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.     

Dose optimization with population pharmacokinetics of ritonavir-boosted lopinavir for Thai people living with HIV with and without active tuberculosis

BackgroundPrior to dolutegravir availability, ritonavir-boosted lopinavir (LPV/r) was an alternative recommendation when first-line drugs could not be used. A high concentration of protease inhibitors was observed in the Thai people living with HIV (PLWH). Thus, dose reduction of LPV/r may be possible. However, the pharmacokinetics and dose optimization of LPV/r have never been investigated. This study aimed to develop a population pharmacokinetic model of LPV/r and provide dosage optimization in Thai PLWH.MethodsLPV and RTV trough concentrations from Thai PLWH were combined with intensive data. The data were analyzed by the nonlinear mixed-effects modeling approach. The influence of RTV concentration on LPV oral clearance (CL/F) was investigated.ResultsRifampicin (RIF) use increased LPV and RTV CL/F by 2.16-fold and 1.99-fold, respectively. The reduced dose of 300/75 and 200/150 mg twice daily provided a comparable percentage of patients achieving LPV target trough concentration to the standard dose for PI-naïve patients. For HIV/TB co-infected patients receiving RIF who could not tolerate the recommended dose, the reduced dose of 600/150 mg twice daily was recommended.ConclusionThe population pharmacokinetic model was developed by integrating the interaction between LPV and RTV. The reduced LPV/r dosage offers sufficient LPV exposure for Thai PLWH.     

Correlation between cow’s milk protein allergy and otitis media: a systematic review

ObjectivesTo review the evidence pertaining to the association between cow’s milk protein allergy and recurrent acute otitis media and otitis media with effusion.MethodsThe CENTRAL, Web of Science, EMBASE, MEDLINE, LILACS databases, and gray literature were searched.ResultsFour studies were included, identifying the prevalence rates: 0.2% of delayed speech due to chronic otitis media with effusion in 382 children with cow’s milk protein allergy, 10.7% of cow’s milk protein allergy in 242 children who underwent ENT procedures, 40% of cow’s milk protein allergy in 25 children with recurrent otitis media with effusion and higher tendency to otitis media in children with cow’s milk protein allergy of 186 children (1.5 + 0.6 vs. 0.4 + 0.1; p < 0.1).ConclusionConsidering the characteristics and methodological variations of the identified studies, it is not possible to state that there is reliable evidence of an association between cow’s milk protein allergy and otitis media.     

Preoperative comprehensive malignancy risk estimation for thyroid nodules: Development and verification of a network-based prediction model

BackgroundIn order to avoid excessive treatment of thyroid nodules in the clinic, it is necessary to find a simple and practical analysis method to comprehensively and accurately reflect benign or malignant thyroid nodules. This study aimed to construct and validate a comprehensive and reliable network-based predictive model using a variety of imaging and laboratory criteria for thyroid nodules to stratify the risk of malignancy prior to surgery.MethodsWe retrospectively analyzed data from patients who underwent surgical treatment for thyroid nodules at the Thyroid and Breast Diagnosis and Treatment Center of Weifang Hospital of Traditional Chinese Medicine between January 2018 and December 2020. Binary logical regression analysis was performed to predict whether nodules were malignant or benign. The developmental dataset included 457 patients (January 2018–December 2020). The validation set included separate data points (n = 225, January 2018–December 2020).ResultsIn this study, criteria that showed significant predictive value for malignant nodules included TI-RADS: 4b (p = 0.065); Bethesda IV, Bethesda V, Bethesda VI (P < 0.0001); BRAF^V600E mutation (P < 0.0001); Calcitonin>5 pg/ml (p = 0.0037); and FNA-Tg>30 ng/ml (p = 0.0003). A 10-grade risk scoring system was developed. The risk of malignancy risk ranged from 2.06% to 100% and was positively associated with increasing risk grade. The areas under the receiver-operating characteristic curve of the development and validation sets were 0.972 and 0.946, respectively.ConclusionA simple, comprehensive and reliable web-based predictive model was designed using a variety of imaging and laboratory criteria to stratify thyroid nodules by probability of malignancy.     

