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Introduction: Vascular anomalies (VAs) constitute a heterogeneous group of tumors and malformations capable of inducing significant clinical events in specific patients, such as the compression of vital organs, pain, functional impairment, or acquired coagulopathy. Molecular investigations into the underlying mechanisms of VAs have unveiled the frequent involvement of the PI3â K/AKT/mTOR pathway. Sirolimus, a specific mTOR inhibitor, has emerged as a potential therapeutic agent; however, its routine clinical application in complex VAs is currently restricted by a lack of extensive clinical experience. Methods: Between 2015 and 2024, we administered sirolimus to 14 pediatric patients with various types of vascular anomalies in two Italian centers, subjecting them to clinical and instrumental follow-up to investigate its efficacy and the possible occurrence of adverse events. Results: An overall improvement in or stability of their vascular anomalies was reported by 86% of patients. We also assessed toxicity, noting a low prevalence of life-threatening adverse events: only one case of sepsis was reported in a patient with a severe clinical condition, and four cases of recurrent aphthosis (28%) were reported. The most common side effect was dyslipidemia, with 43% of patients developing hypercholesterolemia (21%) or hypertriglyceridemia (21%), although these patients generally did not reach severe levels. Discussion: In line with data in the literature, according to our experience, medical therapy with sirolimus should be considered in pediatric patients affected by vascular anomalies.
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PURPOSE: Autoimmune diseases are typically associated with immune checkpoints blockade. This study aims at assessing, in real-life clinical practice, the prevalence and impact of thyroid disorders induced by immune checkpoint inhibitors. METHODS: 52 patients (30 F; age 61 ± 13 years) with advanced melanoma treated with ipilimumab (3 mg/kg i.v./3 weeks; 4 doses) were included. For disease progression, 29 (16 F) of them received nivolumab (3 mg/kg i.v./2 weeks) or pembrolizumab (2 mg/kg i.v./3 weeks). Thyroid function and autoimmunity were assessed before, after 6 weeks, at the end of ipilimumab, as well as before and every 3 months during nivolumab/pembrolizumab treatment. RESULTS: During ipilimumab, 7 (4 F) patients developed thyroid dysfunction (4 thyroiditis, 1 associated with hypothyroidism; 2 thyrotoxicosis in a previously euthyroid multinodular goiter; 1 hypothyroidism worsened). During PD1 inhibitors, 7 patients (3 F) developed hypothyroidism with severe manifestations in 6 of them; 3 patients suffered from euthyroid autoimmune thyroiditis from baseline, one after ipilimumab; 2 patients developed after transient thyrotoxicosis. Mean follow-up after anti-CTLA4 inhibitors treatment was 36 ± 28 months. Thyroid disorders occurred 45.1 ± 20.8 and 151 ± 67 days after the initiation of CTLA4 and PD1 inhibitors, respectively. Autoimmune disorders and BRAF mutation were associated with a better clinical response to CTLA4 followed by PD1 treatment. CONCLUSIONS: Immune checkpoint blockade is burdened by a high incidence of autoimmune thyroid dysfunction, which is often severe. Therefore, early and careful monitoring and, eventually, treatment are crucial to prevent the negative impact of thyroid dysfunction on the clinical outcome.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/efectos adversos , Antígeno CTLA-4/antagonistas & inhibidores , Melanoma/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Enfermedades de la Tiroides/inducido químicamente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Nivolumab , Pronóstico , Estudios Prospectivos , Derivación y Consulta , Enfermedades de la Tiroides/patologíaRESUMEN
The ShcA adaptor protein is engaged by numerous receptor tyrosine kinases (RTKs) in breast cancer cells. Once activated, RTKs phosphorylate three key tyrosine phosphorylation sites (Y239, Y240 and Y317) within ShcA that creates a docking site for Grb2/SOS and Grb2/Gab-containing complexes to activate the MAPK and AKT signaling pathways, respectively. We previously demonstrated that a tyrosine to phenylalanine substitution of the ShcA tyrosine phosphorylation sites (Shc3F-Y239/240/313F) significantly impairs breast tumor growth and angiogenesis in transgenic mouse models, in part, through the regulation of vascular endothelial growth factor (VEGF) production. Despite this fact, the underlying molecular mechanisms by which ShcA transduces pro-tumorigenic signals in breast cancer cells remain poorly defined. In this study, we demonstrate that ShcA-dependent activation of AKT, but not the RAS/MAPK pathway, induces VEGF production by bolstering VEGF mRNA translation. Accordingly, ShcA drives breast tumor growth and angiogenesis in vivo in a 4E-BP-dependent manner. These findings establish ShcA as a biological bridge that links AKT activation downstream of RTKs to cap-dependent VEGF mRNA translation in order to promote mammary tumorigenesis.