Pharmacokinetic study of conventional sorafenib chemoembolization in a rabbit VX2 liver tumor model

PURPOSEUse of oral sorafenib, an antiangiogenic chemotherapeutic agent for hepatocellular carcinoma (HCC), is limited by an unfavorable side effect profile. Transarterial chemoembolization (TACE) employs targeted intravascular drug administration, and has potential as a novel sorafenib delivery method to increase tumoral concentrations and reduce systemic levels. This study aimed to discern the pharmacokinetics of sorafenib TACE in a rabbit VX2 liver tumor model.METHODSA 3 mg/kg dose of sorafenib ethiodized oil emulsion was delivered via an arterial catheter to VX2 liver tumors in seven New Zealand white rabbits. Following TACE, serum sorafenib levels were measured at days 0, 1, 2, 3, 7, 10, and 14 until the time of sacrifice, after which rabbit livers were harvested for analysis of sorafenib concentrations within treated tumors and normal liver. Liquid chromatography tandem mass spectrometry was used for drug quantification.RESULTSSorafenib uptake within liver tumor and nontumorous liver tissue peaked at mean 3.53 and 0.75 μg/mL, respectively, immediately post-procedure (5:1 tumor to normal tissue drug uptake ratio), before decreasing with a 10–18 hour half-life. Serum sorafenib levels peaked immediately after TACE at a mean value of 58.58 μg/mL before normalizing with a 5.2-hour half-life, suggesting early drug washout from liver into the systemic circulation. Hepatic lab parameters showed transient increase 24 hours post-TACE with subsequent resolution.CONCLUSIONWhile targeted transarterial delivery of sorafenib ethiodized oil emulsion shows preferential tumor uptake compared to normal liver, systemic washout occurs with a short half-life, resulting in high circulating drug levels

Does doxorubicin survive thermal ablation? Results of an ex vivo bench top study

PURPOSE:We aimed to test the hypothesis that doxorubicin (DOX) survives thermal ablative heating in an ex vivo model of combined transarterial chemoembolization (TACE) and thermal ablation.METHODS:Fresh porcine psoas major muscle (3 samples, 15×10×3 cm) was submerged in aqueous DOX solution (60 µg/mL, 0.1 M) for 24 hours to passively saturate tissue. DOX-infused tissue was then dried and treated with microwave ablation (MWA) using a 2.45 GHz antenna at 65 W for 2, 5, and 10 minutes. Ablations were repeated in triplicate (9 total). Tissue was then sampled at both ablated and unablated control sites, and DOX concentration was quantified via ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS), with samples analyzed in triplicate. Tissue DOX levels in ablation and control groups were compared using one-way ANOVA.RESULTS:Homogeneous DOX uptake into porcine tissue was evident in all three samples. Mean DOX concentration in unablated tissue was 8.0±2.2 µg/mL. MWA was technically successful in all 9 procedures (100%), with tissue heating to 95–100°C. Mean tissue DOX concentration showed progressive reduction with increasing ablation time, measuring 6.7±1.3, 4.9±0.9, and 4.8±1.3 µg/mL in MWA-treated tissue after 2, 5, and 10 minutes, respectively. Differences in tissue DOX levels between unablated tissue and MWA groups were statistically significant (P < 0.001).CONCLUSION:Contrary to the initial hypothesis, tissue DOX concentration progressively decreased after MWA of longer ablation times. These results suggest that TACE followed by ablation may result in lower intratumoral DOX than would otherwise be anticipated for TACE alone

Protect European green agricultural policies for future food security

Instituto de Ciencias Forestales (ICIFOR-INIA).European green agricultural policies have been relaxed to allow cultivation of fallow land to produce animal feed and meet shortfalls in exports from Ukraine and Russia. However, conversion of semi-natural habitats will disproportionately impact long term biodiversity and food security.This paper contributes to project REMEDINAL TE-CM P2018/EMT-4338 of Comunidad de Madrid.Peer reviewe

Attitude towards and factors affecting uptake of population based BRCA testing in the Ashkenazi Jewish population: a cohort study

