Analysis of patient-reported outcomes from the LUME-Lung 1 trial: A randomised,double-blind,placebo-controlled,Phase III study of second-line nintedanib in patients with advanced non-small cell lung cancer

IntroductionThe LUME-Lung 1 trial (NCT00805194; Study 1199.13) demonstrated a significant overall survival (OS) advantage for nintedanib plus docetaxel compared with placebo plus docetaxel as second-line therapy for patients with advanced non-small cell lung cancer (NSCLC) and adenocarcinoma histology. Patient-reported outcomes (PROs) for symptoms and health-related quality of life (QoL) are reported here.MethodsPROs were assessed at screening, on Day 1 of each 21-day treatment cycle, at the end of active treatment, and at the first follow-up visit. PRO instruments were the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Lung Cancer-13 supplement, and the EuroQol disease-generic questionnaire (EQ-5D and EQ-VAS). Analyses of PRO items for lung cancer-specific symptoms of cough, dyspnoea and pain were prespecified.ResultsRates of questionnaire completion were high. There was no significant difference in time to deterioration of global health status/QoL, or symptoms of cough, dyspnoea or pain, between the treatment groups for both the overall study population and the adenocarcinoma population. Time to deterioration of some gastrointestinal events was shorter with nintedanib versus placebo. Longitudinal analysis for the adenocarcinoma population showed comparable changes between the groups in symptom scores over time, with numerical differences in favour of nintedanib for cough and pain scales, and significant reductions in some pain items with nintedanib versus placebo. There was no statistically significant difference in EQ-5D or EQ-VAS between the groups.ConclusionThe significant OS benefit observed with the addition of nintedanib to docetaxel therapy was achieved with no detrimental effect on patient self-reported QoL.     

New anti-angiogenesis agents: review of the clinical experience with carboxyamido-triazole (CAI), thalidomide, TNP-470 and interleukin-12

Angiogenesis was postulated to be a critical prognostic factor and therapeutic focus for malignancy more than two decades ago. Recent studies indicate quantitative assessments of microvessel count to be an independent prognostic variable for disease-free and overall survival in a wide variety of tumors, and that angiogenesis may be a feasible target against which to intervene pharmacologically. Several new and old agents have been found to have anti-angiogenic activity and have reached clinical trial. This review will focus on four agents under investigation in the US: carboxyamido-triazole (CAI), thalidomide, TNP-470 and interleukin (IL)-12. CAI, originally identified for its anti-invasive capacity, has been shown to inhibit tumor and endothelial cell proliferation by inhibition of calcium uptake. It is administered orally, is generally well tolerated, and has been shown to induce disease stabilization and occasional reductions in tumor mass. Thalidomide was shown to inhibit growth factor-induced neovessel formation, a process that can also explain its earlier devastating clinical toxicity. It is administered orally, and is currently in phase II clinical trials for prostate cancer, glioblastoma multiforme and breast cancer. TNP-470 is a fumagillin analog that has been shown in in vivo models to be a potent inhibitor of angiogenesis at concentrations that are cytostatic to endothelial cells and tumor cells. Lastly, IL-12 may exert its anti-angiogenic effects through activation of interferon- to up-regulate interferon-inducible protein-10, an anti-angiogenic cytokine. Phase I clinical trials of IL-12 have shown disease stabilization in several tumor types in response to s.c. administration or using genetically engineered IL-12-expressing patient fibroblasts. These promising new agents join the matrix metalloproteinase inhibitors as important new drugs in the anti-cancer armamentarium.     

Gold nanoparticles in ophthalmology

Many research projects are underway to improve the diagnosis and therapy in ophthalmology. Indeed, visual acuity deficits affect 285 million people worldwide and different strategies are being developed to strengthen patient care. One of these strategies is the use of gold nanoparticles (GNP) for their multiple properties and their ability to be used as both diagnosis and therapy tools. This review exhaustively details research developing GNPs for use in ophthalmology. The toxicity of GNPs and their distribution in the eye are described through in vitro and in vivo studies. All publications addressing the pharmacokinetics of GNPs administered in the eye are extensively reviewed. In addition, their use as biosensors or for imaging with optical coherence tomography is illustrated. The future of GNPs for ophthalmic therapy is also discussed. GNPs can be used to deliver genes or drugs through different administration routes. Their antiangiogenic and anti-inflammatory properties are of great interest for different ocular pathologies. Finally, GNPs can be used to improve stereotactic radiosurgery, brachytherapy, and photothermal therapy because of their many properties.     

