Non-clinical pharmacokinetics and pharmacodynamics of rVIII-SingleChain,a novel recombinant single-chain factor VIII

Introduction

rVIII-SingleChain (CSL627), a novel recombinant coagulation factor VIII (FVIII), is under investigation in a phase I/III clinical programme (AFFINITY) for the treatment of haemophilia A. Non-clinical studies were conducted to investigate the pharmacokinetic/pharmacodynamic profile of rVIII-SingleChain in comparison with full-length recombinant FVIII.

Materials and Methods

Binding affinity of rVIII-SingleChain for von Willebrand factor was investigated by surface plasmon resonance analysis. The pharmacokinetic profile of rVIII-SingleChain was compared with a marketed full-length recombinant FVIII concentrate (Advate^®) in haemophilia A mice, von Willebrand factor knock-out mice, Crl:CD (SD) rats, rabbits and cynomolgus monkeys. Systemic FVIII activity or antigen levels were recorded. Procoagulant activity was measured in an FeCl₃-induced arterial occlusion model and by recording thrombin generation activity (ex vivo) after administration of 200–250 IU/kg rVIII-SingleChain or full-length FVIII to haemophilia A mice.

Results

rVIII-SingleChain displayed a high affinity for von Willebrand factor (K_D = 44 pM vs. 139 pM for full-length recombinant FVIII). In all animal species tested, rVIII-SingleChain had more favourable pharmacokinetic properties than full-length recombinant FVIII: clearance was decreased and area under the curve and terminal half-life were enhanced vs. full-length recombinant FVIII, while in vivo recovery and volume of distribution were equivalent. rVIII-SingleChain showed a prolonged thrombin generation potential and prolonged procoagulant activity vs. full-length recombinant FVIII in an FeCl₃-induced arterial occlusion model.

Conclusions

rVIII-SingleChain had a higher affinity for von Willebrand factor than full-length recombinant FVIII and displayed favourable pharmacokinetic/pharmacodynamic properties in non-clinical models.     

Replicating and identifying large cell neuroblastoma using high-dose intra-tumoral chemotherapy and automated digital analysis

PurposeLarge cell neuroblastomas (LCN) are frequently seen in recurrent, high-risk neuroblastoma but are rare in primary tumors. LCN, characterized by large nuclei with prominent nucleoli, predict a poor prognosis. We hypothesize that LCN can be created with high-dose intra-tumoral chemotherapy and identified by a digital analysis system.MethodsOrthotopic mouse xenografts were created using human neuroblastoma and treated with high-dose chemotherapy delivered locally via sustained-release silk platforms, inducing tumor remission. After recurrence, LCN populations were identified on H&E sections manually. Clusters of typical LCN and non-LCN cells were divided equally into training and test sets for digital analysis. Marker-controlled watershed segmentation was used to identify nuclei and characterize their features. Logistic regression was developed to distinguish LCN from non-LCN.ResultsImage analysis identified 15,000 nuclei and characterized 70 nuclear features. A 19-feature model provided AUC > 0.90 and 100% accuracy when > 30% nuclei/cluster were predicted as LCN. Overall accuracy was 87%.ConclusionsWe recreated LCN using high-dose chemotherapy and developed an automated method for defining LCN histologically. Features in the model provide insight into LCN nuclear phenotypic changes that may be related to increased activity. This model could be adapted to identify LCN in human tumors and correlated with clinical outcomes.     

Raising suspicion of maltreatment from burns: Derivation and validation of the BuRN-Tool

Background

10–25% of childhood burns arise from maltreatment.

利用CT表现鉴别肾上腺隐匿型嗜铬细胞瘤和皮质腺瘤

目的探讨如何利用CT表现对肾上腺隐匿型嗜铬细胞瘤和肾上腺皮质腺瘤进行鉴别诊断。方法收集2010年1月至2020年1月期间中国医科大学附属第一医院收治的177例肾上腺肿瘤患者进行回顾性分析,对比各组患者之间的一般临床资料和CT表现。结果隐匿型嗜铬细胞瘤56例、皮质醇腺瘤32例、醛固酮腺瘤44例、无功能腺瘤45例,隐匿型嗜铬细胞瘤组在肿瘤侧别上与无功能腺瘤组差异有统计学意义,在肿瘤最大直径、平扫CT值、动脉期和延迟期增强CT值上均显著大于三组肾上腺腺瘤组。以肿瘤直径≥2.95 cm诊断隐匿型嗜铬细胞瘤,曲线下面积(AUC)为0.872,敏感度为87.5%,特异性为76.0%;当平扫CT值≥24.5 Hu时,AUC为0.929,敏感度为94.0%,特异性为82.5%;当动脉期增强CT值≥89.5 Hu时,AUC为0.886,敏感度为72.7%,特异性为90.6%;当延迟期增强CT值≥82.5 Hu时,AUC为0.937,敏感度为84.6%,特异性为95.3%;联合以上四个指标时,AUC为0.981,阈值为≥0.118,敏感度为100%,特异性为90.6%。结论以肿瘤直径2.95 cm、平扫CT值24.5 Hu、动脉期增强CT值89.5 Hu和延迟期增强CT值82.5 Hu为阈值对肾上腺隐匿型嗜铬细胞瘤有较好的鉴别诊断价值。     