Objective To evaluate factors affecting unselected‐population‐based‐BRCA‐testing in Ashkenazi‐Jews (AJ). Design Cohort‐study set within recruitment to the GCaPPS‐trial (ISRCTN73338115). Setting North‐London AJ‐population. Population or Sample AJ women/men >18‐years, recruited through self‐referral. Methods AJ‐women/men underwent pre‐test counselling for BRCA‐testing through recruitment clinics (clusters). Consenting individuals provided blood‐sample for BRCA‐testing. Socio‐demographic/family‐history/knowledge/psychological well‐being data along‐with benefits/risks/cultural‐influences (18‐item‐questionnaire measuring ‘attitude’) were collected. 4‐item likert‐scales analysed initial ‘interest’ and ‘intention‐to‐test’ pre‐counselling. Uni‐&‐multivariable logistic‐regression‐models evaluated factors affecting uptake/interest/intention‐to undergo BRCA‐testing. Statistical inference was based on cluster robust standard‐errors and joint Wald‐tests for significance. Item‐Response‐Theory and graded‐response‐models modelled responses to 18‐item questionnaire. Main Outcome Measures Interest, intention, uptake, attitude towards BRCA‐testing. Results 935 (women=67%/men=33%; mean‐age=53.8(S.D=15.02) years) individuals underwent pre‐test genetic‐counselling. Pre‐counselling 96% expressed interest but 60% indicated clear intention‐to undergo BRCA‐testing. Subsequently 88% opted for BRCA‐testing. BRCA‐related knowledge (p=0.013) and degree‐level education(p=0.01) were positively and negatively (respectively) associated with intention‐to‐test. Being married/cohabiting had four‐fold higher‐odds for BRCA‐testing uptake (p=0.009). Perceived benefits were associated with higher pre‐counselling odds for interest and intention‐to undergo BRCA‐testing. Reduced uncertainty/reassurance were the most important factors contributing to decision‐making. Increased importance/concern towards risks/limitations (confidentiality/insurance/emotional‐impact/inability to prevent cancer/marriage‐ability/ethnic‐focus/stigmatization) were significantly associated with lower‐odds of uptake‐of BRCA‐testing, and discriminated between acceptors and decliners. Male‐gender/degree‐level‐education (p=0.001) had weaker, while having children had stronger (p=0.005) attitudes towards BRCA‐testing. Conclusions BRCA‐testing in the AJ‐population has high acceptability. Pre‐test counselling increases awareness of disadvantages/limitations of BRCA‐testing, influencing final cost‐benefit perception and decision‐making on undergoing testing. This article is protected by copyright. All rights reserved

Economic Evaluation of Population-Based BRCA1/BRCA2 Mutation Testing across Multiple Countries and Health Systems

Clinical criteria/Family history-based BRCA testing misses a large proportion of BRCA carriers who can benefit from screening/prevention. We estimate the cost-effectiveness of population-based BRCA testing in general population women across different countries/health systems. A Markov model comparing the lifetime costs and effects of BRCA1/BRCA2 testing all general population women ≥30 years compared with clinical criteria/FH-based testing. Separate analyses are undertaken for the UK/USA/Netherlands (high-income countries/HIC), China/Brazil (upper–middle income countries/UMIC) and India (low–middle income countries/LMIC) using both health system/payer and societal perspectives. BRCA carriers undergo appropriate screening/prevention interventions to reduce breast cancer (BC) and ovarian cancer (OC) risk. Outcomes include OC, BC, and additional heart disease deaths and incremental cost-effectiveness ratio (ICER)/quality-adjusted life year (QALY). Probabilistic/one-way sensitivity analyses evaluate model uncertainty. For the base case, from a societal perspective, we found that population-based BRCA testing is cost-saving in HIC (UK-ICER = $−5639/QALY; USA-ICER =$−4018/QALY; Netherlands-ICER = $−11,433/QALY), and it appears cost-effective in UMIC (China-ICER =$18,066/QALY; Brazil-ICER = $13,579/QALY), but it is not cost-effective in LMIC (India-ICER =$23,031/QALY). From a payer perspective, population-based BRCA testing is highly cost-effective in HIC (UK-ICER = $21,191/QALY, USA-ICER =$16,552/QALY, Netherlands-ICER = $25,215/QALY), and it is cost-effective in UMIC (China-ICER =$23,485/QALY, Brazil−ICER = $20,995/QALY), but it is not cost-effective in LMIC (India-ICER =$32,217/QALY). BRCA testing costs below $172/test (ICER =$19,685/QALY), which makes it cost-effective (from a societal perspective) for LMIC/India. Population-based BRCA testing can prevent an additional 2319 to 2666 BC and 327 to 449 OC cases per million women than the current clinical strategy. Findings suggest that population-based BRCA testing for countries evaluated is extremely cost-effective across HIC/UMIC health systems, is cost-saving for HIC health systems from a societal perspective, and can prevent tens of thousands more BC/OC cases

90Y Radioembolization for Hepatic Malignancy in Patients with Previous Biliary Intervention: Multicenter Analysis of Hepatobiliary Infections

PurposeTo determine the frequency of hepatobiliary infections after transarterial radioembolization (TARE) with yttrium 90 (90Y) in patients with liver malignancy and a history of biliary intervention.Materials and MethodsFor this retrospective study, records of all consecutive patients with liver malignancy and history of biliary intervention treated with TARE at 14 centers between 2005 and 2015 were reviewed. Data regarding liver function, 90Y dosimetry, antibiotic prophylaxis, and bowel preparation prophylaxis were collected. Primary outcome was development of hepatobiliary infection.ResultsOne hundred twenty-six patients (84 men, 42 women; mean age, 68.8 years) with primary (n = 39) or metastatic (n = 87) liver malignancy and history of biliary intervention underwent 180 procedures with glass (92 procedures) or resin (88 procedures) microspheres. Hepatobiliary infections (liver abscesses in nine patients, cholangitis in five patients) developed in 10 of the 126 patients (7.9%) after 11 of the 180 procedures (6.1%; nine of those procedures were performed with glass microspheres). All patients required hospitalization (median stay, 12 days; range, 2–113 days). Ten patients required percutaneous abscess drainage, three patients underwent endoscopic stent placement and stone removal, and one patient needed insertion of percutaneous biliary drains. Infections resolved in five patients, four patients died (two from infection and two from cancer progression while infection was being treated), and one patient continued to receive suppressive antibiotics. Use of glass microspheres (P = .02), previous liver resection or ablation (P = .02), and younger age (P = .003) were independently predictive of higher infection risk.ConclusionInfectious complications such as liver abscess and cholangitis are uncommon but serious complications of transarterial radioembolization with 90Y in patients with liver malignancy and a history of biliary intervention.© RSNA, 2018Online supplemental material is available for this article