信息化随访干预措施对HBV感染患者依从性影响分析

目的通过信息化随访方式干预慢性乙型病毒性肝炎患者,对比分析其对患者疾病及用药依从性影响。方法收集2014年10月至2017年10月惠州市第六人民医院门诊及住院部诊断为慢性乙型病毒性肝炎、乙肝肝硬化患者,剔除不符合纳入条件患者,共纳入符合条件患者264例,有42例合并肝硬化。对纳入患者采取分层随机抽样方法进行分组,最终微信+电话随访组87例,电话随访组88例,对照组89例。随访并对比三组在2年后肝功能、肝硬化人数及停用恩替卡韦时间等不同差异。结果随访年后三组在失访人数上差异存在统计学意义,其中A组与B组2年后两组在ALT(Z=-3.218,P=0.02)、AST(Z=-2.749,P=0.03)、Alb(Z=1.746,P=0.04)、乙肝病毒DNA(Z=-3.231,P=0.02)指标差异具有统计学意义,而TBil、FIB-4指数、APRI、γ-GT指标差异无统计学意义。A组与C组2年后对比结果显示,两组在ALT(Z=-11.089,P<0.001)、AST(Z=-9.247,P=0.01)、TBil(Z=-7.623,P=0.01)、APRI(Z=-4.834,P=0.01)、γ-GT(Z=-2.867,P=0.03)、Alb(Z=3.187,P=0.02)、乙肝病毒DNA(Z=-10.078,P<0.001)指标差异具有统计学意义,而FIB-4指数指标差异无统计学意义。B组与C组2年后两组对比结果显示,两组在ALT(Z=-1.275,P=0.04)、AST(Z=-2.045,P=0.03)、TBil(Z=-3.762,P=0.02)、APRI(Z=-1.461,P=0.04)、γ-GT(Z=-2.254,P=0.03)、乙肝病毒DNA(Z=-1.782,P=0.04)指标差异具有统计学意义,而Alb、FIB-4指数指标差异无统计学意义。随访2年后A组肝硬化人数为12人,B组为16人,C组为24人。A组与B组(χ²=0.945,P=0.408)、B组与C组肝硬化人数(χ²=2.741,P=0.103)差异无统计学意义,而A、C两组肝硬化人数差异有统计学意义(χ²=6.843,P=0.013)。在2年时间内,A组有15例患者暂停使用恩替卡韦,B组有28例,C组有61例,三组停用恩替卡韦人数差异有统计学意义(χ²=25.061,P<0.001),通过Kaplan-meier分析,结果显示A组使用恩替卡韦时间长于B组(83.0%vs 68.5%,χ²=5.754,P=0.016)及C组(83.0%vs 33.7%,χ²=61.601,P<0.001),而B组使用时间长于C组(63.5%vs 33.7%,χ²=32.451,P<0.001)。结论通过对患者强化信息化干预,可以使患者服用抗乙肝病毒药物依从性提高,降低患者肝功能异常发生及肝硬化发病率。     

Effects of the Cerebral Aneurysm Treatment Method on Coil Packing Density and Its Relationship with the Ostium Area

PurposeTo test the following hypotheses: (a) balloon or stent assistance increases coil packing density (CPD) in the endovascular treatment of intracranial aneurysms, and (b) CPD correlates to ostium area (OA) and aneurysm volume (AV).Materials and MethodsThis retrospective study included 60 aneurysms (54 ruptured and 6 unruptured) treated with simple coiling (SC) (n = 18), balloon-assisted coiling (BAC) (n = 7), or stent-assisted coiling (SAC) (n = 35) at the authors’ institution between August 2017 and December 2019. AV and OA measurements were obtained from 3-dimensional digital subtraction angiography images using commercial software. Coil sizes were retrieved from patient files, and coil volume (CV) measurements were obtained from https://www.angiocalc.com/. Analysis of covariance, multivariate covariance analysis, and Pearson correlation analyses were performed.ResultsThe median value for AV, CV, CPD, and OA was 63.4 mm³ (range, 5.5–1,771.4 mm³), 23.13 mm³ (range, 2.03–296.95 mm³), 33.29% (range, 13.41%–81.02%), and 10.7 mm² (range, 2.7–49.9 mm²), respectively. Multivariate analysis showed that the CPD values were not significantly different among the treatment groups, although OA significantly differed between the SC and SAC groups (P < .05). Pearson correlations showed that similar to AV, OA was negatively correlated with CPD (r = ?0.321, P < .05).ConclusionsThe CPD value in cerebral aneurysms treated with BAC or SAC did not differ from that in aneurysms treated with SC.     

Genetically predicted childhood obesity and adult atrial fibrillation: A mendelian randomization study

Background and aimsIt is unclear whether the association of childhood obesity with adult atrial fibrillation observed in observational studies reflects causal effects. The aim of this study was to evaluate the association of childhood obesity with adult atrial fibrillation using genetic instruments.Methods and resultsWe used a two-sample Mendelian randomization (MR) design to evaluate the association between childhood obesity and adult atrial fibrillation. Two sets of genetic variants (15 single nucleotide polymorphisms [SNPs] for childhood body mass index [BMI] and 12 SNPs for dichotomous childhood obesity) were selected as instruments. Summary data on SNP-childhood obesity and SNP-atrial fibrillation associations were obtained from recently published genome-wide association studies. Effect estimates were evaluated using inverse-variance weighted (IVW) methods. Other MR analyses, including MR-Egger, simple and weighted median, weighted MBE and MR-PRESSO methods were performed in sensitivity analyses.The IVW models showed that both a genetically predicted one-standard deviation increase in childhood BMI (kg/m²) and higher log-odds of childhood obesity were associated with a substantial increase in the risk of atrial fibrillation (OR = 1.22, 95% CI: 1.11–1.34, P < 0.001; OR = 1.09, 95% CI: 1.04–1.14, P < 0.001). MR-Egger regression showed no evidence of genetic pleiotropy for childhood BMI (intercept = 0.000, 95% CI: ?0.024 to 0.023), but for childhood obesity (intercept = ?0.036, 95% CI: ?0.057 to ?0.015). Similar results were observed using leave-one-out and other MR methods in sensitivity analyses.ConclusionsThis MR analysis found a consistent association between genetically predicted childhood obesity and an increased risk of adult atrial fibrillation. Further research is warranted to validate our findings.