Efficacy and safety of nilotinib in patients with KIT-mutated metastatic or inoperable melanoma: final results from the global, single-arm, phase II TEAM trial.

BACKGROUND: The single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated the KIT-selective tyrosine kinase inhibitor nilotinib in patients with KIT-mutated advanced melanoma without prior KIT inhibitor treatment. PATIENTS AND METHODS: Forty-two patients with KIT-mutated advanced melanoma were enrolled and treated with nilotinib 400 mg twice daily. TEAM originally included a comparator arm of dacarbazine (DTIC)-treated patients; the design was amended to a single-arm trial due to an observed low number of KIT-mutated melanomas. Thirteen patients were randomized to DTIC before the protocol amendment removing this study arm. The primary endpoint was objective response rate (ORR), determined according to Response Evaluation Criteria In Solid Tumors. RESULTS: ORR was 26.2% (n = 11/42; 95% CI, 13.9%-42.0%), sufficient to reject the null hypothesis (ORR ≤10%). All observed responses were partial responses (PRs; median response duration, 7.1 months). Twenty patients (47.6%) had stable disease and 10 (23.8%) had progressive disease; 1 (2.4%) response was unknown. Ten of the 11 responding patients had exon 11 mutations, four with an L576P mutation. The median progression-free survival and overall survival were 4.2 and 18.0 months, respectively. Three of the 13 patients on DTIC achieved a PR, and another patient had a PR following switch to nilotinib. CONCLUSION: Nilotinib activity in patients with advanced KIT-mutated melanoma was similar to historical data from imatinib-treated patients. DTIC treatment showed potential activity, although the low patient number limits interpretation. Similar to previously reported results with imatinib, nilotinib showed greater activity among patients with an exon 11 mutation, including L576P, suggesting that nilotinib may be an effective treatment option for patients with specific KIT mutations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01028222.

Difference in breathing strategies during exercise between trained elderly men and women.

This study compared the ventilatory responses and exercise tidal flow-volume (Vt) loops during exercise in order to analyze the influence of gender on breathing strategy in a fit aging population. Sixteen trained elderly men (63.0+/-2.9 years) and eight peer women (62.3 +/- 5.5 years) performed an incremental test on a cycle ergometer. At 90% maximal oxygen consumption (VO2max), the women presented a significantly higher expiratory flow limitation (EFL) than the men (38 +/- 10 vs 17 +/- 8% of Vt, respectively) (P<0.01) and a lower value of expiratory reserve volume relative to forced vital capacity (FVC) compared with the men (16.8 +/- 5.3% vs 23.0 +/- 5.2%, respectively) (P<0.05). Inspiratory reserve volume relative to FVC was significantly higher in women than men at 50% (P<0.05), 70% (P<0.01) and 90%VO2max (25.2 +/- 5.4% vs 12.2 +/- 4.2%, respectively, at 90%VO2max) (P<0.01). Mechanical ventilatory constraints occurred in trained elderly men and women. However, different breathing strategies were observed relative to gender. A significantly higher EFL was measured in women, whereas men rather presented a dynamic hyperinflation. This specific breathing strategy measured in trained elderly women would induce lower ventilatory efficiency than in peer men.

Optimal exercise intensity in trained elderly men and women.

The purpose of our investigation was to suggest a new approach to determine exercise intensities in master elderly athletes. Sixteen trained elderly men (63.0 +/- 2.9 years) and 8 trained elderly women (62.3 +/- 5.5 years), performed an exhaustive exercise test on a cycle ergometer. Rating of perceived exertion (RPE) and heart rate reserve (HRr) were determined at the first and second ventilatory thresholds (VT1 and VT2). There was no significant difference between genders in RPE and HRr, whatever the exercise intensity. RPE scores corresponded to 12.4 +/- 0.9 in men and 12.7 +/- 1.3 in women at VT1. At VT2, RPE was 15.2 +/- 0.8 and 15.3 +/- 1.1 in men and women, respectively. HR at VT1 corresponded to 59.3 +/- 7.0% in men and 59.5 +/- 5.1% in women, whereas at VT2, HR was measured at 80.5 +/- 6.4% and 79.5 +/- 5.9% HRr, in men and women, respectively. Because it is not practical to measure VT1 and VT2 in routine clinical practice, the present study indicated that, in trained older men and women, the RPE value of 12 - 13 and/or 60 % HRr might be used to detect the exercise intensity at VT1. An RPE score of 15 and/or 80 % HRr would appear to be good indexes in the prescription of exercise intensity at VT2.

