“Being Guided”: What Oncofertility Patients’ Decisions Can Teach Us About the Efficacy of Autonomy, Agency, and Decision-Making Theory in the Contemporary Critical Encounter

Recent research on patient decision-making reveals a disconnect between theories of autonomy, agency, and decision-making and their practice in contemporary clinical encounters. This study examines these concepts in the context of female patients making oncofertility decisions in the United Kingdom in light of the phenomenon of “being guided.” Patients experience being guided as a way to cope with, understand, and defer difficult treatment decisions. Previous discussions condemn guided decision-making, but this research suggests that patients make an informed, autonomous decision to be guided by doctors. Thus, bioethicists must consider the multifaceted ways that patients enact their autonomy in medical encounters

Inhibitor-Sensitive FGFR2 and FGFR3 Mutations in Lung Squamous Cell Carcinoma

A comprehensive description of genomic alterations in lung squamous cell carcinoma (lung SqCC) has recently been reported, enabling the identification of genomic events that contribute to the oncogenesis of this disease. In lung SqCC, one of the most frequently altered receptor tyrosine kinase families is the fibroblast growth factor receptor (FGFR) family, with amplification or mutation observed in all four family members. Here, we describe the oncogenic nature of mutations observed in FGFR2 and FGFR3, which are each observed in 3% of samples, for a mutation rate of 6% across both genes. Using cell culture and xenograft models, we show that several of these mutations drive cellular transformation. Transformation can be reversed by small molecule FGFR inhibitors currently being developed for clinical use. We also show that mutations in the extracellular domains of FGFR2 lead to constitutive FGFR dimerization. Additionally, we report a patient with an FGFR2-mutated oral squamous cell carcinoma who responded to the multi-targeted tyrosine kinase inhibitor pazopanib. These findings provide new insights into driving oncogenic events in a subset of lung squamous cancers, and recommend future clinical studies with FGFR inhibitors in patients with lung and head and neck SqCC

Health services users with diabetes mellitus: from knowledge to the use of healthcare rights

This descriptive study with qualitative approach analyzes the knowledge of individuals with diabetes mellitus (DM) concerning their health rights. Open interviews were conducted with 12 individuals with DM in a university center in the interior of Sao Paulo, Brazil. Content analysis enabled the identification of two categories: the users’ (lack of) knowledge concerning their rights and the unaware exercise of their rights. The results revealed that despite the legal advancements achieved in public policies, most users with DM are unaware of their rights, although they use the benefits that accrue from law in an unconscious way. Providing complete and sufficient information is essential so that individuals are able to make the best decision in relation to their treatment, preserving their autonomy.Se trata de un estudio descriptivo de abordaje cualitativo, con el objetivo de analizar el conocimiento de los usuarios de los servicios de salud con diabetes mellitus (DM) acerca de sus derechos. Participaron 12 personas con DM atendidas en un centro universitario del interior paulista en 2008, por medio de entrevista abierta. El análisis de contenido temático de los datos posibilitó identificar dos categorías: el (des)conocimiento de los usuarios de los servicios de salud con diabetes sobre sus derechos y el ejercicio no consciente de sus derechos por las personas con DM. Fue posible constatar que, a pesar de los avances legalmente alcanzados por las políticas públicas, la mayoría de los usuarios de los servicios de salud con DM desconoce sus derechos, a pesar de que utilizan los beneficios provenientes de la legislación, de manera no consciente. Se resalta como punto fundamental proveer informaciones completas y suficientes para que la persona pueda tomar la mejor decisión en relación a su tratamiento, preservando su autonomía en los servicios de salud.Estudo descritivo de abordagem qualitativa, e teve como objetivo analisar o conhecimento dos usuários dos serviços de saúde com diabetes mellitus (DM), acerca dos seus direitos. Participaram 12 pessoas com DM, atendidas em um centro universitário do interior paulista, em 2008, por meio de entrevista aberta. A análise de conteúdo temática dos dados possibilitou identificar duas categorias: o (des)conhecimento dos usuários dos serviços de saúde com diabetes sobre seus direitos e o exercício não consciente dos seus direitos pelas pessoas com DM. Foi possível constatar que, apesar dos avanços legalmente alcançados pelas políticas públicas, a maioria dos usuários dos serviços de saúde com DM desconhece seus direitos, embora utilize, de maneira não consciente, os benefícios advindos da legislação. Ressalta-se como ponto fundamental prover informações completas, suficientes para que a pessoa possa tomar a melhor decisão em relação ao seu tratamento, preservando sua autonomia, nos serviços de saúde

Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors

The success in lung cancer therapy with Programmed Death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased cytotoxic T cells and increased markers of T cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape, and mechanistically link treatment response to PD-1 inhibition

Characterization of DDR2 Inhibitors for the Treatment of DDR2 Mutated Nonsmall Cell Lung Cancer

Despite advances in precision medicine approaches over the past decade, the majority of nonsmall cell lung cancers (NSCLCs) are refractory to treatment with targeted small molecule inhibitors. Previous work has identified mutations in the Discoidin Domain Receptor 2 (DDR2) kinase as potential therapeutic targets in NSCLCs. While DDR2 is potently targeted by several multitargeted kinase inhibitors, most notably dasatinib, toxicity has limited the clinical application of anti-DDR2 therapy. Here, we have characterized compound 1 and other tool compounds demonstrating selectivity for DDR2 and show that while these compounds inhibit DDR2 in lung cancer model systems, they display limited antiproliferative activity in DDR2 mutated cell lines as compared to dual DDR2/SRC inhibitors. We show that DDR2 and SRC are binding partners, that SRC activity is tied to DDR2 activation, and that dual inhibition of both DDR2 and SRC leads to enhanced suppression of DDR2 mutated lung cancer cell lines. These results support the further evaluation of dual SRC/DDR2 targeting in NSCLC, and we report a tool compound, compound 5, which potently inhibits both SRC and DDR2 with a distinct selectivity profile as compared to dasatinib