Subject(s)
Biomedical Research/economics , Cardiovascular Diseases/economics , National Heart, Lung, and Blood Institute (U.S.)/economics , Neovascularization, Pathologic/economics , Neovascularization, Physiologic/physiology , Research Support as Topic/economics , Biomedical Research/trends , Cardiovascular Diseases/therapy , Humans , National Heart, Lung, and Blood Institute (U.S.)/trends , National Institutes of Health (U.S.)/economics , National Institutes of Health (U.S.)/trends , Neovascularization, Pathologic/therapy , Research Support as Topic/trends , United States/epidemiologyABSTRACT
INTRODUCTION: Forty percent of Down syndrome (DS) fetuses have congenital heart defects (CHD). An abnormal angiogenic environment has been described in euploid fetuses with CHD. However, the underlying pathophysiologic pathway that contributes to CHD in DS remains unknown. The objective was to compare the expression of angiogenic factors and chronic hypoxia genes in heart tissue from DS and euploid fetuses with and without CHD. METHODS: The gene expression profile was determined by real-time PCR quantification in heart tissue from 33 fetuses with DS, 23 euploid fetuses with CHD and 23 control fetuses. RESULTS: Angiogenic factors mRNA expression was significantly increased in the DS group compared to the controls (soluble fms-like tyrosine kinase-1, 81%, p = 0.007; vascular endothelial growth factor A, 57%, p = 0.006, and placental growth factor, 32%, p = 0.0227). Significant increases in the transcript level of hypoxia-inducible factor-2α and heme oxygenase 1 were also observed in the DS group compared to the controls. The expression of angiogenic factors was similar in DS fetuses and CHD euploid fetuses with CHD. CONCLUSION: Abnormal angiogenesis was detected in the hearts of DS fetuses with and without CHD. Our results suggest that DS determines an intrinsically angiogenic impairment that may be present in the fetal heart.
Subject(s)
Angiogenic Proteins/metabolism , Down Syndrome/metabolism , Heart Defects, Congenital/metabolism , Myocardium/metabolism , Neovascularization, Pathologic/economics , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Down Syndrome/complications , Down Syndrome/pathology , Female , Gene Expression Profiling , Heart Defects, Congenital/complications , Heart Defects, Congenital/pathology , Heme Oxygenase-1/genetics , Heme Oxygenase-1/metabolism , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Male , Placenta Growth Factor/genetics , Placenta Growth Factor/metabolism , RNA, Messenger/metabolism , Superoxide Dismutase-1/genetics , Superoxide Dismutase-1/metabolism , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-1/genetics , Vascular Endothelial Growth Factor Receptor-1/metabolismABSTRACT
UNLABELLED: Regorafenib is an oral multitargeted kinase inhibitor with potent antiangiogenic activity. In this phase I trial we evaluated the safety, pharmacokinetics, and efficacy of regorafenib with cisplatin and pemetrexed for patients with advanced nonsquamous non-small-cell lung cancers (nsNSCLCs). Nine patients enrolled before premature termination of the study. Five of 9 (56%) patients had a partial response and the median progression-free survival was 7 months (range, 1.5-15.1 months). Regorafenib had acceptable tolerability and minor pharmacokinetic interactions in combination with standard doses of cisplatin and pemetrexed in patients with advanced nsNSCLCs. BACKGROUND: The combination of bevacizumab, an antiangiogenesis agent, with cytotoxic chemotherapy improves survival in patients with advanced nonsquamous non-small-cell lung cancers (nsNSCLCs). Regorafenib is an oral multitargeted kinase inhibitor with potent antiangiogenic activity that is approved for patients with advanced colorectal cancer and gastrointestinal stromal tumors. In this phase I trial we evaluated the safety, pharmacokinetics (PK), and efficacy of regorafenib with cisplatin and pemetrexed for patients with advanced nsNSCLCs. PATIENTS AND METHODS: Chemotherapy-naive patients with advanced nsNSCLCs were treated with regorafenib 60 mg/d continuously and cisplatin 75 mg/m(2) with pemetrexed 500 mg/m(2) once every 21 days for up to 6 cycles. Thereafter, regorafenib with or without pemetrexed could be continued as maintenance. RESULTS: Nine patients enrolled before premature termination of the study because of slow recruitment and a change in the development strategy of regorafenib by the study sponsor. Five patients experienced at least 1 treatment-related Grade 3 adverse event. No Grade 4 or 5 toxicity occurred. Five of 9 (56%) patients had a partial response and the median progression-free survival was 7 months (range, 1.5-15.1 months). Minor PK interactions between regorafenib and chemotherapy were observed. CONCLUSION: Regorafenib had acceptable tolerability and minor PK interactions in combination with standard doses of cisplatin and pemetrexed in patients with advanced nsNSCLCs. Encouraging activity was appreciated in chemotherapy-naive patients with advanced nsNSCLCs. However, the small number of patients treated limits conclusions that can be drawn from these results.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/economics , Phenylurea Compounds/administration & dosage , Pyridines/administration & dosage , Adult , Aged , Bevacizumab , Carcinoma, Non-Small-Cell Lung/mortality , Cisplatin/administration & dosage , Cisplatin/adverse effects , Contraindications , Drug Interactions , Female , Humans , Lung Neoplasms/mortality , Male , Middle Aged , Neoplasm Staging , Pemetrexed/administration & dosage , Pemetrexed/adverse effects , Phenylurea Compounds/adverse effects , Pyridines/adverse effects , Survival Analysis , Treatment OutcomeABSTRACT
Neovascular age-related macular degeneration (nvAMD) is a chronic, progressive disease of the central retina, and its prevalence is expected to rise with the ageing population. Using a bottom-up approach based on retrospective data, this cross-sectional study estimated average annual direct costs of nvAMD to be £4,047, and average annual indirect costs to be £449. An attempt to measure intangible costs through willingness-to-pay yielded a lower response rate and estimated intangible costs to be 11.5% of monthly income. Direct costs were significantly higher for male participants, for those who have mild or moderate visual impairment in both eyes, and for those who have been diagnosed for a shorter time. The findings of this study suggest that the availability of early diagnosis, effective treatment, support services, and sustained research into the management of nvAMD may reduce the burden of visual impairment caused by nvAMD to affected individuals and the state.
