Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA)

Background Several commercial and academic autologous chimeric antigen receptor T-cell (CAR-T) products targeting CD19 have been approved in Europe for relapsed/refractory B-cell acute lymphoblastic leukemia, high-grade B-cell lymphoma and mantle cell lymphoma. Products for other diseases such as multiple myeloma and follicular lymphoma are likely to be approved by the European Medicines Agency in the near future. Design The European Society for Blood and Marrow Transplantation (EBMT)-Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association collaborated to draft best practice recommendations based on the current literature to support health care professionals in delivering consistent, high-quality care in this rapidly moving field. Results Thirty-six CAR-T experts (medical, nursing, pharmacy/laboratory) assembled to draft recommendations to cover all aspects of CAR-T patient care and supply chain management, from patient selection to long-term follow-up, post-authorisation safety surveillance and regulatory issues. Conclusions We provide practical, clinically relevant recommendations on the use of these high-cost, logistically complex therapies for haematologists/oncologists, nurses and other stakeholders including pharmacists and health sector administrators involved in the delivery of CAR-T in the clinic

Immune effector cell-associated hematotoxicity (ICAHT): EHA/EBMT consensus grading and best practice recommendations

Hematological toxicity represents the most common adverse event following chimeric antigen receptor (CAR) T-cell therapy. Cytopenias can be profound, long-lasting, and can predispose for severe infectious complications. In a recent worldwide survey, we demonstrated that there remains considerable heterogeneity in regards to current practice patterns. Here, we sought to build consensus on the grading and management of Immune Effector Cell Associated Hemato-Toxicity (ICAHT) following CAR-T therapy. For this purpose, a joint effort between the European society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA) involved an international panel of 36 CAR-T experts who met in a series of virtual conferences, culminating in a 2-day meeting in Lille, France. On the basis of these deliberations, best practice recommendations were developed. For the grading of ICAHT, a classification system based on depth and duration of neutropenia was developed for early (day 0-30) and late cytopenia (after day +30). Detailed recommendations on risk factors, available pre-infusion scoring systems (e.g. CAR-HEMATOTOX score), and diagnostic work-up are provided. A further section focuses on identifying hemophagocytosis in the context of severe hematotoxicity. Finally, we review current evidence and provide consensus recommendations for the management of ICAHT, including growth factor support, anti-infectious prophylaxis, transfusions, autologous hematopoietic cell boost, and allogeneic hematopoietic cell transplantation. In conclusion, we propose ICAHT as a novel toxicity category following immune effector cell therapy, provide a framework for its grading, review literature on risk factors, and outline expert recommendations for the diagnostic work-up and short- and long-term management

Absorption, distribution and excretion of aflatoxin-derived ammoniation products in lactating cows

Peanut meal naturally contaminated with 3.5mg/kg aflatoxin B1 (AFB1) was spiked with radiolabelled AFB1 (meal14C-I0) and decontaminated by a smallscale copy of an industrial ammoniation process (meal 14C-I1). During the process 15␘f the radioactivity was lost, whereas 90␘f the remaining radiolabel could not be extracted from the meal. In the extractable part, AFB1 accounted for 10␘f the radiolabel, consistent with a total AFB1 reduction of more than 99ÐNo degradation products were observed in the extracts. Four lactating cows were fed with a diet containing 15␘f either meal 14C-I0 or 14C-I1 for 10 days. On day 9 of this treatment, respectively 23 and 67␘f the radiolabel was excreted in the urine and faeces of cows fed meal 14C-I0, as compared with 2 and 101␒n the case of cows fed meal 14C-I1. Milk contained respectively 1.35 (meal 14C-I0) and 0.25ømeal 14C-I1) of the radiolabel. Milk samples taken during the equilibrium stage contained respectively 5 and 0.5 ng/ml of AFB1-derived compounds. Aflatoxin M1 (AFM1) accounted for 50-80␘f these compounds in the case of milk from cows fed 14C-I0, as compared with 6-20␒n the case of 14C-I1. AFB1 to AFM1 carry-over rates for 14C-I0 or 14C-I1 were estimated to be respectively 0.5 and 5.9ÐOnly liver and kidney samples contained detectable levels of the radiolabel, being respectively 260 and 37 w g/kg for cows fed meal 14C-I0, and 10 and 3 w g/kg for those fed meal 14C-I1. In the latter case, more than 55␘f the radiolabel in the liver could not be extracted, as compared with 90␒n the group fed meal 14C-I1. A small part of the extractable radiolabel in the livers of 14C-I0 could be attributed to AFB1 and cows fed meal AFM1 (less than 1␘f total radioactivity). In the case of the animals fed 14C-I1 there were indications for the presence of AFB1 and AFM1 (6␘f total radioactivity). Decontamination of the highly contaminated (non-radiolabelled) peanut meal by two different industrial ammoniation processes, resulted in a similar reduction of the initial AFB1 levels of 3.5mg/kg to 15 mu g/kg. Feeding of diets containing 15␘f the nontreated and two treated peanut meals to cows for a period of 10 days, resulted in AFM1 levels in milk of respectively 2.1, 0.04 and 0.07 ng/ml. AFB1 to AFM1 carry-over rates were calculated to be respectively 0.5, 2.0, and 3.6ÐIt is concluded that the efficient reduction of aflatoxin levels by ammoniation of contaminated peanut meal results in a strong reduction of aflatoxin-related residues in milk and meat of cows, most likely caused by a decreased bioavailability of the degradation product

