Early intervention in myelofibrosis and impact on outcomes: A pooled analysis of the COMFORT-I and COMFORT-II studies

Background

In a pooled analysis of the phase 3 Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment I (COMFORT-I) and COMFORT-II clinical trials, adult patients with intermediate-2 or high-risk myelofibrosis who received oral ruxolitinib at randomization or after crossover from placebo or best available therapy (BAT) had improved overall survival (OS).

Methods

This post hoc analysis of pooled COMFORT data examined relevant disease outcomes based on the disease duration (≤12 or >12 months from diagnosis) before ruxolitinib initiation.

Results

The analysis included 525 patients (ruxolitinib: ≤12 months, n = 84; >12 months, n = 216; placebo/BAT: ≤12 months, n = 66; >12 months, n = 159); the median age was 65.0–70.0 years. Fewer thrombocytopenia and anemia events were observed among patients who initiated ruxolitinib treatment earlier. At Weeks 24 and 48, the spleen volume response (SVR) was higher for patients who initiated ruxolitinib earlier (47.6% vs. 32.9% at Week 24, p = .0610; 44.0% vs. 26.9% at Week 48, p = .0149). In a multivariable analysis of factors associated with spleen volume reduction, a logistic regression model that controlled for confounding factors found that a significantly greater binary reduction was observed among patients with shorter versus longer disease duration (p = .022). At Week 240, OS was significantly improved among patients who initiated ruxolitinib earlier (63% [95% CI, 51%‒73%] vs. 57% [95% CI, 49%‒64%]; hazard ratio, 1.53; 95% CI, 1.01‒2.31; p = .0430). Regardless of disease duration, a longer OS was observed for patients who received ruxolitinib versus those who received placebo/BAT.

Conclusions

These findings suggest that earlier ruxolitinib initiation for adult patients with intermediate-2 and high-risk myelofibrosis may improve clinical outcomes, including fewer cytopenia events, durable SVR, and prolonged OS.

Plain Language Summary

• Patients with myelofibrosis, a bone marrow cancer, often do not live as long as the general population. These patients may also have an enlarged spleen and difficult symptoms such as fatigue.
• Two large clinical trials showed that patients treated with the drug ruxolitinib lived longer and had improved symptoms compared to those treated with placebo or other standard treatments.
• Here it was examined whether starting treatment with ruxolitinib earlier (i.e., within a year of diagnosis) provided benefits versus delaying treatment.
• Patients who received ruxolitinib within a year of diagnosis lived longer and experienced fewer disease symptoms than those whose treatment was delayed.

     

Synthesis of 13C-labeled parabens from isotopically enriched phenols using the Houben–Hoesch reaction

Parabens are antimicrobial additives found in a wide array of consumer products. However, the halogenated compounds formed from parabens during wastewater disinfection are a potential environmental concern. In order to identify these transformation products and investigate their mechanism of formation, a synthetic route to ethyl parabens labeled with the stable isotope carbon-13 at specific positions within the benzene ring was developed. This efficient two-step procedure starts from commercially available ¹³C-labeled phenols and involves (1) initial acylation of the phenol via a Houben–Hoesch reaction with trichloroacetonitrile followed by (2) a modified haloform reaction of the resulting trichloromethyl ketone to afford the corresponding ¹³C-labeled ethyl parabens in 65%–80% overall yield. The scope of the modified haloform reaction was also investigated, allowing for the synthesis of other parabens derived from primary or secondary alcohols, including ¹³C- and deuterium-labeled esters. In addition, 4-hydroxybenzoic acid can be formed directly from the common trichloromethyl ketone intermediate upon treatment with lithium hydroxide. This protocol complements existing methods for preparing ¹³C-labeled paraben derivatives and offers the specific advantages of exhibiting complete regioselectivity in the Houben–Hoesch reaction (to form the para-disubstituted product) and avoiding the need for protecting groups in the modified haloform reaction that forms the paraben esters.     

