This study emphasizes that both antifibrotic drugs appeared to be a good therapeutic choice in terms of functional stabilization, also in older patients.
The treatment of patients affected by non-small cell lung cancer (NSCLC) has been revolutionised by the discovery of druggable mutations. ROS1 (c-ros oncogene) is one gene with druggable mutations in NSCLC. ROS1 is currently targeted by several specific tyrosine kinase inhibitors (TKIs), but only two of these, crizotinib and entrectinib, have received Food and Drug Administration (FDA) approval. Crizotinib is a low molecular weight, orally available TKI that inhibits ROS1, MET and ALK and is considered the gold standard first-line treatment with demonstrated significant activity for lung cancers harbouring ROS1 gene rearrangements. However, crizotinib resistance often occurs, making the treatment of ROS1-positive lung cancers more challenging. A great effort has been undertaken to identify a new generation or ROS1 inhibitors. In this review, we briefly introduce the biology and role of ROS1 in lung cancer and discuss the underlying acquired mechanisms of resistance to crizotinib and the promising new agents able to overcome resistance mechanisms and offer alternative efficient therapies.
The symptom of breathlessness is an important outcome measure in the management of patients with chronic obstructive pulmonary disease (COPD). Clinical ratings of dyspnea and routine lung function are weakly related to each other. However, in the clinical setting breathlessness in COPD is encountered under conditions of increased respiratory effort, impeded respiratory muscle action, or functional weakness. Thus, the present study was carried out to determine whether and to what extent clinical ratings of dyspnea and respiratory muscle dysfunction relate to each other. In 21 patients with COPD two methods were used to rate dyspnea: a modified Medical Research Council Scale (MRC) and the Baseline Dyspnea Index (BDI), which is a multidimensional instrument for measuring dyspnea based on three components: magnitude of task, magnitude of effort, and functional impairment. A baseline focal score was obtained as the sum of the three components. Measures were: pulmonary volumes; arterial blood gases; maximal voluntary ventilation (MVV); maximal inspiratory and expiratory pressures (MIP and MEP, respectively); and breathing patterns ventilation (VE), tidal volume (VT), and respiratory frequency (Rf). In 15 patients pleural pressure was also measured during both quiet breathing (Pplsw) and maximal inspiratory sniff maneuver at FRC (Pplsn). BDI and MRC ratings related to each other and showed comparable weak associations with standard parameters (FEV1, PaCO2, VT), MIP, and MEP. In contrast, MVV closely and similarly related to both ratings. Pplsw (%Pplsn), a measure of respiratory effort, and Pplsw (%Pplsn)/VT(%VC), an index of neuroventilatory dissociation, related significantly to both the BDI (r2 = -0.77 and r2 = -0.75, respectively) and the MRC (r2 = 0.81 and r2 = 0.74, respectively). Using MVV, Pplsw (%Pplsn), and Pplsw (%Pplsn)/VT(%VC) in a stepwise multiple regression as independent variables with BDI rating as dependent variable, MVV explained an additional 14.5% of the variance of the BDI over the 67.8% predicted by Pplsw (%Pplsn). Our results demonstrate that the level of chronic exertional dyspnea in COPD increases as the ventilatory muscle derangement increases. The level of the relationships among dyspnea ratings and MVV and respiratory effort helps to explain some of the mechanisms of chronic dyspnea of COPD. These measures should be considered for therapeutic intervention to reduce dyspnea.
Concomitant radio-chemotherapy is the best approach according to our experience. Our results show a benefit of prophylactic cranial irradiation in distant metastasis-free survival.
