A Phase I Dose Escalation Study of the Safety,Tolerability, and Pharmacokinetics of Ipilimumab in Chinese Patients with Select Advanced Solid Tumors

Lessons Learned

• The overall safety profiles of ipilimumab 3 mg/kg and 10 mg/kg administered every 3 weeks, were consistent between Chinese patients with solid tumors in the current study and patients from previous U.S. ipilimumab monotherapy studies. No new safety signals were identified.
• The mean systemic exposures to ipilimumab (assessed by first dose area under the curve during the dosing interval and maximum serum concentration) were numerically lower in the Chinese patient population than in U.S. patients for both 3 mg/kg and 10 mg/kg doses; however, the range of serum concentrations in the Chinese and U.S. populations overlapped (3 mg/kg and 10 mg/kg), suggesting that ipilimumab pharmacokinetics was ethnically insensitive in this study.

BackgroundThis phase I, open‐label study assessed ipilimumab safety, tolerability, pharmacokinetics (PK), immunogenicity, and antitumor activity in Chinese patients with unresectable, metastatic, recurrent malignant melanoma (MM) or nasopharyngeal carcinoma (NPC).MethodsOf 39 patients enrolled, 25 received ipilimumab (11 patients received 3 mg/kg, and 14 patients received 10 mg/kg). Reasons for not receiving treatment were withdrawal of consent (3 patients), no longer meeting the criteria (10 patients), and one recorded as “other.” During the induction phase, patients received ipilimumab (3 mg/kg, i.v.), on day 1 of a 3‐week cycle, to a maximum of four doses or progressive disease (PD). During the maintenance phase at week 24, patients received ipilimumab (3 mg/kg, i.v.) on day 1 of a 12‐week cycle, to a maximum of 3 years or PD. Considering the co‐primary safety and PK endpoints, the successive dosing required nine patients with two or fewer dose‐limiting toxicities during the 42‐day observation period to proceed with a new cohort of nine patients at 10 mg/kg.ResultsIpilimumab safety and PK profiles were similar in Chinese and predominantly White populations. Ipilimumab was well tolerated. Most adverse events (AEs) were grades 1–2 and experienced by 11 patients treated with 3 mg/kg and 14 patients treated with 10 mg/kg. There were no new safety concerns. Incidence of anti‐ipilimumab antibodies was low (1 of 10 in the 3 mg/kg patients and 2 of 13 in the 10 mg/kg patients) and without safety implications. In the 3 mg/kg group, 8 of 11 patients had PD. In the 10 mg/kg group (all NPC, 0 MM patients), 11 of 14 patients had PD. Three patients had stable disease (one at 3 mg/kg and two at 10 mg/kg).ConclusionIpilimumab was well tolerated in Chinese patients, showing similar safety and PK to previous studies in predominantly White populations.     

Collimating micro-lens fiber array for noncontact near-infrared diffuse correlation tomography

Near-infrared diffuse correlation spectroscopy/tomography (DCS/DCT) has recently emerged as a noninvasive measurement/imaging technology for tissue blood flow. In DCT studies, the high-dense collection of light temporal autocorrelation curves (g₂(τ)) via fiber array are critical for image reconstruction of blood flow. Previously, the camera-based fiber array limits the field of view (FOV), precluding its applications on large-size human tissues. The line-shape fiber probe based on lens combination, which is predominantly used in current DCT studies, requires rotated-scanning over the surface of target tissue, substantially prolonging the measurement time and increasing the system instability. In this study, we design a noncontact optical probe for DCT based on collimating micro-lens fiber array, termed as FA-nc-DCT system. For each source/detector fiber, a single optical path was collimated by coupling with one micro-lens in the fiber array that is integrated in a square-shape base. Additionally, an 8×8 optical switch is used to share the hardware laser and detectors without spatial scanning. The FA-nc approach for the precise collection of g₂(τ) curves was validated through a speed-varied phantom experiment and the human experiments of cuff occlusion, from which the expected value of the blood flow index (BFI) was obtained. Furthermore, the flow anomaly in the phantom and the ischemic muscle in human were accurately reconstructed from the FA-nc-DCT system, which is combined with the imaging framework based on the Nth-order linear algorithm that we recently created. Those outcomes demonstrated the great potential of FA-nc-DCT technology for fast and robust imaging of various diseases such as human breast cancers.     

