Phase I Dose-Escalation Study of SCB01A,a Microtubule Inhibitor with Vascular Disrupting Activity,in Patients with Advanced Solid Tumors

Lessons Learned

• SCB01A is a novel microtubule inhibitor with vascular disrupting activity.
• This first‐in‐human study demonstrated SCB01A safety, pharmacokinetics, and preliminary antitumor activity.
• SCB01A is safe and well tolerated in patients with advanced solid malignancies with manageable neurotoxicity.

BackgroundSCB01A, a novel microtubule inhibitor, has vascular disrupting activity.MethodsIn this phase I dose‐escalation and extension study, patients with advanced solid tumors were administered intravenous SCB01A infusions for 3 hours once every 21 days. Rapid titration and a 3 + 3 design escalated the dose from 2 mg/m² to the maximum tolerated dose (MTD) based on dose‐limiting toxicity (DLT). SCB01A‐induced cellular neurotoxicity was evaluated in dorsal root ganglion cells. The primary endpoint was MTD. Safety, pharmacokinetics (PK), and tumor response were secondary endpoints.ResultsTreatment‐related adverse events included anemia, nausea, vomiting, fatigue, fever, and peripheral sensorimotor neuropathy. DLTs included grade 4 elevated creatine phosphokinase (CPK) in the 4 mg/m² cohort; grade 3 gastric hemorrhage in the 6.5 mg/m² cohort; grade 2 thromboembolic event in the 24 mg/m² cohort; and grade 3 peripheral sensorimotor neuropathy, grade 3 elevated aspartate aminotransferase, and grade 3 hypertension in the 32 mg/m² cohort. The MTD was 24 mg/m², and average half‐life was ~2.5 hours. The area under the curve‐dose response relationship was linear. Nineteen subjects were stable after two cycles. The longest treatment lasted 24 cycles. SCB01A‐induced neurotoxicity was reversible in vitro.ConclusionThe MTD of SCB01A was 24 mg/m² every 21 days; it is safe and tolerable in patients with solid tumors.     

Outcomes after neoadjuvant or adjuvant chemotherapy for cT2-4N0-1 non–small cell lung cancer: A propensity-matched analysis

Objective

Comparative survival between neoadjuvant chemotherapy and adjuvant chemotherapy for patients with cT2-4N0-1M0 non–small cell lung cancer has not been extensively studied.

Same-Day Yttrium-90 Radioembolization: Feasibility with Resin Microspheres

Purpose

To evaluate the feasibility of a same-day yttrium-90 (⁹⁰Y) radioembolization protocol with resin microspheres (including pretreatment angiography, lung shunt fraction [LSF] determination, and radioembolization) for the treatment of hepatocellular carcinoma (HCC) and liver metastases.

多巴酚丁胺负荷实验对家猪急性冬眠心肌模型QT离散度影响的实验研究

目的 观察多巴酚丁胺负荷期间QT离散度(QTd)的变化情况,探讨其临床意义.方法 对13只小型中国家猪采用闭胸介入法制备急性冬眠心肌模型(右冠状动脉为靶血管),利用多巴酚丁胺超声负荷实验(DSE,0～40 μg·Kg-1·min-1)检出冬眠心肌,之后成功复灌,处死动物,对心脏行TTC大体染色及光镜检查.分别于模型制备前后、DSE期间及复灌后观察QTd的变化情况.结果 ①10只动物(76.92%)成功制备成模型,病理检查未示心肌坏死改变.②模型制备成功后QTd较正常状态明显增加[(68.75±5.33)ms和(25.00±1.77)ms,P＜0.05];复灌后明显降低[(35.62±3.47)ms和(68.75±5.33)ms,P＜0.05],与正常状态差异无统计学意义[(35.62±3.47)ms和(25.00±1.77)ms,P＞0.05].③DSE期间QTd呈现先降低后增加的双相反应的变化趋势.④模型制备成功后的QTd与DSE检出的急性冬眠心肌节段数呈中等程度的负相关(r=-0.64,P＜0.05).结论 ①.急性冬眠心肌动物模型的QTd明显增加,早期有效复灌可降低QTd.②DSE期间急性冬眠心肌模型的QTd呈现双相反应趋势.③急性冬眠心肌模型的QTd是反映冬眠心肌数量的指标之一.     

