The efficacy of inhaled sympathomimetic and anticholinergic agents on airway obstruction in cystic fibrosis (CF) has been proven in several studies. However, studies comparing combined therapy with monotherapy led to divergent results, probably due to different study designs, different dosages, and the small numbers of patients investigated. Therefore, we wanted to answer the question which inhalation has the best short term effect: a sympathomimetic or an anticholinergic agent, or the combination of both. We investigated 17 patients with CF on 4 successive days in the morning, using pulmonary function testing before and 30 min after inhalation. Each patient received aerosolized salbutamol (SB, maximum dose (max.) 2.5 mg), ipratropium bromide (IB, max. 0.5 mg), the combination of both, or placebo (normal saline) in a randomized, double-blind crossover design. The mean forced expiratory volume in the first second improved significantly (adjusted P-value < 0.017) after each treatment compared to placebo. Analysis of variance showed that SB and combination therapy with SB and IB were superior to IB alone, without significant difference between SB and combination therapy. Response of a patient to combined therapy was usually associated with response to SB. Long-term efficacy and side effects of treatment with bronchodilators still remain to be investigated after this short term study. We conclude that in CF patients bronchodilator therapy with sympathomimetic agents is usually sufficient. Only in cases with proven additional benefit from inhalation by anticholinergics should combination therapy be recommended.

Introduction Somatic evolution of the cancer genome resulting in genetically different subclones is thought to be involved in the development of treatment resistance but might also offer new therapeutic opportunities in metastatic breast cancer. No data are available if clonal evolution differs in patients treated with chemotherapy or CDK4/6 inhibitors given with endocrine treatment (CE treatment). Methods We performed a prospective analysis of circulating tumor DNA(ctDNA) by targeted next generation sequencing in 46 patients before the beginning of a systemic firstline (n=37) or second-line (n=9) treatment. Ct DNA was analyzed again upon disease progression. Results New mutations in ctDNA of patients with progressive disease were detected in 1/11 patients who started chemotherapy, in 4/9 patients treated with chemotherapy followed by CE maintenance treatment and in 9/26 patients receiving CE therapy. The number of acquired new mutations did not differ significantly between the three therapy cohorts (all p-values >0.05). However, in patients classified as secondary resistant (n=37), occurrence of new mutations significantly differed between patients who started chemotherapy (0/9) compared to patients treated with chemotherapy followed by CE (4/11; p=0.041) and patients receiving CE therapy (8/19; p=0.024), respectively. Conclusion Clonal evolution might differ significantly between metastatic breast cancer patients with HR positive and HER-2 negative disease treated with chemotherapy or CDK4/6 inhibitors. These results should be confirmed in larger patient cohorts.

<b><i>Introduction:</i></b> Cyclin-dependent 4/6 kinase (CDK4/6) inhibitors given with endocrine therapy until disease progression are standard of care in the treatment of women with advanced HR-positive Her-2-negative breast cancer. No data are available if therapy can be safely de-escalated to endocrine monotherapy in patients with long-lasting disease control. <b><i>Methods:</i></b> We performed a retrospective analysis on the clinical course of 22 patients at our center who received CDK4/6 inhibitors with aromatase inhibitors or fulvestrant. All patients had at least stable disease for &#x3e;6 months and made a joint decision with their provider to electively discontinue CDK4/6 inhibitors. Best objective response (BOR) at treatment discontinuation, progression-free survival, and re-treatment characteristics were recorded. <b><i>Results:</i></b> Of 138 patients who received CDK4/6 inhibitors as first- or second-line therapy at our center, 22 met the inclusion criteria. Median duration of CDK4/6 treatment was 18 months (range 6–45). BOR was complete response in 1, partial response in 8, and stable disease in 13 patients. After a median duration of endocrine monotherapy of 9.5 months (range 5–44 months), 6 of 22 patients had progressive disease (1 local relapse and 5 systemic progression). All patients with disease progression had at least stable disease to chemotherapy (<i>N</i> = 1) or re-treatment with CDK4/6 inhibitors (<i>N</i> = 4). <b><i>Conclusion:</i></b> Elective discontinuation of CDK4/6 inhibitors is feasible in patients with long-lasting disease stabilization. This strategy should be evaluated in prospective trials.