Abstract. Idiopathic pulmonary fibrosis (IPF) is a rare interstitial lung disease limited to the lung with an undefined etiopathogenesis and a very short life expectancy (less than 5 years). IPF susceptibility has been associated with several genetic and environmental risk factors and the prognosis isIdiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with poor prognosis and an undefined etiopathogenesis. Several genetic and environmental risk factors for IPF have been identified including cigarette smoking, metal dust and other pollutant exposure, genetic mutations and polymorphisms (1-5). IPF prognosis is really poor (less than 5 years) and is conditioned by comorbidities negatively affecting patients' quality of life and survival (e.g. gastro-esophageal reflux, depression, venous thromboembolism, pulmonary hypertension and other cardiovascular disorders, and lung cancer) (6-10). The incidence of pulmonary neoplasm is much higher in IPF patients than in the general population (11). Ozawa et al. (12) for instance, reported 3.3%, 15.4% and 54.7% of lung cancer incidence in IPF patients after one, five and ten years of follow-up, respectively (12). Common mechanisms shared by the two diseases remain unknown. An aberrant expression of miRNAs regulating non-small cell lung cancer (NSCLC) and IPF has been suggested together with a crucial role of tyrosine kinase inhibitor directed against growth factors (plateletderived growth factor, vascular endothelial growth factor and fibroblast growth factor) (13,14).Lung cancer (LC) significantly reduces survival of IPF patients, including patients with combined pulmonary emphysema and pulmonary fibrosis (15). It generally occurs in the peripheral areas of the lower lobes, where fibrotic changes are predominant. In particular, LC develops from honeycomb areas or in the border between honeycombing and non fibrotic areas and the squamous cell carcinoma is the predominant histological type (16,17). Invasive diagnostic or therapeutic procedures for neoplasms promote the development of Acute exacerbations (AE) in 80% of IPF patients and the lung surgical treatment puts about 1/5 of them at high risk of death (17,18). A perioperative Pirfenidone treatment has recently been proposed to reduce the incidence of postoperative acute events (18)(19)(20). In this context, the therapeutic management of LC is a difficult task and is still questioned, especially in IPF patients with severe fibrotic involvement, whether the tumor should be treated or not (21,22). Although Lee et al. (15) reported that radiotherapy and surgical treatments of LC result in a reduced survival of IPF patients, according to Kumar et al. (19) lung resection in selected cases can improve their survival. Furthermore, Tomassetti and colleagues (21) have suggested that in mild IPF patients the sublobar resection in 773
In adolescent idiopathic thoracic scoliosis (ITS) working capacity may be reduced during exercise. Despite concern about its usefulness, bracing is still being used in ITS. Thus the effects of bracing on exercise performance need to be examined. We studied six females, ages 12-15 years who had mild ITS (Cobb angle range 20-35 degrees). Pulmonary volumes, maximal voluntary ventilation (MVV), breathing pattern, the lowest (most negative in sign) pleural pressure during sniff maneuver (Pplsn), and pleural pressure swings (Pplsw) were measured first. Then, Pplsw, O2 uptake (VO2), CO2 output (VCO2), heart rate (HR) at rest and during progressive incremental exercise on a cycling ergometer (10 watts/min) were recorded. The exercise test was performed under control conditions without bracing (C) and after 7 days of bracing with the braced on (B). Dyspnea was measured by a modified Borg scale. At rest, bracing mildly affected total lung capacity and forced vital capacity (p < 0.03 for both) but not breathing pattern, Pplsn, or Pplsw (%Pplsn), a measure of respiratory effort. Furthermore, bracing did not consistently affect maximum work rate (WRmax). In both B and C VO2 was below (< 70%) the predicted value, VE was below (< 45%) MVV, and HR reserve was < 15 beats/min, indicating some cardiovascular deconditioning. On the other hand, respiratory frequency (Rf) increased more in B than in C (p < 0.03). In addition, Pplsw, Pplsw (%Pplsn), and Pplsw (%Pplsn)/VT, an index of neuroventilatory dissociation (NVD) of the respiratory pump, were greater in B (p < 0.03 for all). At a similar work rate, the Borg rating score was greater with bracing on than off, and the difference (delta Borg) tended to relate to concurrent changes in Pplsw (%Pplsn)/VT (r2 = 0.71; p < 0.07). We conclude that bracing affects respiratory effort, NVD, and dyspnea score during progressive exercise. These effects are consistent with increased lung elastance. Diminished exercise tolerance in patients with mild ITS probably reflects impaired physical fitness but is not affected by bracing. Training programs proposed for this subset of patients to increase peripheral muscle performance might also consider NVD of the respiratory pump.
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