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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 | Role of interleukin-1 and its antagonism of hepatic stellate cell proliferation and liver fibrosis in the Abcb4^(-/-) mouse model显示文摘AIM: To study the interleukin-1(IL-1) pathway as a therapeutic target for liver fibrosis in vitro and in vivo using the ATP-binding cassette transporter b4^(-/-)(Abcb4^(-/-)) mouse model.METHODS: Female and male Abcb4^(-/-) mice from 6 to 13 mo of age were analysed for the degree of cholestasis(liver serum tests), extent of liver fibrosis(hydroxyproline content and Sirius red staining) and tissue-specific activation of signalling pathways such as the IL-1 pathway [quantitative polymerase chain reaction(q PCR)]. For in vivo experiments, murine hepatic stellate cells(HSCs) were isolated via pronasecollagenase perfusion followed by density gradient centrifugation using female mice. Murine HSCs were stimulated with up to 1 ng/m L IL-1β with or without 2.5 μg/m L Anakinra, an IL-1 receptor antagonist, respectively. The proliferation of murine HSCs was assessed via the Brd U assay. The toxicity of Anakinra was evaluated via the fluorescein diacetate hydrolysis(FDH) assay. In vivo 8-wk-old Abcb4^(-/-) mice with an already fully established hepatic phenotype were treated with Anakinra(1 mg/kg body-weight daily intraperitoneally) or vehicle and liver injury and liver fibrosis were evaluated via serum tests, q PCR, hydroxyproline content and Sirius red staining. RESULTS: Liver fibrosis was less pronounced in males than in female Abcb4^(-/-) animals as defined by a lower hydroxyproline content(274 ± 64 μg/g vs 436 ± 80 μg/g liver, respectively; n = 13-15; P < 0.001; MannWhitney U-test) and lower m RNA expression of the profibrogenic tissue inhibitor of metalloproteinase-1(TIMP)(1 ± 0.41 vs 0.66 ± 0.33 fold, respectively; n = 13-15; P < 0.05; Mann-Whitney U-test). Reduced liver fibrosis was associated with significantly lower levels of F4/80 m RNA expression(1 ± 0.28 vs 0.71 ± 0.41 fold, respectively; n = 12-15; P < 0.05; Mann-Whitney U-test) and significantly lower IL-1β m RNA expression levels(1 ± 0.38 vs 0.44 ± 0.26 fold, respectively; n = 13-15; P < 0.001; Mann-Whitney U-test). No gender differences in the serum liver parameters [bilirubin; alanine aminotransferase(ALT); aspartate aminotransferase and alkaline phosphatase(AP)] were found. In vitro, the administration of IL-1β resulted in a significant increase in HSC proliferation [0.94 ± 0.72 arbitrary units(A.U.) in untreated controls, 1.12 ± 0.80 A.U. at an IL-1β concentration of 0.1 ng/m L and 1.18 ± 0.73 A.U. at an IL-1β concentration of 1 ng/m L in samples from n = 6 donor animals; P < 0.001; analyses of variance(ANOVA)]. Proliferation was reduced significantly by the addition of 2.5 μg/m L Anakinra(0.81 ± 0.60 A.U. in untreated controls, 0.92 ± 0.68 A.U. at an IL-1β concentration of 0.1 ng/m L, and 0.91 ± 0.69 A.U. at an IL-1β concentration of 1 ng/m L; in samples from n = 6 donor animals; P < 0.001; ANOVA) suggesting an anti-proliferative effect of this clinically approved IL-1 receptor antagonist. The FDH assay showed this dose to be non-toxic in HSCs. In vivo, Anakinra had no effect on the hepatic hydroxyprolinecontent, liver serum tests(ALT and AP) and profibrotic(collagen 1α1, collagen 1α2, transforming growth factor-β, and TIMP-1) and anti-fibrotic [matrix metalloproteinase 2(MMP2), MMP9 and MMP13 ] gene expression after 4 wk of treatment. Furthermore, the hepatic IL-1β and F4/80 m RNA expression levels were unaffected by Anakinra treatment.CONCLUSION: IL-1β expression is associated with the degree of liver fibrosis in Abcb4^(-/-) mice and promotes HSC proliferation. IL-1 antagonism shows antifibrotic effects in vitro but not in Abcb4^(-/-) mice. | Florian P Reiter Ralf Wimmer Lena Wottke Renate Artmann Jutta M Nagel Manuel O Carranza Doris Mayr Christian Rust Peter Fickert Michael Trauner Alexander L Gerbes Simon Hohenester Gerald U Denk | 2016 | World Journal of Hepatology2016，8，8： | 3 |
