Angiomyolipoma rebound tumor growth after discontinuation of everolimus in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis

Introduction The EXIST-2 (NCT00790400) study demonstrated the superiority of everolimus over placebo for the treatment of renal angiomyolipomas associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (LAM). This post hoc analysis of EXIST-2 study aimed to assess angiomyolipoma tumor behavior among patients who submitted to continued radiographic examination following discontinuation of everolimus in the noninterventional follow-up phase. Methods For patients who discontinued everolimus at the completion of extension phase for reasons other than angiomyolipoma progression, a single CT/MRI scan of the kidney was collected after 1 year of treatment discontinuation. Changes from baseline and from the time of everolimus discontinuation in the sum of volumes of target angiomyolipoma lesions were assessed in the non-interventional follow-up phase (data cutoff date, November 6, 2015). Results Of the 112 patients who received >= 1 dose of everolimus and discontinued treatment by the end of extension phase, 34 (30.4%) were eligible for participation in the non-interventional follow-up phase. Sixteen of 34 patients were evaluable for angiomyolipoma tumor behavior as they had at least one valid efficacy assessment (i.e. kidney CT/MRI scan) after everolimus discontinuation. During the non-interventional follow-up phase, compared with baseline, two patients (12.5%) experienced angiomyolipoma progression (angiomyolipoma-related bleeding [n = 1], increased kidney volume [n = 1]). Five patients out of 16 (31.3%) experienced angiomyolipoma progression when compared with the angiomyolipoma tumor assessment at everolimus discontinuation. The median (range) percentage change in angiomyolipoma tumor volume (cm 3) from baseline was -70.56 (-88.30;-49.64) at time of everolimus discontinuation (n = 11), and -50.55 (-79.40;-23.16) at week 48 (n = 7) after discontinuation of everolimus. One patient death was reported due to angiomyolipoma hemorrhage. Conclusions Angiomyolipoma lesions displayed an increase in volume following discontinuation of everolimus in patients with renal angiomyolipoma or sporadic LAM associated with TSC, but there was no evidence of rapid regrowth

Everolimus Plus Exemestane vs Everolimus or Capecitabine Monotherapy for Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer: The BOLERO-6 Randomized Clinical Trial.

Importance: Everolimus plus exemestane and capecitabine are approved second-line therapies for advanced breast cancer. Objective: A postapproval commitment to health authorities to estimate the clinical benefit of everolimus plus exemestane vs everolimus or capecitabine monotherapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Design: Open-label, randomized, phase 2 trial of treatment effects in postmenopausal women with advanced breast cancer that had progressed during treatment with nonsteroidal aromatase inhibitors. Interventions: Patients were randomized to 3 treatment regimens: (1) everolimus (10 mg/d) plus exemestane (25 mg/d); (2) everolimus alone (10 mg/d); and (3) capecitabine alone (1250 mg/m2 twice daily). Main Outcomes and Measures: Estimated hazard ratios (HRs) of progression-free survival (PFS) for everolimus plus exemestane vs everolimus alone (primary objective) or capecitabine alone (key secondary objective). Safety was a secondary objective. No formal statistical comparisons were planned. Results: A total of 309 postmenopausal women were enrolled, median age, 61 years (range, 32-88 years). Of these, 104 received everolimus plus exemestane; 103, everolimus alone; and 102, capecitabine alone. Median follow-up from randomization to the analysis cutoff (June 1, 2017) was 37.6 months. Estimated HR of PFS was 0.74 (90% CI, 0.57-0.97) for the primary objective of everolimus plus exemestane vs everolimus alone and 1.26 (90% CI, 0.96-1.66) for everolimus plus exemestane vs capecitabine alone. Between treatment arms, potential informative censoring was noted, and a stratified multivariate Cox regression model was used to account for imbalances in baseline characteristics; a consistent HR was observed for everolimus plus exemestane vs everolimus (0.73; 90% CI, 0.56-0.97), but the HR was closer to 1 for everolimus plus exemestane vs capecitabine (1.15; 90% CI, 0.86-1.52). Grade 3 to 4 adverse events were more frequent with capecitabine (74%; n = 75) vs everolimus plus exemestane (70%; n = 73) or everolimus alone (59%; n = 61). Serious adverse events were more frequent with everolimus plus exemestane (36%; n = 37) vs everolimus alone (29%; n = 30) or capecitabine (29%; n = 30). Conclusions and Relevance: These findings suggest that everolimus plus exemestane combination therapy offers a PFS benefit vs everolimus alone, and they support continued use of this therapy in this setting. A numerical PFS difference with capecitabine vs everolimus plus exemestane should be interpreted cautiously owing to imbalances among baseline characteristics and potential informative censoring. Trial Registration: ClinicalTrials.gov identifier: NCT01783444

