO-RT研究纳入曾接受过化疗患者,MDACC研究纳入曾接受过治疗或新诊断患者。2个研究中的患者均未接受过免疫治疗。在PEMBRO-RT研究中患者被等比例随机分配入组,并根据吸烟状态进行分层(分为<10年组和≥10年组)。MDACC研究的患者根据放疗计划可行性被等比例随机分配入2个受试组。由于联合治疗组的干预本质,每个研究中的放疗均不适用盲法。在2个研究中,不论是否进行放疗,均静脉滴入帕博利珠单抗(每3周200 mg)。在PEMBRO-RT研究中,在放疗(24 Gy 3次分割照射)结束后1周给予第1剂帕博利珠单抗。在MDACC研究中,在第1次放疗(50 Gy 4次分割照射或45 Gy 15次分割照射)同时给予帕博利珠单抗。仅检测未经照射病灶的应答。本研究的终点为最佳射野外(远隔)应答率(ARR)、最佳射野外疾病控制率(ACR)、12周时ARR、12周时ACR、无进展生存期(PFS)和总生存期(OS)。2个研究的意向治疗(ITT)人群均纳入分析。PEMBRO-RT研究(NCT02492568)和MDACC研究(NCT02444741)均在ClinicalTrials.gov上注册。发现纳入148例患者,76例接受帕博利珠单抗治疗,72例接受帕博利珠单抗+放疗治疗。所有患者随访时间中位数为33个月[四分位距(IQR):32.4~33.6]。148例患者中124例(84%)组织学特征为非鳞癌,111例(75%)患者曾经接受过化疗。组间没有基线特征差异,包括PD-L1表达状态和转移灶体积。最常见的照射部位为肺转移灶(39%,28/72)、胸腔内淋巴结(21%,15/72)和非原发灶(17%,12/72)。帕博利珠单抗组和联合治疗组的最佳ARR分别为19.7%(15/76)和41.7%(30/72),OR=2.96,95%CI:1.42~6.20,P=0.0039;最佳ACR分别为43.4%(33/76)和65.3%(47/72),OR=2.51,95%CI:1.28~4.91,P=0.0071;PFS中位数分别为4.4(IQR:2.9~5.9)和9.0个月(IQR:6.8~11.2),HR=0.67,95%CI:0.45~0.99,P=0.045;OS中位数分别为8.7(IQR:6.4~11.0)和19.2个月(IQR:14.6~23.8),OR=0.67,95%CI:0.54~0.84,P=0.0004。在汇总分析中没有发现新的安全问题。解读帕博利珠单抗免疫疗法+放疗显著提高转移性NSCLC患者的应答和改善治疗结局。这些结果需要在三期临床试验中进行验证。 | 陈大卫(翻译) 于金明(校对) Willemijn S M E Theelen Vivek Verma Brian P Hobbs Heike M U Peulen Joachim G J V Aerts Idris Bahce Anna Larissa N Niemeijer Joe Y Chang Patricia M de Groot Quynh-Nhu Nguyen Nathan I Comeaux George R Simon Ferdinandos Skoulidis Steven H Lin Kewen He Roshal Patel John Heymach Paul Baas James W Welsh | 2021 | 中华肿瘤防治杂志2021，28，24： | 49 |
| 2 | Destabilization of strigolactone receptor DWARF14 by binding of ligand and E3-1igase signaling effector DWARF3显示文摘 | Li-Hua Zhao X Edward Zhou Wei Yi Zhongshan Wu Yue Liu Yanyong Kang Li Hou Parker W de Waal Suling Li Yi Jiang Adrian Scaffidi Gavin R Flematti Steven M Smith Vinh Q Lam Patrick R Griffin YonghongWang Jiayang Li Karsten Melcher H Eric Xu | 2015 | Cell Research2015，25，11： | 7 |
| 3 | Cholangiocarcinoma, gone without the Wnt?显示文摘Cholangiocarcinoma(CCA) is a relatively rare malignancy of the intra- or extra-hepatic bile ducts that is classified according to its anatomical localization as intrahepatic, perihilar or distal. Overall, CCA has a dismal prognosis due to typical presentation at an advanced irresectable stage, lack of effective non-surgical treatments, and a high rate of disease recurrence. CCA frequently arises on a background of chronic liver inflammation and cholestasis. Chronic inflammation is accompanied by enhanced cell turnover with generation of additional inflammatory stimuli, and a microenvironment rich in pro-inflammatory mediators and proliferative factors that enable accumulation of mutations, transformation and expansion of mutated cells. A recent study by Boulter et al implicates the Wnt signaling cascade in cholangiocarcinogenesis. Wnt ligands Wnt7 B and Wnt10 A were found to be highly overexpressed in human CCA tissue. Wnt7 B protein was present throughout the tumor stroma, and often co-localized with a subset of CD68+ macrophages. To address in a direct manner whether Wnt signaling is engaged in development of CCA, Boulter et al explored the Wnt signaling pathway in an experimental model that recapitulates the multi-stage progression of human CCA.Wnt ligands found to be elevated in human CCA were also upregulated during the course of CCA development following thioacetamide treatment. Wnt10 a increased during the(pre-cancerous) regenerative phase, while Wnt7 b induction paralleled tumor growth. Along with upregulation of target genes, the findings demonstrate that the canonical Wnt pathway is progressively activated during cholangio-carcinogenesis. Macrophage depletion,eliminating a major source of Wnt7 b, prevented activation of the