Qualification and impact of a video-assisted control system in a chemotherapy compounding unit.

OBJECTIVES: Anticancer drug preparation control is essential to ensure quality and patient safety. Drugcam (Eurekam Company) is a digital video-assisted control system based on artificial intelligence methods to identify vials used and volumes withdrawn. As for any control system, qualification is required before use in a chemotherapy compounding unit (CCU). METHODS: We conducted an operational qualification (sensitivity, specificity and accuracy assessment of vials and volumes recognition and quantitative analysis of measured volumes) and a performance qualification (comparison with visual control) of Drugcam in our CCU, as well as an impact study on compounding time and compound supply time. RESULTS: Sensitivity, specificity and accuracy of vials (94%, 98% and 96%, respectively) and volumes (86%, 96% and 91%, respectively) recognition are satisfactory. It depends on both the object presented and the camera tested. False positives, which could lead to release of non-compliant preparation, were detected. Volume reading errors may exceed the tolerance threshold of ±5% for small volumes. Drugcam did not significantly lengthen compounding time and compound supply time. CONCLUSIONS: No recommendations for a qualification method of this new type of control equipment exist. However, a qualification process is essential to understand tool limitations and integrate them into the CCU risk management system. Drugcam enables anticancer drug preparation to be secure and is also useful for initial and continuous staff training.

Dynamic Regulation of NF-κB Response in Innate Immunity: The Case of the IMD Pathway in Drosophila.

Metazoans have developed strategies to protect themselves from pathogenic attack. These preserved mechanisms constitute the immune system, composed of innate and adaptive responses. Among the two kinds, the innate immune system involves the activation of a fast response. NF-κB signaling pathways are activated during infections and lead to the expression of timely-controlled immune response genes. However, activation of NF-κB pathways can be deleterious when uncontrolled. Their regulation is necessary to prevent the development of inflammatory diseases or cancers. The similarity of the NF-κB pathways mediating immune mechanisms in insects and mammals makes Drosophila melanogaster a suitable model for studying the innate immune response and learning general mechanisms that are also relevant for humans. In this review, we summarize what is known about the dynamic regulation of the central NF-κB-pathways and go into detail on the molecular level of the IMD pathway. We report on the role of the nuclear protein Akirin in the regulation of the NF-κB Relish immune response. The use of the Drosophila model allows the understanding of the fine-tuned regulation of this central NF-κB pathway.

Microangiopathy associated with gemcitabine: a drug interaction with nab-paclitaxel? A case series and literature review.

PURPOSE: Gemcitabine and nab-paclitaxel association can be used in first- or second-line treatment for metastatic pancreatic adenocarcinoma. Here, we report five cases of supposed gemcitabine-induced thrombotic microangiopathy (G-TMA), four of them with nab-paclitaxel. We assumed that nab-paclitaxel could be responsible for a potential drug interaction with gemcitabine, increasing the risk of thrombotic microangiopathy occurrence. METHODS: Clinicians reported cases of supposed G-TMA that were declared to the Pharmacovigilance center. We collected the patients' data (clinical and biological characteristics), calculated an incidence rate of G-TMA in our center, and a Naranjo score for each patient. We also reviewed literature on a potential drug interaction between nab-paclitaxel and gemcitabine. RESULTS: Four patients were treated with nab-paclitaxel/gemcitabine and one with gemcitabine alone. The time onset of supposed G-TMA was 2 to 11 months. Patients developed anemia, thrombocytopenia, and renal failure. The incidence rate of supposed G-TMA was 2.7% in our center compared to 0.31% (Meyler's Side Effect of Drugs) and 0.01% in the gemcitabine's summary of product characteristics. Literature review outlined an increase of gemcitabine's plasmatic concentrations induced by nab-paclitaxel (Drugs® website) and a potentiation of gemcitabine's effect by nab-paclitaxel in murine models. This study showed that nab-paclitaxel inhibits cytidine deaminase's activity (responsible for gemcitabine's metabolism) and increases gemcitabine's active metabolite concentrations (gemcitabine triphosphate) in tumor tissues. CONCLUSION: High incidence rate of G-TMA was observed in our cohort due to a potential drug interaction between nab-paclitaxel and gemcitabine with an increased risk of developing G-TMA. Additional pharmacological and pharmaco-epidemiological investigations are mandatory to explore this hypothesis.