探讨肿瘤抗血管生成治疗存在的问题及治疗分析

目的：对肿瘤抗血管生成治疗中存在的问题和解决的措施进行具体分析。方法从我院2012年12月-2014年12月接受抗血管生成治疗的肿瘤患者中随机选取60例作为研究对象,对他们的临床资料进行回顾性分析,总结治疗过程存在的问题,并探讨对应的解决措施。结果经分析,肿瘤抗血管生成治疗中,32例（53.33%）需重复使用大剂量给药或长期治疗,18例（30%）因肿瘤类型不同而无法判断疗效,23例（38.33%）缺乏固定的治疗方案,38例（63.33%）因其他合并症会增加血栓性疾病发生的概率,还有9例（15%）无法直接检查用药后的治疗效果。结论对于肿瘤抗血管生成治疗中存在的问题要采取针对性的解决措施,才能提高肿瘤的药物治疗效果。     

Oridonin exhibits anti-angiogenic activity in human umbilical vein endothelial cells by inhibiting VEGF-induced VEGFR-2 signaling pathway

Oridonin has been found to be a potential anti-angiogenesis agent. However, its functional targets and the underlying mechanisms are still vague. In vitro studies we found that oridonin not only inhibited VEGF-induced cell proliferation, migration and tube formation but also caused G2/M phase arrest and triggered cellular apoptosis in HUVECs. In mechanistic studies revealed that oridonin exhibited the anti-angiogenic potency, at least in part, through the down-regulation of VEGFR2-mediated FAK/MMPs, mTOR/PI3K/Akt and ERK/p38 signaling pathways which led to reduced invasion, migration, and tube formation in HUVECs. Our results could provide evidence that oridonin exerts strong anti-angiogenesis activities via specifically targeting VEGFR2 and its signaling pathway.     

Inhibitory Effects of Corni Fructus Extract on Angiogenesis and Adipogenesis

Natural products in Chonnam, Korea were screened via anti-angiogenesis experiments, and 1 candidate product was identified, Corni fructus, which exerted dose-dependent inhibitory effects against angiogenesis, adipogenesis, and cell adhesion. C. fructus extract (CFE) exhibits an angiogenesis inhibitory effect superior to that of the EGCG from green tea leaves. The expression level of angiogenesis and adipogenesis-related signal molecules in the western blotting was reduced by increasing the amount of added CFE. Moreover, a diet supplemented with CFE was deemed more effective in inducing weight loss in LB mice than a representative synthetic diet drug, orlistat, which incidently caused the side effect of denuding the mice of their hair. These results indicate that C. fructus may prove to be a useful anti-adipogenic compound, and these in vitro results may be reflected later under in vivo conditions.     

化疗联合甲羟孕酮治疗侵蚀性葡萄胎与绒毛膜癌的疗效观察

目的观察化学治疗（化疗）加用甲羟孕酮（MPA）治疗侵蚀性葡萄胎及绒毛膜癌（绒癌）患者的临床疗效。方法侵蚀性葡萄胎及绒癌患者25例，进行自身对照。按常规方法应用氟尿嘧啶、更生霉素8 d疗程，第1疗程不用MPA为对照组，第2疗程开始前1周加用MPA 200 mg·d 1口服为试验组；远期10例Ⅲ期为远期组（未用MPA），近期10例Ⅲ期为近期组（加用MPA）。观察化疗前后两组食欲、恶心、呕吐、口腔溃疡等情况；两组化疗前后白细胞变化及细胞因子白细胞介素 6（IL 6）的变化；比较近期组和远期组化疗疗程数及肺转移结局。结果试验组食欲、恶心、呕吐、口腔溃疡等明显好于对照组（P＜0.01)；试验组化疗前后白细胞无明显变化（P＞0.05），对照组化疗后白细胞明显下降(P＜0.01)；试验组细胞因子IL 6明显低于对照组（P＜0.01)；近期组化疗疗程数明显低于远期组，肺转移灶消失时间短于远期组（P＜0.01）。结论MPA降低了细胞因子IL 6血清水平，改善了肿瘤化疗患者的生活质量；保护骨髓免于化疗毒性作用，增加了患者对化疗的耐受性；MPA良好的临床作用与其抑制肿瘤新生血管作用有关。     