The PPILOW project: Innovations improving welfare in low input and organic pig and poultry farms

International audienceThe PPILOW project aims to co-construct innovations to improve Poultry and Pig Welfare in Low-input outdoor and Organic farming systems through a multi-actor approach. PPILOW implements a participatory approach for proposing and studying welfare-improvement levers. It will provide a combination of practical solutions that can be applied at a pan-European level with specific adjustments depending on citizen’s expectations and the target market. The multi-actor approach consists in involving end-users including farmers, breeding companies, feed producers, consumer associations, retailers, advisers, processors, and scientists in National Practitioner Groups (NPG) in six participating countries. PPILOW partners facilitate the groups by connecting NPG at European level, transferring scientific information, interacting with partners engaged in animal experiments, and co-creating innovations rising from NPG-specific demands. They co-build with PPILOW partners welfare self-assessment tools (development of the PIGLOW app for pigs and refinement of the EBENE® app for poultry), and innovative breeding, feeding, and rearing strategies and techniques to improve the welfare of animals. They co-design protocols, test innovations on farm, and disseminate the results. In turn, they receive insights on methods and scientific results, and inputs from other NPG reinforcing the value of the expected outcomes. Approaches focus on avoiding physical damage and the elimination of layer male chicks, on reducing boar taint of intact male pigs, promoting positive behaviours, animal health, and robustness through field studies with pigs and poultry. Multicriteria analyses of the most effective levers of welfare improvement will be performed to evaluate their economic, social, and environmental impacts based on the ‘One Welfare’ concept; economic and business models will also be developed. To ensure the rapid uptake of the project results by end-users, the close involvement of PPILOW’s NPG throughout the EU will ensure disseminationactivities and the facilitation of change. The PPILOW project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement N°816172. www.ppilow.eu

The PPILOW project: Innovations improving welfare in low input and organic pig and poultry farms

International audienceThe PPILOW project aims to co-construct innovations to improve Poultry and Pig Welfare in Low-input outdoor and Organic farming systems through a multi-actor approach. PPILOW implements a participatory approach for proposing and studying welfare-improvement levers. It will provide a combination of practical solutions that can be applied at a pan-European level with specific adjustments depending on citizen’s expectations and the target market. The multi-actor approach consists in involving end-users including farmers, breeding companies, feed producers, consumer associations, retailers, advisers, processors, and scientists in National Practitioner Groups (NPG) in six participating countries. PPILOW partners facilitate the groups by connecting NPG at European level, transferring scientific information, interacting with partners engaged in animal experiments, and co-creating innovations rising from NPG-specific demands. They co-build with PPILOW partners welfare self-assessment tools (development of the PIGLOW app for pigs and refinement of the EBENE® app for poultry), and innovative breeding, feeding, and rearing strategies and techniques to improve the welfare of animals. They co-design protocols, test innovations on farm, and disseminate the results. In turn, they receive insights on methods and scientific results, and inputs from other NPG reinforcing the value of the expected outcomes. Approaches focus on avoiding physical damage and the elimination of layer male chicks, on reducing boar taint of intact male pigs, promoting positive behaviours, animal health, and robustness through field studies with pigs and poultry. Multicriteria analyses of the most effective levers of welfare improvement will be performed to evaluate their economic, social, and environmental impacts based on the ‘One Welfare’ concept; economic and business models will also be developed. To ensure the rapid uptake of the project results by end-users, the close involvement of PPILOW’s NPG throughout the EU will ensure disseminationactivities and the facilitation of change. The PPILOW project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement N°816172. www.ppilow.eu

PPILOW: innovations for improving animal welfare and human well-being in low-input outdoor and organic poultry and pig production systems

International audienc

PPILOW: innovations for improving animal welfare and human well-being in low-input outdoor and organic poultry and pig production systems

International audienc