Comparison of Stable and Unstable Ethiodized Oil Emulsions for Transarterial Chemoembolization of Hepatocellular Carcinoma: Results of a Single-Center Double-Blind Prospective Randomized Controlled Trial

Purpose

To compare the stability of stable and unstable water-in-oil emulsions and the efficacy and safety of these emulsions in a single-center, prospective double-blind trial of transarterial chemoembolization for hepatocellular carcinoma (HCC).

CT-based total vessel plaque analyses improves prediction of hemodynamic significance lesions as assessed by fractional flow reserve in patients with stable angina pectoris

BackgroundCoronary stenosis and plaque evaluation by coronary computed tomography angiography (CTA) may contribute to identify hemodynamically relevant lesions. We evaluated the most stenotic lesion including plaques proximal to it versus a total vessel analyses combined with stenosis for ischemia.MethodsPatients scheduled for clinically indicated invasive coronary angiography (ICA) for suspected coronary artery disease underwent coronary CTA and ICA including fractional flow reserve (FFR) as part of the NXT trial (clinicaltrials.gov NCT01757678). Stenoses were visually graded ≤50%, 51–70%, and >70% on coronary CTA. Semi-automated plaque analyses were performed using a proximal to the FFR pressure sensor location (including the most severe lesion to the coronary ostium) versus a total vessel (vessel diameter ≥2 mm) approach. Coronary stenosis and plaque parameters were evaluated for discrimination of ischemia by logistic regressions and combined models analyzed using receiver operating characteristics (ROC) with invasive FFR≤ 0.80 as reference standard.ResultsIn 254 patients, mean (±SD) age 64 (±10) years, 64% male, a coronary CTA stenosis >50% was present in 239 (49%) vessels. Invasive FFR was ≤0.80 in 100 (21%) vessels. Coronary stenosis severity and low-density non-calcified plaque (LD-NCP) volume were independent predictors of ischemia in the “proximal” and “total-vessel” analyses. Stenosis severity + total vessel LD-NCP assessment performed better than stenosis severity + proximal LD-NCP evaluation (Area under curve [AUC] (95%CI): 0.83 (0.78–0.87) vs 0.81 (0.76–0.86), p-value = 0.009), whereas stenosis severity + proximal LD-NCP performed better than stenosis alone (AUC (95%CI): 0.81 (0.76–0.86) vs 0.78 (0.73–0.83), p-value = 0.019).ConclusionAdding total vessel high-risk plaque volume to stenosis severity improves discrimination of ischemia in coronary CTA performed in patients with stable angina pectoris.     

The Duration of Measuring Partial AUCs for the Assessment of Bioequivalence

Purpose. To determine favourable sampling conditions for assessing bioequivalence by the comparison of partial AUCs in the early phase of concentration-time profiles. Methods. Two-period crossover trials were simulated. They assumed a wide range of the ratios of absorption rate constants of the test (T) and reference (R) formulations (k_aT/k_aR). Averages and standard deviations of the corresponding ratios of simulated partial AUCs (AUC_pT/AUC_pR) were determined together with the statistical power of assessing bioequivalence, i.e., the percentage of simulated trials in which bioequivalence was declared. Results. The power for stating bioequivalence was high when AUC_P was recorded until the earlier rather than the later of two peaks in each subject. Similarly, power was comparatively high when AUC_P was measured until the time of the reference peak instead of multiples of this time. Power was high also when AUC_p was determined until the fixed true, population mean time of the reference formulation instead of multiples of this time. The pattern for the kinetic sensitivity parallelled that found for the power, while the standard deviations changed generally in the opposite direction. Conclusions. The effectiveness (power) of evaluating bioequivalence in the early phase of concentration-time profiles by partial AUCs generally decreases when the duration for measuring the metric is extended. Among the investigated designs, determination of partial AUCs until the earlier of two peaks in each subject is the most powerful.