A Clinical Decision Support Tool to Find the Best Initial Intravenous Cyclosporine Regimen in Pediatric Hematopoietic Stem Cell Transplantation.

To optimize cyclosporine A (CsA) dosing regimen in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT), we aimed to provide clinicians with a validated decision support tool for determining the most suitable first dose of intravenous CsA. We used a 10-year monocentric data set of pediatric patients undergoing HSCT. Discretization of all variables was performed according to literature or thanks to algorithms using Shannon entropy (from information theory) or equal width intervals. The first 8 years were used to build the Bayesian network model. This model underwent a 10-fold cross-validation, and then a prospective validation with data of the last 2 years. There were 3.3% and 4.1% of missing values in the training and the validation data set, respectively. After prospective validation, the Tree-Augmented Naïve Bayesian network shows interesting prediction performances with an average area under the receiver operating characteristic curve of 0.804, 32.8% of misclassified patients, a true-positive rate of 0.672, and a false-positive rate of 0.285. This validated model allows good predictions to propose an optimized and personalized initial CsA dose for pediatric patients undergoing HSCT. The clinical impact of its use should be further evaluated.

A decision support tool to find the best cyclosporine dose when switching from intravenous to oral route in pediatric stem cell transplant patients.

PURPOSE: Managing the pharmacokinetic variability of immunosuppressive drugs after pediatric hematopoietic stem cell transplantation (HSCT) is a clinical challenge. Thus, the aim of our study was to design and validate a decision support tool predicting the best first cyclosporine oral dose to give when switching from intravenous route. METHODS: We used 10-years pediatric HSCT patients' dataset from 2008 to 2018. A tree-augmented naïve Bayesian network model (method belonging to artificial intelligence) was built with data from the first eight-years, and validated with data from the last two. RESULTS: The Bayesian network model obtained showed good prediction performances, both after a 10-fold cross-validation and external validation, with respectively an AUC-ROC of 0.89 and 0.86, a percentage of misclassified patients of 28.7% and 35.2%, a true positive rate of 0.71 and 0.65, and a false positive rate of 0.12 and 0.14 respectively. CONCLUSION: The final model allows the prediction of the most likely cyclosporine oral dose to reach the therapeutic target specified by the clinician. The clinical impact of using this model needs to be prospectively warranted. Respecting the decision support tool terms of use is necessary as well as remaining critical about the prediction by confronting it with the clinical context.

Intra-individual Pharmacokinetic Variability of Intravenous Busulfan in Hematopoietic Stem Cell-Transplanted Children.

BACKGROUND: Busulfan therapeutic drug monitoring (TDM) is necessary to better achieve the target exposure in children before hematopoietic stem cell transplantation (HSCT). However, TDM-based dosing may be challenging if intra-individual pharmacokinetic variability (also denoted inter-occasion variability [IOV]) occurs during therapy. OBJECTIVES: The objectives of this study were to describe and quantify busulfan IOV in children, and to investigate its potential determinants. METHODS: We performed a new analysis of published data from children who received intravenous busulfan over 4 days before HSCT. We calculated individual pharmacokinetic parameters on each day of therapy using a published population pharmacokinetic model of busulfan and analyzed their changes. Population estimation of IOV was also performed with non-linear mixed effects (NLME) modeling. Potential predictors of significant decrease in busulfan clearance (CL) were assessed by using machine learning approaches. RESULTS: IOV could be assessed in 136 children. Between day (D) 1 and D2, most patients (80%) experienced a decrease in busulfan CL, with a median change of - 7.9%. However, both large decreases (minimum, - 48.5%) and increases in CL (maximum, + 44%) were observed. Over D1-D3 of therapy, mean CL significantly decreased (- 15%), with a decrease of ≥ 20% in 22% of patients. Some patients also showed unstable CL from day to day. NLME modeling of IOV provided a coefficient of variation of 10.6% and 13.1% for volume of distribution (Vd) and CL, respectively. Some determinants of significant decreases in busulfan CL were identified, but predictive performance of the models was limited. CONCLUSIONS: Significant busulfan intra-individual variability may occur in children who receive a HSCT and is hardly predictable. The main risk is busulfan overexposure. Performing TDM repeatedly over therapy appears to be the best way to accurately estimate busulfan exposure and perform precision dosing.