Microarray-based Analysis of Anti-angiogenic Activity of Demethoxycurcumin on Human Umbilical Vein Endothelial Cells: Crucial Involvement of the Down-regulation of Matrix Metalloproteinase

cDNA microarray-based gene expression analysis has been successfully employed to explore the action mechanism and to validate the targets of several drugs. In the present study, we evaluated anti-angiogenic activity of demethoxycurcumin (DC), a structural analog of curcumin, isolated from Curcuma aromatica , and investigated the effect of DC on genetic reprogramming in cultured human umbilical vein endothelial cells (HUVECs) using cDNA microarray analysis. Of 1024 human cancer-focused genes arrayed, 187 genes were up-regulated and 72 genes were down-regulated at least 2-fold by DC. Interestingly, 9 angiogenesis-related genes were down-regulated over 5-fold in response to DC, suggesting that the genetic reprogramming was crucially involved in anti-angiogenesis by the compound. To verify the results obtained from cDNA microarray analysis, matrix metalloproteinase-9 (MMP-9), the product of one of the angiogenesis-related genes down-regulated over 5-fold by DC, was investigated using gelatin zymography. DC potently inhibited the expression of MMP-9, yet showed no direct effect on its activity. These data show that gene expressional change of MMP-9 is a major mediator for angiogenesis inhibition by DC. All genes identified and microarray data are available on the web at http://dasan.sejong.ac.kr/bioprobe/ .     

Novel approaches in the therapy of metastatic renal cell carcinoma

Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, with approximately 40% of patients eventually dying of cancer progression. Approximately one third of patients present with metastatic disease, and up to 40% treated for localized disease have a recurrence. Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of RCC have paved the way for developments that may enhance early diagnosis, better predict tumor prognosis, and improve survival for RCC patients. The recent discovery of molecular tumor markers is expected to revolutionize the staging of RCC in the future and lead to the development of new therapies based on molecular targeting. Cytokine-based immunotherapy can be considered standard therapy in the treatment of metastatic RCC today. However, new therapies such as tumor vaccines, anti-angiogenesis agents, and small molecule inhibitors are being developed to improve efficacy and treat those patients who are unable to tolerate or are resistant to systemic immunotherapy. The aim of this review is to provide an update on current therapeutic approaches and targeted molecular therapy for metastatic RCC.     

A Selective Cyclooxygenase-2 Inhibitor Suppresses Tumor Growth in Nude Mouse Xenografted with Human Head and Neck Squamous Carcinoma Cells

The anti-tumor effect of a selective cyclooxygenase (COX)-2 inhibitor, JTE-522, was examined with the human head and neck squamous cell carcinoma cell line KB. KB cells do not produce prostaglandin (PG)-E2. In vitro , JTE-522 induced an increase of G1 phase-arrested cells, suppression of platelet-derived growth factor (PDGF) production and inhibition of telomerase activity. No cytotoxic effect was detected. In vivo , the growth of the tumor xenografted into nude mice was significantly suppressed by JTE-522. Suppression of angiogenesis at the periphery of the tumor, increase of G1-arrested cells and suppression of telomerase activity were observed, together with an increase of apoptotic cell death in the tumor. Immunological enhancement did not play a role. We concluded that the anti-tumor effect of JTE-522 was caused by anti-angiogenesis action, cell cycle arrest and inhibition of telomerase activity of the tumor cells. These combined effects might induce apoptosis.