The 3-min constant speed shuttle test (CSST) was used to examine the effect of tiotropium/olodaterol compared with tiotropium at reducing activity-related breathlessness in patients with chronic obstructive pulmonary disease (COPD).This was a randomised, double-blind, two-period crossover study including COPD patients with moderate to severe pulmonary impairment, lung hyperinflation at rest and a Mahler Baseline Dyspnoea Index <8. Patients received 6 weeks of tiotropium/olodaterol 5/5 µg and tiotropium 5 µg in a randomised order with a 3-week washout period. The speed for the 3-min CSST was determined for each patient such that an intensity of breathing discomfort ≥4 (“somewhat severe”) on the modified Borg scale was reached at the end of a completed 3-min CSST.After 6 weeks, there was a decrease in the intensity of breathlessness (Borg dyspnoea score) at the end of the 3-min CSST from baseline with both tiotropium (mean –0.968, 95% CI −1.238– −0.698; n=100) and tiotropium/olodaterol (mean −1.325, 95% CI −1.594– −1.056; n=101). The decrease in breathlessness was statistically significantly greater with tiotropium/olodaterol versus tiotropium (treatment difference −0.357, 95% CI −0.661– −0.053; p=0.0217).Tiotropium/olodaterol reduced activity-related breathlessness more than tiotropium in dyspnoeic patients with moderate to severe COPD exhibiting lung hyperinflation.

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Calcineurin inhibitor (CI) therapy has been associated with chronic nephrotoxicity, which limits its long-term utility for suppression of allograft rejection. In order to understand the mechanisms of the toxicity, we analyzed gene expression changes that underlie the development of CI immunosuppressant-mediated nephrotoxicity in male Sprague-Dawley rats dosed daily with cyclosporine (CsA; 2.5 or 25 mg/kg/day), FK506 (0.6 or 6 mg/kg/day), or rapamycin (1 or 10 mg/kg/day) for 1, 7, 14, or 28 days. A significant increase in blood urea nitrogen was observed in animals treated with CsA (high) or FK506 (high) for 14 and 28 days. Histopathological examination revealed tubular basophilia and mineralization in animals given CsA (high) or FK506 (low and high). We identified a group of genes whose expression in rat kidney is correlated with CI-induced kidney injury. Among these genes are two genes, Slc12a3 and kidney-specific Wnk1 (KS-Wnk1), that are known to be involved in sodium transport in the distal nephrons and could potentially be involved in the mechanism of CI-induced nephrotoxicity. The downregulation of NCC (the Na-Cl cotransporter coded by Slc12a3) in rat kidney following CI treatment was confirmed by immunohistochemical staining, and the downregulation of KS-Wnk1 was confirmed by quantitative real-time-polymerase chain reaction (qRT-PCR). We hypothesize that decreased expression of Slc12a3 and KS-Wnk1 could alter the sodium chloride reabsorption in the distal tubules and contribute to the prolonged activation of the renin-angiotensin system, a demonstrated contributor to the development of CI-induced nephrotoxicity in both animal models and clinical settings. Therefore, if validated as biomarkers in humans, SLC12A3 and KS-WNK1 could potentially be useful in the early detection and reduction of CI-related nephrotoxicity in immunosuppressed transplant patients when monitoring the health of kidney xenographs in clinical practice.

Purpose Resistance to HER2 (ErbB2)-targeted therapy may be mediated by other members of the ErbB family. We investigated the efficacy and safety of the irreversible ErbB family blocker, afatinib, alone as first-line therapy in the advanced setting and in combination with vinorelbine or paclitaxel for those who progressed on afatinib monotherapy, in female patients with metastatic breast cancer who had failed or progressed on prior HER2-targeted therapy in the early disease setting. Methods In this phase II, single-arm, two-part study (ClinicalTrials.gov: NCT01271725), patients in part A received afatinib 40 mg/day in 21-day cycles until disease progression or intolerable adverse events (AEs). Patients with progressive disease could then receive afatinib plus weekly vinorelbine 25 mg/m2 or paclitaxel 80 mg/m2 until disease progression or intolerable AEs (part B). The primary endpoint was confirmed objective response rate (RECIST v1.1). Results Eighty-seven patients were enrolled and 74 were treated in part A (median age: 51 years [range 27–76]; 31 [42%] estrogen receptor-positive, 26 [35%] progesterone receptor-positive). Of these, 39 (53%) patients went on to receive afatinib plus vinorelbine (13 patients) or paclitaxel (26 patients) in part B. Thirteen (18%) and 12 (31%) patients achieved an objective response in parts A and B, respectively. The most common treatment-related AEs with afatinib monotherapy (any/grade ≥ 3) were diarrhea (68%/8%) and rash (49%/4%). Combination therapy was generally well tolerated, with no additive toxicity observed. Conclusion Afatinib treatment, alone or in combination with vinorelbine or paclitaxel, was associated with objective responses in ≥ 18% of patients with metastatic breast cancer for whom prior HER2-targeted therapy has failed. Treatment-related AEs were generally manageable, with few grade ≥ 3 AEs reported. Trial registration ClinicalTrials.gov, NCT01271725, registered 1 July 2011.

This exploratory, randomised, double-blind, double-dummy, multicentre, cross-over study explored the effect of 6 weeks of treatment with tiotropium/olodaterol (T/O) versus fluticasone propionate/salmeterol (F/S) on left ventricular filling in patients with chronic obstructive pulmonary disease with functional residual capacity (FRC) >120% predicted and postbronchodilator improvement of FRC ≥7.5%. Overall, 76 patients were randomised across nine sites. Treatment with T/O or F/S increased left ventricular end-diastolic volume index from baseline (adjusted mean change: T/O: 2.317 mL/m2, F/S: 2.855 mL/m2), with no statistically significant difference between treatments. However, T/O resulted in a significantly greater reduction in lung hyperinflation versus F/S (FRC plethysmography absolute change from baseline: F/S: –0.329 L, T/O: –0.581 L).