QT离散度对急危重病人预后的评估

目的　研究QT离散度对急危重病人预后的预测价值。方法　死亡组 4 7例、疾病组 4 0例和正常组 4 3例。记录 12导联心电图 ,人工测量各导联R -R间期和QT间期 ,计算R -R、QTc、QTd和QTcd。结果　死亡组的R -R、QTc、QTd和QTcd分别为 0 5 6 2± 0 2 2 0ms、0 35 6± 0 0 6 9ms、0 0 5 6± 0 0 33ms和 0 0 79± 0 0 4 6ms ;疾病组的R -R、QTc、QTd和QTcd分别为0 80± 0 134ms、0 4 16± 0 0 3ms、0 0 34± 0 0 14ms和 0 0 39± 0 0 16ms;正常组的R -R、QTc、QTd和QTcd分别为 0 82 5± 0 0 88ms、0 4 0 2± 0 0 3ms、0 0 2 7± 0 0 15ms和 0 0 31± 0 0 15ms。比较死亡组、疾病组和正常组发现 ,死亡组和疾病组的R -R、QTc、QTd和QTcd存在显著差异 (P分别 <0 0 0 1、<0 0 0 2 5、<0 0 0 1和 <0 0 0 1)。死亡组和正常组的R -R、QTc、QTd和QTcd存在显著差异 (P分别 <0 0 0 1、<0 0 0 2 5、<0 0 0 1和 <0 0 0 1)。结论　QTd对急危重病人的预后有一定的预测价值 ;但其它临床应用价值存在局限性 ,有待进一步探索。     

改良极化液对充血性心力衰竭QT离散度的影响

目的 :观察改良极化液治疗慢性充血性心力衰竭 (CHF)前后QTd、QTcd变化 ,探讨它对CHF近期预后影响。方法 :将80例住院CHF患者随机分为两组 ,A组 4 0例应用改良极化液 (葡萄糖 -胰岛素 -门冬氨酸钾镁液 )治疗 ,B组 4 0例仅静滴葡萄糖。结果 :两组患者RR间期在治疗前后比较有显著差异 (P <0 .0 1) ,A组治疗后QTd、QTcd与治疗前比较有明显缩短 (QTd分别为 90 .2± 4 0 .7与 5 0 .2± 30 .4 ,QTcd分别为 86 .4± 12 .4与 4 6 .2± 12 .4 ,P <0 .0 1) ,治疗后QTd、QTcd两组间比较有显著差异 (QTd为 5 0 .2± 30 .4与 78.9± 2 0 .2 ,QTcd为 4 6 .2± 12 .4与 70 .3± 16 .8,P <0 .0 1) ,两组间洋地黄过量中毒、恶性室性心率失常发生率比较 ,有显著性差异 (P <0 .0 5 )。结论 :改良极化液可明显缩短CHF患者QTd、QTcd ,减少洋地黄过量中毒、恶性室性心率失常发生 ,对CHF近期预后可能有改善作用     

Long QT interval syndrome with increased QT dispersion

This case report describes the anaesthetic management of a patient with sporadic-type long QT interval syndrome (LQTS), and increased QT dispersion, who presented for removal of an ovarian cyst. Beta adrenergic blockade and adequate depth of anaesthesia for successful management is emphasized. The Successful use of epidural administration of lignocaine and opioids in addition to general anaesthesia is described.     

Axial tissue diffusion can account for the disparity between current models of hepatic elimination for lipophilic drugs

An assumption of previous models of hepatic elimination is that there is negligible axial diffusion in the liver. We show, by construction of a stochastic model and analysis of published data, that compounds which are readily diffusible and partitioned into hepatocytes may undergo axial tissue diffusion. The compounds most likely to be affected by axial tissue diffusion are the lipophilic drugs for which the cell membranes provide little resistance and which are highly extracted, thereby creating steep concentration gradients along the sinusoid at steady state. This phenomenon greatly modifies the availability of the compound under conditions of altered hepatic blood flow and protein binding. For moderately diffusible compounds, these relationships are similar to those predicted by the simplistic venous-equilibrium model. Hence, the paradoxical ability of the venous-equilibrium model to describe the steady-state kinetics of lipophilic drugs such as lidocaine, meperidine, and propranolol may be finally resolved. The effects of axial tissue diffusion and vascular dispersion on hepatic availability of drugs are compared. Vascular dispersion is of major importance to the availability of poorly diffusible compounds, whereas axial tissue diffusion becomes increasingly dominant for highly diffusive and partitioned substances.This study was supported by the National Health and Medical Research Council of Australia.     

聚苯胺/聚合物导电材料研究进展

从制备方法着手综述了近年来聚苯胺/聚合物导电材料研制开发的最新成果，并简介了聚苯胺/聚合物导电材料的应用情况。