Diagnosis, Prevention, Treatment and Surveillance of Anthracycline-Induced Cardiovascular Toxicity in Pediatric Cancer Survivors

Advances in pediatric cancer therapies have dramatically improved the likelihood of survival. As survivors are aging, however, we are now understanding that treatment carries a significant risk of cardiovascular toxicity, which can develop immediately, or even many years after completing therapy. Anthracycline derivates are some of the most commonly used agents in pediatric oncology treatment protocols, which have a dose-dependent correlation with the development of cardiac toxicity. As we learn more about the mechanisms of toxicity, we are developing prevention strategies, including improvements in surveillance, to improve early diagnosis of heart disease. Current survivorship surveillance protocols often include screening echocardiograms to evaluate systolic function by measuring the ejection fraction or fractional shortening. However, these measurements alone are not enough to capture early myocardial changes. The use of additional imaging biomarkers, serum biomarkers, electrocardiograms, as well as cholesterol and blood pressure screening, are key to the early detection of cardiomyopathy and cardiovascular disease. Medical treatment strategies are the same as those used for heart failure from other causes, but earlier recognition and implementation can lead to improved long term outcomes

Follow-up to the ECVAM Prevalidation Study on in vitro Tests for Acute Skin Irritation. ECVAM Skin Irritation Task Force Report 2.

Abstract not availableJRC.I-Institute for Health and Consumer Protection (Ispra

The ECVAM retrospective validation study on cytotoxicity- and cell function-based in vitro assays for eye irritation.

Current European legislations strongly call for alternatives to replace animal testing. In major evaluation studies conducted in the 1990¿s, no single method was found able to fully replace the Draize eye irritation test. However, some alternatives showed good reproducibility and reliability. In 2006, ECVAM initiated the retrospective validation of four assays based on cytotoxicity and cell function: 1) Neutral Red Release (NRR), 2) Red Blood Cell test, 3) Fluorescein Leakage (FL) and 4) Cytosensor Microphysiometer (CM). The study was coordinated by an international Validation Management Group (VMG) including observers from ICCVAM-NICEATM and JaCVAM. The existing data were collected and compiled according to ECVAM Principles of Weight-of-Evidence Validation. The resulting Background Review Document (BRD) for each assay was structured according to the ECVAM Modular Approach to Validation and underwent independent quality control audits. The VMG evaluated the four BRDs and made recommendations concerning the suitability of the assays to be used in the Bottom-Up and Top-Down Approaches for Eye irritation Testing Strategy proposed in a 2005 ECVAM expert meeting, to reduce and replace in vivo studies. In particular, the CM protocol INVITTOX 102-modified and the FL protocol INVITTOX 71 were recommended as suitable to discriminate severe irritants from other classes. Furthermore, the FL protocol INVITTOX 120 and the NRR protocol INVITTOX 54 and PREDISAFETM were recommended as suitable to discriminate non-irritants from other classes. These assays are currently under Peer Review by the ECVAM Scientific Advisory Committee. The ultimate goal is to combine validated in vitro assays for eye irritation based on their performances and applicability domains, to identify the most suitable testing strategies to classify substances according to their irritation potential and ultimately replace the Draize rabbit eye test.JRC.DDG.I.3-In-vitro method

The ECVAM International Validation Study on In Vitro Tests for Acute Skin Irritation: Report on the Validity of the EPISKIN and EpiDerm Assays and on the Skin Integrity Function Test

