Paediatric Strategy Forum for medicinal product development in mitogen-activated protein kinase pathway inhibitors: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

As the mitogen-activated protein kinase (MAPK) signalling pathway is activated in many paediatric cancers, it is an important therapeutic target. Currently, a range of targeted MAPK pathway inhibitors are being developed in adults. However, MAPK signals through many cascades and feedback loops and perturbing the MAPK pathway may have substantial influence on other pathways as well as normal development. In view of these issues, the ninth Paediatric Strategy Forum focused on MAPK inhibitors. Development of MAPK pathway inhibitors to date has been predominantly driven by adult indications such as malignant melanoma. However, these inhibitors may also target unmet needs in paediatric low-grade gliomas, high-grade gliomas, Langerhans cell histiocytosis, juvenile myelomonocytic leukaemia and several other paediatric conditions. Although MAPK inhibitors have demonstrated activity in paediatric cancer, the response rates and duration of responses needs improvement and better documentation. The rapid development and evaluation of combination approaches, based on a deep understanding of biology, is required to optimise responses and to avoid paradoxical tumour growth and other unintended consequences including severe toxicity. Better inhibitors with higher central nervous systempenetration for primary brain tumours and cancers with a propensity for central nervous system metastases need to be studied to determine if they are more effective than agents currently being used, and the optimum duration of therapy with MAPK inhibition needs to be determined. Systematic and coordinated clinical investigations to inform future treatment strategies with MAPK inhibitors, rather than use outside of clinical trials, are needed to fully assess the risks and benefits of these single agents and combination strategies in both front-line and in the refractory/relapse settings. Platform trials could address the investigation of multiple similar products and combinations. Accelerating the introduction of MAPK inhibitors into front-line paediatric studies is a priority, as is ensuring that these studies generate data appropriate for scientific and regulatory purposes. Early discussions with regulators are crucial, particularly if external controls are considered as randomised control trials in small patient populations can be challenging. Functional end-points specific to the populations in which they are studied, such as visual acuity, motor and neuro psychological function are important, as these outcomes are often more reflective of benefit for lower grade tumours (such as paediatric low-grade glioma and plexiform neurofibroma) and should be included in initial study designs for paediatric low-grade glioma. Early prospective discussions and agreements with regulators are necessary. Long-term follow-up of patients receiving MAPK inhibitors is crucial in view of their prolonged administration and the important involvement of this pathway in normal development. Further rational development, with a detailed understanding of biology of this class of products, is crucial to ensure they provide optimal benefit while minimising toxicity to children and adolescents with cancer.

Bis-choline tetrathiomolybdate prevents copper-induced blood-brain barrier damage.

In Wilson disease, excessive copper accumulates in patients' livers and may, upon serum leakage, severely affect the brain according to current viewpoints. Present remedies aim at avoiding copper toxicity by chelation, for example, by D-penicillamine (DPA) or bis-choline tetrathiomolybdate (ALXN1840), the latter with a very high copper affinity. Hence, ALXN1840 may potentially avoid neurological deterioration that frequently occurs upon DPA treatment. As the etiology of such worsening is unclear, we reasoned that copper loosely bound to albumin, that is, mimicking a potential liver copper leakage into blood, may damage cells that constitute the blood-brain barrier, which was found to be the case in an in vitro model using primary porcine brain capillary endothelial cells. Such blood-brain barrier damage was avoided by ALXN1840, plausibly due to firm protein embedding of the chelator bound copper, but not by DPA. Mitochondrial protection was observed, a prerequisite for blood-brain barrier integrity. Thus, high-affinity copper chelators may minimize such deterioration in the treatment of neurologic Wilson disease.

A temporalidade da metapsicologia freudiana: algumas contribuições sobre a transmissão / On the temporality of Freud's metapsychology: some thoughts about transmission / La temporalité de la métapsychologie freudienne: quelques contributions sur la transmission / La temporalidad de la metapsicología freudiana: algunas contribuciones sobre la transmisión

O artigo parte da hipótese de que a pulsão estabelece relações fundamentais com a transmissão. O estudo desta relação pode trazer contribuições para o avanço da psicanálise no que a mesma aposta numa dimensão historicizante do advento do sujeito. Assim, articulamos noções fundamentais para a psicanálise, como as de mito, ficção e trauma, em sua relação com as condições de surgimento particulares que constituem a metapsicologia. Tais desenvolvimentos visam contribuir para estudos que enfrentam dilemas tão presentes nos debates em torno da história e da memória, culminando em um questionamento da noção de representação. O artigo se situa, então, num campo de problematização em torno da transmissão buscando apreender quais as consequências que noções que são vitais à metapsicologia, como as de inconsciente e pulsão, podem aportar ao debate em torno da história e do tempo.

This article is based on the hypothesis that the concept of drive establishes fundamental relations with transmission. Studying this relation may contribute to the advancement of psychoanalysis as it relies on a historicizing dimension of the subject's advent. Thus, we associate fundamental psychoanalytical concepts, such as myth, fiction and trauma in their relation to the particular conditions of emergence that constitutes metapsychology, aiming to contribute to the studies that face the dilemmas of debates on history and memory, and eventually question the concept of representation. Therefore, this article discusses transmission and seeks to understand which consequences of vital concepts of metapsychology, e.g. the unconscious and the drive, may contribute to the debate on history and time.

Cet article suppose que la pulsion établit des relations fondamentales avec la transmission. L'étude de cette relation peut contribuer à l'avancement de la psychanalyse en ce qu'elle signale une dimension historisante de l'avènement du sujet. Ainsi, nous articulons des notions fondamentales pour la psychanalyse, telles que celles de mythe, de fiction et de traumatisme, dans leur relation avec les conditions d'émergence particulières qui constitue la métapsychologie. Ces développements ont pour but de contribuer aux études qui se heurtent aux dilemmes dans les débats sur l'histoire et la mémoire, aboutissant fondamentalement à une remise en question de la notion de représentation. Donc, l'article se situe dans un champ de problématisation autour de la transmission cherchant à comprendre les conséquences que des notions essentielles à la métapsychologie - telles qu'inconscient et pulsion - peuvent contribuer au débat sur l'historicité et le temps.

El artículo asume que la pulsión establece relaciones fundamentales con la transmisión. El estudio de esa relación puede hacer importantes contribuciones al avance del psicoanálisis en el sentido de que esta apuesta por una dimensión historizante del advenimiento del sujeto. Así, articulamos nociones fundamentales para el psicoanálisis, como las de mito, ficción y trauma, en su relación con las condiciones de emergencia particulares que constituyen la metapsicología. Esos desarrollos tienen como objetivo contribuir a los estudios que enfrentan dilemas tan presentes en debates sobre la historia y la memoria, culminando en un cuestionamiento sobre la noción de representación. Por lo tanto, el artículo se sitúa en un campo de problematización sobre la transmisión y busca comprender cómo las consecuencias y nociones que son vitales para la metapsicología, como las del inconsciente y la pulsión, pueden contribuir al debate sobre la historia y el tiempo.