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Background: Due to the effects of climate change, winter sport enthusiasts will be increasingly forced to stay at higher altitudes. High altitude (HA) environmental factors such as cold temperature, physical exertion, and hypoxia with subsequent hypocapnia due to hyperventilation have been shown to induce bronchoconstriction. With bronchial asthma being highly prevalent, asthmatics also will be increasingly exposed to HA environment and might experience increasing symptoms. Methods: We analysed the effects of HA factors at around 2600 m a.s.l. (metres above sea level) on lung function in mild seasonal asthmatics while they were routinely off (January) and on (March, after start of lowland pollen season) low-dose inhaled corticosteroid (ICS) treatment (n = 10), and matched healthy controls (n = 11). Results: Without inhaled corticosteroid (ICS) treatment mean FEV1 in asthmatics was 230 ml lower after exercise at HA compared to low altitude (LA, p < 0.05), while in healthy controls there was no significant difference. This decrease was mainly induced by cold and exercise at HA. During ICS treatment, this decrease was prevented. Methacholine response was reduced at HA compared to LA. Conclusions: The decrease of FEV1 in response to a combination of hypoxia, cold, and exercise is prevented by ICS treatment in mild, seasonal asthmatics. However, the FEV1 response to high altitude factors was overall small.
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INTRODUCTION: Afatinib is an effective first-line treatment in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) and has shown activity in patients progressing on EGFR-tyrosine kinase inhibitors (TKIs). First-line afatinib is also effective in patients with central nervous system (CNS) metastasis. Here we report on outcomes of pretreated NSCLC patients with CNS metastasis who received afatinib within a compassionate use program. METHODS: Patients with NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment received afatinib. Medical history, patient demographics, EGFR mutational status, and adverse events including tumor progression were documented. RESULTS: From 2010 to 2013, 573 patients were enrolled and 541 treated with afatinib. One hundred patients (66% female; median age, 60 years) had brain metastases and/or leptomeningeal disease with 74% having documented EGFR mutation. Median time to treatment failure for patients with CNS metastasis was 3.6 months, and did not differ from a matched group of 100 patients without CNS metastasis. Thirty-five percent (11 of 31) of evaluable patients had a cerebral response, five (16%) responded exclusively in brain. Response duration (range) was 120 (21-395) days. Sixty-six percent (21 of 32) of patients had cerebral disease control on afatinib. Data from one patient with an impressive response showed an afatinib concentration in the cerebrospinal fluid of nearly 1 nMol. CONCLUSION: Afatinib appears to penetrate into the CNS with concentrations high enough to have clinical effect on CNS metastases. Afatinib may therefore be an effective treatment for heavily pretreated patients with EGFR-mutated or EGFR-TKI-sensitive NSCLC and CNS metastasis.