Respiratory muscle oxygenation kinetics: relationships with breathing pattern during exercise.

This work aimed to investigate accessory respiratory muscle oxygenation (RMO(2)) during exercise, using near-infrared spectroscopy, and to study relationships between RMO(2) kinetics and breathing parameters. Nineteen young males (19.3 +/- 1.5 years) performed a maximal incremental test on a cycle ergometer. Changes in breathing pattern were characterized by accelerated rise in the breathing frequency (f (Racc)), plateau of tidal volume (V (Tplateau)) and inflection point in the V. (E)/V (T) relationship (V. (E)/V (T inflection)). First and second ventilatory thresholds (VT1 and VT2) were also determined. RMO (2) kinetics were monitored by NIRS on the serratus anterior. During exercise, all subjects showed reduced RMO (2) (deoxygenation) with a breakdown (B-RMO(2)) at submaximal workload (86 % .VO(2max)). .VO(2) corresponding to B-RMO (2) and to f (Racc), V (Tplateau), .V(E)/V(T inflection), or VT2 were not different. Relationships were found between the .VO(2) at B-RMO(2) and the .VO(2) at f (Racc) (r = 0.88, p < 0.001), V (Tplateau) (r = 0.84, p < 0.001), V. (E)/V (T inflection) (r = 0.58, p < 0.05) or VT2 (r = 0.79, p < 0.001). The amplitude of RMO(2) at maximal workload was weakly related to .VO(2max) (r = 0.58, p < 0.05). B-RMO (2) seems to be due to the change in breathing pattern and especially to the important rise in breathing frequency at the VT2 exercise level. Moreover, subjects who exhibit higher .VO(2max) also exhibit a higher decrease in respiratory muscle oxygenation during exercise.

Evidence of exercise-induced O2 arterial desaturation in non-elite sportsmen and sportswomen following high-intensity interval-training.

The aim of this study was to investigate the development of exercise-induced hypoxemia (EIH defined as an exercise decrease > 4 % in oxygen arterial saturation, i. e. SaO (2) measured with a portable pulse oximeter) in twelve sportsmen and ten sportswomen (18.5 +/- 0.5 years) who were non-elite and not initially engaged in endurance sport or training. They followed a high-intensity interval-training program to improve V.O (2)max for eight weeks. The training running speeds were set at approximately 140 % V.O (2)max running speed up to 100 % 20-m maximal running speed. Pre- and post-training pulmonary gas exchanges and SaO (2) were measured during an incremental running field-test. After the training period, men and women increased their V.O (2)max (p < 0.001) by 10.0 % and 7.8 %, respectively. Nine subjects (seven men and two women) developed EIH. This phenomenon appeared even in sportsmen with low V.O (2)max from 45 ml x min (-1) x kg (-1) and seemed to be associated with inadequate hyperventilation induced by training: because only this hypoxemic group showed 1) a decrease in maximal ventilatory equivalent in O (2) (V.E/V.O (2), p < 0.01) although maximal ventilation increased (p < 0.01) with training, i. e. in EIH-subjects the ventilatory response increased less than the metabolic demand after the training program; 2) a significant relationship between SaO (2) at maximal workload and the matched V.E/V.O (2) (p < 0.05, r = 0.67) which strengthened a relative hypoventilation implication in EIH. In conclusion, in this field investigation the significant decrease in the minimum SaO (2) inducing the development of EIH after high-intensity interval-training indicates that changes in training conditions could be accompanied in approximately 40 % non-endurance sportive subjects by alterations in the degree of arterial oxyhemoglobin desaturation developing during exercise.