电针复合TCI靶控输注在单肺通气食管癌开胸手术麻醉中的应用与安全性＊

目的 探讨电针复合靶控输注（Target Controlled Infusion， TCI）在单肺通气食管癌开胸手术麻醉中的应用价值。方法 选取于我院拟行单肺通气食管癌开胸切除手术患者60例作为研究对象。随机将其分为试验组与对照组，对照组30例采取气管插管全麻及TCI靶控输注维持麻醉深度，试验组30例则在对照组方案基础上辅助电针麻醉，记录两组患者手术麻醉时间、药物用量、苏醒时间、并发症；以及术前（T_Ⅰ）、插管前即刻（T_Ⅱ）、插管后1 min（T_Ⅲ）、切皮即刻（T_Ⅳ）、去骨时（T_Ⅴ）、拔管即刻（T_Ⅵ）时平均动脉压（MAP）、平均心率（HR）、BIS值；术前、术后1天、术后3天简易智能精神状态检查量表（MMSE）；并于麻醉诱导前（T₀）、手术开始2 h（T₁）、术后1天（T₂）、术后3天（T₃）时抽取患者外周静脉血检测IL-1β、IL-6、IL-10、TNF-α浓度。结果 试验组手术用时、麻醉时间略低于对照组，但差异无统计学意义（P>0.05），试验组异丙酚、舒芬太尼用量以及苏醒时间均明显低于对照组（P<0.05）；T_Ⅱ时两组平均动脉压（Mean Arterial Pressure， MAP）、心率（Heartrate， HR）较术前明显降低，且试验组MAP明显低于对照组（P<0.05），但两组T_Ⅱ时HR比较无显著差异（P>0.05）；T_Ⅲ、T_Ⅵ时对照组MAP、HR明显高于T_Ⅰ时，而试验组MAP、HR与T_Ⅰ比较无显著差异（P>0.05）。术后1天、3天试验组简易智能精神状态检查量表（Mini-Mental State Examination， MMSE）评分低于对照组，有显著性差异（P<0.05）。T₁、T₂、T₃时试验组白介素-1β（IL-1β）、白介素-6（IL-6）、肿瘤坏死因子（Tumor Necrosis Factor-α， TNF-α）水平明显低于对照组（P<0.05），白介素-10（IL-10）水平明显高于对照组（P<0.05）。结论 采用电针复合TCI靶控输注麻醉方案可有效提升单肺通气食管癌开胸手术麻醉效果，能够降低患者术后认知功能障碍发生风险。     

Evaluation of vilazodone for the treatment of depressive and anxiety disorders

Introduction: Major Depressive Disorder (MDD) and General Anxiety Disorder (GAD) significantly contribute to the global burden of disease. Vilazodone, a combined serotonin reuptake inhibitor and 5-HT1A partial agonist, is an approved therapy for the treatment of MDD and which has been further investigated for GAD.

Areas covered: This article covers the pharmacokinetics and pharmacodynamics of vilazodone and provides an evaluation of the clinical usefulness of vilazodone for the treatment of MDD and anxiety disorders. A literature search was performed using PubMed/MEDLINE, Web of Science and the Cochrane Library.

Expert opinion: Studies have shown that vilazodone is significantly superior to placebo. However, vilazodone cannot as yet be recommended as a first-line treatment option for MDD as it is unclear whether the drug’s dual mechanism of action provides greater efficacy than prevailing treatment options. Moreover, more phase IV studies are needed to establish its efficacy and long-term safety in larger and more diverse populations. Although vilazodone may have an additional advantage for the treatment of anxiety symptoms in MDD, here also additional studies are required to confirm its efficacy over and above SSRI alternatives and other antidepressant treatments. Therefore, presently, vilazodone should be considered as a second- or third-line treatment option for MDD and GAD.     

Pump Speed Optimization in Patients Implanted With the HeartMate 3 Device

Background

Pump speed optimization in patients implanted with a ventricular assist device represents a major challenge during the follow-up period. We present our findings on whether combined invasive hemodynamic ramp tests and cardiopulmonary exercise testing (CPX) can help optimize patient management.