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.     

宁波市北仑区2013-2014年儿童哮喘流行病学调查

目的调查宁波市北仑区0~14岁儿童哮喘发病率、发病规律及危险因素,为制定防治措施提供参考。方法2013年1月-2014年1月,采用整群抽样法抽取北仑区19所学校0~14岁儿童为调查对象进行问卷调查,对筛查出的疑似哮喘儿童进行确诊,并对其人口学特征进行分析,采用logistic回归方程分析危险因素。结果调查收回有效问卷23 781份,共检出哮喘患儿534例,发病率为2.25%,男女发病率比例为1.92:1。其中发病较轻患儿占44.01%,中度占31.46%,重度占24.53%。发病时间以换季、冬季为主,分别占35.96%、32.02%。多因素logistic回归分析显示,呼吸道感染、药物过敏史、家族过敏史和食物过敏史是儿童哮喘发病的危险因素(P<0.05)。结论北仑区儿童哮喘发病率较高,具有性别和季节发病差异,应加大对患病危险因素的宣传,规范标准化治疗方案,减少儿童哮喘疾病的发生。     

Pathways in the association between sugar sweetened beverages and child asthma traits in the 2nd year of life: Findings from the BRISA cohort

Studies on the exposure of children to sugar-sweetened beverages (SSBs) at an early age may contribute to better understand the common causes and the temporal order of the relationships between obesity and asthma in early childhood. The objective of this study was to estimate the association between SSB and child asthma traits in the 2nd year of life, modeling direct and indirect pathways mediated by the highest BMI-z of the child and allergic inflammation. Data from the BRISA cohort, São Luís-MA, Brazil (n = 1140), were obtained from the baseline and from the follow-up performed at the 2nd year of life. The main explanatory variable was the calories from added sugars in SSBs as a percentage of the total daily energy intake. The outcome child asthma traits was a latent variable deduced from four indicators: medical diagnosis of asthma, wheezing, emergency visit due to intense wheezing, and medical diagnosis of rhinitis. A high percentage of daily calories from sugars added to SSBs was directly associated with higher values of child asthma traits (standardized coefficient (SC = 0.073; P = .030)). High levels of eosinophils were also directly associated with child asthma traits (SC = 0.118; P = .049). No mediation pathways were observed via greater BMI-z or eosinophil counts. Therefore, early exposure of children to SSB may contribute to increased risk of childhood asthma, preceding the link between sugar consumption and overweight/obesity, not yet evident in children in the first 2 years of life.     

Pseudoathetosis: report of three patients.

We report on 3 patients with pseudoathetosis, which are involuntary, slow, writhing movements due to loss of proprioception.     

Primary hypothyroidism presenting as ovarian tumor and precocious puberty in a prepubertal girl.

We report a case of a prepubertal girl with juvenile primary hypothyroidism presenting as ovarian cysts and precocious puberty. The 7-year-old female was referred to our clinic because of a pelvic/abdominal mass and vaginal bleeding. Besides these findings, on physical examination we noticed the thyroid gland globally increased and the presence of secondary sexual characteristics. Based upon the clinical profile and investigations, the patient was diagnosed with juvenile primary hypothyroidism due to autoimmune thyroiditis. The cysts and precocious puberty resolved spontaneously after the simple replacement of thyroid hormone. It is important to bear in mind hypothyroidism in cases of girls presenting ovarian cysts and precocious puberty in order to avoid unnecessary surgery on the ovaries.     

Reactive oxygen species and human spermatozoa: physiology and pathology

The role of reactive oxygen species (ROS) in the pathophysiology of human sperm function has been emphasized in recent years. ROS production in semen has been associated with loss of sperm motility, decreased capacity for sperm–oocyte fusion and loss of fertility. There is a current presumption that the most prolific source of ROS in sperm suspensions is an NADPH oxidase located in leukocytes or in spermatozoa which produces superoxide which is further converted to peroxide by the action of superoxide dismutase. Hydrogen peroxide has been recognized as the most toxic oxidizing species for human spermatozoa, which are very sensitive to lipid peroxidation owing to the high content of polyunsaturated fatty acids in their plasma membrane, though this is not the sole mechanism by which sperm function might be impaired by ROS. Although the excessive production of ROS is detrimental to human spermatozoa, there is a growing body of evidence which suggests that ROS are also involved in the physiological control of some sperm functions. This review focuses on the nature and source of the ROS generated by human spermataozoa as well as their operational mechanisms and their effects, which may be detrimental or beneficial.