Implementation, availability and regulatory status of an OECD accepted Reconstructed Human Epidermis model in Brazil

Introduction: In 2014, Brazil has joined the growing list of countries to ban cosmetic products from being tested on animal models. The new legislation comes into force in 2019. As a result, the interest for validated alternative testing methods for safety assessment has been increasing in academia, industry and associations. However, the lack of specific legislation on the use of biological material of human origin for toxicological tests makes the access to alternative in vitro models difficult. Furthermore, importation to Brazil is not possible on timely manner. Method: In this article, we report the implementation process of a Reconstructed Human Epidermis (SkinEthic™ RHE), an alternative model internationally accepted by OECD, through a technology transfer from EPISKIN® Lyon to Brazil. Regulatory evolution has been motivating the implementation and wide use of alternative methods to animal testing in several industry segments including cosmetic and pharmaceutical. Results: Protocol has been shown to be robust and highly reproducible. Quality control parameters (histological analysis, barrier function test and tissue viability) were performed on 24 batches assembled in Brazil. SkinEthic™ RHE model use allows the full replacement of animal test methods for skin hazards identification. It has regulatory acceptance for several toxicological endpoints, such as the Draize test for skin irritation and corrosion. It allows the reduction and refining of pre-clinical protocols through tiered strategies. Implementation of SkinEthic™ RHE protocol is just a first and important step towards a new approach of toxicological safety testing in Brazil. Conclusion: The implementation was successfully done and reported here. However, in order to follow completely the new legislation up to 2019, the availability of validated models is essential. Quality control tests done on RHE batches produced in Brazil demonstrate that the model met OECD acceptance criteria and therefore can be used for reliable prediction of irritation and corrosion classification.TÍTULO PT: Implementação, disponibilidade e contexto regulatório de um modelo de Epiderme Humana Reconstruída no Brasil aceito pela OECDIntrodução: Em 2014, o Brasil aderiu à crescente lista de países a banir testes de produtos cosméticos em modelos animais. A nova legislação entra em vigor em 2019. Como resultado, o interesse em métodos de testes alternativos validados para avaliação de segurança tem aumentado na academia, indústria e associações. No entanto, a falta de legislação específica sobre o uso de material biológico de origem humana para testes toxicológicos dificulta o acesso aos modelos alternativos in vitro. Além disso, a importação no Brasil não é possível em tempo hábil. Método: Neste artigo, relatamos o processo de implementação de um modelo de Epiderme Humana Reconstruída (SkinEthic™ RHE) internacionalmente aceito pela OECD, através de uma transferência tecnológica da Episkin Lion para o Brasil, bem como discutimos a evolução regulatória que tem motivado a implementação e a ampla utilização de métodos alternativos à experimentação animal em diversos segmentos além do cosmético e farmacêutico. Resultados: O protocolo de fabricação dos tecidos mostrou-se robusto e altamente reprodutível, considerando os parâmetros de controle de qualidade (análise histológica, função barreira e viabilidade tecidual) analisados em 24 lotes fabricados no Brasil. Conclusões: A implementação do modelo SkinEthic™ RHE é apenas um primeiro e importante passo em direção a uma nova abordagem para testes de segurança toxicológica no Brasil, realizada com êxito e aqui relatada. No entanto, para seguir plenamente a nova legislação até 2019, a disponibilidade de modelos validados é essencial. Os testes de controle de qualidade realizados nos lotes RHE produzidos no Brasil demonstram que o modelo atende aos critérios de aceitação da OCDE e, portanto, pode ser usado para uma previsão confiável de irritação e classificação de compostos corrosivos

Switching to daratumumab SC from IV is safe and preferred by patients with multiple myeloma