Bayesian Networks: A New Approach to Predict Therapeutic Range Achievement of Initial Cyclosporine Blood Concentration After Pediatric Hematopoietic Stem Cell Transplantation.

BACKGROUND: Pediatric hematopoietic stem cell transplantation (HSCT) allows the treatment of numerous diseases, both malignant and non-malignant. Cyclosporine, a narrow therapeutic index drug, is the major immunosuppressant used to prevent graft-versus-host disease (GVHD), but may also cause severe adverse effects in case of overdosing. OBJECTIVE: The objective of this study is to predict the initial cyclosporine residual blood concentration value after pediatric HSCT, and consequently the dose necessary to reach the therapeutic range, using a mathematical individual predictive model. METHODS: Clinical and biological data collected from the graft infusion for 2 months after transplantation in 155 pediatric patients undergoing HSCT between 2008 and 2016 were used to generate synthetic data for 1000 subjects which were used to build a Bayesian network model. We compared the characteristics and sensitivity to clinical or biological missing data of this model with four other methods. RESULTS: The tree-augmented Naïve Bayesian network showed the best characteristics, with no missing data (area under the curve of the receiving operator characteristics curve [AUC-ROC] of 0.89 ± 0.02), 18.9 ± 2.6% of patients misclassified, and positive and negative predictive values of 85.9 ± 3.4% and 74.2 ± 5.1%, respectively, and this trend is found in the synthetic dataset from no to 10% missing data. The most relevant variables that could influence whether the initial residual cyclosporine concentration is in the therapeutic range are the last dose before measurement and the mean dose before measurement. CONCLUSIONS: We developed and cross-validated an online Bayesian network to predict the first cyclosporine concentration after pediatric HSCT. This model allows simulation of different dosing regimens, and enables the best dosing regimen to reach the therapeutic range immediately after transplantation to be found, minimizing the risk of adverse effects and GVHD occurrence.

The Drosophila serpins: multiple functions in immunity and morphogenesis.

Members of the serpin superfamily of proteins have been found in all living organisms, although rarely in bacteria or fungi. They have been extensively studied in mammals, where many rapid physiological responses are regulated by inhibitory serpins. In addition to the inhibitory serpins, a large group of noninhibitory proteins with a conserved serpin fold have also been identified in mammals. These noninhibitory proteins have a wide range of functions, from storage proteins to molecular chaperones, hormone transporters, and tumor suppressors. In contrast, until recently, very little was known about insect serpins in general, or Drosophila serpins in particular. In the last decade, however, there has been an increasing interest in the serpin biology of insects. It is becoming clear that, like in mammals, a similar wide range of physiological responses are regulated in insects and that noninhibitory serpin-fold proteins also play key roles in insect biology. Drosophila is also an important model organism that can be used to study human pathologies (among which serpinopathies or other protein conformational diseases) and mechanisms of regulation of proteolytic cascades in health or to develop strategies for control of insect pests and disease vectors. As most of our knowledge on insect serpins comes from studies on the Drosophila immune response, we survey here the Drosophila serpin literature and describe the laboratory techniques that have been developed to study serpin-regulated responses in this model genetic organism.

Prophenoloxidase activation is not required for survival to microbial infections in Drosophila.

The antimicrobial defence of Drosophila relies on cellular and humoral processes, of which the inducible synthesis of antimicrobial peptides has attracted interest in recent years. Another potential line of defence is the activation, by a proteolytic cascade, of phenoloxidase, which leads to the production of quinones and melanin. However, in spite of several publications on this subject, the contribution of phenoloxidase activation to resistance to infections has not been established under appropriate in vivo conditions. Here, we have isolated the first Drosophila mutant for a prophenoloxidase-activating enzyme (PAE1). In contrast to wild-type flies, PAE1 mutants fail to activate phenoloxidase in the haemolymph following microbial challenge. Surprisingly, we find that these mutants are as resistant to infections as wild-type flies, in the total absence of circulating phenoloxidase activity. This raises the question with regard to the precise function of phenoloxidase activation in defence, if any.