| 3 | Endoscopic ultrasonography in the evaluation of leiomyoma and extramucosal cysts of the esophagus显示文摘 | Massari M De Simone M Cioffi U | 1998 | Hepatogastroenterology1998，45，22： | 2 |
| 4 | Farmer Participatory Evaluation of Nursery Bed Treatments for the Control of Root-Knot Nematodes [Meloidogynejavanica (Treub) Chitwood and Meloidogyne incognita (Kofoid and White) Chitwood] in Smallholder Farms in Kenya显示文摘 | D. K. Karanja S. R. Gowen B. Ndung u R. O. Musebe S. Simons A McLeod B. R. Kerry P. K. Karanja B. Pembroke | 2011 | Journal of Agricultural Science and Technology(A)2011，1，5： | 2 |
| 5 | Lesions of rat skeletal muscle after local block of acetylcholinesterase and neuromuscular stimulation显示文摘 | Mense S Simons DG Hoheisel U | | 0，，06： | 1 |
| 6 | Voluntary and involuntary minorities:a cultural-ecological theory of school performance with some implications for education显示文摘 | Ogbu J U Simons H D | | 0，，02： | 1 |
| 7 | Presentation and sur- gicalmanagement of bronchogenic and esophageal duplication cysts inadults显示文摘 | Cioffi U Bonavina LG De Simone M | 1998 | Chest Chicago1998，113，6： | 1 |
| 8 | Charge transport in nanoparticle arrangements显示文摘 | Simon U | 1998 | Adv Mater1998，10，： | 1 |
| 9 | Use of an anti-interleukin-5 antibody in the hypereosinophilic syndrome with eosino- philic dermatitis显示文摘 | Plotz SG Simon HU Darsow U | 2003 | N Engl J Med2003，349，24： | 1 |
| 10 | Activation of the JAK-STAT pathway by reactive oxygen species 显示文摘 | Simon AR Rai U Fanburg BL Cochran BH | 1998 | Am J Physiol Cell Physiol1998，275，： | 1 |
| 11 | Video-assistedsleeve lobeetomy for mucoepidermoid carcinoma of the left lower lobar bronchus: a case report显示文摘 | Santambrogio L Cioffi U De Simone M | 2002 | Chest2002，121，2： | 1 |
| 12 | High-grade stenosis of the internal carotid artery assessed by color and power Doppler imaging显示文摘 | Sliwka U Simon SG | 1998 | J Clin Ultrasound1998，26，2： | 1 |
| 13 | VOC photodegradation at the gas-solid interface of a TiO2 photo-catalyst part I :1 - butanol and 1 - butylanmine 显示文摘 | Benoit Marqui6 F Wilkenh6ner U Simon V | 2000 | Journal of Photochemistry and Photobiology A: Chemistry2000，132，3： | 1 |
| 14 | Role of reactive oxygen species (ROS) in apoptosis induction显示文摘 | SIMON H U HAJ-YEHIA A LEVI-SCHAFFER F | 2000 | Apoptosis2000，5，5： | 1 |
| 15 | Hypersurfaces with prescribed affine Gauss-Kronecker curvature显示文摘 | Li A M Simon U Zhao G S | 2000 | Geometriae Dedicata2000，81，： | 1 |
| 16 | Structure and density of crosslinks in natural rubber vulcanizates : A combined analysis by NMR spectroscopy, mechanical measurements and rubber elastic theory 显示文摘 | Gronski W Hoffmann U Simon G | 1992 | Rubb Chem Technol1992，65，2： | 1 |
| 17 | Prediction of fracture callus mechanical properties using micro-CT images and voxel-based finite element analysis显示文摘 | Shefelbine S.J Simon U Claes L | | 0，，03： | 1 |
| 18 | Multiple right-sid-ed pulmonary nodules : metastatic cancer or resectable earlystage tumor? 显示文摘 | Cioffi U Raveglia F De Simone M | 2011 | J Cardiothorac Surg2011，6，： | 1 |
| 19 | A new method for the nonlinear transformation of means and covariances in filters and estimators显示文摘 | Simon J Jeffery U Hugh D | 2000 | IEEE Trans on Automatic Control2000，45，3： | 1 |
| 20 | Analysis of heat conduction in deep penetration welding with a time-modulated laser beam 显示文摘 | Simon G Gratzke U Kroos J | 1993 | Joumal of Physics D: Applied Physics1993，26，5： | 1 |
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