[Introduction]: Two phase 3 studies demonstrated superior efficacy of intravenous daratumumab (DARA IV) plus bortezomib/melphalan/prednisone (ALCYONE) or lenalidomide/dexamethasone (Rd; MAIA) versus standard-of-care regimens for transplant-ineligible newly diagnosed multiple myeloma. In these studies, patients could switch from DARA IV to subcutaneous daratumumab (DARA SC) while receiving daratumumab monotherapy in ALCYONE (as of Cycle 11) or daratumumab plus Rd in MAIA. The phase 3 COLUMBA study demonstrated noninferiority of DARA SC to DARA IV. DARA SC reduced administration time, allowing patients to spend less time in healthcare settings, a relevant practical consideration for patient care in the COVID-19 pandemic/settings of limited healthcare resources.[Methods]: DARA SC 1800 mg was administered every 4 weeks, per approved dosing schedules. We evaluated safety and patient-reported experience (ALCYONE only) among patients who switched from DARA IV to DARA SC.[Results]: Fifty-seven patients in ALCYONE and 135 in MAIA switched to DARA SC. Three (2.2%; MAIA) patients reported injection-site reactions, all of which were mild. No infusion-related reactions occurred with DARA SC. In ALCYONE, >80% of patients preferred DARA SC over DARA IV. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 5.3% of patients in ALCYONE and 25.9% in MAIA; one (0.7%; MAIA) patient experienced a TEAE with an outcome of death.[Conclusion]: For transplant-ineligible newly diagnosed multiple myeloma, DARA SC (monotherapy/with Rd) was safe and preferred over DARA IV. ClinicalTrials.gov, NCT02195479/NCT02252172.This work was supported by the Janssen Research & Development, LLC.Peer reviewe

Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma

[Excerpt] Multiple myeloma (MM) is the third most common hematological malignancy, after Non-Hodgkin Lymphoma and Leukemia. MM is generally preceded by Monoclonal Gammopathy of Undetermined Significance (MGUS) [1], and epidemiological studies have identified older age, male gender, family history, and MGUS as risk factors for developing MM [2]. The somatic mutational landscape of sporadic MM has been increasingly investigated, aiming to identify recurrent genetic events involved in myelomagenesis. Whole exome and whole genome sequencing studies have shown that MM is a genetically heterogeneous disease that evolves through accumulation of both clonal and subclonal driver mutations [3] and identified recurrently somatically mutated genes, including KRAS, NRAS, FAM46C, TP53, DIS3, BRAF, TRAF3, CYLD, RB1 and PRDM1 [3,4,5]. Despite the fact that family-based studies have provided data consistent with an inherited genetic susceptibility to MM compatible with Mendelian transmission [6], the molecular basis of inherited MM predisposition is only partly understood. Genome-Wide Association (GWAS) studies have identified and validated 23 loci significantly associated with an increased risk of developing MM that explain ~16% of heritability [7] and only a subset of familial cases are thought to have a polygenic background [8]. Recent studies have identified rare germline variants predisposing to MM in KDM1A [9], ARID1A and USP45 [10], and the implementation of next-generation sequencing technology will allow the characterization of more such rare variants. [...]French National Cancer Institute (INCA) and the Fondation Française pour la Recherche contre le Myélome et les Gammapathies (FFMRG), the Intergroupe Francophone du Myélome (IFM), NCI R01 NCI CA167824 and a generous donation from Matthew Bell. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank the Association des Malades du Myélome Multiple (AF3M) for their continued support and participation. Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organizatio

Le protocole mylofrance (évaluation de l'efficacité et de la tolérance du gemtuzumab ozogamicine à dose fractionnée en monothérapie dans le traitement des lam de l'adulte en première rechute)

Les rechutes de leucémie aiguë myéloblastique (LAM) surviennent dans 60 à 80 % des cas ; en l absence d allogreffe la survie sans maladie à long terme n excède pas 10 %. Le Gemtuzumab Ozogamicine (GO) est un anticorps monoclonal anti-CD33 couplé à la calicheamicine qui a été évalué en monothérapie dans une étude de phase II chez des adultes en première rechute de LAM. A la posologie de 9 mg/m2 à J1 et J14, le taux de réponse globale obtenu a été de 26 % au prix de toxicités hématologiques et hépatiques marquées. En s appuyant sur des études in vitro suggérant une re-expression du CD33 à la surface des blastes après exposition au GO, nous avons émis l hypothèse que l administration fractionnée de GO pouvait être aussi efficace et moins toxique. Dans une étude prospective multicentrique, 57 adultes ayant une première rechute de LAM ont reçu trois injections de GO (3 mg/m2 à J1, J4 et J7). Le taux de réponse globale a été de 30 % et la survie médiane sans maladie de 11 mois. Une faible activité des protéines d efflux P-gp et MRP1 paraît être l un des facteurs pronostiques majeurs de l obtention d une RC. Les durées médianes de neutropénie <500/mm3 et de thrombopénie <50 000/mm3 ont été respectivement de 23 et 21 jours. Aucune toxicité hépatique de grade 3 ou 4, ni aucun cas de MVO n ont été observés. L administration du GO à doses fractionnées est donc efficace et très bien tolérée permettant d envisager son association à d autres molécules de chimiothérapie ou à des modulateurs de la P-gpPARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Implementation, availability and regulatory status of an OECD accepted Reconstructed Human Epidermis model in Brazil

