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BACKGROUND Activation of the mesenchymal-epidermal transition factor (MET) tyrosine kinase and its ligand, hepatocyte growth factor (HGF), is implicated in resistance to epidermal growth factor receptor (EGFR) inhibitors. In this phase 1/2 trial, rilotumumab (an anti-HGF antibody) combined with erlotinib was evaluated in patients with metastatic, previously treated non–small cell lung cancer. METHODS In phase 1, a dose de-escalation design was adopted with rilotumumab starting at 15 mg/kg intravenously every 3 weeks and oral erlotinib 150 mg daily. In phase 2, the disease control rate (DCR) (according to Response Evaluation Criteria in Solid Tumors) of the combination was evaluated using a Simon 2-stage design. The biomarkers examined included 10 plasma-circulating molecules associated with the EGFR and MET pathways. RESULTS Without indications for de-escalation, the recommended phase 2 dose was dose level 0. Overall, 45 response-evaluable patients were enrolled (13 with squamous carcinoma, 32 with adenocarcinoma; 2 had confirmed EGFR mutations, 33 had confirmed wild-type [WT] EGFR, and 7 had KRAS mutations). The DCR for all patients was 60% (90% confidence interval [CI], 47.1%-71.3%). Median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 6.6 months (90% CI, 5.6-8.9 months). Among patients with WT EGFR, the DCR was 60.6% (90% CI, 46.3%-73.3%), median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 7.0 months (90% CI, 5.6-13.4 months). Elevated baseline levels of neuregulin 1 were associated with longer progression-free survival (hazard ratio, 0.41; 95% CI, 0.19-0.87), whereas elevated amphiregulin levels were associated with more rapid progression (hazard ratio, 2.14; 95% CI, 1.48-3.08). CONCLUSIONS Combined rilotumumab and erlotinib had an acceptable safety profile, and the DCR met the prespecified criteria for success. In the EGFR WT group, the DCR exceeded published reports for erlotinib alone. High circulating levels of neuregulin 1 may indicate sensitivity to this combination. Cancer 2017;123:2936–44. © 2017 American Cancer Society.

Background Topically applied opioids promote angiogenesis and healing of ischemic wounds in rats. We examined if topical fentanyl stimulates wound healing in diabetic rats by stimulating growth-promoting signaling, angiogenesis, lymphangiogenesis and nerve regeneration. Methods We used Zucker diabetic fatty rats that develop obesity and diabetes on a high fat diet due to a mutation in the Leptin receptor. Fentanyl blended with hydrocream was applied topically on ischemic wounds twice daily, and wound closure was analyzed regularly. Wound histology was analyzed by hematoxylin and eosin staining. Angiogenesis, lymphangiogenesis, nerve fibers and phospho-platelet derived growth factor receptor-β (PDGFR-β) were visualized by CD31-, lymphatic vessel endothelium-1, protein gene product 9.5- and anti-phospho PDGFR-β-immunoreactivity, respectively. Nitric oxide synthase (NOS) and PDGFR-β signaling were analyzed using Western immunoblotting. Results Fentanyl significantly promoted wound closure as compared to phosphate-buffered saline (PBS). Histology scores were significantly higher in fentanyl-treated wounds, indicative of increased granulation tissue formation, reduced edema and inflammation, and increased matrix deposition. Fentanyl treatment resulted in increased wound angiogenesis, lymphatic vasculature, nerve fibers, nitric oxide, NOS and PDGFR-β signaling as compared to PBS. Phospho-PDGFR-β co-localized with CD31 co-staining for vasculature. Conclusions Topically applied fentanyl promotes closure of ischemic wounds in diabetic rats. Increased angiogenesis, lymphangiogenesis, peripheral nerve regeneration, NO and PDGFR-β signaling are associated with fentanyl-induced tissue remodeling and wound healing. 摘要 背景： 局部应用罂粟碱类可以促进大鼠血管的生成与缺血性伤口的愈合。我们的目的是调查局部芬太尼麻醉是否通过刺激促生长信号、血管生成、淋巴管生成以及神经再生来促进糖尿病大鼠伤口的愈合。 方法： 我们使用的Zucker糖尿病肥胖大鼠由于瘦素受体基因突变在高脂饮食下出现了肥胖与糖尿病。对缺血性伤口每日2次局部使用混合了芬太尼的保湿乳剂，定期分析伤口闭合情况。使用苏木精-伊红染色分析伤口组织学切片。血管生成、淋巴管生成、神经纤维以及磷酸化血小板衍生生长因子受体-β（PDGFR-β）分别使用CD31-、淋巴管内皮细胞-1、蛋白基因产物9.5-以及抗磷酸化PDGFR-β-免疫反应性抗体来显像。使用免疫印迹法分析一氧化氮合酶与PDGFR-β信号。 结果： 与磷酸盐缓冲的生理盐水相比，芬太尼可以显著地促进伤口闭合。在使用芬太尼治疗的伤口中组织学评分显著更高，提示肉芽组织形成增加，水肿与炎症减少，以及基质沉积增加。与磷酸盐缓冲的生理盐水相比，使用芬太尼治疗后可以导致伤口的血管生成、淋巴管系统、神经纤维、一氧化氮、一氧化氮合酶以及PDGFR-β信号都有所增加。脉管系统中的磷酸-PDGFR-β使用CD31来辅助染色定位。 结论： 糖尿病大鼠局部应用芬太尼可以促进缺血性伤口闭合。增加的血管生成、淋巴管生成、周围神经再生、一氧化氮以及PDGFR-β信号与芬太尼诱导的组织重构以及伤口愈合有关。