Phase 0 Study of Vandetanib-Eluting Radiopaque Embolics as a Preoperative Embolization Treatment in Patients with Resectable Liver Malignancies

PurposeTo assess the safety and tolerability of a vandetanib-eluting radiopaque embolic (BTG-002814) for transarterial chemoembolization (TACE) in patients with resectable liver malignancies.Materials and MethodsThe VEROnA clinical trial was a first-in-human, phase 0, single-arm, window-of-opportunity study. Eligible patients were aged ≥18 years and had resectable hepatocellular carcinoma (HCC) (Child-Pugh A) or metastatic colorectal cancer (mCRC). Patients received 1 mL of BTG-002814 transarterially (containing 100 mg of vandetanib) 7–21 days prior to surgery. The primary objectives were to establish the safety and tolerability of BTG-002814 and determine the concentrations of vandetanib and the N-desmethyl vandetanib metabolite in the plasma and resected liver after treatment. Biomarker studies included circulating proangiogenic factors, perfusion computed tomography, and dynamic contrast-enhanced magnetic resonance imaging.ResultsEight patients were enrolled: 2 with HCC and 6 with mCRC. There was 1 grade 3 adverse event (AE) before surgery and 18 after surgery; 6 AEs were deemed to be related to BTG-002814. Surgical resection was not delayed. Vandetanib was present in the plasma of all patients 12 days after treatment, with a mean maximum concentration of 24.3 ng/mL (standard deviation ± 13.94 ng/mL), and in resected liver tissue up to 32 days after treatment (441–404,000 ng/g). The median percentage of tumor necrosis was 92.5% (range, 5%–100%). There were no significant changes in perfusion imaging parameters after TACE.ConclusionsBTG-002814 has an acceptable safety profile in patients before surgery. The presence of vandetanib in the tumor specimens up to 32 days after treatment suggests sustained anticancer activity, while the low vandetanib levels in the plasma suggest minimal release into the systemic circulation. Further evaluation of this TACE combination is warranted in dose-finding and efficacy studies.     

双源CT多定量参数对胃癌的诊断价值及与HER2的相关性

目的:探讨门脉期双源CT多个定量参数与胃腺癌病理分化程度及HER2的相关性。方法: 回顾性分析2018年7月至2019年4月间于陕西省人民医院行双源CT双能量扫描的48例经胃镜活检(21例)或手术病理证实（27例）的胃腺癌及30例正常胃的影像学资料，其中27例HER2指标明确，通过西门子第二代双源CT扫描获得静脉期双能量图像，利用syngo.via软件获得曲线斜率、门脉期碘浓度、标准化碘浓度；将患者分为胃腺癌与正常胃壁组，高、中、低分化胃腺癌组，HER2阳性组（+，++，+++）与HER2阴性组（-）。统计学方法采用Kappa一致性检验、ROC曲线法、两独立样本t检验及方差分析。结果:活检与术后病理结果具有较强的一致性（Kappa系数为0.701），两者无明显差异；胃腺癌与正常胃壁两组间能谱曲线斜率（1.35±0.24、2.19±0.71）及标准化碘浓度（0.31±0.079、0.54±0.157）均具有统计学意义（P<0.05），曲线下面积分别为0.992、0.919；低分化、中分化及高分化胃腺癌能谱曲线斜率值（3.07±0.67，2.63±0.57，2.01±0.39）组间及组内差异均具有统计学意义（P<0.05），低分化、中分化及高分化胃腺癌门脉期标准化碘浓度(0.60±0.167，0.52±0.089，0.36±0.039)组间差异具有统计学意义（P<0.05），中分化组与低分化组差异无统计学意义（P>0.05），高分化组与中、低分化组均具有统计学差异（P<0.05）。HER2阳性组与阴性组的能谱曲线斜率及标准化碘浓度值无统计学差异（P>0.05）。结论:能谱曲线斜率及门脉期标准化碘浓度值有助于对胃腺癌进行诊断并推测病理分化程度；双源CT定量参数与免疫组化指标HER2无相关性。     

Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo

Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [¹²⁵I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.     

双吲哚马来酰亚胺衍生物L6诱导白血病细胞凋亡机制的研究

目的探讨双吲哚马来酰亚胺衍生物L6诱导白血病细胞的凋亡作用及其分子机制。方法采用MTT比色法检测L6对白血病细胞HEL、K562、KG1a的杀伤作用。流式细胞术检测L6对HEL细胞凋亡、周期和分化的影响。Western blotting法检测细胞凋亡相关蛋白的表达。通过体内实验研究L6治疗小鼠白血病的作用效果。结果 MTT比色法结果显示L6对HEL、K562、KG1a细胞具有比阳性对照米哚妥林(PKC412)更显著的抑制活性,半数抑制浓度(IC50)分别为(0.05±0.03)、(0.32±0.01)、(0.19±0.10)μmol/L。L6可以诱导HEL细胞发生凋亡和G2/M期阻滞,诱导HEL细胞向巨核细胞方向分化,且呈剂量效应。Western blotting检测结果表明L6主要通过激活Caspase-3执行细胞凋亡。小鼠肝组织苏木精-伊红(HE)染色显示肝组织内HEL细胞浸润有所减轻,但L6组减轻的效果更明显,表明其可延缓白血病细胞的转移,且效果优于米哚妥林。结论双吲哚马来酰亚胺衍生物L6有较强的抗白血病活性,为新型白血病药物的研发提供参考。     