canonical Wnt cascade, and resulted in reduced number and volume of tumors in this model. Moreover,specific inhibitors of the canonical Wnt pathway(ICG-001 and C-59) caused reduction of tumor area and number,in xenograft and thioacetamide models of CCA. The aggregated findings show that experimental, and presumably human CCA, is a Wnt-driven tumor. Modulation of Wnt signaling, alone or in combination with surgicalor chemotherapy approaches, holds promise in the management of this fatal malignancy. | Anne T R Noll Thorsten Cramer Steven W M Olde Damink Frank G Schaap | 2016 | World Journal of Hepatology2016，8，26： | 3 |
| 4 | Investigating Semantic Similarity Measures Across the Gene Ontology: The Relationship Between Sequence and Annotation 显示文摘 | Lord P W Stevens R D Brass A | 2003 | Bioinformatics2003，19，10： | 1 |
| 5 | Pattern of liver enzyme elevations in acute ST - elevation myocardial in- farction显示文摘 | LOFTHUS D M STEVENS S R ARMSTRONG P W | 2012 | Coron Artery Dis2012，23，1： | 1 |
| 6 | General Case SimulationInstruction and the Establishment and Maintenance of WoricPerformance 显示文摘 | William W Steven R | 1987 | Research in Developmental Disabilities1987，，8： | 1 |
| 7 | Kinetic Resolution of Racemic Glycidyl Butyrate Using a Multiphase Membrane and Model Verification 显示文摘 | Steven M C Georges B | 1993 | Biotechnology and Bioengeering1993，41，： | 1 |
| 8 | Regulation of Retinal Cone Bipolar Cell Differentiation and Photopic Vision by the CVC Homeobox Gene Vsx1显示文摘 | Akihira Ohtoshi Steven W Wang Hidetaka Maeda Shannon M Saszik Laura J Frishman William H Klein Richard R Behringer | 2004 | Current Biology2004，，6： | 1 |
| 9 | Optimal control of a liberating eleetrodynamie tether performing a muhirevolution orbitehange 显示文摘 | Stevens R E Baker W P | 2009 | Journal of Guidance Control and Dynamics2009，32，5： | 1 |
| 10 | Mechanical and load-settle ment characteristics of two lunar soil stimulants显示文摘 | Steven W P Craig R M | | 0，，01： | 1 |
| 11 | Advanced programming in the UNIX environment显示文摘 | STEVENS W R | 1992 | Addison-Wesley1992，，3： | 1 |
| 12 | Visibility and aerosol composition in Houston,Texas显示文摘 | Dzubay T G Stevens R K Lewis C W | 1982 | Environ Sci Technol1982，16，8： | 1 |
| 13 | The influence of grooves on the fully wetted and aerated flow between open clutch plates显示文摘 | CHINAR R A WILLIAM W S STEVEN L C | 2010 | ASME Journal of Tribology2010，132，： | 1 |
| 14 | Alzheimer's & Dementia:Assessment of memantine treatment effects on language asmine Fokkens 显示文摘 | Steven F Philippe R Bengt W | 2008 | The Journal of the Alzheimer''s Association2008，4，4： | 1 |
| 15 | An operational remote sensing algorithm of land surface evaporation显示文摘 | Kenlo Nishida Remakrishna R N Steven W R | 2003 | J Geophys2003，108，9： | 1 |
| 16 | Kinetic resolution of racemic glycidyl butyrate using a multiphase membrane and model Verification显示文摘 | Dauh R W Steven M C Georges B | 1993 | Biotechnology and Bioengeering1993，41，： | 1 |
| 17 | Treatment of pesticide-contaminated soils with thermal desorption technologies显示文摘 | Troxler William L Goh Steven K Kicks Lynton W R | 1993 | Air & Waste1993，43，： | 1 |
| 18 | Habitual physi- cal activity behavior of patients after primary total hip arthro- plasty显示文摘 | Wagenmakers R Stevens M Zijlstra W | 2008 | Phys Ther2008，88，9： | 1 |
| 19 | 显示文摘 | Li Jilaong Steven R Nutt Keven W Kirby | 1999 | J Am Cerum Soc1999，82，11： | 1 |
| 20 | RAGE signaling mediates post-injury arterial neointima formation by suppression of liver kinase B1 and AMPK activity显示文摘 | Yu W Liu-Bryyan R Stevens | 2012 | Atherosclerosis2012，222，2： | 1 |
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