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.     

In Vivo Kinematics of Functional Ankle Instability Patients and Lateral Ankle Sprain Copers During Stair Descent

Patients with mechanic ankle instability experience increased tibiotalar and subtalar joint laxity. However, in vivo joint kinematics in functional ankle instability (FAI) patients and lateral ankle sprain (LAS) copers, especially during dynamic activities, are poorly understood. Ten FAI patients, 10 LAS copers, and 10 healthy controls were included in this study. A dual fluoroscopic imaging system was used to analyze the tibiotalar and subtalar joint kinematics during stair descent. Five key poses of stair descent were analyzed. Kinematic data from six degrees of freedom were calculated utilizing a solid modeling software. The range of motion and joint positions in each degree of freedom were compared among the three groups. The tibiotalar joints of FAI patients and LAS copers were significantly more inverted than those of healthy controls during the foot strike (p = 0.016, = 0.264). The subtalar joints of FAI patients were significantly more anteriorly translated (pose 2, p = 0.003, = 0.352; pose 3, p < 0.001, = 0.454; pose 4, p = 0.004, = 0.334), inverted (pose 4, p = 0.027, = 0.234; pose 5,p = 0.034, = 0.221), and externally rotated (pose 4, p = 0.037, = 0.217; pose 5; p = 0.004, = 0.331) than those of healthy controls during the mid‐stance and the heel off. The FAI patients showed excessive tibiotalar inversion and subtalar joint hypermobility during stair descent. Meanwhile, the LAS copers maintained subtalar joint stability, and only showed excessive tibiotalar inversion in foot strike. These data provide insight into the mechanisms behind the development of FAI after initial LAS. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1860–1867, 2019     

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喘鸣是婴幼儿时期呼吸道疾病中最常见的症状,病因很多,并非所有的喘鸣均由哮喘引起。气管、支气管炎及气管、支气管软骨软弱、异物、血管畸形,胸内肿瘤以及支气管淋巴结核等,均可引起喘鸣。分析天津市儿童医院收治的以喘鸣为主要症状的3岁以下婴幼儿196例,其主要病因见表1。表1天津市儿童医院收治的196例以喘鸣为主要症状的婴幼儿喘鸣病因病因例数大气道阻塞气管、支气管异物21气管、支气管淋巴结核51先天性气管、支气管、肺发育畸形12支气管软骨软化3纵隔囊肿和(或)肿瘤19血管畸形1中叶综合征5小气道阻塞毛细支气管炎30以喘息为表型的婴幼…     

颗粒松质骨压紧植骨全髋关节置换术治疗创伤性髋关节炎的疗效

目的探讨颗粒松质骨压紧植骨全髋关节置换术(THA)治疗髋臼骨折继发创伤性髋关节炎的疗效。方法1998年12月-2005年5月,对15例髋臼骨折继发创伤性髋关节炎患者行颗粒松质骨压紧植骨THA,所有患者髋臼假体均采用骨水泥固定,颗粒骨均取自体骨,术后24h后开始被动活动,3个月后开始全负重锻炼。临床随访采用Harris髋关节评分(HSS)系统评分,对任何原因引起髋臼假体翻修均视为临床失败。根据Conn等影像学评价法观察颗粒骨长人情况,根据DeLee的三区法测量臼杯、骨水泥与移植骨间的界面宽度,臼杯的移位程度则依据其相对于泪点间线的距离而定。结果14例患者获得平均4．3年(1．0-7．5年)随访,HHS评分由术前平均42分(10-62分)提高到随访结束时平均84分(58-98分)。1例髋部有轻度疼痛,无患者行翻修手术。大部分髋部恢复了其正常的旋转中心,仅有2例高出对侧0．8 mm。大多数患者影像学表现稳定,2例在Ⅰ区和Ⅲ区出现进行性增宽的透亮带,1例在Ⅲ区出现非进行性增宽的透亮带。1例臼杯假体在术后7年出现明显移位(6 mm),但并没有行翻修手术。结论颗粒骨压紧植骨技术作为一种生物学髋臼重建方法,其联合THA治疗髋臼骨折后继发创伤性关节炎伴髋臼缺损的疗效令人满意,能够恢复髋关节的正常解剖和功能活动。     

对医学院校伪贫困生的思考

目的 深入剖析医学院校出现伪贫困生的原因，提出一套治理伪贫困现象的方案。方法 从外部环境、学校、学生本身等3个方面分析出现伪贫困生现象的基本原因。结果 治理伪贫困现象的对策是：加强诚信教育、讲述贫困故事、建立监管机制、形成文化自觉。结论 只有治理高校里的伪贫困现象，才能使扶贫资金使用得当，体现公平的原则。     

Efficacy and safety of herbal medicines for idiopathic Parkinson's disease: a systematic review.

The objective of this study is to assess the efficacy and safety of herbal medicines (HMs), as a monotherapy or adjunct therapy, compared to placebo or conventional approaches in the treatment of idiopathic Parkinson's disease (PD). We conducted a systematic review of randomized controlled trials from both conventional and alternative medicine sources. Outcome measures were overall improvement, quality of life, reduction of levodopa dose, and adverse events. Nine studies were included, each testing a different HM. Six of the trials had limited internal validity due to major flaws in design, including the lack of proper randomization; insufficient blinding; unclear inclusive criteria in terms of diagnostic criteria, baseline staging, and duration of disease; lack of proper sample size calculation; and insufficient data analysis. Imbalances in gender and ethnicity among the patients in the included trials were observed. No major adverse events emerged, and no specific pattern was detected from the trials describing such data. In addition to major methodological defects, heterogeneity in (1) HM tested, (2) control treatment, and (3) outcome measure hindered in-depth data analysis and synthesis. Current evidence is insufficient to evaluate the efficacy and safety of various HMs. Further studies with improved trial design and reporting, with assessment on cost-effectiveness, quality of life, and qualitative data are warranted.     

小儿糖尿病血胰岛细胞抗体与胰岛素自身抗体

报道并分析20例小儿糖尿病患儿的临床资料及血胰岛细胞抗体(ICA)及胰岛素自身抗体(IAA)的测定资料。在20例患儿中,临床表现多不典型。在酮症酸中毒的治疗中小剂量胰岛素疗法方法简便,安全可靠,并发症少。本组患儿ICA阳性率55%,IAA阳性率30%,经卡方检验均显著高于对照组,推测病毒感染引起自身免疫反应,产生ICA及IAA而致本病发生。