A prognostic signature based on immune-related genes for cervical squamous cell carcinoma and endocervical adenocarcinoma

Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) is the fourth commonest female malignancy worldwide. CESC progresses in immune-microenvironment mainly composed of infiltrating immune and stromal cells. Here, we performed an integrated analysis incorporating the expression profiles from the Cancer Genome Atlas (TCGA) database and scores of immune and stromal cells calculated by Estimation of Stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm. A two-gene signature (CD1C and CD6 genes) was established to predict the prognosis of CESC. Based on this signature, patients were divided into the high- and low-risk groups, and this signature showed good prognostic performance according to the results of Kaplan-Meier analysis and receiver operating characteristic (ROC) analysis in train set and two validation sets. A nomogram was built for evaluating the clinical applicability of this signature. In addition, based on Tumor Immune Estimation Resource (TIMER) database, 2 hub genes showed negative correlations with tumor purity and positive correlations with infiltrating levels of immune filtrating cells. What’s more, we propose new treatment strategies for the two prognostic subtypes. Low- risk patients were found presenting with a higher level of immune checkpoint molecules and showing higher immunogenicity in immunophenoscore (IPS) analysis, which indicated a better response for immunotherapy. Meanwhile, estimated by Genomics of Drug Sensitivity in Cancer (GDSC) database, the high-risk patients showed sensitive responses to five chemotherapy drugs. Finally, 10 candidate small-molecule drugs for CESC were defined. In summary, the CD1C-CD6 signature can accurately predict the prognosis of CESC.     

万古霉素药物暴露量阈值与肾毒性的相关性分析

目的探讨万古霉素药物暴露量与肾毒性发生的相关性,并确定其上限阈值。方法前瞻性收集2018年5月-2019年1月接受静脉注射万古霉素治疗的成人住院患者信息。使用贝叶斯最大后验概率法计算药时曲线下面积(AUC)并采用分类和回归树(CART)的方法分析和确定万古霉素初始剂量及与肾毒性相关的稳态AUC阈值。通过受试者工作特征(ROC)曲线评估上述方法所得AUC阈值的预测性能及对万古霉素相关肾毒性的诊断价值,并采用多因素logistic回归分析量化肾毒性发生风险因素。结果共纳入患者155例,其中发生肾毒性患者13例(8.39%)。经CART分析得到AUC0-24、AUC24-48、AUCss0-24对肾毒性预测的最佳阈值点分别为622 mg·h/L、617 mg·h/L、578 mg·h/L。经多因素logistic回归分析,AUC超过最佳阈值点时肾毒性发生率显著提高(P≤0.01),联合使用肾毒性药物与肾毒性发生独立相关,会提高约6倍的肾毒性发生率(P<0.01)。结论万古霉素暴露量超过阈值时会大幅提高肾毒性发生风险,提示AUC监测对预测肾毒性发生有很高的临床价值。     

Assessing the impact of blood alcohol concentration on the rate of in-hospital mortality following traumatic motor vehicle crash injury: A matched analysis of the National Trauma Data Bank

Background

The purpose of this study was to compare the outcomes of trauma patients who were injured in a motor vehicle crash and tested positive for alcohol upon hospital arrival versus those who tested negative.

Efficacy,immunogenicity, and safety of available vaccines in children on biologics: A systematic review and meta-analysis

Vaccinations are essential for preventing infectious diseases in children with chronic diseases as they have increased risk of infection from frequent use of biologics. Response to immunizations in this group is not well known.ObjectiveA systematic review was performed to evaluate three primary outcomes: efficacy; immunogenicity; and safety of vaccines in children with chronic conditions treated with biologics.MethodsThe protocol for our systematic review and meta-analysis was registered and published with PROSPERO. We searched electronic bibliographic databases for studies published from 2009 to 2019, focusing on vaccinations in children with chronic conditions treated with biologics.ResultsWe retrieved 532 records. Thirty-one full-text articles were selected, and 14 were included in the meta-analysis. No significant publication bias was found. Efficacy: limited data are available regarding the efficacy of vaccination, as most studies have focused on immunogenicity as surrogate outcome for efficacy. Immunogenicity: patients receiving anti-TNF-alpha therapy had a statistically significant risk of poor seroconversion (p = 0.028) and seroprotection by the serotype B influenza vaccine [inflammatory bowel disease (IBD) p = 0.013; juvenile idiopathic arthritis (JIA) p = 0.004]. We found adequate responses with H1N1 and H3N2 serotypes. Few studies existed for pneumococcal, hepatitis A virus, hepatitis B virus, varicella-zoster virus, Measles Mumps Rubella virus, and multiple vaccine administration. Safety: vaccine administration was not associated with serious side effects, but JIA patients on anti-TNF alpha therapy had a statistically significant risk of presenting with myalgia or arthralgia postinfluenza vaccine (p = 0.014).ConclusionsMore evidence concerning efficacy, immunogenicity, and safety of vaccinations is needed to guide physicians in the vaccine decision process for this pediatric population.