Role of surgical treatments in high-grade or advanced gastroenteropancreatic neuroendocrine neoplasms

Over the last 40 years, the incidence and prevalence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) have continued to increase. Compared to other epithelial neoplasms in the same organ, GEP-NENs exhibit indolent biological behavior, resulting in more chances to undergo surgery. However, the role of surgery in high-grade or advanced GEP-NENs is still controversial. Surgery is associated with survival improvement of well-differentiated high-grade GEP-NENs, whereas poorly differentiated GEP-NENs that may benefit from resection require careful selection based on Ki67 and other tissue biomarkers. Additionally, surgery also plays an important role in locally advanced and metastatic disease. For locally advanced GEP-NENs, isolated major vascular involvement is no longer an absolute contraindication. In the setting of metastatic GEP-NENs, radical intended surgery is recommended for patients with low-grade and resectable metastases. For unresectable metastatic disease, a variety of surgical approaches, including cytoreduction of liver metastasis, liver transplantation, and surgery after neoadjuvant treatment, show survival benefits. Primary tumor resection in GEP-NENs with unresectable metastatic disease is associated with symptom control, prolonged survival, and improved sensitivity toward systemic therapies. Although there is no established neoadjuvant or adjuvant strategy, increasing attention has been given to this emerging research area. Some studies have reported that neoadjuvant therapy effectively reduces tumor burden, improves the effectiveness of subsequent surgery, and decreases surgical complications.     

Hepatotoxicity of cantharidin is associated with the altered bile acid metabolism

Cantharidin (CTD) is an effective antitumor agent. However, it exhibits significant hepatotoxicity, the mechanism of which remains unclear. In this study, biochemical and histopathological analyses complemented with ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS)-based targeted metabolomic analysis of bile acids (BAs) were employed to investigate CTD-induced hepatotoxicity in rats. Sixteen male and female Sprague–Dawley rats were randomly divided into two groups: control and CTD (1.0 mg/kg) groups. Serum and liver samples were collected after 28 days of intervention. Biochemical, histopathological, and BA metabolomic analyses were performed for all samples. Further, the key biomarkers of CTD-induced hepatotoxicity were identified via multivariate and metabolic pathway analyses. In addition, metabolite–gene–enzyme network and Kyoto Encyclopedia of Genes and Genomes pathway analyses were used to identify the signaling pathways related to CTD-induced hepatotoxicity. The results revealed significantly increased levels of biochemical indices (alanine aminotransferase, aspartate aminotransferase, and total bile acid). Histopathological analysis revealed that the hepatocytes were damaged. Further, 20 endogenous BAs were quantitated via UHPLC-MS/MS, and multivariate and metabolic pathway analyses of BAs revealed that hyocholic acid, cholic acid, and chenodeoxycholic acid were the key biomarkers of CTD-induced hepatotoxicity. Meanwhile, primary and secondary BA biosynthesis and taurine and hypotaurine metabolism were found to be associated with the mechanism by which CTD induced hepatotoxicity in rats. This study provides useful insights for research on the mechanism of CTD-induced hepatotoxicity.     

A High Order Bound Preserving Finite Difference Linear Scheme for Incompressible Flows

We propose a high order finite difference linear scheme combined with a high order bound preserving maximum-principle-preserving (MPP) flux limiter to solve the incompressible flow system. For such problem with highly oscillatory structure but not strong shocks, our approach seems to be less dissipative and much less costly than a WENO type scheme, and has high resolution due to a Hermite reconstruction. Spurious numerical oscillations can be controlled by the weak MPP flux limiter. Numerical tests are performed for the Vlasov-Poisson system, the 2D guiding-center model and the incompressible Euler system. The comparison between the linear and WENO type schemes, with and without the MPP flux limiter, will demonstrate the good performance of our proposed approach.     