ECVAM sponsored a formal validation study on three in vitro tests for skin irritation, two employing reconstituted human epidermis models (EPISKIN, EpiDerm) and the skin integrity function test (SIFT), which employs ex vivo mouse skin. The goal of the study was to assess whether the in vitro tests would predict in vivo classifications according to the EU classification scheme, R 38 and No-label (i.e. non-irritant). 58 chemicals (25 irritants and 33 non-irritants) were tested, having been selected to give broad coverage of physico-chemical properties, and an adequate distribution of irritancy scores derived from in vivo rabbit skin irritation tests. In Phase 1, 20 of these chemicals (9 irritants and 11 non-irritants) were tested with coded identity by a single (lead) laboratory for each of the methods, to confirm the suitability of the protocol improvements introduced after a prevalidation phase. When cell viability (evaluated by the MTT reduction test) was used as the endpoint, the predictive ability of both EpiDerm and EPISKIN was considered sufficient to justify their progression to Phase 2, while the predictive ability of the SIFT was inadequate. Since both the skin models provided false predictions around the in vivo classification border (rabbit Draize test score 2), the release of the cytokine, interleukin-1a (IL-1¿), was also determined. In Phase 2, each human skin model was tested in three laboratories, with 58 chemicals. The main endpoint measured for both EpiDerm and EPISKIN was cell viability. In samples from chemicals which gave MTT assay results above the threshold of 50% viability, IL-1a release was also measured, to determine whether the additional endpoint would improve the predictive ability of the tests. For EPISKIN, the sensitivity was 75% and the specificity was 81% (MTT assay only); assessed with the combination of the MTT and IL-1a assays, the sensitivity increased to 91%, with a specificity of 79%. For EpiDerm, the sensitivity was 57% and the specificity was 85% (MTT assay only), while the predictive capacity of EpiDerm was not improved by the measurement of IL-1a release. Following independent peer review, in April 2007 the ECVAM Scientific Advisory Committee endorsed the scientific validity of the EPISKIN test as a replacement for the rabbit skin irritation method, and of the EpiDerm method for identifying skin irritants as part of a tiered testing strategy. This new alternative approach will probably be the first in vitro toxicity test to replace the Draize rabbit skin irritation test in Europe and internationally, since, in the very near future, new EU and OECD Test Guidelines will be proposed for regulatory acceptance.JRC.I.2-Validation of biomedical testing method

The Principles of Weight of Evidence Validation of Test Methods and Testing Strategies

This is the report of the XX of a series of workshops organised by the European Centre for the Validation of Alternative Methods (ECVAM). The main objective of ECVAM, as defined in 1993 by its Scientific Advisory Committee, is to promote the scientific and regulatory acceptance of alternative methods which are of importance to the biosciences, and which reduce, refine or replace the use of laboratory animals. One of the first priorities set by ECVAM was the implementation of procedures that would enable it to become well informed about the state of the art of non-animal test development and validation, and of opportunities for the possible incorporation of alternative methods into regulatory procedures. It was decided that this would be achieved through a programme of ECVAM workshops, each addressing a specific topic, and at which selected groups of independent international experts would review the current status of various types of in vitro tests and their potential uses, and make recommendations about the best ways forward (1). The workshop was organised by Michael Balls and Valérie Zuang, and took place on 5-7 May 2004, at the Hotel Lido, Angera (VA), Italy, with participants from academia, industry, research, and national and validation authorities. The aim was to discuss and define principles and criteria for validation via weight-of-evidence approaches, and to provide guidance on the performance of this type of validation. The outcome of the discussions and the recommendations agreed by the workshop participants are summarised in this report, which also takes into account some subsequent events and publications.JRC.I.2-Validation of biomedical testing method

Development and Validation of Non-Animal Tests and Testing Strategies: the Identification of a Coordinated Response to the Challenge and the Opportunity Presented by the Sixth Amendment to the Cosmetics Directive (76/768/EEC).

This workshop report has been produced jointly by ECVAM and DGXXIV (Consumer Policy Service). 42 conclusions and recommendations are made concerning the development and validation of non-annimal tests and testing strategies, in the context of the Sixth Amendment to the EU Cosmetics Directive.JRC.(EI)-Environment Institut

Health Care Policy and Congenital Heart Disease: 2020 Focus on Our 2030 Future

The congenital heart care community faces a myriad of public health issues that act as barriers toward optimum patient outcomes. In this article, we attempt to define advocacy and policy initiatives meant to spotlight and potentially address these challenges. Issues are organized into the following 3 key facets of our community: patient population, health care delivery, and workforce. We discuss the social determinants of health and health care disparities that affect patients in the community that require the attention of policy makers. Furthermore, we highlight the many needs of the growing adults with congenital heart disease and those with comorbidities, highlighting concerns regarding the inequities in access to cardiac care and the need for multidisciplinary care. We also recognize the problems of transparency in outcomes reporting and the promising application of telehealth. Finally, we highlight the training of providers, measures of productivity, diversity in the workforce, and the importance of patient– family centered organizations in advocating for patients. Although all of these issues remain relevant to many subspecialties in medicine, this article attempts to illustrate the unique needs of this population and highlight ways in which to work together to address important opportunities for change in the cardiac care community and beyond. This article provides a framework for policy and advocacy efforts for the next decade