Telomere-related gene (TRG) pathogenic variants are detected in ∼30% of familial pulmonary fibrosis (PF) cases. Danazol, a synthetic sex hormone with androgenic properties, has been found associated with telomere elongation and hematologic response in patients with short telomeres. The objective of the ANDROTELO multicenter, prospective, open-label single-arm phase II clinical trial ( NCT03710356 ) was to evaluate the efficacy and safety of danazol in carriers of TRG mutations with PF or bone-marrow failure (BMF).Included patients were carriers of a pathogenic or likely pathogenic TRG variant and presented a PF lung involving ≥10% parenchymal involvement on chest CT (PF group) and/or severe BMF (BMF group). Treatment was danazol 400 mg twice a day for 12 months. We included 25 patients with PF (16 males) and 5 with BMF (2 males). One PF patient withdrew consent. At inclusion, the median age in the PF group was 62.5 years, FVC 69% (interquartile range 40;120) and DLCO 44% (29;84). Ten of 24 PF patients (42%) completed the 12-month treatment. Causes of premature treatment discontinuation were side effects (n=9), death (n=3), lung transplantation (n=1), and disease progression (n=1). Fourteen PF patients were evaluated at month 12: 8 showed a relative decline of FVC of <5%. The median relative decrease in FVC and DLCO was −10% (interquartile range −14;−2) and −10.3% (−22.7;4.2). The 5 patients in the BMF group completed the 12-month treatment and exhibited at least partial response. Danazol was poorly tolerated in patients with TRG-related PF in this study, thus precluding efficacy assessment.
Background: The sequential use of anti-programmed cell death (ligand)-1 [PD-(L)1] immune-checkpoint inhibitors (ICIs) followed by targeted tyrosine-kinase inhibitors (TKIs) for advanced non-small cell lung cancer (NSCLC) with oncogenic alterations raises questions about tolerance and efficacy. Recent study results suggested an increased risk of adverse events (AEs) with this sequence. Methods: Multicenter retrospective study on advanced NSCLC patients treated with ICIs followed by targeted therapies between 2015 and 2021. The primary endpoint was the rate of grade 3–5 adverse events (AEs). Main secondary endpoints were progression-free survival (PFS), time-to-treatment failure and overall survival (OS). Results: The analysis included 109 patients (most with EGFR, 30.3%; BRAF, 17.4%; MET exon-14, 17.4%; ALK, 10.1%; and RET, 6.4% gene alterations); 28/109, which is 25.7% of the patients, experienced grade 3/4 AEs and 4/109 (3.7%) experienced grade 5 AEs, leading to the definitive cessation of targeted therapy treatment in 14/32 (44%) of cases; higher grade 3–5 rates were observed with the dabrafenib–trametinib combination (12/16, 75%), capmatinib (4/8, 50%) and crizotinib (8/16, 50%). A last ICI-administration-to-targeted therapy-start interval of <90 days appeared to be associated with grade ≥ 3 AEs (32/82, 39% vs. 0/27 p = 0.001). In these sequential strategies, effectiveness of targeted therapies, in this second-line or later setting, appears to be lower than that in the published historical data. Conclusion: According to this analysis, sequential ICI–targeted therapy use for advanced NSCLC appeared to be associated with more grade 3–5 AEs.
Il pectus excavatum è di gran lunga la malformazione toracica congenita più frequente (90%). Le sue ripercussioni funzionali cardiopolmonari sono raramente all'origine della richiesta di correzione, che è il più delle volte motivata da ragioni estetiche e da un disagio sociale. La progettazione assistita da computer (CAD) si basa su una tomografia computerizzata (TC) toracica in sezioni sottili millimetriche. L'immagine digitale del riempimento anatomico perfetto, la prototipazione 3D, il modellamento e poi lo stampaggio del silicone e la sua polimerizzazione sono le fasi di una progettazione-fabbricazione assistita da computer (CAD/CAM). La procedura chirurgica è rapida (1 h), in un solo tempo e senza rischi: l'impianto è posizionato con precisione nella sua loggia profonda, sottopettorale cranialmente e sottoaponeurotico caudalmente sui muscoli retti dell'addome. La tecnica è efficace in tutte le forme asintomatiche, profonde o superficiali, asimmetriche, soprattutto nelle donne, e nelle forme basse con spina xifoidea (pectus arcuatum), molto frequenti e raramente citate in letteratura.
While most relatives of TRG-variant carriers report exposure to inhaled toxics, few make behavioural changes within a year of genetic counselling https://bit.ly/4iEGBBN.