基于网络药理学和分子对接技术探讨黄芪干预腹膜纤维化的机制

目的 运用网络药理学方法及分子对接技术探讨黄芪干预腹膜纤维化的可能机制。方法 利用中药系统药理学数据库及分析平台(TCMSP)检索黄芪的主要化学成分及靶点,并补充文献报道相关药理作用的成分作为潜在活性成分。以"peritoneal fibrosis"为关键词分别在OMIM、Genecards获取目前已知的与腹膜纤维化相关的疾病靶点,后取两者的交集靶点;对交集基因通过STRING数据库与Cytoscape 3.7.2软件构建"药物-成分-靶点-疾病"网络及蛋白互作(PPI)网络并筛选核心网络。基于R软件使用Bioconductor生物信息软件对核心靶点进行GO及KEGG富集分析,最终采用AutoDock软件将主要有效成分与核心靶点进行分子对接,得出其结合能力。结果 筛选出20个黄芪活性成分及文献报道有相关药理作用4个, 457药物作用靶点,与674个腹膜纤维化病靶点取交集,得到86个共同靶点。GO功能富集分析提示黄芪拮抗腹膜纤维化主要参与了蛋白激酶B信号转导的调节、细胞对化学的应激反应、炎症反应的调节等通路; KEGG通路富集分析主要涉及调控肿瘤、磷脂酰肌醇-3-羟激酶-蛋白激酶B(PI3K-Akt)、晚期糖基化终末产物/晚期糖基化终末产物受体(AGE-RAGE)、人类巨细胞病毒感染、HIF-1信号通路等;分子对接结果显示关键靶点与活性成分具有较好的结合能力。结论 黄芪治疗腹膜纤维化的分子机制,可能与抑制炎症及氧化应激反应、调节多种信号通路等相关。     

以宫腔积液为首发症状的胃型宫颈腺癌1例报道并文献复习

宫腔积液指宫腔内液体积存(积水、积血或积脓),是绝经后女性常见体征之一,常于超声检查时发现。持续宫腔积液患者,需宫腔镜检查寻找病因。本文报道1例以宫腔积液为首发症状,经宫腔镜检查确诊为胃型宫颈腺癌的患者。通过病例回顾并文献复习,以期为更多绝经后宫腔积液及宫颈病变的诊断提供参考,避免漏诊及误诊。1病例资料患者67岁,女,主因"绝经18年,不规则阴道出血2月"于2020年5月就诊于首都医科大学附属北京妇产医院妇科微创中心。     

Influences of simulated gastrointestinal environment on physicochemical properties of gold nanoparticles and their implications on intestinal epithelial permeability

Gold nanoparticles (Au NPs) hold great promise in food, industrial and biomedical applications due to their unique physicochemical properties. However, influences of the gastrointestinal tract (GIT), a likely route for Au NPs administration, on the physicochemical properties of Au NPs has been rarely evaluated. Here, we investigated the influence of GIT fluids on the physicochemical properties of Au NPs (5, 50, and 100?nm) and their implications on intestinal epithelial permeability in vitro. Au NPs aggregated in fasted gastric fluids and generated hydroxyl radicals in the presence of H₂O₂. Cell studies showed that GIT fluids incubation of Au NPs affected the cellular uptake of Au NPs but did not induce cytotoxicity or disturb the intestinal epithelial permeability.     

不同丙戊酸负荷量对癫痫持续状态的治疗效果分析

目的了解不同丙戊酸负荷量对癫痫持续状态患儿的治疗效果。方法收集2013年1月1日至2017年12月31日在浙江大学医学院附属儿童医院重症监护室住院治疗的癫痫持续状态患儿的病例资料,根据丙戊酸负荷量进行分组,了解各组患儿癫痫持续状态的控制情况。结果(1)66例癫痫持续状态患儿,包括癫痫36例(54.5%),颅内感染16例(24.2%),缺氧窒息3例(4.5%),颅内肿瘤2例(3.0%),脑发育异常2例(3.0%),颅内出血2例(3.0%),病因不明确5例(7.6%)。(2)所有癫痫持续状态患儿根据不同的丙戊酸负荷量(0 mg/kg,10~15 mg/kg,16~39 mg/kg,40 mg/kg)分为4组,各组间的性别、年龄差异无统计学意义,癫痫持续状态控制时间和癫痫控制情况差异无统计学意义(P=0.402、0.340)。(3)所有患儿予丙戊酸钠应用后都有监测肝功能,无一例患儿出现肝功能损害的表现。结论不同丙戊酸负荷量对于癫痫持续状态患儿的治疗效果无明显差异,并且接受负荷量为40 mg/kg治疗的癫痫持续状态患儿未出现相关不良反应。