Introduction: In 2014, Brazil has joined the growing list of countries to ban cosmetic products from being tested on animal models. The new legislation comes into force in 2019. As a result, the interest for validated alternative testing methods for safety assessment has been increasing in academia, industry and associations. However, the lack of specific legislation on the use of biological material of human origin for toxicological tests makes the access to alternative in vitro models difficult. Furthermore, importation to Brazil is not possible on timely manner. Method: In this article, we report the implementation process of a Reconstructed Human Epidermis (SkinEthic™ RHE), an alternative model internationally accepted by OECD, through a technology transfer from EPISKIN® Lyon to Brazil. Regulatory evolution has been motivating the implementation and wide use of alternative methods to animal testing in several industry segments including cosmetic and pharmaceutical. Results: Protocol has been shown to be robust and highly reproducible. Quality control parameters (histological analysis, barrier function test and tissue viability) were performed on 24 batches assembled in Brazil. SkinEthic™ RHE model use allows the full replacement of animal test methods for skin hazards identification. It has regulatory acceptance for several toxicological endpoints, such as the Draize test for skin irritation and corrosion. It allows the reduction and refining of pre-clinical protocols through tiered strategies. Implementation of SkinEthic™ RHE protocol is just a first and important step towards a new approach of toxicological safety testing in Brazil. Conclusion: The implementation was successfully done and reported here. However, in order to follow completely the new legislation up to 2019, the availability of validated models is essential. Quality control tests done on RHE batches produced in Brazil demonstrate that the model met OECD acceptance criteria and therefore can be used for reliable prediction of irritation and corrosion classification

Characterization of a New Reconstructed Full Thickness Skin Model, T-Skin™, and its Application for Investigations of Anti-Aging Compounds

Background: We have characterized a new reconstructed full-thickness skin model, T-Skin&#8482;, compared to normal human skin (NHS) and evaluated its use in testing anti-aging compounds. Methods: The structure and layer-specific markers were compared with NHS using histological and immunohistological staining. In anti-aging experiments, T-SkinTM was exposed to retinol (10 &#181;M) or vitamin C (200 &#181;M) for 5 days, followed by immunohistological staining evaluation. Results: T-Skin&#8482; exhibits a well stratified, differentiated and self-renewing epidermis with a dermal compartment of functional fibroblasts. Epidermal (cytokeratin 10, transglutaminase 1), dermo&#8722;epidermal junction (DEJ) (laminin 5, collagen-IV, collagen VII) and dermally-located (fibrillin 1, procollagen I) biomarkers were similar to those in NHS. Treatment of T-Skin&#8482; with retinol decreased the expression of differentiation markers, cytokeratin 10 and transglutaminase 1 and increased the proliferation marker, Ki67, in epidermis basal-layer cells. Vitamin C increased the expression of DEJ components, collagen IV and VII and dermal procollagen 1. Conclusions: T-Skin&#8482; exhibits structural and biomarker location characteristics similar to NHS. Responses of T-Skin&#8482; to retinol and vitamin C treatment were consistent with those of their known anti-aging effects. T-Skin&#8482; is a promising model to investigate responses of epidermal, DEJ and dermal regions to new skin anti-ageing compounds

Risk factors and decision criteria for intensive chemotherapy in older patients with acute myeloid leukemia.

International audienceBACKGROUND: There is a need for standardization of treatment decisions in older patients with acute myeloid leukemia. The aim of the present study was to analyze the decisional value of poor risk factors in 416 elderly patients treated in the ALFA-9803 trial in order to derive a decisional index. DESIGN AND METHODS: Standard multivariate analysis was used to identify risk factors for overall survival. Risk factors were then considered as good decision tools if associated with a frequency >10% and a false positive rate or =75 years, performance status > or =2, and white cell count > or =50 x 10(9)/L. This simple two-class decisional index, which was validated in an independent patient set, enabled us to discriminate 100 patients (24%) who had an estimated overall survival of only 19% at 12 months, with a good 9% false positive rate. CONCLUSIONS: We propose waiting for cytogenetic information before making treatment decisions in elderly patients with acute myeloid leukemia. Those patients with unfavorable cytogenetics, as well as patients with at least two of the following features, age > or =75 years, performance status > or =2, and white cell count > or =50 x 10(9)/L, should not be considered for standard intensive chemotherapy (ClinicalTrials.gov identifier: NCT00363025)