A Comparison of Machine Learning and Classical Demand Forecasting Methods: A Case Study of Ecuadorian Textile Industry

[EN] This document presents a comparison of demand forecasting methods, with the aim of improving demand forecasting and with it, the production planning system of Ecuadorian textile industry. These industries present problems in providing a reliable estimate of future demand due to recent changes in the Ecuadorian context. The impact on demand for textile products has been observed in variables such as sales prices and manufacturing costs, manufacturing gross domestic product and the unemployment rate. Being indicators that determine to a great extent, the quality and accuracy of the forecast, generating also, uncertainty scenarios. For this reason, the aim of this work is focused on the demand forecasting for textile products by comparing a set of classic methods such as ARIMA, STL Decomposition, Holt-Winters and machine learning, Artificial Neural Networks, Bayesian Networks, Random Forest, Support Vector Machine, taking into consideration all the above mentioned, as an essential input for the production planning and sales of the textile industries. And as a support, when developing strategies for demand management and medium-term decision making of this sector under study. Finally, the effectiveness of the methods is demonstrated by comparing them with different indicators that evaluate the forecast error, with the Multi-layer Neural Networks having the best results with the least error and the best performance.The authors are greatly grateful by the support given by the SDAS Research Group (https://sdas-group.com/).Lorente-Leyva, LL.; Alemany Díaz, MDM.; Peluffo-Ordóñez, DH.; Herrera-Granda, ID. (2021). 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An unusual presentation of Castleman's Disease:a case report

BACKGROUND: Castleman's disease (CD), a rare condition of uncertain etiology, involves a massive proliferation of lymphoid tissues and typically presents as mediastinal masses. We describe a patient with CD who presented with diffuse adenopathy involving the inguinal, paratracheal, retroperitoneal, axillary, and pelvic regions. CASE PRESENTATION: Case report describing presentation, work-up, management and clinical course of a patient with Castleman's disease in the setting of a county hospital in metropolitan area. Patient was treated with chemotherapeutic agents. CONCLUSIONS: To our knowledge, this represents the first case of CD involving an HIV-positive patient with a negative Human Herpes Virus (HHV-8) viral panel. Because patients with similar clinical histories are at high risk for the development of non-Hodgkin's lymphoma and Kaposi sarcoma, regular medical surveillance is recommended

Interprofessional and interdisciplinary simulation-based training leads to safe sedation procedures in the emergency department

BACKGROUND Sedation is a procedure required for many interventions in the Emergency department (ED) such as reductions, surgical procedures or cardioversions. However, especially under emergency conditions with high risk patients and rapidly changing interdisciplinary and interprofessional teams, the procedure caries important risks. It is thus vital but difficult to implement a standard operating procedure for sedation procedures in any ED. Reports on both, implementation strategies as well as their success are currently lacking. This study describes the development, implementation and clinical evaluation of an interprofessional and interdisciplinary simulation-based sedation training concept. METHODS All physicians and nurses with specialised training in emergency medicine at the Berne University Department of Emergency Medicine participated in a mandatory interdisciplinary and interprofessional simulation-based sedation training. The curriculum consisted of an individual self-learning module, an airway skill training course, three simulation-based team training cases, and a final practical learning course in the operating theatre. Before and after each training session, self-efficacy, awareness of emergency procedures, knowledge of sedation medication and crisis resource management were assessed with a questionnaire. Changes in these measures were compared via paired tests, separately for groups formed based on experience and profession. To assess the clinical effect of training, we collected patient and team satisfaction as well as duration and complications for all sedations in the ED within the year after implementation. We further compared time to beginning of procedure, time for duration of procedure and time until discharge after implementation with the one year period before the implementation. Cohen's d was calculated as effect size for all statistically significant tests. RESULTS Fifty staff members (26 nurses and 24 physicians) participated in the training. In all subgroups, there is a significant increase in self-efficacy and knowledge with high effect size (d z  = 1.8). The learning is independent of profession and experience level. In the clinical evaluation after implementation, we found no major complications among the sedations performed. Time to procedure significantly improved after the introduction of the training (d = 0.88). DISCUSSION Learning is independent of previous working experience and equally effective in raising the self-efficacy and knowledge in all professional groups. Clinical outcome evaluation confirms the concepts safety and feasibility. CONCLUSION An interprofessional and interdisciplinary simulation-based sedation training is an efficient way to implement a conscious sedation concept in an ED