Immune predictors of response to immune checkpoint inhibitors in mismatch repair-deficient endometrial cancer.

BACKGROUND: Patients with mismatch repair-deficient (MMRd) endometrial cancer (EC) can derive great benefit from immune checkpoint inhibitors (ICI). However not all responses and predictors of primary resistance are lacking. METHODS: We compared the immune tumor microenvironment of MMRd EC ICI-responders (Rs) and ICI non-responders (NRs), using spatial multiplexed immune profiling and unsupervised hierarchical clustering analysis. RESULTS: Overall, NRs exhibited drastically lower CD8+, absent terminally differentiated T cells, lack of mature tertiary lymphoid structures and dendritic cells, as well as loss of human leukocyte antigen class I. However, no single marker could predict R versus NR with confidence. Clustering analysis identified a combination of four immune features that demonstrated that accurately predicted ICI response, with a discriminative power of 92%. Finally, 80% of NRs lacked programmed death-ligand 1, however, 60% exhibited another actionable immune checkpoint (T-cell immunoglobulin and mucin containing protein-3, indoleamine 2,3-dioxygenase 1, or lymphocyte activation gene 3). CONCLUSIONS: These findings underscore the potential of immune tumor microenvironment features for identifying patients with MMRd EC and primary resistance to ICI who should be oriented towards trials testing novel immunotherapeutic combinations.

Impact of Early Relational Trauma on Psychic Processes: Implications for Treatment of vulnerable Children and Families / Impacto do Trauma Relacional Precoce nos Processos Psíquicos em Famílias Vulneráveis: Implicações para o Tratamento de Crianças e Famílias

ABSTRACT Numerous works and clinical research conducted in various institutions have cast fresh light on the notion of trauma and have contributed to the emergence of the concept of early relational trauma. Early relational trauma is a form of trauma rendered complex by the multiplicity of its sources and its modes of expression. Its main features are often attachment and acting-out disturbances. In families where such trauma occurs, links could sometimes be perverted and form a narcissistic configuration. This mode of functioning, organized around negativity, impacts the plurality of psychic processes and interferes with the treatment approaches of multidisciplinary teams. In order to promote a multifocal approach to care tailored to differences in situations, educational and socio-judicial practitioners.

RESUMO Inúmeros trabalhos e pesquisas clínicas realizados em diversas instituições trouxeram à luz a noção de trauma e contribuíram para o surgimento do conceito de trauma relacional precoce. O trauma relacional precoce é uma forma de trauma complexo pela multiplicidade de suas fontes e seus modos de expressão. Suas principais características são frequentemente distúrbios de apego e atuação. Nas famílias onde ocorre tal trauma que às vezes pode ser pervertido em configurações narcísicas, esse modo de funcionamento organizado em torno da negatividade impacta a pluralidade do psíquico e interfere nas abordagens de tratamento das equipes multidisciplinares. Para promover uma abordagem multifocal de cuidados adaptados às diferenças de situações, profissionais de educação e sócio judiciais.