A Phase I Trial of Trametinib in Combination with Sorafenib in Patients with Advanced Hepatocellular Cancer

Lessons Learned

• The combination of trametinib and sorafenib has an acceptable safety profile, albeit at doses lower than approved for monotherapy.
• Maximum tolerated dose is trametinib 1.5 mg daily and sorafenib 200 mg twice daily.
• The limited anticancer activity observed in this unselected patient population does not support further exploration of trametinib plus sorafenib in patients with hepatocellular carcinoma.

BackgroundThe RAS/RAF/MEK/ERK signaling pathway is associated with proliferation and progression of hepatocellular carcinoma (HCC). Preclinical data suggest that paradoxical activation of the MAPK pathway may be one of the resistance mechanisms of sorafenib; therefore, we evaluated trametinib plus sorafenib in HCC.MethodsThis was a phase I study with a 3+3 design in patients with treatment‐naïve advanced HCC. The primary objective was safety and tolerability. The secondary objective was clinical efficacy.ResultsA total of 17 patients were treated with three different doses of trametinib and sorafenib. Two patients experienced dose‐limiting toxicity, including grade 4 hypertension and grade 3 elevation of aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/bilirubin over 7 days. Maximum tolerated dose was trametinib 1.5 mg daily and sorafenib 200 mg twice a day. The most common grade 3/4 treatment‐related adverse events were elevated AST (37%) and hypertension (24%). Among 11 evaluable patients, 7 (63.6%) had stable disease with no objective response. The median progression‐free survival (PFS) and overall survival (OS) were 3.7 and 7.8 months, respectively. Phosphorylated‐ERK was evaluated as a pharmacodynamic marker, and sorafenib plus trametinib inhibited phosphorylated‐ERK up to 98.1% (median: 81.2%) in peripheral blood mononuclear cells.ConclusionTrametinib and sorafenib can be safely administered up to trametinib 1.5 mg daily and sorafenib 200 mg twice a day with limited anticancer activity in advanced HCC.     

妇科腹腔镜围手术期碳水化合物口服疗法对术后胰岛素抵抗影响的研究

目的观察妇科腹腔镜手术围术期碳水化合物口服疗法和传统禁饮食方案两种不同的临床处理措施对于术后胰岛素抵抗（IR）的影响。 方法选取2018年2月至8月入住徐州医科大学附属医院妇科，行腹腔镜下全子宫切除手术的非糖尿病患者共98例，将采用围术期碳水化合物口服疗法者作为观察组（50例），采用传统禁饮食方案者作为对照组（48例）。检测所有病例的术前、术后第1天及第3天的空腹血糖（FPG）及空腹胰岛素（FINS），并利用稳态模式评估法计算稳态模型胰岛素抵抗指数（HOME-IR）。对于观察组与对照组患者术前、术后第1天和术后第3天的FPG、FINS和HOME-IR等指标，组间比较采用独立样本t检验。两组患者术后腹胀、术后24 h通气、术后发热的发生情况的比较采用确切概率法检验。 结果观察组与对照组比较，术前和术后第1天FPG差异无统计学意义（P均>0.05），术后第3天FPG明显降低［（4.34±0.59）mmol/L vs （4.96±0.64）mmol/L］，差异有统计学意义（t=-4.96，P=0.002）。观察组与对照组比较，术前和术后第1天FINS差异无统计学意义（P均>0.05），术后第3天FINS明显降低［（45.39±13.55）mIU/L vs （51.18±9.34） mIU/L］，差异有统计学意义（t=-2.46，P=0.033）。观察组与对照组比较，术前HOME-IR差异无统计学意义（P>0.05），术后第1天和术后第3天HOME-IR明显降低［（13.08±4.80）vs （15.03±4.11）；（9.37±3.65）vs （11.30±2.55）］，差异有统计学意义（t=-0.69，P=0.042；t=-3.99，P=0.033）。两组患者术后其他观察指标比较，观察组术后24 h通气率与对照组比较明显增高（76.0% vs 64.6%），差异有统计学意义（P=0.045）。两组患者在术后腹胀、术后发热的发生率方面差异无统计学意义（P均>0.05）。两组患者均未发生术中误吸。 结论妇科腹腔镜手术围术期应用碳水化合物口服疗法较传统禁饮食方案，能有效减轻术后IR程度，促进术后康复进程，且不增加围术期并发症的发生率。     

Identification of key genes and pathways in discoid lupus skin via bioinformatics analysis

Discoid lupus erythematosus (DLE) is the most common skin manifestation of lupus; however, the molecular mechanisms underlying DLE remain unknown. Therefore, we aimed to identify key differentially expressed genes (DEGs) in discoid lupus skin and investigate their potential pathways.To identify candidate genes involved in the occurrence and development of the disease, we downloaded the microarray datasets {"type":"entrez-geo","attrs":{"text":"GSE52471","term_id":"52471"}}GSE52471 and {"type":"entrez-geo","attrs":{"text":"GSE72535","term_id":"72535"}}GSE72535 from the Gene Expression Database (GEO). DEGs between discoid lupus skin and normal controls were selected using the GEO2R tool and Venn diagram software (http://bioinformatics.psb.ugent.be/webtools/Venn/). The Database for Annotation, Visualization, and Integrated Discovery (DAVID), Enrichr, and Cytoscape ClueGo were used to analyze the Kyoto Encyclopedia of Gene and Genome pathways and gene ontology. Protein-protein interactions (PPIs) of these DEGs were further assessed using the Search Tool for the Retrieval Interacting Genes version 10.0.Seventy three DEGs were co-expressed in both datasets. DEGs were predominantly upregulated in receptor signaling pathways of the immune response. In the PPI network, 69 upregulated genes were selected. Furthermore, 4 genes (CXCL10, ISG15, IFIH1, and IRF7) were found to be significantly upregulated in the RIG-I-like receptor signaling pathway, from analysis of Enrichr and Cytoscape ClueGo.The results of this study may provide new insights into the potential molecular mechanisms of DLE. However, further experimentation is required to confirm these findings.     

Development of a Simulation-Based Mastery Learning Curriculum for Breaking Bad News

Introduction

Physician communication impacts patient outcomes. However, communication skills, especially around difficult conversations, remain suboptimal, and there is no clear way to determine the validity of entrustment decisions. The aims of this study were to 1) describe the development of a simulation-based mastery learning (SBML) curriculum for breaking bad news (BBN) conversation skills and 2) set a defensible minimum passing standard (MPS) to ensure uniform skill acquisition among learners.