Differences detected in vivo between samples of aflatoxin-contaminated peanut meal, following decontamination by two ammonia-based processes

A sample of peanut meal, highly contaminated with aflatoxins, has been subjected to decontamination by two commercial ammonia-based processes. The original contaminated and the two decontaminated meals were fed to rats for 90 days. No lesions associated with aflatoxin-induced hepatocarcinogenesis were detected histologically following feeding with the two detoxified meals. There were, however, clear differences between the two meals in respect of growth rates of the rats. In addition, feeding one of the detoxified meals resulted in hepatic abnormalities detected using novel immunohistochemical reagents. Differences between the two detoxified meals were also indicated by the results of studies using meals 'spiked' with [14C]-aflatoxin B1 prior to being subjected to the detoxification processes. The meals differed in the bioavailability of the label. It was concluded that peanut meal where an initial, unacceptable level of contamination with aflatoxins had been reduced by two ammonia-based processes to comparable, acceptable levels, may still have different effects in vivo when incorporated into animal diets

Genotoxicity testing of extracts from aflatoxin-contaminated peanut meal, following chemical decontamination

One of the most important concerns in the decontamination of aflatoxin-containing feed commodities is the safety of the products for food-producing animals and for human consumption of products derived from these animals. A new method, based on the use of florisil and C18 solid phase extraction columns, was developed for the preparation of extracts from decontaminated peanut meal, which allowed testing with in vitro genotoxicity assays without interference of the residual aflatoxin B1. Recovery of degradation products in the extracts was evaluated by the use of radiolabelled \\[14C]-aflatoxin B1 (AFB1) added to naturallycontaminated peanut meal (3.5mg AFB1/kg). The meal was treated by a small-scale version of an industrial decontamination process based on ammoniation. Following decontamination, more than 90␘f the label could not be extracted from the meal. AFB1 accounted for about 10␘f the radiolabel present in the extractable fraction, indicating a total AFB reduction of more than 99ÐDecontamination of the meal by a number of other small- and industrial-scale ammonia-based processes resulted in similar efficiencies. Application of the extraction procedure resulted in AFB1-rich and AFB1-poor fractions, the latter containing half of the extractable decontamination products but less than 1␘f the residual AFB1. Testing in the Salmonella /microsome mutagenicity assay (TA 100, with S9-mix) of the original crude extracts and AFB1 rich fractions prepared from non-treated and decontaminated meal, showed the positive results expected from the AFB1 contents as determined by HPLC analysis. Analysis and testing of the AFB1-poor fractions showed that the various decontamination processes not only resulted in a successful degradation of AFB1 but also did not produce other potent mutagenic compounds. Slight positive results obtained with these extracts were similar for the untreated and treated meals and may be due to unknown compounds originally present in the meal. Results obtained with an unscheduled DNA synthesis (UDS) and Comet assay with rat hepatocytes supported this conclusion. Positive results obtained with the micronucleus assay, using immortalized mouse hepatocytes (GKB), did not clearly reflect the mycotoxin levels and require further examination. It is concluded that the newly developed extraction procedure yields highly reproducible fractions and hence is very suitable for examining the possible formation of less potent degradation products of aflatoxins in short-term genotoxicity tests

What Has Nonviolence Got To Do With The EU?

Nonviolence has an established tradition in several disciplines, including political theory, international relations and political science. But its potential for the European Union (EU) has not been appraised yet. Thus, we set out to explore nonviolence as an analytical and normative framework for the study of the EU. At the outset, we introduce nonviolence and define our approach to this concept. We then apply our analytical and normative framework to three critical issues concerning the nature of EU power, the democratic deficit and the narrative of integration. We find that nonviolence re‐defines the core dimensions of power and democracy, and imagines the EU in non‐state‐morphic ways, situating praxis at the roots of the integration process and its narrative

Clinical Practice Guideline on management of patients with diabetes and chronic kidney disease stage 3b or higher (eGFR < 45 mL/min)

Clinical epidemiolog