Thyroid cancer is the most common endocrine cancer, with a good prognosis in most cases. However, some cancers of follicular origin are metastatic or recurrent and eventually become radioiodine refractory thyroid cancers (RAIR-TC). These more aggressive cancers are a clinical concern for which the therapeutic arsenal remains limited. Molecular biology of these tumors has highlighted a hyper-activation of the Mitogen-Activated Protein Kinases (MAPK) pathway (RAS-RAF-MEK-ERK), mostly secondary to the BRAF^V600E hotspot mutation occurring in about 60% of papillary cancers and 45% of anaplastic cancers. Therapies targeting the different protagonists of this signaling pathway have been tested in preclinical and clinical models: first and second generation RAF inhibitors and MEK inhibitors. In clinical practice, dual therapies with a BRAF inhibitor and a MEK inhibitor are being recommended in anaplastic cancers with the BRAF^V600E mutation. Concerning RAIR-TC, these inhibitors can be used as anti-proliferative drugs, but their efficacy is inconsistent due to primary or secondary resistance. A specific therapeutic approach in thyroid cancers consists of performing a short-term treatment with these MAPK pathway inhibitors to evaluate their capacity to redifferentiate a refractory tumor, with the aim of retreating the patients by radioactive iodine therapy in case of re-expression of the sodium–iodide symporter (NIS). In this work, we report data from recent preclinical and clinical studies on the efficacy of MAPK pathway inhibitors and their resistance mechanisms. We will also report the different preclinical and clinical studies that have investigated the redifferentiation with these therapies.

Pediatric chronic intestinal failure (CIF) requires long-term home parenteral nutrition (HPN) to support growth and health. Transitioning to adult care is a critical period, and long-term outcomes remain underexplored. This nationwide study assessed long-term survival, HPN dependence, psychosocial status and characteristics of CIF management in adult patients with pediatric-onset CIF who received HPN during childhood and transition to adulthood. We conducted a multicenter retrospective study of patients who started HPN for CIF in childhood and transitioned to adult care still receiving HPN between 1995 and 2020. Clinical characteristics and risk factors for survival and HPN dependence were analysed. Ninety-seven patients (46% female) transitioned at a mean age of 19.2 ± 2.6 years, after HPN began at a median age of 1 year (IQR: 0-8). CIF was caused by short bowel syndrome (60%), motility disorders (27%), and mucosal disease (13%). Management included teduglutide (13%), autologous gastrointestinal reconstruction (6%) and intestinal transplantation (5%). After a median follow-up of 8 years, survival was 91% and HPN dependence 95%. Catheter-related bloodstream infections were the leading cause of death (62%). In multivariate analysis, daily HPN requirement (HR = 5.7, 95%CI: 1.2-26.0, p= 0.03) and intestinal transplantation (HR = 5.9, 95%CI: 1.5-23.0, p= 0.01) were associated with mortality. Teduglutide was the only factor associated with reduced HPN dependence (HR = 10.0, 95%CI: 1.1-88.9, p= 0.04). At last follow-up, 58% of patients were employed or studying, 51% had left the family home, 28% were in a relationship, 20% had psychiatric comorbidities and 14% opioid dependence. Pediatric-onset CIF patients show high survival into adulthood despite persistent HPN dependence. GLP-2 analogues may reduce HPN dependence and improve long-term outcomes.